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Akabane M, Imaoka Y, Kawashima J, Pawlik TM. Advancing precision medicine in hepatocellular carcinoma: current challenges and future directions in liquid biopsy, immune microenvironment, single nucleotide polymorphisms, and conversion therapy. Hepat Oncol 2025; 12:2493457. [PMID: 40260687 PMCID: PMC12026093 DOI: 10.1080/20450923.2025.2493457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 04/11/2025] [Indexed: 04/24/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a health concern characterized by heterogeneity and high mortality. Surgical resection, radiofrequency ablation, trans-arterial chemoembolization, and liver transplantation offer potentially curative treatments for early-stage disease, but recurrence remains high. Most patients present with advanced-stage HCC, where locoregional therapies are less effective, and systemic treatments-primarily multi-kinase inhibitors and immune checkpoint inhibitors-often yield limited responses. Precision medicine aims to tailor therapy to molecular and genetic profiles, yet its adoption in HCC is hindered by inter-/intra-tumoral heterogeneity and limited biopsy availability. Advances in molecular diagnostics support reintroducing tissue sampling to better characterize genetic, epigenetic, and immunological features. Liquid biopsy offers a minimally invasive method for capturing real-time tumor evolution, overcoming spatial and temporal heterogeneity. Artificial intelligence and machine learning are revolutionizing biomarker discovery, risk stratification, and treatment planning by integrating multi-omics data. Immunological factors such as tumor-infiltrating lymphocytes, natural killer cells, macrophages, and fibroblasts have emerged as determinants of HCC progression and treatment response. Conversion therapy-combining systemic agents with locoregional treatments-has showndemonstrated promise in downstaging unresectable HCC. Ongoing efforts to refine biomarker-driven approaches and optimize multi-modality regimens underscore precision medicine's potential to improve outcomes. PubMed (January 2002-February 2025) was searched for relevant studies.
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Affiliation(s)
- Miho Akabane
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Yuki Imaoka
- Division of Abdominal Transplant, Department of Surgery, Stanford University, CA, USA
| | - Jun Kawashima
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Timothy M. Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
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Agrawal H, Goswami B, Gupta N, Singh N. Liquid biopsy in hepatobiliary and pancreatic cancers: A paradigm shift in early detection, prognostic stratification, and perioperative monitoring. World J Meta-Anal 2025; 13:107997. [DOI: 10.13105/wjma.v13.i2.107997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 04/10/2025] [Accepted: 05/08/2025] [Indexed: 06/16/2025] Open
Abstract
BACKGROUND Hepatobiliary and pancreatic cancers are among the most lethal malignancies due to late-stage diagnosis and limited treatment options. Liquid biopsy has emerged as a minimally invasive tool for early cancer detection, prognosis, and therapeutic monitoring.
AIM To concise the available data on liquid biopsy and establish its role in hepatobiliary surgeries.
METHODS This systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 guidelines. A comprehensive literature search was performed using PubMed, Scopus, Web of Science, and EMBASE for studies published up to March 2025. Studies assessing the role of circulating tumor DNA, circulating tumor cells, exosomes, and other liquid biopsy markers in hepatobiliary and pancreatic cancers were included. The risk of bias was evaluated using the Newcastle-Ottawa Scale for observational studies and the Cochrane Risk of Bias Tool for clinical trials.
RESULTS Liquid biopsy demonstrated significant potential for early cancer detection, perioperative risk stratification, intraoperative surgical decision-making, and postoperative monitoring of minimal residual disease. However, challenges remain regarding standardization, sensitivity, and clinical validation.
CONCLUSION Liquid biopsy represents a paradigm shift in hepatobiliary and pancreatic cancer management. Advancements in next-generation sequencing and artificial intelligence may enhance its clinical utility. Further large-scale studies are needed to establish standardized protocols for routine implementation.
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Affiliation(s)
- Himanshu Agrawal
- Department of Surgery, University College of Medical Sciences (University of Delhi), GTB Hospital, Delhi 110095, India
| | - Binita Goswami
- Department of Biochemistry, Maulana Azad Medical College, New Delhi 110002, India
| | - Nikhil Gupta
- Department of Surgery, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Hospital, Delhi 110001, India
| | - Nilanjana Singh
- Department of Surgery, University College of Medical Sciences (University of Delhi), GTB Hospital, Delhi 110095, India
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Lin HY, Jeon AJ, Chen K, Lee CJM, Wu L, Chong SL, Anene-Nzelu CG, Foo RSY, Chow PKH. The epigenetic basis of hepatocellular carcinoma - mechanisms and potential directions for biomarkers and therapeutics. Br J Cancer 2025; 132:869-887. [PMID: 40057667 DOI: 10.1038/s41416-025-02969-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/23/2025] [Accepted: 02/20/2025] [Indexed: 05/17/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth leading cancer worldwide and has complex pathogenesis due to its heterogeneity, along with poor prognoses. Diagnosis is often late as current screening methods have limited sensitivity for early HCC. Moreover, current treatment regimens for intermediate-to-advanced HCC have high resistance rates, no robust predictive biomarkers, and limited survival benefits. A deeper understanding of the molecular biology of HCC may enhance tumor characterization and targeting of key carcinogenic signatures. The epigenetic landscape of HCC includes complex hallmarks of 1) global DNA hypomethylation of oncogenes and hypermethylation of tumor suppressors; 2) histone modifications, altering chromatin accessibility to upregulate oncogene expression, and/or suppress tumor suppressor gene expression; 3) genome-wide rearrangement of chromatin loops facilitating distal enhancer-promoter oncogenic interactions; and 4) RNA regulation via translational repression by microRNAs (miRNAs) and RNA modifications. Additionally, it is useful to consider etiology-specific epigenetic aberrancies, especially in viral hepatitis and metabolic dysfunction-associated steatotic liver disease (MASLD), which are the main risk factors of HCC. This article comprehensively explores the epigenetic signatures in HCC, highlighting their potential as biomarkers and therapeutic targets. Additionally, we examine how etiology-specific epigenetic patterns and the integration of epigenetic therapies with immunotherapy could advance personalized HCC treatment strategies.
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Affiliation(s)
- Hong-Yi Lin
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Ah-Jung Jeon
- Department of Research and Development, Mirxes, Singapore, Singapore
| | - Kaina Chen
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore
| | - Chang Jie Mick Lee
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Research Institute, National University Heart Centre, Singapore, Singapore
| | - Lingyan Wu
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore
| | - Shay-Lee Chong
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore
| | | | - Roger Sik-Yin Foo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Research Institute, National University Heart Centre, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, Singapore, Singapore
| | - Pierce Kah-Hoe Chow
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore.
- Department of Hepato-pancreato-biliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore, Singapore.
- Surgery Academic Clinical Programme, Duke-NUS Medical School, Singapore, Singapore.
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Guo Q, Shan L, Luo J, Huang Y, Bao Y, Wang X, Ma L, Wang G. Novel strategies in liquid biopsy. Clin Chim Acta 2025:120385. [PMID: 40414270 DOI: 10.1016/j.cca.2025.120385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2025] [Revised: 05/21/2025] [Accepted: 05/22/2025] [Indexed: 05/27/2025]
Abstract
Cancer, a leading global cause of death, involves complex processes and multiple components. Due to the lack of effective and accurate early diagnostic methods, many patients are diagnosed with advanced cancer. Traditional tissue biopsy, while common, may increase the risk of metastasis. In contrast, liquid biopsy technology utilizes bodily fluids such as blood, urine, and saliva to analyze tumor-associated information, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes, and various molecular markers. This technology has undergone rapid advancements, enabling its routine clinical use in cancer patients and broadening research horizons. ctDNA and CTCs can be isolated and analyzed from blood sample, providing valuable insights for therapeutic choices. However, technical and clinical challenges remain, such as the low proportion of ctDNA in circulating free DNA, the short half-life of ctDNA in blood, and the low concentration and heterogeneity of CTCs. Exosomes, abundant and stable vesicles released by most cells, carry bioactive molecules and play a pivotal role in intercellular communication, tumorigenesis, and progression. They offer advantages over CTCs and ctDNA but also present challenges in isolation, detection, and specificity. This review summarizes recent technologies for detecting ctDNA, CTCs, and exosomes in liquid biopsies, including nanotechnology, sensor technology, spectroscopy, microfluidic technology, and aptamers. It highlights their clinical applications and future development directions, elucidating their promising prospects in diagnosing cancer patients, monitoring disease progression, and predicting prognosis.
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Affiliation(s)
- Qinyue Guo
- Department of Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Shanghai, PR China
| | - Liang Shan
- Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jizhuang Luo
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Yiman Huang
- Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Yunxia Bao
- Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Xianzhao Wang
- Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lifang Ma
- Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Gang Wang
- Department of Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Shanghai, PR China.
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Alampritis G, Thoukididou SN, Ramos M, Georgiou P, Kalofonou M, Simillis C. Diagnostic value of genetic and epigenetic biomarker panels for colorectal cancer detection: a systematic review. Int J Colorectal Dis 2025; 40:125. [PMID: 40402271 PMCID: PMC12098509 DOI: 10.1007/s00384-025-04904-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/29/2025] [Indexed: 05/23/2025]
Abstract
PURPOSE Exploration of effective screening methods is imperative to improve current screening for colorectal cancer (CRC). Our aim was to systematically search the literature to identify and assess the diagnostic accuracy of both genetic and epigenetic biomarker panels for CRC detection using liquid biopsies for circulating tumour DNA (ctDNA) from stool, blood, or urine. METHODS A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) with searches in Medline, Embase, CENTRAL, and Web Of Science from inception up to March 20, 2025, using pre-defined keywords. Study quality assessment was performed using QUADAS-2 tool (Quality Assessment for Diagnostic Accuracy Studies 2). Primary and secondary outcomes were panel performance (sensitivity and specificity) for CRC, advanced precancerous lesions (APL), and staging of disease. RESULTS Forty-four studies were included. Exceptional performance for both CRC (sensitivity and specificity) and APL (sensitivity) was displayed by biomarker panels including methylated SDC2 with methylated SFRP1/2 (CRC: 91.5%/97.3%, APL: 89.2%) or methylated TFPI2 (CRC: 94.9%/98.1%, APL: 100%), and a 5-biomarker panel of mutational targets APC, Bat-26, KRAS, L-DNA, and p53 (CRC: 91.0%/93.0%, APL: 82.0%). Suboptimal APL sensitivities up to 57.0% were exhibited by Cologuard and variant panels (including KRAS, methylated BMP3, methylated NDRG4, FIT), and 47.8% for combinations including methylated SEPT9. CONCLUSIONS High-performance, candidate ctDNA biomarker panels with exceptional diagnostic accuracy for both CRC and APL have been identified. Further work should focus on the development of large-scale studies to justify their clinical implementation.
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Affiliation(s)
- Georgios Alampritis
- Department of Surgery, University of Cambridge, Cambridge, UK
- Cambridge Colorectal Unit, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Sarah Nohelia Thoukididou
- Department of Surgery, University of Cambridge, Cambridge, UK
- Cambridge Colorectal Unit, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Maria Ramos
- Department of Electrical and Electronic Engineering, Imperial College London, London, UK
| | - Pantelis Georgiou
- Department of Electrical and Electronic Engineering, Imperial College London, London, UK
| | - Melpomeni Kalofonou
- Department of Electrical and Electronic Engineering, Imperial College London, London, UK
| | - Constantinos Simillis
- Department of Surgery, University of Cambridge, Cambridge, UK.
- Cambridge Colorectal Unit, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
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Galant N, Grenda A, Krawczyk P, Pięt M, Milanowski J. Liquid biopsy in diagnosis and monitoring of treatment efficacy in patients with small cell lung cancer. Mol Biol Rep 2025; 52:455. [PMID: 40358752 PMCID: PMC12075280 DOI: 10.1007/s11033-025-10569-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 05/02/2025] [Indexed: 05/15/2025]
Abstract
Small-cell lung cancer (SCLC) remains one of the deadliest cancers worldwide. Patients' survival remains poor due to its rapid growth, high metastatic rate and limited possibilities of treatment. For many years, SCLC management has been based mostly on chemo and radiotherapy. However, new therapeutic approaches have been proposed in the past few years, including immunotherapy, which is currently implemented in clinical practice. Unfortunately, in many cases, response to therapy, especially chemotherapy, remains poor, or the patient becomes resistant to initially effective treatment. One of the crucial problems during SCLC patient care is a lack of appropriate predictive biomarkers for various therapeutic approaches. Another critical issue is the scarcity of collected tissue during biopsy, which may be insufficient or of too poor quality for analysis. A liquid biopsy might be the key to solving both of those problems as it is collected in a non-invasive way and enables the measurement of various biomarkers, including circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs). In this review, we discuss various approaches to potentially incorporating liquid biopsy into clinical application - as a companion to imaging during SCLC diagnostics, a new approach to molecular subtyping, and a material enabling predictive or prognostic biomarkers assessment. We also summarize ongoing clinical trials encompassing SCLC patients in which liquid biopsy is collected and examined.
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Affiliation(s)
- Natalia Galant
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland.
| | - Anna Grenda
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
| | - Paweł Krawczyk
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
| | - Mateusz Pięt
- Department of Virology and Immunology, Maria Curie-Skłodowska University, Lublin, Poland
| | - Janusz Milanowski
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
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Shu Z, Ye T, Wu W, Su M, Wang J, Zhang M, Qian Z, Huang H, Zheng S, Xia Q. Preoperative plasma cell-free DNA chromosomal instability predicts microvascular invasion in hepatocellular carcinoma: a prospective study. BMC Cancer 2025; 25:867. [PMID: 40361115 PMCID: PMC12076900 DOI: 10.1186/s12885-025-14268-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 05/05/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Microvascular invasion (MVI) has been recognized as a risk factor for early recurrence after hepatectomy in patients with hepatocellular carcinoma (HCC). This study aimed to estimate the performance of an ultrasensitive chromosomal aneuploidy detector (UCAD) model for preoperative MVI prediction in operable HCC patients based on plasma cell-free DNA (cfDNA). METHODS A prospective study included HCC patients who underwent surgery in 2021. Preoperative peripheral plasma samples of eligible patients were collected to extract cfDNA, which was then subject to next generation sequencing. Low-coverage whole-genome sequencing data were analyzed for chromosomal instability using different parameters, including Z-score, chromosomal instability score (CIN score), tumor fraction (TFx) and a UCAD model (UCAD = CIN score + TFx + Z-score of all chromosomes). Receiver operating characteristic (ROC) curve was used to evaluate the performance of these parameters in preoperative MVI prediction. RESULTS Finally, a total of 74 patients with HCC who undergone hepatectomy were prospectively enrolled. Chromosomal instability was evaluated by copy number alterations and oncogenes MCL1 (located at 1q), MYC (located at 8q), TERT (located at 5p), EGFR (located at 7p), and VEGFA (located at 6p) were identified in plasma cfDNA. The UCAD model was a superior parameter in predicting preoperative MVI, with an area under curve (AUC) value 0.749 with a sensitivity of 0.938 specificity of 0.466. Univariate analysis revealed that tumor size (≥ 5 cm) and UCAD (> 0.199) significantly increased the risk of MVI, which were further demonstrated by multivariate analysis, with odd ratio of 1.338 (95%CI, 1.060-1.689) and 2.028 (95%CI, 1.053-3.908) (P < 0.05). CONCLUSIONS Our cfDNA-based UCAD model has shown a promising performance for preoperative MVI prediction in operable HCC patients. TRIAL REGISTRATION This study was registered at https://clinicaltrials.gov/ on 16 May 2022, retrospectively registered, Registration number: NCT05371873.
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Affiliation(s)
- Zheyue Shu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China
- Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Ting Ye
- Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Wei Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China
| | - Menghan Su
- Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Jingcheng Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, 310003, China
| | - Min Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, 310003, China
| | - Ziliang Qian
- The First People's Hospital of Chenzhou, Chenzhou, 424512, China
| | - Haifen Huang
- The First People's Hospital of Chenzhou, Chenzhou, 424512, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China.
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China.
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, 310003, China.
| | - Qi Xia
- Zhejiang University School of Medicine, Hangzhou, 310058, China.
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China.
- Key Laboratory for Biomedical Engineering of Ministry of Education, Zhejiang University, Hangzhou, 310003, China.
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Yang W, Nguyen R, Safri F, Shiddiky MJA, Warkiani ME, George J, Qiao L. Liquid Biopsy in Hepatocellular Carcinoma: ctDNA as a Potential Biomarker for Diagnosis and Prognosis. Curr Oncol Rep 2025:10.1007/s11912-025-01681-3. [PMID: 40343687 DOI: 10.1007/s11912-025-01681-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2025] [Indexed: 05/11/2025]
Abstract
PURPOSE OF REVIEW Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with rising incidence and mortality. Early-stage HCC is often asymptomatic, and the lack of reliable early diagnostic markers leads to late-stage diagnosis with limited treatment options. Current treatment relies on tumour staging and patient status, but accurate staging requires invasive procedures that fail to capture tumour heterogeneity and progression. There is an urgent need for less invasive diagnostic strategies, such as liquid biopsy technologies, which allow for repeated sampling and real-time analysis of tumour dynamics. Liquid biopsies, including circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA), offer the potential to monitor recurrence, metastasis, and treatment responses, potentially transforming HCC clinical management by enabling earlier intervention and personalised treatment strategies. RECENT FINDINGS Recent studies emphasise the potential of ctDNA as a non-invasive biomarker by targeting DNA methylation for early HCC detection, enabling timely intervention and personalised treatment to improve patient outcomes. Comparative analyses have shown that ctDNA mutation testing outperforms alpha-fetoprotein (AFP), with a sensitivity of 85% and a specificity of 92%, compared to 60% sensitivity and 80% specificity for AFP. Additionally, profiling the ctDNA mutation landscape of 100 HCC patients has identified recurrent mutations in genes such as TP53, CTNNB1, and AXIN1. ctDNA appears to be a promising non-invasive biomarker in the clinical management of HCC patients, with the sensitivity and specificity improving by 41.67% and 15% respectively. The ctDNA mutations, particularly those targeting DNA methylation, highlight great potential for precision medicine, critical for early diagnosis and prognosis of HCC.
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Affiliation(s)
- William Yang
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Romario Nguyen
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Fatema Safri
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Muhammad J A Shiddiky
- Rural Health Research Institute (RHRI), Charles Sturt University, Orange, NSW, 2800, Australia
| | - Majid E Warkiani
- School of Biomedical Engineering, The University of Technology Sydney, Ultimo, NSW, 2007, Australia
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia.
- Storr Liver Centre, Westmead Institute for Medical Research (WIMR), the University of Sydney, Westmead, NSW, 2145, Australia.
| | - Liang Qiao
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia.
- Storr Liver Centre, Westmead Institute for Medical Research (WIMR), the University of Sydney, Westmead, NSW, 2145, Australia.
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Lei W, Zhou K, Lei Y, Li Q, Zhu H. Pathogenesis and Systemic Treatment of Hepatocellular Carcinoma: Current Status and Prospects. Mol Cancer Ther 2025; 24:692-708. [PMID: 39417575 DOI: 10.1158/1535-7163.mct-24-0403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/14/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024]
Abstract
Hepatocellular carcinoma (HCC) remains one of the major threats to human health worldwide. The emergence of systemic therapeutic options has greatly improved the prognosis of patients with HCC, particularly those with advanced stages of the disease. In this review, we discussed the pathogenesis of HCC, genetic alterations associated with the development of HCC, and alterations in the tumor immune microenvironment. Then, important indicators and emerging technologies related to the diagnosis of HCC are summarized. Also, we reviewed the major advances in treatments for HCC, offering insights into future prospects for next-generation managements.
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Affiliation(s)
- Wanting Lei
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Kexun Zhou
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ye Lei
- College of Liberal Arts, Neijiang Normal University, Neijiang, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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Ma J, Wang Y, Zhang Z, Cai X, Xiang X, Chen Y, Sun F, Dong J. Peripheral Blood T-Cell Receptor Repertoire Diversity as a Potential Biomarker in the Diagnosis and Treatment Evaluation of Colorectal and Lung Cancers: A Prospective Observational Study. Cancer Med 2025; 14:e70937. [PMID: 40387418 PMCID: PMC12086972 DOI: 10.1002/cam4.70937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 04/24/2025] [Accepted: 04/27/2025] [Indexed: 05/20/2025] Open
Abstract
BACKGROUND T-cell receptor (TCR) diversity 50 (D50) values could assess peripheral blood (PB) TCR diversity and immunity. This study aimed to evaluate the potential D50 value in the diagnosis and treatment evaluation of colorectal cancer (CRC) and nonsmall-cell lung cancer (NSCLC). METHODS This prospective observational study enrolled patients with CRC, benign colorectal disease (BCD), NSCLC, or benign nodule controls (BNC) and healthy donors (HD) at Yunnan Cancer Hospital between January 2021 and June 2022. PB specimens were used for TCRβ sequencing, and D50 was calculated and compared within different groups. The area under the curve (AUC) was used to evaluate the diagnostic performance of D50 in CRC and NSCLC. RESULTS A total of 114 HD and 115 CRC, 31 BCD, 67 NSCLC, and 25 BNC patients were enrolled. Both CRC and NSCLC patients exhibited significantly lower D50 compared with HDs (p < 0.001), whereas BCD and BNC patients showed a modest decrease in TCR diversity (p < 0.05). NSCLC patients with lymph node metastases had markedly lower D50 than those without lymph node metastasis (0.05 vs. 0.11, p < 0.01). Higher D50 was found in CRC and NSCLC patients with normal carcinoembryonic antigen (CEA) levels (p < 0.05). The potential of D50 value for early detection of CRC and NSCLC was demonstrated, with an area under the receiver operating characteristic curve (AUC) of 0.736 for CRC (sensitivity: 71.30%, specificity: 68.42%) and 0.768 for NSCLC (sensitivity: 83.58%, specificity: 60.53%). Significant differences in D50 values were observed between patients with tumor regression grade (TRG) 0-1 and those with TRG 2-3 (p = 0.027), with an AUC of 0.731 (sensitivity: 68.75%, specificity: 76.92%). CONCLUSION These findings suggest that the PB TCR D50 values may have significant clinical value in cancer diagnosis and in evaluating the efficacy of neoadjuvant therapies.
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MESH Headings
- Humans
- Male
- Female
- Middle Aged
- Lung Neoplasms/diagnosis
- Lung Neoplasms/blood
- Lung Neoplasms/therapy
- Lung Neoplasms/immunology
- Lung Neoplasms/genetics
- Prospective Studies
- Colorectal Neoplasms/diagnosis
- Colorectal Neoplasms/blood
- Colorectal Neoplasms/therapy
- Colorectal Neoplasms/immunology
- Colorectal Neoplasms/genetics
- Aged
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- Carcinoma, Non-Small-Cell Lung/diagnosis
- Carcinoma, Non-Small-Cell Lung/blood
- Carcinoma, Non-Small-Cell Lung/therapy
- Carcinoma, Non-Small-Cell Lung/immunology
- Carcinoma, Non-Small-Cell Lung/genetics
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/blood
- Adult
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Affiliation(s)
- Jilong Ma
- Key Laboratory of Cell Therapy Technology Transformation Medicine of Yunnan Province, the Han Weidong Expert Workstation of Yunnan Province, Yunnan Provincial Engineering Research Centre of Cell Therapy and Quality Control System, the Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer HospitalKunmingYunnanChina
| | - Yuanbiao Wang
- Key Laboratory of Cell Therapy Technology Transformation Medicine of Yunnan Province, the Han Weidong Expert Workstation of Yunnan Province, Yunnan Provincial Engineering Research Centre of Cell Therapy and Quality Control System, the Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer HospitalKunmingYunnanChina
| | - Zhixin Zhang
- Department of TechnologyChengdu ExAb Biotechnology, LTDChengduSichuanChina
| | - Xinyi Cai
- Department of Colorectal SurgeryThe Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer HospitalKunmingYunnanChina
| | - Xudong Xiang
- Department of Thoracic Surgery IIThe Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer HospitalKunmingYunnanChina
| | - Yan Chen
- Key Laboratory of Cell Therapy Technology Transformation Medicine of Yunnan Province, the Han Weidong Expert Workstation of Yunnan Province, Yunnan Provincial Engineering Research Centre of Cell Therapy and Quality Control System, the Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer HospitalKunmingYunnanChina
| | - Fengqiong Sun
- Department of Colorectal SurgeryThe Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer HospitalKunmingYunnanChina
| | - Jian Dong
- Key Laboratory of Cell Therapy Technology Transformation Medicine of Yunnan Province, the Han Weidong Expert Workstation of Yunnan Province, Yunnan Provincial Engineering Research Centre of Cell Therapy and Quality Control System, the Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer HospitalKunmingYunnanChina
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11
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Rui H, Yueqin N, Wei W, Bangtao L, Li X. Combining AFP, PIVKA-II, and GP73 has diagnostic utility for hepatitis B-associated hepatocellular carcinoma and is consistent with liver pathology results. Sci Rep 2025; 15:14869. [PMID: 40295542 PMCID: PMC12037889 DOI: 10.1038/s41598-025-92067-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Accepted: 02/25/2025] [Indexed: 04/30/2025] Open
Abstract
Although liquid biopsy has garnered increasing attention in recent years for diagnosing hepatocellular carcinoma (HCC), serum biomarkers continue to hold significant value for HCC diagnosis due to their simple operation, cost-effectiveness, and high efficiency. This study aimed to screen for the optimal diagnostic combinations of alpha fetoprotein (AFP), a protein induced by vitamin K deficiency or antagonist II (PIVKA-II), golgi glycoprotein 73 (GP73), and routine clinical indicators for diagnosing hepatitis B-associated HCC (HBV-HCC). A retrospective analysis was conducted on 358 HBV-HCC patients treated at Taizhou People's Hospital from August 2015 to October 2021; 124 patients with chronic hepatitis B (CHB) and 241 patients with hepatitis B cirrhosis composed the control group. With liver pathology as the gold standard, the concordance between the screened indicators and liver pathology for HCC diagnosis was analyzed by Cohen's kappa coefficient. In the CHB group, AFP, PIVKA-II, and GP73 were statistical significance, and the triple biomarker combination achieved the highest AUC (0.908) for HCC diagnosis, surpassing the efficacy of both individual indicators and two biomarker combinations. In both the Child‒Pugh A and Child‒Pugh B&C cirrhosis groups, AFP and PIVKA-II were significantly different between patients with and without HCC, and the AUC values of AFP combined with PIVKA-II for HCC diagnosis were 0.969 and 0.956, respectively. Using liver pathology as the gold standard, the Kappa values of the above combinations in the three groups were 0.866, 0.780, and 0.800, respectively. The triple combination of AFP, PIVKA-II, and GP73 in the CHB group and the combination of AFP and PIVKA-II in both the Child‒Pugh A and Child‒Pugh B&C cirrhosis groups had excellent diagnostic accuracy for HCC, consistent with liver pathology, and were superior to the diagnostic ability of individual biomarkers.
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Affiliation(s)
- Hu Rui
- Department of Hepatology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou City, 225300, Jiangsu Province, China
- The First People's Hospital of Shaoguan, Shaoguan City, 512099, Guangdong Province, China
| | - Ni Yueqin
- Department of Hepatology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou City, 225300, Jiangsu Province, China
| | - Wang Wei
- Department of Hepatology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou City, 225300, Jiangsu Province, China
| | - Li Bangtao
- Department of Hepatology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou City, 225300, Jiangsu Province, China.
| | - Xiao Li
- Department of Hepatology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou City, 225300, Jiangsu Province, China.
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12
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Liu ZH, Shi JJ, Zhang M, Dang SS. Advances in application of serum biomarkers for screening and early diagnosis of hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2025; 33:251-260. [DOI: 10.11569/wcjd.v33.i4.251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 04/12/2025] [Accepted: 04/17/2025] [Indexed: 04/28/2025] Open
Abstract
Hepatocellular carcinoma (HCC) represents a major global health challenge, with early detection through surveillance of high-risk populations remaining critical for improving clinical outcomes. Serum biomarkers play a crucial role in the early detection of HCC. Currently, commonly used serological markers for HCC include alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin, and the Lens culinaris agglutinin-reactive fraction of AFP. Other potential biomarkers under investigation include glypican-3, osteopontin, alpha-L-fucosidase, Dickkopf-1, heat shock protein 90α, and Golgi protein 73. With the advancement of liquid biopsy technologies, novel markers such as circulating tumor DNA, circulating tumor cells, microRNAs, and long non-coding RNAs have emerged as promising tools for early screening and diagnosis of HCC. This review aims to summarize the research progress and clinical applications of these biomarkers related to liver cancer, providing scientific evidence to enhance early diagnosis rates, improve prognosis, and ultimately reduce HCC-related mortality.
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Affiliation(s)
- Zi-Han Liu
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 71004, Shaanxi Province, China
| | - Juan-Juan Shi
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 71004, Shaanxi Province, China
| | - Meng Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 71004, Shaanxi Province, China
| | - Shuang-Suo Dang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 71004, Shaanxi Province, China
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13
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Tan W, Zhu Y, Chen S. Innovative approach to the detection of circulating tumor biomarkers: multi-dimensional application of liposome technology. Lipids Health Dis 2025; 24:160. [PMID: 40295973 PMCID: PMC12036244 DOI: 10.1186/s12944-025-02578-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 04/19/2025] [Indexed: 04/30/2025] Open
Abstract
Malignant tumors represent a significant worldwide health challenge, with elevated morbidity and mortality rates necessitating enhanced early identification and individualized treatment. Liposomes, as biomimetic lipid-based nanovesicles, have developed as a multifaceted platform for detecting and treating malignant tumors due to their excellent biocompatibility, stability, and membrane fusion properties. Circulating tumor markers, such as circulating tumor cells (CTCs), extracellular vesicles (EVs), circulating tumor proteins (CTPs), and circulating tumor nucleic acids (ctNAs), play a key role in early cancer diagnosis, disease progression monitoring, and personalized therapy. Liposome-based platforms enable effective molecular recognition, targeted detection, and signal amplification by targeting circulating tumor biomarkers, significantly increasing the potential for early tumor diagnosis and treatment. This review systematically summarizes advancements in the study of liposomes concerning circulating tumor markers, including applications in targeted recognition, early detection, and disease diagnosis, while discussing present problems and prospective applications of existing technology.
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Affiliation(s)
- Weichu Tan
- Department of Laboratory Medicine, Medical Research Center of Nanfang Hospital, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Provincial Key Laboratory of Single-Cell and Extracellular Vesicles, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Yitong Zhu
- Department of Laboratory Medicine, Medical Research Center of Nanfang Hospital, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Provincial Key Laboratory of Single-Cell and Extracellular Vesicles, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Siting Chen
- Department of Laboratory Medicine, Medical Research Center of Nanfang Hospital, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Provincial Key Laboratory of Single-Cell and Extracellular Vesicles, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China.
- The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong, 511518, People's Republic of China.
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14
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Liu ZH, Shi JJ, Zhang M, Dang SS. Advances in application of serum biomarkers for screening and early diagnosis of hepatocellular carcinoma. WORLD CHINESE JOURNAL OF DIGESTOLOGY 2025; 33:251-260. [DOI: https:/dx.doi.org/10.11569/wcjd.v33.i4.251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2025]
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15
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Wang J, Tang J, Liang A, Cui Z, Huo J, Li Q, Ke B, Yang D, Yao C. A Smart DNA Network-Based Diagnostic System for Enrichment and Detection of Circulating Tumor Cells in Cancer Liquid Biopsy. Anal Chem 2025; 97:8065-8072. [PMID: 40185686 DOI: 10.1021/acs.analchem.5c00648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2025]
Abstract
Circulating tumor cells (CTCs) have emerged as critical biomarkers in liquid biopsy for noninvasive tumor diagnosis and real-time monitoring of cancer progression. However, the isolation of CTCs is often required before detection due to their ultralow abundance in peripheral blood. These isolation processes are typically time-consuming and prone to cell loss, which limits the utility of CTC-based liquid biopsy. Herein, we present a DNA network-based diagnostic system that enables specific recognition, selective enrichment, and accurate detection of CTCs directly from blood samples. The DNA network comprises ultralong DNA chains embedded with polyvalent aptamers and fluorescence detection modules. The polyvalent aptamers selectively bind to the epithelial cell adhesion molecule (EpCAM) on a CTC membrane, facilitating their enrichment through base pairing-driven DNA network formation. This system semiquantitatively detects the expression level of cancer-associated microRNA within CTCs using ratiometric fluorescence imaging based on the chemical assembly of two fluorescence modules. In clinical blood samples, this diagnostic system achieves 100% precision and 96% accuracy in distinguishing breast cancer patients from healthy donors, highlighting its promising potential for clinical breast cancer diagnosis.
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Affiliation(s)
- Jing Wang
- State Key Laboratory of Synthetic Biology, Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (MOE), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, P.R. China
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, College of Chemistry and Materials, Fudan University, Shanghai 200438, P.R. China
| | - Jianpu Tang
- State Key Laboratory of Synthetic Biology, Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (MOE), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, P.R. China
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, College of Chemistry and Materials, Fudan University, Shanghai 200438, P.R. China
| | - Aiqi Liang
- State Key Laboratory of Synthetic Biology, Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (MOE), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, P.R. China
| | - Zhen Cui
- State Key Laboratory of Synthetic Biology, Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (MOE), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, P.R. China
| | - Jiale Huo
- State Key Laboratory of Synthetic Biology, Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (MOE), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, P.R. China
| | - Qian Li
- State Key Laboratory of Synthetic Biology, Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (MOE), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, P.R. China
| | - Bin Ke
- Department of Gastric Surgery, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
| | - Dayong Yang
- State Key Laboratory of Synthetic Biology, Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (MOE), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, P.R. China
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, College of Chemistry and Materials, Fudan University, Shanghai 200438, P.R. China
| | - Chi Yao
- State Key Laboratory of Synthetic Biology, Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (MOE), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, P.R. China
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16
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Zhu Z, Lian X, Hu J, Wang Z, Zhong Y, Zhao Y, Lu L, Pan Y, Zhou M, Xu J. DPHC from Alpinia officinarum Hance specifically modulates the function of CENPU in the cell cycle and apoptosis to ameliorate hepatocellular carcinoma. JOURNAL OF ETHNOPHARMACOLOGY 2025; 345:119598. [PMID: 40058474 DOI: 10.1016/j.jep.2025.119598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 03/04/2025] [Accepted: 03/06/2025] [Indexed: 03/18/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Alpinia officinarum Hance (A. officinarum), a perennial herb used in the treatment of digestive system cancers, holds significant value for the Li people of Hainan as a traditional Chinese medicine. (R)-5-hydroxy-1,7-diphenyl-3-heptanone (DPHC), a diarylheptanoid component is derived from A. officinarum. Diarylheptanoids have demonstrated anti-proliferative effects on breast cancer cells, neuroblastoma cells, and other tumor cells. However, the pharmacological activity of DPHC in improving hepatocellular carcinoma (HCC) remains undefined. AIM OF THE STUDY To elucidate the anti-HCC effects of DPHC derived from A. officinarum and explore its underlying mechanistic pathways both in vivo and in vitro. MATERIAL AND METHODS The effects of DPHC on HCC cell lines were evaluated in vitro using cell counting kit-8, EdU cell proliferation assays, a wound healing assay, a three-dimensional tumor spheroid model, and flow cytometry. The ability of DPHC to ameliorate HCC was assessed in vivo via a nude mouse subcutaneous xenograft tumor model, serum biochemical marker detection, and hematoxylin-eosin staining. The molecular mechanism of DPHC in HCC was elucidated through a combination of transcriptome sequencing, cell transfection, immunohistochemistry assay, immunofluorescence staining, quantitative reverse transcription-PCR, and western blot analysis. RESULTS DPHC induced significant G0/G1 phase arrest and apoptosis in HepG2 and HCCLM3 cells while also markedly inhibiting tumor growth in nude mice. Mechanically, DPHC directly interacted with centromere-associated protein U (CENPU) to suppress its expression. The reduced expression of CENPU results in decreased interaction with the transcription factor E2F6, thereby affecting the transcriptional activity of the transcription factor E2F1. This subsequently inhibits the expression of downstream cell cycle factors (CCND1, CDK4, and CDK1) and increases apoptosis factors (Caspase 3 and Caspase 9). CONCLUSIONS DPHC from A. officinarum specifically modulates the function of CENPU in the cell cycle and apoptosis to ameliorate HCC. Our study revealed the anti-HCC effect and underlying mechanism of DPHC, offering new insights and potential targets for HCC treatment.
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Affiliation(s)
- Zhe Zhu
- Hepatobiliary and Liver Transplantation Department of Hainan Digestive Disease Center, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, China
| | - Xiuxia Lian
- Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education & International Joint Research Center of Human-machine Intelligent Collaborative for Tumor Precision Diagnosis and Treatment of Hainan Province & Hainan Provincial Key Laboratory of Research and Development on Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou, Hainan, 571199, China
| | - Jicheng Hu
- Hepatobiliary and Liver Transplantation Department of Hainan Digestive Disease Center, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, China
| | - Zhe Wang
- Hepatobiliary and Liver Transplantation Department of Hainan Digestive Disease Center, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, China
| | - Yinghong Zhong
- Hepatobiliary and Liver Transplantation Department of Hainan Digestive Disease Center, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, China
| | - Yuan Zhao
- Hepatobiliary and Liver Transplantation Department of Hainan Digestive Disease Center, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, China
| | - Lu Lu
- Hepatobiliary and Liver Transplantation Department of Hainan Digestive Disease Center, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, China
| | - Yipeng Pan
- Hepatobiliary and Liver Transplantation Department of Hainan Digestive Disease Center, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, China.
| | - Mingyan Zhou
- Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, China.
| | - Jian Xu
- Hepatobiliary and Liver Transplantation Department of Hainan Digestive Disease Center, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, China; Key Laboratory of Emergency and Trauma of Ministry of Education, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China.
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17
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Galli E, Patelli G, Villa F, Gri N, Mazzarelli C, Mangoni I, Sgrazzutti C, Ghezzi S, Sartore-Bianchi A, Belli LS, De Carlis L, Vanzulli A, Siena S, Bencardino K. Circulating blood biomarkers for minimal residual disease in hepatocellular carcinoma: A systematic review. Cancer Treat Rev 2025; 135:102908. [PMID: 40058162 DOI: 10.1016/j.ctrv.2025.102908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 02/24/2025] [Accepted: 02/25/2025] [Indexed: 04/08/2025]
Abstract
BACKGROUND Relapse after radical treatment remains a major concern in hepatocellular carcinoma (HCC), affecting 50-75 % of early-stage cases within 5 years. Early recurrence prediction is a clinical unmet need. Circulating blood biomarkers could provide a minimally invasive approach to detect minimal residual disease (MRD) post-intervention. Although alpha-fetoprotein has been the primary biomarker in this setting, its MRD sensitivity is limited to 50-70 %. This systematic review aims to summarize available evidence regarding the clinical validity and potential utility of emerging circulating blood biomarkers for MRD detection in HCC patients. METHODS We searched PubMed and Embase for peer-reviewed articles and abstracts published up to 2025, and ClinicalTrials.gov for ongoing trials on circulating blood biomarkers for MRD in HCC. RESULTS A total of 91 studies (74 with results and 17 ongoing, out of 2,386) were retrieved. We evaluated various blood biomarkers, including circulating DNA (cDNA, N = 24), circulating tumor cells (CTCs, N = 20), circulating RNA (cRNA, N = 8), and other miscellaneous (N = 22) for MRD detection in HCC. These biomarkers demonstrated encouraging results, albeit with notable heterogeneity. In particular, circulating tumor DNA (ctDNA) and CTCs stand as the most robust novel approaches, with 50-80 % sensitivity and specificity up to 94 %. Nonetheless, none of the 17 ongoing studies involve biomarker-driven intervention to prove clinical utility. CONCLUSIONS Novel circulating blood biomarkers are mature for MRD detection in HCC. However, variability in methodologies and results highlights the need for further validation. We encourage the investigation of CTCs and/or ctDNA in interventional trials to assess clinical utility. This biomarker-driven approach may enhance adjuvant treatment effectiveness in MRD-positive cases while minimizing toxicity in MRD-negative patients.
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Affiliation(s)
- Edoardogregorio Galli
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy; Niguarda Cancer Center, Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Giorgio Patelli
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy; Niguarda Cancer Center, Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy; IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy.
| | - Federica Villa
- Niguarda Cancer Center, Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Nicole Gri
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy; Niguarda Cancer Center, Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Chiara Mazzarelli
- Hepatology and Gastroenterology Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Iacopo Mangoni
- Department of General Surgery and Transplantation, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | | | - Silvia Ghezzi
- Niguarda Cancer Center, Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Andrea Sartore-Bianchi
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy; Niguarda Cancer Center, Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Division of Clinical Research and Innovation, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Luca Saverio Belli
- Hepatology and Gastroenterology Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Luciano De Carlis
- Department of General Surgery and Transplantation, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Angelo Vanzulli
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy; Department of Radiology, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Salvatore Siena
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy; Niguarda Cancer Center, Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Katia Bencardino
- Niguarda Cancer Center, Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy
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18
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Martella S, Wekking D, Lai E, Lambertini M, Pettinato A, Parrino A, Semonella F, Sanna G, Maccioni A, Scartozzi M, Addeo A, Solinas C. Liquid biopsy: An innovative tool in oncology. Where do we stand? Semin Oncol 2025; 52:152343. [PMID: 40233447 DOI: 10.1016/j.seminoncol.2025.152343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 03/12/2025] [Accepted: 03/13/2025] [Indexed: 04/17/2025]
Abstract
The Liquid Biopsy (LB) represents an ideal surrogate of tumor Tissue Biopsy (TB) when the aim is to obtain useful information on patient prognosis and personalized therapy. This technique renders it possible to isolate circulating tumor cells, circulating tumor DNA and other molecules from biological fluids. The most commonly used fluid for liquid biopsy is blood, but depending on the case it could be necessary to isolate the tumor components from other biological fluids such as urine, pleural effusion, cerebrospinal fluid, and others. The main advantages of liquid biopsy are the minimally invasive nature of the procedure and the possibility of analyzing all tumor clones. Limitations include difficulties in the isolation of tumor components and the requirement for highly sensitive analysis methods to avoid the risk of technical artifacts. In our review we will focus on describing circulating tumor biomarkers to illustrate the variety of information that can be obtained from biological fluids, particularly blood. We will then discuss the advanced biotechnological techniques suitable for the identification and analysis of Circulating Tumor DNA (ctDNA), examining both the potential and limitations of analytical methods and the clinical applicability of liquid biopsy for cancer diagnosis, monitoring, and therapeutic prediction. Additionally, we will explore strategies to enhance this valuable alternative to the more invasive tissue biopsy, with a dedicated focus on ongoing clinical studies, currently approved tests, and guideline recommendations.
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Affiliation(s)
- Serafina Martella
- University of Catania Department of Biomedical and Biotechnological Sciences, Catania, Italy
| | - Demi Wekking
- Location Academic Medical Centre, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Matteo Lambertini
- Department of Internal Medicine and Medical Specialties, School of Medicine, University of Genoa, Genoa, Italy; Department of Medical Oncology, U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | | | - Alissa Parrino
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | | | | | | | | | - Alfredo Addeo
- Oncology Department, University Hospital Geneva (HUG), Geneva, Switzerland
| | - Cinzia Solinas
- Medical Oncology, AOU Cagliari, Policlinico Duilio Casula Monserrato (CA), Cagliari, Italy.
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19
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Wu Y, Qiao Y, Yang C, Chen Y, Shen X, Deng C, Yao Q, Sun N. Accelerated Exosomal Metabolic Profiling Enabled by Robust On-Target Array Sintering with Metal-Organic Frameworks. SMALL METHODS 2025; 9:e2401238. [PMID: 39263996 DOI: 10.1002/smtd.202401238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/06/2024] [Indexed: 09/13/2024]
Abstract
Pancreatic cancer is highly lethal, and survival chances improve only with early detection at a precancerous stage. However, there remains a significant gap in developing tools for large-scale, rapid screening. To this end, a high-throughput On-Target Array Extraction Platform (OTAEP) by direct sintering of a series of metal-organic frameworks (MOFs) for dual in situ extraction, encompassing both exosomes and their metabolic profiles, is developed. Based on the principle of geometry-dependent photothermal conversion efficiency and standard testing, the appropriate MOF functional unit is identified. This unit enables exosome enrichment within 10 min and metabolic fingerprint extraction in under 1 s of laser irradiation, with over five reuse. To further accelerate and enhance the quality of metabolic profile analysis, the application of Surrogate Variable Analysis to eliminate hidden confounding factors within the profiles is proposed, and five biomarkers demonstrated by MS/MS experiments are identified. These biomarkers enable early diagnosis, risk stratification, and staging of pancreatic cancer simultaneously, with sensitivity of 94.1%, specificity of 98.8%, and precision of 94.9%. This work represents a breakthrough for overcoming throughput challenges in large-scale testing and for addressing confounding factors in big data analysis.
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Affiliation(s)
- Yun Wu
- Department of Chemistry, Institutes of Biomedical Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200433, P. R. China
| | - Yiming Qiao
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Chenyu Yang
- Department of Chemistry, Institutes of Biomedical Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200433, P. R. China
| | - Yueying Chen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Xizhong Shen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Chunhui Deng
- Department of Chemistry, Institutes of Biomedical Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200433, P. R. China
| | - Qunyan Yao
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, P. R. China
| | - Nianrong Sun
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
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Guo X, Wang W, Cheng X, Song Q, Wang X, Wei J, Xu S, Lv X, Ji G. Diagnostic efficacy of an extracellular vesicle-derived lncRNA-based liquid biopsy signature for the early detection of early-onset gastric cancer. Gut 2025:gutjnl-2024-333657. [PMID: 40113244 DOI: 10.1136/gutjnl-2024-333657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 02/25/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND Early-onset gastric cancer (EOGC) is a lethal malignancy. It differs from late-onset gastric cancer (LOGC) in clinical and molecular characteristics. The current strategies for EOGC detection have certain limitations in diagnostic performance due to the rising trend in EOGC. OBJECTIVE We developed a liquid biopsy signature for EOGC detection. DESIGN We use a systematic discovery approach by analysing genome-wide transcriptomic profiling data from EOGC (n=43), LOGC (n=31) and age-matched non-disease controls (n=37) tissue samples. An extracellular vesicle-derived long non-coding RNA (EV-lncRNA) signature was identified in blood samples from a training cohort (n=299), and subsequently confirmed by qPCR in two external validation cohorts (n=462 and n=438), a preoperative/postoperative cohort (n=66) and a gastrointestinal tumour cohort (n=225). RESULTS A three EV-lncRNA (NALT1, PTENP1 and HOTTIP) liquid biopsy signature was developed for EOGC detection with an area under the receiver operating characteristic curve (AUROC) of 0.924 (95% CI 0.889 to 0.953). This EV-lncRNA signature provided robust diagnostic performance in two external validation cohorts (Xi'an cohort: AUROC, 0.911; Beijing cohort: AUROC, 0.9323). Furthermore, the EV-lncRNA signature reliably identified resectable stage EOGC patients (stage I/II) and demonstrated better diagnostic performance than traditional GC-related biomarkers in distinguishing early-stage EOGC (stage I) from precancerous lesions. The low levels of this biomarker in postsurgery and other gastrointestinal tumour plasma samples indicated its GC specificity. CONCLUSIONS The newly developed EV-lncRNA signature effectively identified EOGC patients at a resectable stage with enhanced precision, thereby improving the prognosis of patients who would have otherwise missed the curative treatment window.
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Affiliation(s)
- Xin Guo
- Department of General Surgery, Xijing 986th Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Weidong Wang
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xin Cheng
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Qiying Song
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xinxin Wang
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jiangpeng Wei
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Shenhui Xu
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xiaohui Lv
- Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Gang Ji
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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Pinto E, Lazzarini E, Pelizzaro F, Gambato M, Santarelli L, Potente S, Zanaga P, Zappitelli T, Cardin R, Burra P, Farinati F, Romualdi C, Boscarino D, Tosello V, Indraccolo S, Russo FP. Somatic Copy Number Alterations in Circulating Cell-Free DNA as a Prognostic Biomarker for Hepatocellular Carcinoma: Insights from a Proof-of-Concept Study. Cancers (Basel) 2025; 17:1115. [PMID: 40227625 PMCID: PMC11988118 DOI: 10.3390/cancers17071115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 03/13/2025] [Accepted: 03/21/2025] [Indexed: 04/15/2025] Open
Abstract
BACKGROUND/OBJECTIVES Despite advances in hepatocellular carcinoma (HCC) management, prognosis remains poor. Advanced-stage diagnosis often excludes curative treatments, and current biomarkers (e.g., alpha-fetoprotein [AFP]) have limited utility in early detection. Liquid biopsy has emerged as a promising cancer detection tool, with circulating cell-free DNA (ccfDNA) showing significant diagnostic potential. This proof-of-concept study aimed to investigate the potential role of tumor fraction (TF) within ccfDNA as a biomarker in HCC patients. METHODS A total of sixty patients were recruited, including thirteen with chronic liver disease (CLD), twenty-four with cirrhosis, and twenty-three with HCC. Plasma samples were collected, and ccfDNA was extracted for shallow whole genome sequencing (sWGS) analysis. The TF was calculated by focusing on somatic copy number alterations (SCNAs) within the ccfDNA. RESULTS Among patients with CLD and cirrhosis (n = 37), ctDNA was undetectable in all but one cirrhotic patient who exhibited a significant tumor fraction (TF) of 17% and subsequently developed HCC. Conversely, five out of twenty-three HCC patients (21.7%) displayed detectable ctDNA with TF levels ranging from 3.0% to 32.6%. Patients with detectable ctDNA were characterized by more aggressive oncological features, including a higher number of nodules (p = 0.005), advanced-stage disease (60% BCLC C, p = 0.010), and poorer response to therapy (80% PD, p = 0.001). Moreover, the overall survival (OS) was significantly reduced in patients with detectable ctDNA (median OS: 17 months; CI 95% 4.5-26.5) compared to those without (median OS: 24.0 months; CI 95% 7.0-66.0; log-rank p = 0.002). CONCLUSIONS Our results suggest that the analysis of TF by sWGS is a promising non-invasive tool for the identification of HCC with aggressive clinical behavior, whereas it is not sensitive enough for early HCC detection. This molecular assay can improve prognostic stratification in HCC patients.
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Affiliation(s)
- Elisa Pinto
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35121 Padua, Italy; (E.P.); (F.P.); (M.G.); (P.Z.); (T.Z.); (P.B.); (F.F.); (S.I.)
- Gastroenterology Unit, Azienda Ospedale-Università di Padova, 35121 Padua, Italy;
| | - Elisabetta Lazzarini
- Basic and Translational Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35121 Padua, Italy; (E.L.); (L.S.); (V.T.)
| | - Filippo Pelizzaro
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35121 Padua, Italy; (E.P.); (F.P.); (M.G.); (P.Z.); (T.Z.); (P.B.); (F.F.); (S.I.)
- Gastroenterology Unit, Azienda Ospedale-Università di Padova, 35121 Padua, Italy;
| | - Martina Gambato
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35121 Padua, Italy; (E.P.); (F.P.); (M.G.); (P.Z.); (T.Z.); (P.B.); (F.F.); (S.I.)
- Gastroenterology Unit, Azienda Ospedale-Università di Padova, 35121 Padua, Italy;
| | - Laura Santarelli
- Basic and Translational Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35121 Padua, Italy; (E.L.); (L.S.); (V.T.)
| | - Sara Potente
- Department of Biology, University of Padova, 35121 Padua, Italy; (S.P.); (C.R.)
| | - Paola Zanaga
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35121 Padua, Italy; (E.P.); (F.P.); (M.G.); (P.Z.); (T.Z.); (P.B.); (F.F.); (S.I.)
- Gastroenterology Unit, Azienda Ospedale-Università di Padova, 35121 Padua, Italy;
| | - Teresa Zappitelli
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35121 Padua, Italy; (E.P.); (F.P.); (M.G.); (P.Z.); (T.Z.); (P.B.); (F.F.); (S.I.)
- Gastroenterology Unit, Azienda Ospedale-Università di Padova, 35121 Padua, Italy;
| | - Romilda Cardin
- Gastroenterology Unit, Azienda Ospedale-Università di Padova, 35121 Padua, Italy;
| | - Patrizia Burra
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35121 Padua, Italy; (E.P.); (F.P.); (M.G.); (P.Z.); (T.Z.); (P.B.); (F.F.); (S.I.)
- Gastroenterology Unit, Azienda Ospedale-Università di Padova, 35121 Padua, Italy;
| | - Fabio Farinati
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35121 Padua, Italy; (E.P.); (F.P.); (M.G.); (P.Z.); (T.Z.); (P.B.); (F.F.); (S.I.)
- Gastroenterology Unit, Azienda Ospedale-Università di Padova, 35121 Padua, Italy;
| | - Chiara Romualdi
- Department of Biology, University of Padova, 35121 Padua, Italy; (S.P.); (C.R.)
| | | | - Valeria Tosello
- Basic and Translational Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35121 Padua, Italy; (E.L.); (L.S.); (V.T.)
| | - Stefano Indraccolo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35121 Padua, Italy; (E.P.); (F.P.); (M.G.); (P.Z.); (T.Z.); (P.B.); (F.F.); (S.I.)
- Basic and Translational Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35121 Padua, Italy; (E.L.); (L.S.); (V.T.)
| | - Francesco Paolo Russo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35121 Padua, Italy; (E.P.); (F.P.); (M.G.); (P.Z.); (T.Z.); (P.B.); (F.F.); (S.I.)
- Gastroenterology Unit, Azienda Ospedale-Università di Padova, 35121 Padua, Italy;
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Karageorgos FF, Karakasi KE, Kofinas A, Antoniadis N, Katsanos G, Tsoulfas G. Evolving Transplant Oncology: Evolving Criteria for Better Decision-Making. Diagnostics (Basel) 2025; 15:820. [PMID: 40218170 PMCID: PMC11988714 DOI: 10.3390/diagnostics15070820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 03/10/2025] [Accepted: 03/21/2025] [Indexed: 04/14/2025] Open
Abstract
Transplant oncology integrates a wide variety of fields, such as surgery, oncology, and transplant medicine, intending to increase the range of studies and treatments for hepatobiliary cancers and other liver-related malignant lesions. Liver transplantation (LT) has proven to be an effective treatment for hepatocellular carcinoma. While the Milan criteria are still the gold standard, several new, more inclusive criteria have been proposed, and hepatocellular carcinoma has become a major indication for liver transplantation. The continuous evolution of diagnostic technologies supported this with higher image quality and more accurate staging. This review describes the current applications of transplant oncology in hepatocellular carcinoma, cholangiocarcinoma, neuroendocrine tumors, and liver metastatic disease from colorectal cancer and discusses the path that led to the development of transplant oncology as an organized approach to managing gastrointestinal malignancies through transplantation. More importantly, the significance of a multidisciplinary approach and criteria in the selection of suitable candidates are discussed. In addition, newer aspects of transplant oncology, such as immunotherapy, circulating tumor DNA (ctDNA), novel surgical techniques, and the utilization of artificial intelligence, are presented. Finally, the opportunities and challenges involved in the field's future, as well as the evolution of the criteria used over the years and insightful thoughts for the future of the criteria, are discussed.
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Affiliation(s)
| | | | | | | | | | - Georgios Tsoulfas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, 54642 Thessaloniki, Greece; (F.F.K.)
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Chi H, Shi L, Gan S, Fan G, Dong Y. Innovative Applications of Nanopore Technology in Tumor Screening: An Exosome-Centric Approach. BIOSENSORS 2025; 15:199. [PMID: 40277513 PMCID: PMC12024935 DOI: 10.3390/bios15040199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/28/2025] [Accepted: 03/05/2025] [Indexed: 04/26/2025]
Abstract
Cancer remains one of the leading causes of death worldwide. Its complex pathogenesis and metastasis pose significant challenges for early diagnosis, underscoring the urgent need for innovative and non-invasive tumor screening methods. Exosomes, small extracellular vesicles that reflect the physiological and pathological states of their parent cells, are uniquely suited for cancer liquid biopsy due to their molecular cargo, including RNA, DNA, and proteins. However, traditional methods for exosome isolation and detection are often limited by inadequate sensitivity, specificity, and efficiency. Nanopore technology, characterized by high sensitivity and single-molecule resolution, offers powerful tools for exosome analysis. This review highlights its diverse applications in tumor screening, such as magnetic nanopores for high-throughput sorting, electrochemical sensing for real-time detection, nanomaterial-based assemblies for efficient capture, and plasmon resonance for ultrasensitive analysis. These advancements have enabled precise exosome detection and demonstrated promising potential in the early diagnosis of breast, pancreatic, and prostate cancers, while also supporting personalized treatment strategies. Additionally, this review summarizes commercialized products for exosome-based cancer diagnostics and examines the technical and translational challenges in clinical applications. Finally, it discusses the future prospects of nanopore technology in advancing liquid biopsy toward clinical implementation. The continued progress of nanopore technology not only accelerates exosome-based precision medicine but also represents a significant step forward in next-generation liquid biopsy and tumor screening.
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Affiliation(s)
- Heng Chi
- BGI Research, Shenzhen 518083, China; (H.C.); (L.S.)
| | - Liuxin Shi
- BGI Research, Shenzhen 518083, China; (H.C.); (L.S.)
| | | | | | - Yuliang Dong
- BGI Research, Shenzhen 518083, China; (H.C.); (L.S.)
- BGI Research, Hangzhou 310030, China;
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24
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Liu P, Zhang Q, Liu F. Biological roles and clinical applications of EpCAM in HCC. Discov Oncol 2025; 16:319. [PMID: 40087210 PMCID: PMC11909382 DOI: 10.1007/s12672-025-02095-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 03/07/2025] [Indexed: 03/17/2025] Open
Abstract
Epithelial cell adhesion molecule (EpCAM) is an important biomarker in tumors. In hepatocellular carcinoma (HCC), EpCAM + cells exhibit high invasiveness, tumorigenic ability, therapeutic resistance, and self-renewal ability, often identified as liver cancer stem cells (CSCs). Detecting EpCAM + cells in tumor lesions and circulation is valuable for predicting patient prognosis and monitoring therapeutic outcomes, emphasizing its clinical significance. Given its broad expression in HCC, especially in CSCs and circulating tumor cells (CTCs), EpCAM-targeting agents have garnered substantial research interest. However, the role of EpCAM in HCC progression and its regulatory mechanisms remains poorly understood. Furthermore, clinical applications of EpCAM, such as liquid biopsy and targeted therapies, are still controversial. This review summarizes the biological properties of EpCAM + HCC cells, explores the regulatory mechanisms governing EpCAM expression, and discusses its clinical significance of using EpCAM as a prognostic marker and therapeutic target.
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Affiliation(s)
- Peng Liu
- Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qun Zhang
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Fengchao Liu
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China.
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Wang Y, Huang S, Cai Y, Wang T, Zhao H, Lin X, Wang X, Li P. Programmed cell death protein 5 inhibits hepatocellular carcinoma progression by inducing pyroptosis through regulation of TGF-β/Smad2/3/Snail pathway. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167696. [PMID: 39884472 DOI: 10.1016/j.bbadis.2025.167696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/11/2024] [Accepted: 01/22/2025] [Indexed: 02/01/2025]
Abstract
BACKGROUND Programmed cell death protein 5 (PDCD5) is involved in apoptosis and is regarded as a tumor suppressor in various tumors. However, its role and underlying molecular mechanisms in hepatocellular carcinoma (HCC) remain unclear. METHODS PDCD5-overexpressing cell and xenograft tumor models were developed. Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine, wound healing, Transwell, flow cytometry, immunohistochemistry, and hematoxylin-eosin staining were employed to explore the effects of PDCD5 on HCC cell behaviors and tumor growth. The enzyme-linked immunosorbent assay and western blot were used to detect pyroptosis-related marker levels. The molecular mechanisms underlying PDCD5's role in HCC were investigated through transcriptome sequencing and coimmunoprecipitation. SRI-011381, a TGF-β signaling activator, was applied to evaluate the impact of PDCD5 in modulating the TGF-β/Smad2/3/Snail pathway. RESULTS PDCD5 expression was reduced in HCC cells. Overexpression of PDCD5 inhibited HCC cell proliferation, migration, invasion, and xenograft tumor growth. Additionally, PDCD5 overexpression promoted apoptosis and pyroptosis, with corresponding increases in inflammatory factors and Caspase-1, GSDMD, and NLRP3 protein levels. Mechanistically, PDCD5 bound to receptor-regulated Smads (Smad2/3), inhibiting the TGF-β pathway. Treatment with the TGF-β pathway activator SRI-011381 significantly counteracted the inhibitory effects of PDCD5 overexpression on HCC progression. CONCLUSION Our findings suggest that PDCD5 impedes the progression of HCC by promoting pyroptosis via regulation of TGF-β/Smad2/3/Snail pathway, which could be a possible therapeutic target for HCC.
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Affiliation(s)
- Yiqiao Wang
- Department of Hepatobiliary and Pancreatic Surgery, Yueqing City People's Hospital, No. 338 Qingyuan Road, Chengnan Street, Yueqing City 325699, Zhejiang Province, China
| | - Shihao Huang
- Department of Hepatobiliary and Pancreatic Surgery, Yueqing City People's Hospital, No. 338 Qingyuan Road, Chengnan Street, Yueqing City 325699, Zhejiang Province, China
| | - Yangbai Cai
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Hainan Medical University, No. 48 Baishuitang Road, Haikou City 570100, Hainan Province, China
| | - Taicheng Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Hainan Medical University, No. 48 Baishuitang Road, Haikou City 570100, Hainan Province, China
| | - Hongyan Zhao
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Hainan Medical University, No. 48 Baishuitang Road, Haikou City 570100, Hainan Province, China
| | - Xianke Lin
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Hainan Medical University, No. 48 Baishuitang Road, Haikou City 570100, Hainan Province, China
| | - Xueguo Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Hainan Medical University, No. 48 Baishuitang Road, Haikou City 570100, Hainan Province, China
| | - Peng Li
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Hainan Medical University, No. 48 Baishuitang Road, Haikou City 570100, Hainan Province, China.
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Sun Z, Li X. A promising mesoporous silica carrier material for the diagnosis and treatment of liver diseases: recent research advances. J Mater Chem B 2025; 13:1935-1960. [PMID: 39801308 DOI: 10.1039/d4tb01822b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
The therapeutic diagnosis of liver diseases has garnered significant interest within the medical community. In recent years, mesoporous silica nanoparticles (MSNs) have emerged as crucial nanocarriers for the treatment of liver ailments. Their remarkable diagnostic capabilities enable them to be used in techniques such as high-throughput mass spectrometry (MS), magnetic resonance imaging (MRI), near-infrared (NIR) fluorescence imaging, photoacoustic imaging (PAI), and ultrasonography (US), attracting considerable attention. Furthermore, the introduction of amino and carboxyl group modifications in MSNs has facilitated their use as drug delivery carriers for treating liver diseases, including hepatocellular carcinoma. This paper reviews the preparation methods, in vitro diagnostic capabilities, and in vivo therapeutic delivery systems of MSNs for liver disease treatment. It also summarizes relevant toxicity studies, aiming to provide a comprehensive overview of the diagnostic and therapeutic applications of MSNs in the treatment of liver diseases, particularly hepatocellular carcinoma. Through this review, we seek to offer theoretical insights into the potential of MSNs for diagnostic and therapeutic applications in liver disease treatment.
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Affiliation(s)
- Zihao Sun
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xiaofang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
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27
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Zorina ES, Naryzhny SN. Biomarkers of hepatocellular carcinoma: status and prospects. BIOMEDITSINSKAIA KHIMIIA 2025; 71:7-18. [PMID: 40045719 DOI: 10.18097/pbmcr1543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/13/2025]
Abstract
Hepatocellular carcinoma (HCC) also known as hepatocellular cancer is one of the most common and aggressive types of primary malignant liver neoplasms. This type of cancer accounts for up to 90% of all primary liver tumors and is the third leading cause of cancer death worldwide. Despite the advances in modern medicine, diagnostics and treatment of HCC remain challenging, especially in the later stages, when the patient's prognosis significantly worsens and treatment options are very limited. More than half a century has passed since Yu.S. Tatarinov discovered embryo-specific α-globulin in the blood of people with primary liver cancer in 1963, which was later called alpha-fetoprotein (AFP), but unfortunately, the number of specific and sensitive biomarkers for HCC remains very limited. In this regard, many scientific papers are devoted to the search and study of potential HCC biomarkers, which are essential for early diagnostics, prognosis, and development of new therapeutic strategies. Proteomic studies represent one of the promising approaches to investigate both molecular mechanisms of HCC occurrence and HCC biomarkers. Identification of specific protein profiles characteristic of tumor cells can contribute to the identification of new biomarkers that can be used not only for early detection of the disease, but also for monitoring its progression, assessing the response to therapy and predicting the clinical outcome. This review discusses current achievements in the search for potential biomarkers of HCC, as well as the prospects for their clinical use.
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Affiliation(s)
- E S Zorina
- Institute of Biomedical Chemistry, Moscow, Russia
| | - S N Naryzhny
- Petersburg Institute of Nuclear Physics B.P. Konstantinova National Research Center "Kurchatov Institute", Gatchina, Leningrad Region, Russia
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Jiang Y, Qi S, Zhang R, Zhao R, Fu Y, Fang Y, Shao M. Diagnosis of hepatocellular carcinoma using liquid biopsy-based biomarkers: a systematic review and network meta-analysis. Front Oncol 2025; 14:1483521. [PMID: 39935848 PMCID: PMC11810725 DOI: 10.3389/fonc.2024.1483521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 12/31/2024] [Indexed: 02/13/2025] Open
Abstract
Introduction The diagnostic performance of liquid biopsy-based biomarkers for HCC was comprehensively compared in this network meta-analysis (NMA). Methods A thorough literature search was conducted to identify all comparative studies from January 1, 2000, to January 11, 2024. The QUADAS-2 tool was utilized to appraise the quality of studies involving diagnostic performance. R (v4.3.3) and an ANOVA model-based NMA were used to assess the diagnostic accuracy of each biomarker. Results This study included 82 studies comprising a total of 15,024 patients.CircRNA demonstrated significantly superior performance in distinguishing HCC from healthy populations (superiority index: 3.550 (95% CI [0.143-3])) compared to other diagnostic biomarkers for HCC. "mRNA exhibited significantly superior performance in distinguishing HCC from liver disease patients (superiority index:10.621 (95% CI [7-11])) compared to other diagnostic biomarkers for HCC. Further subgroup analysis of the top-ranking liquid biopsy-based diagnostic biomarkers revealed that hsa_circ_000224 (superiority index: 3.091 (95% CI[0.143-9]) ranked remarkably higher in distinguishing HCC from both healthy populations and liver disease patients. Subgroup analysis of mRNA demonstrated that KIAA0101 mRNA (superiority index: 2.434 (95% CI [0.2-5]) ranked remarkably higher in distinguishing HCC from healthy populations and liver disease patients, respectively. Discussion The results of this meta-analysis show that circRNA and mRNA are the first choice for HCC diagnosis. Subsequent analysis of circRNA and mRNA highlighted hsa_circ_000224, hsa_circ_0003998, KIAA0101 mRNA and GPC-3mRNA as the optimal diagnostic biomarkers for distinguishing HCC from healthy populations and liver disease patients, respectively. Well-structured prospective studies are crucial to comprehensively validate these findings. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/,identifier CRD42024521299.
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Affiliation(s)
- Yutong Jiang
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, China
| | - Shangwen Qi
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, China
| | - Rongrong Zhang
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, China
| | - Ruixia Zhao
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yu Fu
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yuxuan Fang
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, China
| | - Mingyi Shao
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
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Shi J, Zhu X, Yang JB. Advances and challenges in molecular understanding, early detection, and targeted treatment of liver cancer. World J Hepatol 2025; 17:102273. [PMID: 39871899 PMCID: PMC11736488 DOI: 10.4254/wjh.v17.i1.102273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/12/2024] [Accepted: 11/27/2024] [Indexed: 01/06/2025] Open
Abstract
In this review, we explore the application of next-generation sequencing in liver cancer research, highlighting its potential in modern oncology. Liver cancer, particularly hepatocellular carcinoma, is driven by a complex interplay of genetic, epigenetic, and environmental factors. Key genetic alterations, such as mutations in TERT, TP53, and CTNNB1, alongside epigenetic modifications such as DNA methylation and histone remodeling, disrupt regulatory pathways and promote tumorigenesis. Environmental factors, including viral infections, alcohol consumption, and metabolic disorders such as nonalcoholic fatty liver disease, enhance hepatocarcinogenesis. The tumor microenvironment plays a pivotal role in liver cancer progression and therapy resistance, with immune cell infiltration, fibrosis, and angiogenesis supporting cancer cell survival. Advances in immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies have shown potential, but the unique immunosuppressive milieu in liver cancer presents challenges. Dysregulation in pathways such as Wnt/β-catenin underscores the need for targeted therapeutic strategies. Next-generation sequencing is accelerating the identification of genetic and epigenetic alterations, enabling more precise diagnosis and personalized treatment plans. A deeper understanding of these molecular mechanisms is essential for advancing early detection and developing effective therapies against liver cancer.
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Affiliation(s)
- Ji Shi
- Department of Research and Development, Ruibiotech Company Limited, Beijing 100101, China
| | - Xu Zhu
- Department of Research and Development, Ruibiotech Company Limited, Beijing 100101, China
| | - Jun-Bo Yang
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518000, Guangdong Province, China.
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30
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Du X, Li H, Shen S, Tian C, Cao X, Xu X, Xu N, Wang S, Tian Q. Labeling tumor-associated extracellular vesicles with antibody-DNA conjugates for quantitative analysis. Front Mol Biosci 2025; 12:1531108. [PMID: 39911266 PMCID: PMC11794122 DOI: 10.3389/fmolb.2025.1531108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 01/06/2025] [Indexed: 02/07/2025] Open
Abstract
Introduction Extracellular vesicles (EVs) shed from tumor cells into peripheral circulation or other body fluids are promising biomarkers for cancer diagnosis with enormously long circulation. Consequently, precise methods for differentiating normal and tumor-associated EVs (TAEs) are required. Methods This study used quantifiable antibody-DNA conjugate-assisted quantitative methods combined with proximity ligation technology to detect TAEs. The antibody-DNA conjugate contained one antibody associated with three oligonucleotides for signal amplification. The antibody in the conjugate can recognize the surface tumor antigens of TAEs. Simultaneously, DNA in the conjugate is attached to the surfaces of TAEs and holds the signal amplification post, converting protein identities to DNA amplification for protein detection, even at the molecular level. Results These findings revealed that TAEs can be quantitatively detected using DNA-mediated quantitative polymerase chain reaction (qPCR). Antibody-DNA conjugates were used to recognize the epithelial cell adhesion molecule (EpCAM) antigen on the TAE surface and quantify the antigen using qPCR for cancer analysis. Discussion This method proposed a new quantitative detection approach for TAEs, which aim to identify specific EV-associated markers for diagnostic or therapeutic, this method could inspire a new idea for tumor diagnosis and detection of other diseases.
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Affiliation(s)
- Xiao Du
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Hongxiu Li
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Shiyi Shen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Chao Tian
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Xiaohuan Cao
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Xingang Xu
- Laboratory of Chinese Medicine Preparation, Shandong Research Academy of Traditional Chinese Medicine, Jinan, China
| | - Nan Xu
- Laboratory of Chinese Medicine Preparation, Shandong Research Academy of Traditional Chinese Medicine, Jinan, China
| | - Shuling Wang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Qingchang Tian
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
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Takahashi Y, Ijiri Y, Fujino S, Elnaz N, Kishimoto A, Shirai K, Iwanaga S, Yanagida M, Bhagat AAS, Miyoshi N. Detection and Characterization of Circulating Tumor Cells in Colorectal Cancer Patients via Epithelial-Mesenchymal Transition Markers. Cancers (Basel) 2025; 17:303. [PMID: 39858085 PMCID: PMC11763958 DOI: 10.3390/cancers17020303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 01/12/2025] [Accepted: 01/14/2025] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Liquid biopsy methods have gained prominence as minimally invasive tools to improve cancer treatment outcomes. Circulating tumor cells (CTCs) offer valuable insights into both primary and metastatic lesions. However, validating the CTC test results requires confirmation that the detected cells originate from cancer tissue. While studies have identified CTCs in colorectal cancer (CRC) patients using molecular markers, simultaneous validation of their cancer tissue origin remains unexplored. Methods: This study introduces a simple approach to detect adenomatous polyposis coli (APC) gene abnormalities alongside established CTC markers using a molecular imaging flow cytometer (MI-FCM). Given that APC gene abnormalities occur in 60-70% of CRC patients, their detection serves as strong evidence of cancer origin. Results: Our method achieved 92% concordance with DNA sequence analysis of tumor-derived cells. In a proof-of-concept study using 5 mL of whole blood from CRC patients, we observed a high frequency of cells exhibiting APC abnormalities, cytokeratin (CK), and vimentin (Vim) expression. Extending the study to 80 CRC patients across pathological stages I-IV confirmed CK and Vim as valid CTC markers. Three distinct cell populations were identified in blood: CK+/Vim-, CK+/Vim+, and CK-/Vim+. CTC number and frequency increased progressively with cancer stage. Conclusions: This is the first report demonstrating CK and Vim as effective markers for direct CTC detection in CRC patients. Our findings provide evidence-based validation of CTC markers, offering new insights and advancing approaches for patient care.
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Affiliation(s)
- Yusuke Takahashi
- Department of Central Research Laboratories, Sysmex Corporation, Kobe 651-2271, Japan; (Y.T.); (Y.I.); (N.E.); (A.K.); (K.S.); (S.I.); (M.Y.)
| | - Yuichi Ijiri
- Department of Central Research Laboratories, Sysmex Corporation, Kobe 651-2271, Japan; (Y.T.); (Y.I.); (N.E.); (A.K.); (K.S.); (S.I.); (M.Y.)
| | - Shiki Fujino
- Department of Gastroenterology, Central Clinical School, Monash University, Melbourne 3004, Australia;
- Innovative Oncology Research and Regenerative Medicine, Osaka International Cancer Institute, Osaka 541-8567, Japan
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan
| | - Nakhaei Elnaz
- Department of Central Research Laboratories, Sysmex Corporation, Kobe 651-2271, Japan; (Y.T.); (Y.I.); (N.E.); (A.K.); (K.S.); (S.I.); (M.Y.)
| | - Ayuko Kishimoto
- Department of Central Research Laboratories, Sysmex Corporation, Kobe 651-2271, Japan; (Y.T.); (Y.I.); (N.E.); (A.K.); (K.S.); (S.I.); (M.Y.)
| | - Kentaro Shirai
- Department of Central Research Laboratories, Sysmex Corporation, Kobe 651-2271, Japan; (Y.T.); (Y.I.); (N.E.); (A.K.); (K.S.); (S.I.); (M.Y.)
| | - Shigeki Iwanaga
- Department of Central Research Laboratories, Sysmex Corporation, Kobe 651-2271, Japan; (Y.T.); (Y.I.); (N.E.); (A.K.); (K.S.); (S.I.); (M.Y.)
| | - Masatoshi Yanagida
- Department of Central Research Laboratories, Sysmex Corporation, Kobe 651-2271, Japan; (Y.T.); (Y.I.); (N.E.); (A.K.); (K.S.); (S.I.); (M.Y.)
| | - Ali Asgar S. Bhagat
- Biolidics Limited, Singapore 577177, Singapore;
- Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore 119276, Singapore
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore 117575, Singapore
| | - Norikatsu Miyoshi
- Innovative Oncology Research and Regenerative Medicine, Osaka International Cancer Institute, Osaka 541-8567, Japan
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan
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Liu Y, Peng F, Wang S, Jiao H, Zhou K, Guo W, Guo S, Dang M, Zhang H, Zhou W, Guo X, Xing J. Aberrant fragmentomic features of circulating cell-free mitochondrial DNA enable early detection and prognosis prediction of hepatocellular carcinoma. Clin Mol Hepatol 2025; 31:196-212. [PMID: 39406379 PMCID: PMC11791606 DOI: 10.3350/cmh.2024.0527] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 10/10/2024] [Accepted: 10/11/2024] [Indexed: 02/05/2025] Open
Abstract
BACKGROUND/AIMS Early detection and effective prognosis prediction in patients with hepatocellular carcinoma (HCC) provide an avenue for survival improvement, yet more effective approaches are greatly needed. We sought to develop the detection and prognosis models with ultra-sensitivity and low cost based on fragmentomic features of circulating cell free mtDNA (ccf-mtDNA). METHODS Capture-based mtDNA sequencing was carried out in plasma cell-free DNA samples from 1168 participants, including 571 patients with HCC, 301 patients with chronic hepatitis B or liver cirrhosis (CHB/LC) and 296 healthy controls (HC). RESULTS The systematic analysis revealed significantly aberrant fragmentomic features of ccf-mtDNA in HCC group when compared with CHB/LC and HC groups. Moreover, we constructed a random forest algorithm-based HCC detection model by utilizing ccf-mtDNA fragmentomic features. Both internal and two external validation cohorts demonstrated the excellent capacity of our model in distinguishing early HCC patients from HC and highrisk population with CHB/LC, with AUC exceeding 0.983 and 0.981, sensitivity over 89.6% and 89.61%, and specificity over 98.20% and 95.00%, respectively, greatly surpassing the performance of alpha-fetoprotein (AFP) and mtDNA copy number. We also developed an HCC prognosis prediction model by LASSO-Cox regression to select 20 fragmentomic features, which exhibited exceptional ability in predicting 1-year, 2-year and 3-year survival (AUC=0.8333, 0.8145 and 0.7958 for validation cohort, respectively). CONCLUSION We have developed and validated a high-performing and low-cost approach in a large clinical cohort based on aberrant ccf-mtDNA fragmentomic features with promising clinical translational application for the early detection and prognosis prediction of HCC patients.
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Affiliation(s)
- Yang Liu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
- Department of Clinical Diagnosis, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
| | - Fan Peng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Siyuan Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Huanmin Jiao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Kaixiang Zhou
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Wenjie Guo
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Shanshan Guo
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Miao Dang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Huanqin Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Weizheng Zhou
- Department of General Surgery, Changhai Hospital, Navy Medical University, Shanghai, China
| | - Xu Guo
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Jinliang Xing
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
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Büdeyri I, Guckelberger O, Oppermann E, Roy D, Sliwinski S, Becker F, Struecker B, Vogl TJ, Pascher A, Bechstein WO, Lorentzen A, Heikenwalder M, Juratli MA. Ezrin Polarization as a Diagnostic Marker for Circulating Tumor Cells in Hepatocellular Carcinoma. Cells 2024; 14:6. [PMID: 39791707 PMCID: PMC11720075 DOI: 10.3390/cells14010006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 12/08/2024] [Accepted: 12/24/2024] [Indexed: 01/12/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related death worldwide, with no precise method for early detection. Circulating tumor cells (CTCs) expressing the dynamic polarity of the cytoskeletal membrane protein, ezrin, have been proposed to play a crucial role in tumor progression and metastasis. This study investigated the diagnostic and prognostic potential of polarized circulating tumor cells (p-CTCs) in HCC patients. CTCs were isolated from the peripheral blood of 20 HCC patients and 18 patients with nonmalignant liver disease (NMLD) via an OncoQuick® kit and immunostained with Ezrin-Alexa Fluor 488®, CD146-PE, and CD45-APC. A fluorescence microscopy was then performed for analysis. The HCC group exhibited significantly higher levels of p-CTCs, with median values of 0.56 p-CTCs/mL, compared to 0.02 p-CTCs/mL (p = 0.03) in the NMLD group. CTCs were detected in 95% of the HCC patients, with a sensitivity of 95% and specificity of 89%. p-CTCs were present in 75% of the HCC patients, with a sensitivity of 75% and a specificity of 94%. Higher p-CTC counts were associated with the significantly longer overall survival in HCC patients (p = 0.05). These findings suggest that p-CTCs could serve as valuable diagnostic and prognostic markers for HCC. The incorporation of p-CTCs into diagnostic strategies could enhance therapeutic decision-making and improve patient outcomes.
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Affiliation(s)
- Ibrahim Büdeyri
- Department of General, Visceral and Transplant Surgery, University Hospital Muenster, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany; (I.B.)
| | - Olaf Guckelberger
- Department of General, Visceral and Transplant Surgery, University Hospital Muenster, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany; (I.B.)
| | - Elsie Oppermann
- Department of General, Visceral and Transplant Surgery, Frankfurt University Hospital, 60596 Frankfurt, Germany
| | - Dhruvajyoti Roy
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Svenja Sliwinski
- Department of General, Visceral and Transplant Surgery, Frankfurt University Hospital, 60596 Frankfurt, Germany
| | - Felix Becker
- Department of General, Visceral and Transplant Surgery, University Hospital Muenster, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany; (I.B.)
| | - Benjamin Struecker
- Department of General, Visceral and Transplant Surgery, University Hospital Muenster, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany; (I.B.)
| | - Thomas J. Vogl
- Department of Diagnostic and Interventional Radiology, Frankfurt University Hospital, Goethe University, 60596 Frankfurt, Germany
| | - Andreas Pascher
- Department of General, Visceral and Transplant Surgery, University Hospital Muenster, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany; (I.B.)
| | - Wolf O. Bechstein
- Department of General, Visceral and Transplant Surgery, Frankfurt University Hospital, 60596 Frankfurt, Germany
| | - Anna Lorentzen
- Department of Biomedicine, Aarhus University, 8200 Aarhus, Denmark
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Mazen A. Juratli
- Department of General, Visceral and Transplant Surgery, University Hospital Muenster, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany; (I.B.)
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Solhi R, Pourhamzeh M, Zarrabi A, Hassan M, Mirzaei H, Vosough M. Novel biomarkers for monitoring and management of hepatocellular carcinoma. Cancer Cell Int 2024; 24:428. [PMID: 39719624 DOI: 10.1186/s12935-024-03600-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 12/05/2024] [Indexed: 12/26/2024] Open
Abstract
Due to current challenges in the early detection, less than 40% of individuals diagnosed with hepatocellular carcinoma (HCC) are viable candidates for surgical intervention. Therefore, validating and launching of a novel precise diagnostic approach is essential for early diagnosis. Based on developing evidence using circulating tumor cells and their derivatives, circulating miRNAs, and extracellular vesicles (EVs), liquid biopsy may offer a reliable platform for the HCC's early diagnosis. Each liquid biopsy analyte may provide significant areas for diagnosis, prognostic assessment, and treatment monitoring of HCC patients depending on its kind, sensitivity, and specificity. The current review addresses potential clinical applications, current research, and future developments for liquid biopsy in HCC management.
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Affiliation(s)
- Roya Solhi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mahsa Pourhamzeh
- Departments of Pathology and Medicine, UC San Diego, La Jolla, CA, USA
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, 34396, Turkey
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran.
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
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Chen J, Li H, Zhuo J, Lin Z, Hu Z, He C, Wu X, Jin Y, Lin Z, Su R, Sun Y, Wang R, Sun J, Wei X, Zheng S, Lu D, Xu X. Impact of immunosuppressants on tumor pulmonary metastasis: new insight into transplantation for hepatocellular carcinoma. Cancer Biol Med 2024; 21:j.issn.2095-3941.2024.0267. [PMID: 39718153 PMCID: PMC11667780 DOI: 10.20892/j.issn.2095-3941.2024.0267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 11/25/2024] [Indexed: 12/25/2024] Open
Abstract
Pulmonary metastasis is a life-threatening complication for patients with hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). In addition to the common mechanisms underlying tumor metastasis, another inevitable factor is that the application of immunosuppressive agents, including calcineurin inhibitors (CNIs) and rapamycin inhibitors (mTORis), after transplantation could influence tumor recurrence and metastasis. In recent years, several studies have reported that mTORis, unlike CNIs, have the capacity to modulate the tumorigenic landscape post-liver transplantation by targeting metastasis-initiating cells and reshaping the pulmonary microenvironment. Therefore, we focused on the effects of immunosuppressive agents on the lung metastatic microenvironment and how mTORis impact tumor growth in distant organs. This revelation has provided profound insights into transplant oncology, leading to a renewed understanding of the use of immunosuppressants after LT for HCC.
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Affiliation(s)
- Jinyan Chen
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Huigang Li
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Jianyong Zhuo
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People’s Hospital, Hangzhou 310006, China
| | - Zuyuan Lin
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou 310053, China
| | - Zhihang Hu
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Chiyu He
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Xiang Wu
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Yiru Jin
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Zhanyi Lin
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Renyi Su
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Yiyang Sun
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310063, China
| | - Rongsen Wang
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou 310053, China
| | - Jiancai Sun
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People’s Hospital, Hangzhou 310006, China
| | - Shusen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou 310022, China
| | - Di Lu
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), School of Clinical Medicine, Hangzhou Medical College, Hangzhou 310014, China
| | - Xiao Xu
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), School of Clinical Medicine, Hangzhou Medical College, Hangzhou 310014, China
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China
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Miceli RT, Chen T, Nose Y, Tichkule S, Brown B, Fullard JF, Saulsbury MD, Heyliger SO, Gnjatic S, Kyprianou N, Cordon‐Cardo C, Sahoo S, Taioli E, Roussos P, Stolovitzky G, Gonzalez‐Kozlova E, Dogra N. Extracellular vesicles, RNA sequencing, and bioinformatic analyses: Challenges, solutions, and recommendations. J Extracell Vesicles 2024; 13:e70005. [PMID: 39625409 PMCID: PMC11613500 DOI: 10.1002/jev2.70005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 09/20/2024] [Accepted: 10/07/2024] [Indexed: 12/06/2024] Open
Abstract
Extracellular vesicles (EVs) are heterogeneous entities secreted by cells into their microenvironment and systemic circulation. Circulating EVs carry functional small RNAs and other molecular footprints from their cell of origin, and thus have evident applications in liquid biopsy, therapeutics, and intercellular communication. Yet, the complete transcriptomic landscape of EVs is poorly characterized due to critical limitations including variable protocols used for EV-RNA extraction, quality control, cDNA library preparation, sequencing technologies, and bioinformatic analyses. Consequently, there is a gap in knowledge and the need for a standardized approach in delineating EV-RNAs. Here, we address these gaps by describing the following points by (1) focusing on the large canopy of the EVs and particles (EVPs), which includes, but not limited to - exosomes and other large and small EVs, lipoproteins, exomeres/supermeres, mitochondrial-derived vesicles, RNA binding proteins, and cell-free DNA/RNA/proteins; (2) examining the potential functional roles and biogenesis of EVPs; (3) discussing various transcriptomic methods and technologies used in uncovering the cargoes of EVPs; (4) presenting a comprehensive list of RNA subtypes reported in EVPs; (5) describing different EV-RNA databases and resources specific to EV-RNA species; (6) reviewing established bioinformatics pipelines and novel strategies for reproducible EV transcriptomics analyses; (7) emphasizing the significant need for a gold standard approach in identifying EV-RNAs across studies; (8) and finally, we highlight current challenges, discuss possible solutions, and present recommendations for robust and reproducible analyses of EVP-associated small RNAs. Overall, we seek to provide clarity on the transcriptomics landscape, sequencing technologies, and bioinformatic analyses of EVP-RNAs. Detailed portrayal of the current state of EVP transcriptomics will lead to a better understanding of how the RNA cargo of EVPs can be used in modern and targeted diagnostics and therapeutics. For the inclusion of different particles discussed in this article, we use the terms large/small EVs, non-vesicular extracellular particles (NVEPs), EPs and EVPs as defined in MISEV guidelines by the International Society of Extracellular Vesicles (ISEV).
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Affiliation(s)
- Rebecca T. Miceli
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Tzu‐Yi Chen
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Yohei Nose
- Department of ImmunologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Oncological SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Swapnil Tichkule
- Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Briana Brown
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - John F. Fullard
- Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Genetics and Genomics SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Center for Disease Neurogenetics, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Marilyn D. Saulsbury
- Department of Pharmaceutical Sciences, School of PharmacyHampton UniversityHamptonVirginiaUSA
| | - Simon O. Heyliger
- Department of Pharmaceutical Sciences, School of PharmacyHampton UniversityHamptonVirginiaUSA
| | - Sacha Gnjatic
- Department of ImmunologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Oncological SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Natasha Kyprianou
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Oncological SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of UrologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Carlos Cordon‐Cardo
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Susmita Sahoo
- Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Cardiovascular Research Institute, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Emanuela Taioli
- Department of Population Health and ScienceIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Thoracic SurgeryIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Panos Roussos
- Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Genetics and Genomics SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Center for Disease Neurogenetics, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Center for Precision Medicine and Translational TherapeuticsJames J. Peters VA Medicinal CenterBronxNew YorkUSA
- Mental Illness Research Education and Clinical Center (MIRECC)James J. Peters VA Medicinal CenterBronxNew YorkUSA
| | - Gustavo Stolovitzky
- Department of Genetics and Genomics SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Biomedical Data Sciences Hub (Bio‐DaSH), Department of Pathology, NYU Grossman School of MedicineNew YorkNew YorkUSA
| | - Edgar Gonzalez‐Kozlova
- Department of ImmunologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Oncological SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Navneet Dogra
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Genetics and Genomics SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Icahn Genomics Institute, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- AI and Human HealthIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
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Vengateswaran HT, Habeeb M, You HW, Aher KB, Bhavar GB, Asane GS. Hepatocellular carcinoma imaging: Exploring traditional techniques and emerging innovations for early intervention. MEDICINE IN NOVEL TECHNOLOGY AND DEVICES 2024; 24:100327. [DOI: 10.1016/j.medntd.2024.100327] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2024] Open
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Zhang C, Li T, Zhao Q, Ma R, Hong Z, Huang X, Gao P, Liu J, Zhao J, Wang Z. Advances and Prospects in Liquid Biopsy Techniques for Malignant Tumor Diagnosis and Surveillance. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2404709. [PMID: 39082395 DOI: 10.1002/smll.202404709] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 07/07/2024] [Indexed: 11/02/2024]
Abstract
Liquid biopsy technology provides invaluable support for the early diagnosis of tumors and surveillance of disease course by detecting tumor-related biomarkers in bodily fluids. Currently, liquid biopsy techniques are mainly divided into two categories: biomarker and label-free. Biomarker liquid biopsy techniques utilize specific antibodies or probes to identify and isolate target cells, exosomes, or molecules, and these techniques are widely used in clinical practice. However, they have certain limitations including dependence on tumor markers, alterations in cell biological properties, and high cost. In contrast, label-free liquid biopsy techniques directly utilize physical or chemical properties of cells, exosomes, or molecules for detection and isolation. These techniques have the advantage of not needing labeling, not impacting downstream analysis, and low detection cost. However, most are still in the research stage and not yet mature. This review first discusses recent advances in liquid biopsy techniques for early tumor diagnosis and disease surveillance. Several current techniques are described in detail. These techniques exploit differences in biomarkers, size, density, deformability, electrical properties, and chemical composition in tumor components to achieve highly sensitive tumor component identification and separation. Finally, the current research progress is summarized and the future research directions of the field are discussed.
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Affiliation(s)
- Chengzhi Zhang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, 110001, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
- Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
| | - Tenghui Li
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, 110001, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
- Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
| | - Qian Zhao
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
- Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
| | - Rui Ma
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, 110001, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
- Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
| | - Zhengchao Hong
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, 110001, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
- Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
| | - Xuanzhang Huang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, 110001, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
- Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
| | - Peng Gao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, 110001, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
- Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
| | - Jingjing Liu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, 110001, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
- Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
| | - Junhua Zhao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, 110001, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
- Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, 110001, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
- Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, 110122, China
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Xu L, Wu Q, Zhao K, Li X, Yao W. Prognostic prediction signature and molecular subtype for liver cancer: A CTC/CTM‑related gene prediction model and independent external validation. Oncol Lett 2024; 28:531. [PMID: 39290961 PMCID: PMC11406422 DOI: 10.3892/ol.2024.14664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 07/31/2024] [Indexed: 09/19/2024] Open
Abstract
Liver cancer is the second leading cause of tumor-related death worldwide, and a serious threat to lives and health. Circulating tumor cells (CTCs) facilitate the progression of various cancers, including liver cancer. The relationship between CTC/circulating tumor microemboli-related genes (CRGs) and the prognosis of liver cancer is unclear. The aim of the present study was to identify CTC/circulating tumour microemboli-related genes (CRGs) in hepatocellular carcinoma and to investigate their clinical significance. Transcriptomic data from The Cancer Genome Atlas (International Cancer Genome Consortium (ICGC) and GSE117623 databases were combined, and differentially expressed CRGs were identified. These were subsequently analyzed via least absolute shrinkage and selection operator and multivariate Cox analyses, and a five-gene risk signature was constructed. The signature was validated in the ICGC and GSE14520 dataset with survival analysis and receiver operating characteristic curve analysis. Immunocyte infiltration, tumor mutation burden (TMB), tumor immune dysfunction and exclusion (TIDE), and the somatic mutation rate were also compared between high- and low-risk groups, based on the median predictive index, to further evaluate the immunotherapeutic value of the model. Molecular subtypes of liver cancer were characterized by the non-negative matrix factorization method and potential therapeutic compounds were evaluated for different subtypes. Nomograms were utilized to predict the prognosis of patients, and the signature was compared with previous literature models. Additionally, the biological function of one of the CRGs, tumor protein p53 inducible protein 3 (TP53I3), in liver cancer was further explored through in vitro experiments. Analysis of the prognostic characteristics of the five CRGs led to the identification of two liver cancer subtypes. Patients in the low-risk group had a longer survival compared with those in the high-risk group, and patients in the latter group were associated with a higher TMB, immunocyte infiltration and somatic mutation rate, and lower TIDE scores. The prognostic profile was validated in the ICGC and GSE14520 datasets and exhibited a good predictive performance. In vitro analysis showed that the knockdown of TP53I3 suppressed liver cancer cell proliferation. In summary, CRGs were used to develop a new prognostic signature to predict the prognosis of patients with liver cancer. This signature may be used to assess the prognosis of patients and may provide new insights for clinical management strategies. In addition, TP53I3 is potentially a therapeutic target for liver cancer.
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Affiliation(s)
- Ling Xu
- Department of Nursing, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Qiansheng Wu
- Department of Nursing, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Kai Zhao
- Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Xiangyu Li
- Department of Thoracic Surgery, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Wei Yao
- Department of Oncology, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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40
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Zhu M, Gao Y, Zhu K, Yuan Y, Bai H, Meng L. Exosomal miRNA as biomarker in cancer diagnosis and prognosis: A review. Medicine (Baltimore) 2024; 103:e40082. [PMID: 39432619 PMCID: PMC11495718 DOI: 10.1097/md.0000000000040082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 09/26/2024] [Indexed: 10/23/2024] Open
Abstract
Exosomes, which are extracellular vesicles with a diameter ranging from 40 to 160 nm, are abundantly present in various body fluids. Exosomal microRNA (ex-miR), due to its exceptional sensitivity and specificity, has garnered significant attention. Notably, ex-miR is consistently detected in almost all bodily fluids, highlighting its potential as a reliable biomarker. This attribute of ex-miR has piqued considerable interest in its application as a diagnostic tool for the early detection, continuous monitoring, and prognosis evaluation of cancer. Given the critical role of exosomes and their cargo in cancer biology, this review explores the intricate processes of exosome biogenesis and uptake, their multifaceted roles in cancer development and progression, and the potential of ex-miRs as biomarkers for tumor diagnosis and prognosis.
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Affiliation(s)
- Mingliao Zhu
- Medical School of Shaoxing University, Yuecheng, Shaoxing, Zhejiang Province, People’s Republic of China
| | - Yuan Gao
- Department of Breast and Thyroid Surgery, Shaoxing People’s Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang Province, People’s Republic of China
| | - Kaijun Zhu
- Medical School of Shaoxing University, Yuecheng, Shaoxing, Zhejiang Province, People’s Republic of China
| | - Ying Yuan
- Medical School of Shaoxing University, Yuecheng, Shaoxing, Zhejiang Province, People’s Republic of China
| | - Haoyang Bai
- Medical School of Shaoxing University, Yuecheng, Shaoxing, Zhejiang Province, People’s Republic of China
| | - Liwei Meng
- Department of Breast and Thyroid Surgery, Shaoxing People’s Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang Province, People’s Republic of China
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Lin XT, Luo YD, Mao C, Gong Y, Hou Y, Zhang LD, Gu YP, Wu D, Zhang J, Zhang YJ, Tan DH, Xie CM. Integrated ubiquitomics characterization of hepatocellular carcinomas. Hepatology 2024:01515467-990000000-01044. [PMID: 39348425 DOI: 10.1097/hep.0000000000001096] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 09/02/2024] [Indexed: 10/02/2024]
Abstract
BACKGROUND AND AIMS Patients with aggressive HCC have limited therapeutic options. Therefore, a better understanding of HCC pathogenesis is needed to improve treatment. Genomic studies of HCC have improved our understanding of cancer biology. However, the ubiquitomic characteristics of HCC remain poorly understood. We aimed to reveal the ubiquitomic characteristics of HCC and provide clinical feature biomarkers of the aggressive HCC that may be used for diagnosis or therapy in the clinic. APPROACH AND RESULTS The comprehensive proteomic, phosphoproteomic, and ubiquitomic analyses were performed on tumors and adjacent normal liver tissues from 85 patients with HCC. HCCs displayed overexpression of drugable targets CBR1-S151 and CPNE1-S55. COL4A1, LAMC1, and LAMA4 were highly expressed in the disease free survival-poor patients. Phosphoproteomic and ubiquitomic features of HCC revealed cross talk in metabolism and metastasis. Ubiquitomics predicted diverse prognosis and clarified HCC subtype-specific proteomic signatures. Expression of biomarkers TUBA1A, BHMT2, BHMT, and ACY1 exhibited differential ubiquitination levels and displayed high prognostic risk scores, suggesting that targeting these proteins or their modified forms may be beneficial for future clinical treatment. We validated that TUBA1A K370 deubiquitination drove severe HCC and labeled an aggressive subtype of HCCs. TUBA1A K370 deubiquitination was at least partly attributed to protein kinase B-mediated USP14 activation in HCC. Notably, targeting AKT-USP14-TUBA1A complex promoted TUBA1A degradation and blocked liver tumorigenesis in vivo. CONCLUSIONS This study expands our knowledge of ubiquitomic signatures, biomarkers, and potential therapeutic targets in HCC.
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Affiliation(s)
- Xiao-Tong Lin
- Department of Hepatobiliary Surgery, Key Laboratory of Hepatobiliary and Pancreatic Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yuan-Deng Luo
- Department of Hepatobiliary Surgery, Key Laboratory of Hepatobiliary and Pancreatic Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Department of Hepatobiliary Surgery, General Hospital of Xinjiang Military Region, Urumchi, Xinjiang, China
| | - Cui Mao
- Department of Hepatobiliary Surgery, Key Laboratory of Hepatobiliary and Pancreatic Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yi Gong
- Department of Hepatobiliary Surgery, Key Laboratory of Hepatobiliary and Pancreatic Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yu Hou
- Department of Hepatobiliary Surgery, Key Laboratory of Hepatobiliary and Pancreatic Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Department of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Lei-Da Zhang
- Department of Hepatobiliary Surgery, Key Laboratory of Hepatobiliary and Pancreatic Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yong-Peng Gu
- Department of Hepatobiliary Surgery, Key Laboratory of Hepatobiliary and Pancreatic Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Di Wu
- Department of Hepatobiliary Surgery, Key Laboratory of Hepatobiliary and Pancreatic Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Jie Zhang
- Department of Hepatobiliary Surgery, Key Laboratory of Hepatobiliary and Pancreatic Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yu-Jun Zhang
- Department of Hepatobiliary Surgery, Key Laboratory of Hepatobiliary and Pancreatic Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - De-Hong Tan
- Department of Hepatobiliary Surgery, Key Laboratory of Hepatobiliary and Pancreatic Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Chuan-Ming Xie
- Department of Hepatobiliary Surgery, Key Laboratory of Hepatobiliary and Pancreatic Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
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Wang Y, Jia J, Wang F, Fang Y, Yang Y, Zhou Q, Yuan W, Gu X, Hu J, Yang S. Pre-metastatic niche: formation, characteristics and therapeutic implication. Signal Transduct Target Ther 2024; 9:236. [PMID: 39317708 PMCID: PMC11422510 DOI: 10.1038/s41392-024-01937-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 06/29/2024] [Accepted: 07/23/2024] [Indexed: 09/26/2024] Open
Abstract
Distant metastasis is a primary cause of mortality and contributes to poor surgical outcomes in cancer patients. Before the development of organ-specific metastasis, the formation of a pre-metastatic niche is pivotal in promoting the spread of cancer cells. This review delves into the intricate landscape of the pre-metastatic niche, focusing on the roles of tumor-derived secreted factors, extracellular vesicles, and circulating tumor cells in shaping the metastatic niche. The discussion encompasses cellular elements such as macrophages, neutrophils, bone marrow-derived suppressive cells, and T/B cells, in addition to molecular factors like secreted substances from tumors and extracellular vesicles, within the framework of pre-metastatic niche formation. Insights into the temporal mechanisms of pre-metastatic niche formation such as epithelial-mesenchymal transition, immunosuppression, extracellular matrix remodeling, metabolic reprogramming, vascular permeability and angiogenesis are provided. Furthermore, the landscape of pre-metastatic niche in different metastatic organs like lymph nodes, lungs, liver, brain, and bones is elucidated. Therapeutic approaches targeting the cellular and molecular components of pre-metastatic niche, as well as interventions targeting signaling pathways such as the TGF-β, VEGF, and MET pathways, are highlighted. This review aims to enhance our understanding of pre-metastatic niche dynamics and provide insights for developing effective therapeutic strategies to combat tumor metastasis.
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Affiliation(s)
- Yuhang Wang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Jiachi Jia
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Fuqi Wang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Yingshuai Fang
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Yabing Yang
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Quanbo Zhou
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Weitang Yuan
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Xiaoming Gu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China.
| | - Junhong Hu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China.
| | - Shuaixi Yang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China.
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Li B, Hao K, Li M, Wang A, Tang H, Xu L, Ma C, Du W, Sun L, Hou X, Jia T, Liu A, Gao Q, Zhao Z, Jin R, Yang R. Five miRNAs identified in fucosylated extracellular vesicles as non-invasive diagnostic signatures for hepatocellular carcinoma. Cell Rep Med 2024; 5:101716. [PMID: 39241773 PMCID: PMC11525029 DOI: 10.1016/j.xcrm.2024.101716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 05/25/2024] [Accepted: 08/13/2024] [Indexed: 09/09/2024]
Abstract
Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer that presents significant challenges for early detection. This study introduces the GlyExo-Capture method for isolating fucosylated extracellular vesicles (Fu-EVs) from serum. We analyze microRNA (miRNA) profiles from Fu-EVs in 88 HCC patients and 179 non-HCC controls using next-generation sequencing (NGS) and identify five miRNAs (hsa-let-7a, hsa-miR-21, hsa-miR-125a, hsa-miR-200a, and hsa-miR-150) as biomarkers for HCC diagnosis. The five-miRNA panel demonstrates exceptional HCC diagnostic performance, with a sensitivity of 0.90 and specificity of 0.92 in a combined cohort of 194 HCC and 412 non-HCC controls, significantly surpassing the performance of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP). Notably, the miRNA model achieves recall rates of 85.7% and 90.8% for stage 0 and stage A early-stage HCC, respectively, identifies 88.1% of AFP-negative HCC cases, and effectively differentiates HCC from other cancers. This study provides a high-throughput, rapid, and non-invasive approach for early HCC detection.
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Affiliation(s)
- Boan Li
- Department of Laboratory Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Kun Hao
- Beijing Hotgen Biotech Co., Ltd., Beijing, China; State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Mengyang Li
- The Faculty of Hepatopancreatobiliary Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ailan Wang
- Beijing Hotgen Biotech Co., Ltd., Beijing, China
| | - Huixue Tang
- Beijing Hotgen Biotech Co., Ltd., Beijing, China
| | - Lida Xu
- Beijing Hotgen Biotech Co., Ltd., Beijing, China
| | - Cuidie Ma
- Beijing Hotgen Biotech Co., Ltd., Beijing, China
| | - Wenqian Du
- Beijing Hotgen Biotech Co., Ltd., Beijing, China
| | - Lijuan Sun
- Beijing Youngen Technology Co., Ltd., Beijing, China
| | - Xufeng Hou
- Beijing Youngen Technology Co., Ltd., Beijing, China
| | - Tianye Jia
- Department of Laboratory Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Aixia Liu
- Department of Laboratory Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Qi Gao
- Beijing Hotgen Biotech Co., Ltd., Beijing, China; Beijing Youngen Technology Co., Ltd., Beijing, China.
| | - Zhiming Zhao
- The Faculty of Hepatopancreatobiliary Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
| | - Ronghua Jin
- Capital Medical University Affiliated Beijing Ditan Hospital, Beijing, China.
| | - Ruifu Yang
- Beijing Key Laboratory of POCT for Bioemergency and Clinic (No. BZ0329), Beijing, China; State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
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Wang YY, Yang WX, Du QJ, Liu ZH, Lu MH, You CG. Construction and evaluation of a liver cancer risk prediction model based on machine learning. World J Gastrointest Oncol 2024; 16:3839-3850. [PMID: 39350987 PMCID: PMC11438789 DOI: 10.4251/wjgo.v16.i9.3839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 07/31/2024] [Accepted: 08/07/2024] [Indexed: 09/09/2024] Open
Abstract
BACKGROUND Liver cancer is one of the most prevalent malignant tumors worldwide, and its early detection and treatment are crucial for enhancing patient survival rates and quality of life. However, the early symptoms of liver cancer are often not obvious, resulting in a late-stage diagnosis in many patients, which significantly reduces the effectiveness of treatment. Developing a highly targeted, widely applicable, and practical risk prediction model for liver cancer is crucial for enhancing the early diagnosis and long-term survival rates among affected individuals. AIM To develop a liver cancer risk prediction model by employing machine learning techniques, and subsequently assess its performance. METHODS In this study, a total of 550 patients were enrolled, with 190 hepatocellular carcinoma (HCC) and 195 cirrhosis patients serving as the training cohort, and 83 HCC and 82 cirrhosis patients forming the validation cohort. Logistic regression (LR), support vector machine (SVM), random forest (RF), and least absolute shrinkage and selection operator (LASSO) regression models were developed in the training cohort. Model performance was assessed in the validation cohort. Additionally, this study conducted a comparative evaluation of the diagnostic efficacy between the ASAP model and the model developed in this study using receiver operating characteristic curve, calibration curve, and decision curve analysis (DCA) to determine the optimal predictive model for assessing liver cancer risk. RESULTS Six variables including age, white blood cell, red blood cell, platelet counts, alpha-fetoprotein and protein induced by vitamin K absence or antagonist II levels were used to develop LR, SVM, RF, and LASSO regression models. The RF model exhibited superior discrimination, and the area under curve of the training and validation sets was 0.969 and 0.858, respectively. These values significantly surpassed those of the LR (0.850 and 0.827), SVM (0.860 and 0.803), LASSO regression (0.845 and 0.831), and ASAP (0.866 and 0.813) models. Furthermore, calibration and DCA indicated that the RF model exhibited robust calibration and clinical validity. CONCLUSION The RF model demonstrated excellent prediction capabilities for HCC and can facilitate early diagnosis of HCC in clinical practice.
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Affiliation(s)
- Ying-Ying Wang
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Wan-Xia Yang
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Qia-Jun Du
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Zhen-Hua Liu
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Ming-Hua Lu
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Chong-Ge You
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, Gansu Province, China
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Chan YT, Zhang C, Wu J, Lu P, Xu L, Yuan H, Feng Y, Chen ZS, Wang N. Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma. Mol Cancer 2024; 23:189. [PMID: 39242496 PMCID: PMC11378508 DOI: 10.1186/s12943-024-02101-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 08/23/2024] [Indexed: 09/09/2024] Open
Abstract
Liver cancer is a global health challenge, causing a significant social-economic burden. Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, which is highly heterogeneous in terms of molecular and cellular signatures. Early-stage or small tumors are typically treated with surgery or ablation. Currently, chemotherapies and immunotherapies are the best treatments for unresectable tumors or advanced HCC. However, drug response and acquired resistance are not predictable with the existing systematic guidelines regarding mutation patterns and molecular biomarkers, resulting in sub-optimal treatment outcomes for many patients with atypical molecular profiles. With advanced technological platforms, valuable information such as tumor genetic alterations, epigenetic data, and tumor microenvironments can be obtained from liquid biopsy. The inter- and intra-tumoral heterogeneity of HCC are illustrated, and these collective data provide solid evidence in the decision-making process of treatment regimens. This article reviews the current understanding of HCC detection methods and aims to update the development of HCC surveillance using liquid biopsy. Recent critical findings on the molecular basis, epigenetic profiles, circulating tumor cells, circulating DNAs, and omics studies are elaborated for HCC diagnosis. Besides, biomarkers related to the choice of therapeutic options are discussed. Some notable recent clinical trials working on targeted therapies are also highlighted. Insights are provided to translate the knowledge into potential biomarkers for detection and diagnosis, prognosis, treatment response, and drug resistance indicators in clinical practice.
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Affiliation(s)
- Yau-Tuen Chan
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Cheng Zhang
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Junyu Wu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Pengde Lu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Lin Xu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Hongchao Yuan
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Yibin Feng
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Zhe-Sheng Chen
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY, 11439, USA.
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
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Gu X, Wei S, Lv X. Circulating tumor cells: from new biological insights to clinical practice. Signal Transduct Target Ther 2024; 9:226. [PMID: 39218931 PMCID: PMC11366768 DOI: 10.1038/s41392-024-01938-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 05/31/2024] [Accepted: 07/29/2024] [Indexed: 09/04/2024] Open
Abstract
The primary reason for high mortality rates among cancer patients is metastasis, where tumor cells migrate through the bloodstream from the original site to other parts of the body. Recent advancements in technology have significantly enhanced our comprehension of the mechanisms behind the bloodborne spread of circulating tumor cells (CTCs). One critical process, DNA methylation, regulates gene expression and chromosome stability, thus maintaining dynamic equilibrium in the body. Global hypomethylation and locus-specific hypermethylation are examples of changes in DNA methylation patterns that are pivotal to carcinogenesis. This comprehensive review first provides an overview of the various processes that contribute to the formation of CTCs, including epithelial-mesenchymal transition (EMT), immune surveillance, and colonization. We then conduct an in-depth analysis of how modifications in DNA methylation within CTCs impact each of these critical stages during CTC dissemination. Furthermore, we explored potential clinical implications of changes in DNA methylation in CTCs for patients with cancer. By understanding these epigenetic modifications, we can gain insights into the metastatic process and identify new biomarkers for early detection, prognosis, and targeted therapies. This review aims to bridge the gap between basic research and clinical application, highlighting the significance of DNA methylation in the context of cancer metastasis and offering new avenues for improving patient outcomes.
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Affiliation(s)
- Xuyu Gu
- Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shiyou Wei
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xin Lv
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
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Qin C, Li T, Lin C, Zhao B, Li Z, Zhao Y, Wang W. The systematic role of pancreatic cancer exosomes: distant communication, liquid biopsy and future therapy. Cancer Cell Int 2024; 24:264. [PMID: 39054529 PMCID: PMC11271018 DOI: 10.1186/s12935-024-03456-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 07/18/2024] [Indexed: 07/27/2024] Open
Abstract
Pancreatic cancer remains one of the most lethal diseases worldwide. Cancer-derived exosomes, benefiting from the protective role of the lipid membrane, exhibit remarkable stability in the circulatory system. These exosomes, released by tumor microenvironment, contain various biomolecules such as proteins, RNAs, and lipids that plays a pivotal role in mediating distant communication between the local pancreatic tumor and other organs or tissues. They facilitate the transfer of oncogenic factors to distant sites, contributing to the compromised body immune system, distant metastasis, diabetes, cachexia, and promoting a microenvironment conducive to tumor growth and metastasis in pancreatic cancer patients. Beyond their intrinsic roles, circulating exosomes in peripheral blood can be detected to facilitate accurate liquid biopsy. This approach offers a novel and promising method for the diagnosis and management of pancreatic cancer. Consequently, circulating exosomes are not only crucial mediators of systemic cell-cell communication during pancreatic cancer progression but also hold great potential as precise tools for pancreatic cancer management and treatment. Exosome-based liquid biopsy and therapy represent promising advancements in the diagnosis and treatment of pancreatic cancer. Exosomes can serve as drug delivery vehicles, enhancing the targeting and efficacy of anticancer treatments, modulating the immune system, and facilitating gene editing to suppress tumor growth. Ongoing research focuses on biomarker identification, drug delivery systems, and clinical trials to validate the safety and efficacy of exosome-based therapies, offering new possibilities for early diagnosis and precision treatment in pancreatic cancer. Leveraging the therapeutic potential of exosomes, including their ability to deliver targeted drugs and modulate immune responses, opens new avenues for innovative treatment strategies.
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Affiliation(s)
- Cheng Qin
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tianyu Li
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chen Lin
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bangbo Zhao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zeru Li
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yutong Zhao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weibin Wang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Xu H, Kim D, Zhao YY, Kim C, Song G, Hu Q, Kang H, Yoon J. Remote Control of Energy Transformation-Based Cancer Imaging and Therapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2402806. [PMID: 38552256 DOI: 10.1002/adma.202402806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 03/24/2024] [Indexed: 04/06/2024]
Abstract
Cancer treatment requires precise tumor-specific targeting at specific sites that allows for high-resolution diagnostic imaging and long-term patient-tailorable cancer therapy; while, minimizing side effects largely arising from non-targetability. This can be realized by harnessing exogenous remote stimuli, such as tissue-penetrative ultrasound, magnetic field, light, and radiation, that enable local activation for cancer imaging and therapy in deep tumors. A myriad of nanomedicines can be efficiently activated when the energy of such remote stimuli can be transformed into another type of energy. This review discusses the remote control of energy transformation for targetable, efficient, and long-term cancer imaging and therapy. Such ultrasonic, magnetic, photonic, radiative, and radioactive energy can be transformed into mechanical, thermal, chemical, and radiative energy to enable a variety of cancer imaging and treatment modalities. The current review article describes multimodal energy transformation where a serial cascade or multiple types of energy transformation occur. This review includes not only mechanical, chemical, hyperthermia, and radiation therapy but also emerging thermoelectric, pyroelectric, and piezoelectric therapies for cancer treatment. It also illustrates ultrasound, magnetic resonance, fluorescence, computed tomography, photoluminescence, and photoacoustic imaging-guided cancer therapies. It highlights afterglow imaging that can eliminate autofluorescence for sustained signal emission after the excitation.
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Affiliation(s)
- Hai Xu
- Department of Chemistry and Nanoscience, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Dahee Kim
- Department of Materials Science and Engineering, Korea University, Seoul, 02841, Republic of Korea
| | - Yuan-Yuan Zhao
- Department of Chemistry and Nanoscience, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Chowon Kim
- Department of Materials Science and Engineering, Korea University, Seoul, 02841, Republic of Korea
| | - Guosheng Song
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China
| | - Qiongzheng Hu
- Qilu University of Technology (Shandong Academy of Sciences), Shandong Analysis and Test Center, Jinan, 250014, China
| | - Heemin Kang
- Department of Materials Science and Engineering, Korea University, Seoul, 02841, Republic of Korea
- College of Medicine, Korea University, Seoul, 02841, Republic of Korea
| | - Juyoung Yoon
- Department of Chemistry and Nanoscience, Ewha Womans University, Seoul, 03760, Republic of Korea
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Sun W, You X, Zhao X, Zhang X, Yang C, Zhang F, Yu J, Yang K, Wang J, Xu F, Chang Y, Qu B, Zhao X, He Y, Wang Q, Chen J, Qing G. Precise Capture and Dynamic Release of Circulating Liver Cancer Cells with Dual-Histidine-Based Cell Imprinted Hydrogels. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2402379. [PMID: 38655900 DOI: 10.1002/adma.202402379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 04/22/2024] [Indexed: 04/26/2024]
Abstract
Circulating tumor cells (CTCs) detection presents significant advantages in diagnosing liver cancer due to its noninvasiveness, real-time monitoring, and dynamic tracking. However, the clinical application of CTCs-based diagnosis is largely limited by the challenges of capturing low-abundance CTCs within a complex blood environment while ensuring them alive. Here, an ultrastrong ligand, l-histidine-l-histidine (HH), specifically targeting sialylated glycans on the surface of CTCs, is designed. Furthermore, HH is integrated into a cell-imprinted polymer, constructing a hydrogel with precise CTCs imprinting, high elasticity, satisfactory blood compatibility, and robust anti-interference capacities. These features endow the hydrogel with excellent capture efficiency (>95%) for CTCs in peripheral blood, as well as the ability to release CTCs controllably and alive. Clinical tests substantiate the accurate differentiation between liver cancer, cirrhosis, and healthy groups using this method. The remarkable diagnostic accuracy (94%), lossless release of CTCs, material reversibility, and cost-effectiveness ($6.68 per sample) make the HH-based hydrogel a potentially revolutionary technology for liver cancer diagnosis and single-cell analysis.
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Affiliation(s)
- Wenjing Sun
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, P. R. China
- State Key Laboratory of Medical Proteomics, National Chromatographic R&A Center, CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, P. R. China
| | - Xin You
- Department of Respiratory Medicine, The Second Hospital of Dalian Medical University, Dalian, 116023, P. R. China
| | - Xinjia Zhao
- State Key Laboratory of Medical Proteomics, National Chromatographic R&A Center, CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, P. R. China
| | - Xiaoyu Zhang
- State Key Laboratory of Medical Proteomics, National Chromatographic R&A Center, CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, P. R. China
| | - Chunhui Yang
- Department of Respiratory Medicine, The Second Hospital of Dalian Medical University, Dalian, 116023, P. R. China
| | - Fusheng Zhang
- State Key Laboratory of Medical Proteomics, National Chromatographic R&A Center, CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, P. R. China
- College of Chemistry and Chemical Engineering, Wuhan Textile University, Wuhan, 430200, P. R. China
| | - Jiaqi Yu
- College of Chemistry and Chemical Engineering, Wuhan Textile University, Wuhan, 430200, P. R. China
| | - Kaiguang Yang
- State Key Laboratory of Medical Proteomics, National Chromatographic R&A Center, CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, P. R. China
| | - Jixia Wang
- Ganjiang Chinese Medicine Innovation Center, Nanchang, 330000, P. R. China
| | - Fangfang Xu
- Ganjiang Chinese Medicine Innovation Center, Nanchang, 330000, P. R. China
| | - Yongxin Chang
- State Key Laboratory of Medical Proteomics, National Chromatographic R&A Center, CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, P. R. China
| | - Boxin Qu
- Department of Respiratory Medicine, The Second Hospital of Dalian Medical University, Dalian, 116023, P. R. China
| | - Xinmiao Zhao
- School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, P. R. China
| | - Yuxuan He
- School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, P. R. China
| | - Qi Wang
- Department of Respiratory Medicine, The Second Hospital of Dalian Medical University, Dalian, 116023, P. R. China
| | - Jinghua Chen
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, P. R. China
| | - Guangyan Qing
- State Key Laboratory of Medical Proteomics, National Chromatographic R&A Center, CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, P. R. China
- College of Chemistry and Chemical Engineering, Wuhan Textile University, Wuhan, 430200, P. R. China
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Yao J, Wan H, Zhang J, Shen W, Wei X, Shi C, Ou B, Liu D, Ge L, Fei J, Zeng X. Tubuloside B, a major constituent of Cistanche deserticola, inhibits migration of hepatocellular carcinoma by inhibiting Hippo-YAP pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155552. [PMID: 38552378 DOI: 10.1016/j.phymed.2024.155552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 11/20/2023] [Accepted: 03/19/2024] [Indexed: 05/30/2024]
Abstract
BACKGROUND Studies have shown that phenylethanoid glycosides (PhGs) have multiple pharmacological effects such as anti-inflammatory, hepatoprotective or neuroprotective functions, whereas their anti-tumor effects are rarely studied. Tubuloside B (Tub B) is a PhG isolated from Cistanche deserticola, a traditional Chinese medicine. To date, there is a lack of comprehensive research regarding the biological activity of Tub B. PURPOSE The subject of the current study was to investigate the anti-hepatocellular carcinoma (HCC) cell activity and the underlying mechanism of Tub B. METHODS We evaluated the in vitro anti-migratory effect of Tub B by scratch and transwell assays. RNA-seq was employed to identify the differential genes by Tub B. Besides, the functional mechanism of Tub B was investigated by distinct molecular biology techniques including immunofluorescent staining, quantitative PCR, as well as western blot analysis. Subsequently, we utilized Hep3B cells for in vivo metastasis assays through spleen injection and evaluated the anti-migratory effect of Tub B in hepatocellular carcinoma (HCC). RESULTS Tub B exhibited in vitro and in vivo inhibition of HCC cell migration. Tub B decreased the expression of transcriptional target genes downstream of the Hippo pathway, including CTGF, CYR61, and N-cadherin as determined by RNA-seq. Furthermore, mechanistic studies confirmed that Tub B increased phosphorylation of YAP at S127, which contributes to YAP cytoplasmic localization. Additionally, overexpression of YAP abrogated Tub B-induced inhibition of HCC migration and the mRNA levels of CTGF, CYR61, and N-cadherin. CONCLUSIONS Taken together, these results illustrated that Tub B demonstrated great potential in inhibiting migration of HCC, and a portion of its impact can be attributed to the modulation of the Hippo-YAP pathway.
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Affiliation(s)
- Jie Yao
- Shenzhen Clinical Research Centre for Geriatrics, Department of Hepatobiliary and Pancreatic Surgery and Center Lab of Longhua Branch, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, PR China; Department of Pathology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518120, Guangdong Province, PR China
| | - Haoqiang Wan
- Shenzhen Clinical Research Centre for Geriatrics, Department of Hepatobiliary and Pancreatic Surgery and Center Lab of Longhua Branch, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, PR China; Department of Pathology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518120, Guangdong Province, PR China
| | - Jingmei Zhang
- Shenzhen Clinical Research Centre for Geriatrics, Department of Hepatobiliary and Pancreatic Surgery and Center Lab of Longhua Branch, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, PR China; Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen 518104, Guangdong Province, PR China
| | - Wanying Shen
- Shenzhen Clinical Research Centre for Geriatrics, Department of Hepatobiliary and Pancreatic Surgery and Center Lab of Longhua Branch, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, PR China; College of pharmacy, Gansu University of Chinese Medicine, Lanzhou 73000, Gansu Province, PR China
| | - Xiaofang Wei
- Shenzhen Clinical Research Centre for Geriatrics, Department of Hepatobiliary and Pancreatic Surgery and Center Lab of Longhua Branch, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, PR China; College of pharmacy, Gansu University of Chinese Medicine, Lanzhou 73000, Gansu Province, PR China
| | - Chenyan Shi
- Shenzhen Clinical Research Centre for Geriatrics, Department of Hepatobiliary and Pancreatic Surgery and Center Lab of Longhua Branch, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, PR China; Department of Pathology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518120, Guangdong Province, PR China
| | - Baoru Ou
- Shenzhen Clinical Research Centre for Geriatrics, Department of Hepatobiliary and Pancreatic Surgery and Center Lab of Longhua Branch, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, PR China; Department of Pathology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518120, Guangdong Province, PR China
| | - Dongyu Liu
- Shenzhen Clinical Research Centre for Geriatrics, Department of Hepatobiliary and Pancreatic Surgery and Center Lab of Longhua Branch, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, PR China; Department of Pathology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518120, Guangdong Province, PR China
| | - Lanlan Ge
- Shenzhen Clinical Research Centre for Geriatrics, Department of Hepatobiliary and Pancreatic Surgery and Center Lab of Longhua Branch, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, PR China; Department of Pathology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518120, Guangdong Province, PR China
| | - Jia Fei
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, PR China.
| | - Xiaobin Zeng
- Shenzhen Clinical Research Centre for Geriatrics, Department of Hepatobiliary and Pancreatic Surgery and Center Lab of Longhua Branch, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, PR China; Department of Pathology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518120, Guangdong Province, PR China.
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