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Wan X, Zou Y, Zhou Q, Tang Q, Zhu G, Jia L, Yu X, Mo H, Yang X, Wang S. Tumor Prognostic Risk Model Related to Monocytes/Macrophages in Hepatocellular Carcinoma Based on Machine Learning and Multi-Omics. Biol Proced Online 2025; 27:9. [PMID: 40065214 PMCID: PMC11892220 DOI: 10.1186/s12575-025-00270-9] [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: 12/10/2024] [Accepted: 02/13/2025] [Indexed: 03/14/2025] Open
Abstract
Tumor-associated macrophages (TAMs) are crucial in hepatocellular carcinoma (HCC) development and invasion. This study explores monocyte/ macrophage-associated gene expression profiles in HCC, constructs a prognostic model based on these genes, and examines its relationship with drug resistance and immune therapy responses. Single-cell RNA sequencing(scRNA-seq) data from 10 HCC tissue biopsy samples, totaling 24,597 cells, were obtained from the GEO database to identify monocyte/macrophage-associated genes. A prognostic model was constructed and validated using external datasets and Western blot. Relationships between the model, clinical correlates, drug sensitivity, and immune therapy responses were investigated. From scRNA-seq data, 2,799 monocyte/macrophage marker genes were identified. Using the TCGA dataset, a prognostic model based on the single-gene UQCRH was constructed, stratifying patients into high-risk and low-risk groups based on overall survival rates. High-risk group patients showed reduced survival rates and higher UQCRH expression in tumor tissues. Western blot analysis further confirmed the elevated expression of UQCRH in HCC cell lines. Spatial transcriptomics analysis revealed that high UQCRH expression co-localized with malignant cells in the tumor tissue. Drug sensitivity analysis revealed that the high-risk group had lower sensitivity to sorafenib and axitinib. Immune therapy response analysis indicated poorer outcomes in the high-risk group, with more pronounced APC inhibition and a weaker IFN-II response. Clinical indicator analysis showed a positive correlation between high UQCRH expression and tumor invasion. Enrichment analysis of UQCRH and associated molecules indicated involvement in oxidative phosphorylation and mitochondrial electron transport. This study introduces a prognostic model for HCC patients based on monocyte/macrophage marker genes. The single-gene model predicts HCC patient survival and treatment outcomes, identifying high-risk individuals with varying drug sensitivities and immune suppression states.
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Affiliation(s)
- Xinliang Wan
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Chinese Medicine Guangdong Laboratory, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, 510120, China
| | - Yongchun Zou
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Chinese Medicine Guangdong Laboratory, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, 510120, China
| | - Qichun Zhou
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Chinese Medicine Guangdong Laboratory, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, 510120, China
| | - Qing Tang
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Chinese Medicine Guangdong Laboratory, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, 510120, China
| | - Gangxing Zhu
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Chinese Medicine Guangdong Laboratory, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, 510120, China
| | - Luyu Jia
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Chinese Medicine Guangdong Laboratory, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, 510120, China
| | - Xiaoyan Yu
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Chinese Medicine Guangdong Laboratory, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, 510120, China
| | - Handan Mo
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Chinese Medicine Guangdong Laboratory, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, 510120, China
| | - Xiaobing Yang
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Chinese Medicine Guangdong Laboratory, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, 510120, China.
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Chinese Medicine Guangdong Laboratory, 111 Dade Rd, Guangzhou, Guangdong Province, 510120, China.
| | - Sumei Wang
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Chinese Medicine Guangdong Laboratory, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, 510120, China.
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Chinese Medicine Guangdong Laboratory, 111 Dade Rd, Guangzhou, Guangdong Province, 510120, China.
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Priya S, Kma L. Identification of novel microRNAs: Biomarkers for pathogenesis of hepatocellular carcinoma in mice model. Biochem Biophys Rep 2025; 41:101896. [PMID: 39881957 PMCID: PMC11774814 DOI: 10.1016/j.bbrep.2024.101896] [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: 10/24/2024] [Revised: 11/26/2024] [Accepted: 12/09/2024] [Indexed: 01/31/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the most fatal cancer that has affected both male and female populations globally. With poor diagnosis and patient survival rates, it has become a global need for scientists to come to the aid. The main objective of the study was to profile the miRNAs in the serum of Control and DEN-treated mice at different time intervals (4 Weeks, 8 Weeks, 12 Weeks, and 16 Weeks) and identify HCC-associated miRNA as putative early biomarkers along with the miRNA regulated candidate gene which may be involved in HCC. Our study group involves 4,8,12, & 16 weeks 16-week-old treated male mice. Each group was sacrificed and analyzed for the stages of HCC. We employed in silico techniques for the small RNA-Seq and bioinformatics pipeline for further analysis. Our analysis revealed over 400 differentially expressed miRNAs in each treated sample and 10 novel miRNAs. The downstream analysis of these differentially expressed miRNAs, and their target genes opened an arena of different biological processes and pathways that these miRNAs affect during the development of HCC. The work has a promising role as the miRNAs predicted through this study can be used as biomarkers for early detection of HCC.
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Affiliation(s)
- Shivani Priya
- Department of Chemistry & Biochemistry, Sharda School of Basic Sciences & Research, Sharda University, Noida, UP, India
| | - Lakhon Kma
- Department of Biochemistry, North Eastern Hill University, Shillong, India
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Zhang B, Ma X, Zhou Y, Zhu B, Yu J, Liu H, Ma Y, Luan Y, Chen M. Diagnostic Value of Circulating microRNAs for Hepatocellular Carcinoma: Results of a Meta-analysis and Validation. Biochem Genet 2025:10.1007/s10528-024-11001-2. [PMID: 39751721 DOI: 10.1007/s10528-024-11001-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 12/09/2024] [Indexed: 01/04/2025]
Abstract
Mounting evidence suggests that circulating microRNAs (miRNAs) hold diagnostic value in various malignancies. To identify circulating miRNAs for the early diagnosis of hepatocellular carcinoma (HCC), we conducted a meta-analysis to evaluate the diagnostic utility of miRNAs in HCC and further validated the results of the meta-analysis. English articles published prior to December 2023 were retrieved from databases including PubMed, Embase, and Web of Science. A random-effects or fixed-effects model was applied depending on the heterogeneity among studies. The pooled sensitivity, specificity, and the area under the summary receiver operating characteristic curve (AUC) were calculated to assess diagnostic accuracy. Additionally, RT-qPCR and receiver operating characteristic (ROC) analyses were employed to further validate the findings. A total of 36 studies were included, involving 3362 patients with HCC and 2150 patients with chronic hepatitis. The pooled sensitivity, specificity, and diagnostic odds ratio were 0.79 (95% CI 0.75-0.82), 0.79 (95% CI 0.73-0.84), and 14 (95% CI 9-22), respectively; the positive and negative likelihood ratios were 4.0 and 0.27, respectively; the area under the curve (AUC) in the summary receiver operating characteristic (ROC) was 0.85 (95% CI 0.82-0.88). Validation indicated a significant upregulation of miR-1246, miR-21, and miR-221 in HCC patients compared to those with chronic hepatitis (P < 0.01), while miR-122 and miR-26a were significantly downregulated (P < 0.01). Moreover, the validation results also demonstrated that serum levels of miR-21, miR-26a, miR-122, miR-221, and miR-1246 exhibit high sensitivity and specificity in the diagnosis of HCC. Circulating miRNAs may be promising biomarkers for HCC diagnosis.
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Affiliation(s)
- Bingqiang Zhang
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China
| | - Xiaoyan Ma
- Department of Oncology, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, 266111, Shandong, People's Republic of China
| | - Yang Zhou
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China
| | - Boyang Zhu
- School of Clinical and Basic Medical Sciences, Shandong First Medical, University& Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, People's Republic of China
| | - Junmei Yu
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China
| | - He Liu
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China
| | - Yongchao Ma
- College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao, 266111, Shandong, People's Republic of China
| | - Yansong Luan
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China.
| | - Mengmeng Chen
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China.
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Hu Y, Zhang Y, Wang S, Wang R, Yuan Q, Zhu L, Xia F, Xue M, Wang Y, Li Y, Yuan C. LINC00667: A Novel Vital Oncogenic LincRNA. Curr Med Chem 2025; 32:678-687. [PMID: 37855347 DOI: 10.2174/0109298673248494231010044348] [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: 02/24/2023] [Revised: 06/14/2023] [Accepted: 09/11/2023] [Indexed: 10/20/2023]
Abstract
Long intergenic noncoding RNAs (lincRNAs) have a variety of properties that differ from those of messenger RNAs (mRNAs) encoding proteins. Long intergenic nonprotein coding RNA 667 (LINC00667) is a non-coding transcript located on chromosome 18p11.31. Recently, many studies have found that LINC00667 can enhance the progression of various cancers and play a key part in a lot of diseases, such as tumorigenesis. Therefore, LINC00667 can be recognized as a potential biomarker and therapeutic target. So, we reviewed the biological functions, relevant mechanisms, as well as clinical significance of LINC00667 in several human cancers in detail.
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Affiliation(s)
- Yaqi Hu
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Yifan Zhang
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Shuwen Wang
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Rui Wang
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Qi Yuan
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Medicine and Health Science, China Three Gorges University, Yichang, 443002, China
| | - Leiqi Zhu
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Fangqi Xia
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Mengzhen Xue
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Yaqi Wang
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Yuanyang Li
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Medicine and Health Science, China Three Gorges University, Yichang, 443002, China
| | - Chengfu Yuan
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
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Cheishvili D, Wong C, Karim MM, Golam Kibria M, Jahan N, Chandra Das P, Khair Yousuf A, Islam A, Chandra Das D, Noor-E-Alam SM, Alam S, Rahman M, Khan WA, Al-Mahtab M, Szyf M. Clinical validation of peripheral blood mononuclear cell DNA methylation markers for accurate early detection of hepatocellular carcinoma in Asian patients. COMMUNICATIONS MEDICINE 2024; 4:220. [PMID: 39472687 PMCID: PMC11522327 DOI: 10.1038/s43856-024-00652-2] [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: 01/07/2024] [Accepted: 10/22/2024] [Indexed: 11/02/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC), a leading cause of cancer-related deaths globally, poses significant challenges in early detection. Improved diagnostic accuracy can drastically influence patient outcomes, emphasizing the need for innovative, non-invasive biomarkers. METHODS This study utilized a cohort of 402 participants, including healthy controls, chronic hepatitis patients, and HCC patients from Bangladesh, to evaluate DNA methylation signatures in peripheral blood mononuclear cells (PBMC). We performed targeted next-generation sequencing on selected genes previously identified to assess their methylation dynamics. The development of M8 and M4 scores was based on these dynamics, using Receiver Operating Characteristic (ROC) analysis to determine their effectiveness in detecting early-stage HCC alongside existing markers such as epiLiver and alpha-fetoprotein (AFP). RESULTS Integration of M8 and M4 scores with epiLiver and AFP significantly enhances diagnostic sensitivity for early-stage HCC. The M4+epiLiver score achieves a sensitivity of 79.4% in Stage A HCC, while combining M4 with AFP increases sensitivity to 88.2-95.7% across all stages, indicating a superior diagnostic performance compared to each marker used alone. CONCLUSIONS Our study confirms that combining gene methylation profiles with established diagnostic markers substantially improves the sensitivity of detecting early-stage HCC. This integrated diagnostic approach holds promise for advancing non-invasive cancer diagnostics, potentially leading to earlier treatment interventions and improved survival rates for high-risk patients.
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Affiliation(s)
- David Cheishvili
- HKG Epitherapeutics Ltd. Unit 313-315, 3/F Biotech Center 2, 11 Science Park West Avenue, Shatin, Hong Kong, SAR, China
- Gerald Bronfman Department of Oncology, McGill University Montreal, Montreal, Canada
| | - Chifat Wong
- HKG Epitherapeutics Ltd. Unit 313-315, 3/F Biotech Center 2, 11 Science Park West Avenue, Shatin, Hong Kong, SAR, China
| | - Mohammad Mahbubul Karim
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr, b), Dhaka, Bangladesh
| | - Mohammad Golam Kibria
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr, b), Dhaka, Bangladesh
| | - Nusrat Jahan
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr, b), Dhaka, Bangladesh
| | - Pappu Chandra Das
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr, b), Dhaka, Bangladesh
| | - Abul Khair Yousuf
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Atikul Islam
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Dulal Chandra Das
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | | | - Sarwar Alam
- Department of Clinical Oncology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Mustafizur Rahman
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr, b), Dhaka, Bangladesh
| | - Wasif A Khan
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr, b), Dhaka, Bangladesh
| | - Mamun Al-Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Moshe Szyf
- HKG Epitherapeutics Ltd. Unit 313-315, 3/F Biotech Center 2, 11 Science Park West Avenue, Shatin, Hong Kong, SAR, China.
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Zhu S, Yu Y, Yang M, Liu X, Lai M, Zhong J, Zhao X, Lu L, Liu Y. Hepatic artery infusion chemotherapy combined with the FOLFOX regimen for the treatment of hepatocellular carcinoma: recent advances and literature review. Expert Rev Anticancer Ther 2024; 24:423-434. [PMID: 38651280 DOI: 10.1080/14737140.2024.2346624] [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: 02/03/2024] [Accepted: 04/19/2024] [Indexed: 04/25/2024]
Abstract
INTRODUCTION The incidence of primary liver cancer (PLC) has experienced a significant global increase, primarily attributed to the rise in hepatocellular carcinoma (HCC). Unfortunately, HCC is often diagnosed in advanced stages, leaving patients with limited treatment options. Therefore, transformation therapy is a crucial approach for long-term survival and radical resection in patients with advanced HCC. Conversion therapy has demonstrated promise in the treatment of advanced HCC. When integrated with the FOLFOX regimen, hepatic artery infusion chemotherapy (HAIC) can significantly improve tumor response efficiency, leading to high conversion and resection rates. AREAS COVERED We reviewed landmark trials of HAIC in combination with different drugs or means for the treatment of HCC to determine the clinical value of HAIC-centric translational therapies in HCC treatment. Furthermore, we specifically emphasize the advantages associated with employing FOLFOX-HAIC in the treatment of advanced HCC. EXPERT OPINION The combination of HAIC with the FOLFOX regimen can help prevent the low intratumoral accumulation and high adverse reaction rate caused by the FOLFOX alone, holding significant potential in the comprehensive treatment of future HCC patients.
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Affiliation(s)
- Suqi Zhu
- Zhuhai Interventional Medical Center, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
| | - Yahan Yu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
| | - Mingqi Yang
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
| | - Xin Liu
- Zhuhai Precision Medical Center, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
| | - Mingkai Lai
- Zhuhai Interventional Medical Center, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
| | - Jieren Zhong
- Zhuhai Interventional Medical Center, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
| | - Xiaoguang Zhao
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
| | - Ligong Lu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
| | - Yanyan Liu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
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Salim EI, Alabasy MM, Nashar EME, Al-Zahrani NS, Alzahrani MA, Guo Z, Beltagy DM, Shahen M. Molecular interactions between metformin and D-limonene inhibit proliferation and promote apoptosis in breast and liver cancer cells. BMC Complement Med Ther 2024; 24:185. [PMID: 38711049 PMCID: PMC11071183 DOI: 10.1186/s12906-024-04453-x] [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: 06/19/2023] [Accepted: 03/22/2024] [Indexed: 05/08/2024] Open
Abstract
BACKGROUND Cancer is a fatal disease that severely affects humans. Designing new anticancer strategies and understanding the mechanism of action of anticancer agents is imperative. HYPOTHESIS/PURPOSE In this study, we evaluated the utility of metformin and D-limonene, alone or in combination, as potential anticancer therapeutics using the human liver and breast cancer cell lines HepG2 and MCF-7. STUDY DESIGN An integrated systems pharmacology approach is presented for illustrating the molecular interactions between metformin and D-limonene. METHODS We applied a systems-based analysis to introduce a drug-target-pathway network that clarifies different mechanisms of treatment. The combination treatment of metformin and D-limonene induced apoptosis in both cell lines compared with single drug treatments, as indicated by flow cytometric and gene expression analysis. RESULTS The mRNA expression of Bax and P53 genes were significantly upregulated while Bcl-2, iNOS, and Cox-2 were significantly downregulated in all treatment groups compared with normal cells. The percentages of late apoptotic HepG2 and MCF-7 cells were higher in all treatment groups, particularly in the combination treatment group. Calculations for the combination index (CI) revealed a synergistic effect between both drugs for HepG2 cells (CI = 0.14) and MCF-7 cells (CI = 0.22). CONCLUSION Our data show that metformin, D-limonene, and their combinations exerted significant antitumor effects on the cancer cell lines by inducing apoptosis and modulating the expression of apoptotic genes.
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Affiliation(s)
- Elsayed I Salim
- Department of Zoology, Research Lab of Molecular Carcinogenesis, Faculty of Science, Tanta University, Tanta, 31527, Egypt.
| | - Mona M Alabasy
- Department of Zoology, Research Lab of Molecular Carcinogenesis, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Eman M El Nashar
- Department of Anatomy, College of Medicine, King Khalid University, Abha, 62529, Saudi Arabia
| | - Norah S Al-Zahrani
- Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, 62529, Saudi Arabia
| | - Mohammed A Alzahrani
- Internal Medicine Department, College of Medicine, King Khalid University, Abha, 62529, Saudi Arabia
| | - Zihu Guo
- College of Life Science, Center of Bioinformatics, Northwest A and F University, Yangling, Shaanxi, 712100, China
| | - Doha M Beltagy
- Biochemistry Department, Faculty of Science, Damanhour University, Damanhour, Egypt
| | - Mohamed Shahen
- Department of Zoology, Research Lab of Molecular Carcinogenesis, Faculty of Science, Tanta University, Tanta, 31527, Egypt.
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Sayed GI, Solyman M, El Gedawy G, Moemen YS, Aboul-Ella H, Hassanien AE. Circulating miRNA's biomarkers for early detection of hepatocellular carcinoma in Egyptian patients based on machine learning algorithms. Sci Rep 2024; 14:4989. [PMID: 38424116 PMCID: PMC10904762 DOI: 10.1038/s41598-024-54795-2] [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: 12/26/2023] [Accepted: 02/16/2024] [Indexed: 03/02/2024] Open
Abstract
Liver cancer, which ranks sixth globally and third in cancer-related deaths, is caused by chronic liver disorders and a variety of risk factors. Despite therapeutic improvements, the prognosis for Hepatocellular Carcinoma (HCC) remains poor, with a 5-year survival rate for advanced cases of less than 12%. Although there is a noticeable decrease in the frequency of cases, liver cancer remains a significant worldwide health concern, with estimates surpassing one million cases by 2025. The prevalence of HCC has increased in Egypt, and it includes several neoplasms with distinctive messenger RNA (mRNA) and microRNA (miRNA) expression profiles. In HCC patients, certain miRNAs, such as miRNA-483-5P and miRNA-21, are upregulated, whereas miRNA-155 is elevated in HCV-infected people, encouraging hepatocyte proliferation. Short noncoding RNAs called miRNAs in circulation have the potential as HCC diagnostic and prognostic markers. This paper proposed a model for examining circulating miRNAs as diagnostic and predictive markers for HCC in Egyptian patients and their clinical and pathological characteristics. The proposed HCC detection model consists of three main phases: data preprocessing phase, feature selection based on the proposed Binary African Vulture Optimization Algorithm (BAVO) phase, and finally, classification as well as cross-validation phase. The first phase namely the data preprocessing phase tackle the main problems associated with the adopted datasets. In the feature selection based on the proposed BAVO algorithm phase, a new binary version of the BAVO swarm-based algorithm is introduced to select the relevant markers for HCC. Finally, in the last phase, namely the classification and cross-validation phase, the support vector machine and k-folds cross-validation method are utilized. The proposed model is evaluated on three studies on Egyptians who had HCC. A comparison between the proposed model and traditional statistical studies is reported to demonstrate the superiority of using the machine learning model for evaluating circulating miRNAs as diagnostic markers of HCC. The specificity and sensitivity for differentiation of HCC cases in comparison with the statistical-based method for the first study were 98% against 88% and 99% versus 92%, respectively. The second study revealed the sensitivity and specificity were 97.78% against 90% and 98.89% versus 92.5%, respectively. The third study reported 83.2% against 88.8% and 95.80% versus 92.4%, respectively. Additionally, the results show that circulating miRNA-483-5p, 21, and 155 may be potential new prognostic and early diagnostic biomarkers for HCC.
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Affiliation(s)
- Gehad Ismail Sayed
- School of Computer Science, Canadian International College (CIC), Cairo, Egypt
- Scientific Research Group in Egypt (SRGE), Cairo, Egypt
| | - Mona Solyman
- Faculty of Computers and Artificial Intelligence, Cairo University, Giza, Egypt
- Scientific Research Group in Egypt (SRGE), Cairo, Egypt
| | - Gamalat El Gedawy
- Clinical Biochemistry and Molecular Diagnostics Department, National Liver Institute, Menofia University, Menofia, Egypt
- Scientific Research Group in Egypt (SRGE), Cairo, Egypt
| | - Yasmine S Moemen
- Clinical Pathology Department, National Liver Institute, Menofia University, Menofia, Egypt
- Scientific Research Group in Egypt (SRGE), Cairo, Egypt
| | - Hassan Aboul-Ella
- Department of Microbiology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.
| | - Aboul Ella Hassanien
- Faculty of Computers and Artificial Intelligence, Cairo University, Giza, Egypt
- College of Business Administration, Kuwait University, Al Shadadiya, Kuwait
- Scientific Research Group in Egypt (SRGE), Cairo, Egypt
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9
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Liu C, Shi J, Jiang Z, Jiang S, Wu Y, Peng D, Tang J, Guo L. RP11-495P10.1 promotes HCC cell proliferation by regulating reprogramming of glucose metabolism and acetylation of the NR4A3 promoter via the PDK1/PDH axis. Acta Biochim Biophys Sin (Shanghai) 2024; 56:44-53. [PMID: 37905340 PMCID: PMC10875365 DOI: 10.3724/abbs.2023242] [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: 05/04/2023] [Accepted: 07/27/2023] [Indexed: 11/02/2023] Open
Abstract
The incidence and related death of hepatocellular carcinoma (HCC) have increased over the past decades. However, the molecular mechanisms underlying HCC pathogenesis are not fully understood. Long noncoding RNA (lncRNA) RP11-495P10.1 has been proven to be closely associated with the progression of prostate cancer, but its role and specific mechanism in HCC are still unknown. Here, we identify that RP11-495P10.1 is highly expressed in HCC tissues and cells and contributes to the proliferation of HCC cells. Moreover, this study demonstrates that RP11-495P10.1 affects the proliferation of HCC by negatively regulating the expression of nuclear receptor subfamily 4 group a member 3 (NR4A3). Glycometabolism reprogramming is one of the main characteristics of tumor cells. In this study, we discover that RP11-495P10.1 regulates glycometabolism reprogramming by changing the expression of pyruvate dehydrogenase kinase 1 (PDK1) and pyruvate dehydrogenase (PDH), thus contributing to the proliferation of HCC cells. Furthermore, knockdown of RP11-495P10.1 increases enrichment of H3K27Ac in the promoter of NR4A3 by promoting the activity of PDH and the production of acetyl-CoA, which leads to the increased transcription of NR4A3. Altogether, RP11-495P10.1 promotes HCC cell proliferation by regulating the reprogramming of glucose metabolism and acetylation of the NR4A3 promoter via the PDK1/PDH axis, which provides an lncRNA-oriented therapeutic strategy for the diagnosis and treatment of HCC.
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MESH Headings
- Humans
- Male
- Acetylation
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Cell Proliferation/genetics
- DNA-Binding Proteins/genetics
- Gene Expression Regulation, Neoplastic
- Glucose
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Receptors, Steroid/genetics
- Receptors, Steroid/metabolism
- Receptors, Thyroid Hormone/genetics
- Receptors, Thyroid Hormone/metabolism
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism
- Pyruvate Dehydrogenase Complex/metabolism
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Affiliation(s)
- Chi Liu
- Department of Biochemistry & Molecular BiologyHarbin Medical UniversityHarbin150000China
- Department of Anatomy and HistologySchool of Preclinical MedicineChengdu UniversityChengdu610000China
| | - Jie Shi
- Department of Biochemistry & Molecular BiologyHarbin Medical UniversityHarbin150000China
| | - Zhengyuan Jiang
- Department of Biochemistry & Molecular BiologyHarbin Medical UniversityHarbin150000China
| | - Shan Jiang
- Department of Biochemistry & Molecular BiologyHarbin Medical UniversityHarbin150000China
| | - Yuan Wu
- General MedicinePeople’s Hospital of Ningxia Hui Autonomous RegionYinchuan750000China
| | - Dongqian Peng
- General MedicinePeople’s Hospital of Ningxia Hui Autonomous RegionYinchuan750000China
| | - Jiebing Tang
- Department of Gastrointestinal Medical OncologyHarbin Medical University Cancer HospitalHarbin150086China
| | - Linchi Guo
- General MedicinePeople’s Hospital of Ningxia Hui Autonomous RegionYinchuan750000China
- Department of Endocrinology and GeriatricsAffiliated Renhe Hospital of Sanxia UniversityYichang443000China
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10
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Lampimukhi M, Qassim T, Venu R, Pakhala N, Mylavarapu S, Perera T, Sathar BS, Nair A. A Review of Incidence and Related Risk Factors in the Development of Hepatocellular Carcinoma. Cureus 2023; 15:e49429. [PMID: 38149129 PMCID: PMC10750138 DOI: 10.7759/cureus.49429] [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: 11/26/2023] [Indexed: 12/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver malignancy, ranking as the seventh most common cancer globally and the second leading cause of deaths due to cancer. This review examines the incidence of HCC, its associated risk factors, and constantly changing global trends. Incidence has been noted to be varying worldwide, particularly due to environmental and infectious risk factors. Chronic hepatitis B (HBV) and C (HCV) virus infections, alcohol abuse, aflatoxin exposure, diabetes, obesity, and tobacco consumption are some of the leading risk factors noted. Eastern Asia and sub-Saharan Africa were noted to have the highest disease burden for HCC, with China representing a considerably large majority. On the contrary, the United States reports a lower HCC incidence overall due to improved vaccination programs against HBV; however, with a rising incidence of prominent risk factor in non-alcoholic fatty liver disease (NAFLD), the trend may very well change. Gender disparities were noted to be evident with men experiencing higher rates of HCC compared to women, which may be due to various environmental and biological factors, including alcohol intake, smoking, and androgen hormone levels. Currently, efforts to reduce the overall incidence of HCC include universal HBV vaccinations, antiviral therapies, aflatoxin prevention measures, genetic screening for hereditary hemochromatosis, and early ultrasound evaluation in patients with liver cirrhosis. Understanding these evolving trends and risk factors is essential in combating the rising HCC incidence, especially in Western countries, where risk factors, such as obesity, diabetes, and metabolic disorders, are on the rise.
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Affiliation(s)
| | - Tabarak Qassim
- School of Medicine, Royal College of Surgeons in Ireland - Medical University of Bahrain, Busaiteen, BHR
| | - Rakshaya Venu
- College of Medicine, Saveetha Medical College, Chennai, IND
| | - Nivedita Pakhala
- College of Medicine, Sri Padmavathi Medical College for Women, Tirupati, IND
| | - Suchita Mylavarapu
- College of Medicine, Malla Reddy Medical College for Women, Hyderabad, IND
| | - Tharindu Perera
- General Medicine, Grodno State Medical University, Grodno, BLR
| | - Beeran S Sathar
- College of Medicine, Jagadguru Jayadeva Murugarajendra Medical College, Davanagere, IND
| | - Arun Nair
- Pediatrics, Saint Peter's University Hospital, Somerset, USA
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11
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Sharma M, Kumar N. Improved hepatocellular carcinoma fatality prognosis using ensemble learning approach. JOURNAL OF AMBIENT INTELLIGENCE AND HUMANIZED COMPUTING 2022; 13:5763-5777. [DOI: 10.1007/s12652-021-03256-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 03/29/2021] [Indexed: 01/04/2025]
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12
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Damaskos C, Garmpis N, Dimitroulis D, Garmpi A, Psilopatis I, Sarantis P, Koustas E, Kanavidis P, Prevezanos D, Kouraklis G, Karamouzis MV, Marinos G, Kontzoglou K, Antoniou EA. Targeted Therapies for Hepatocellular Carcinoma Treatment: A New Era Ahead-A Systematic Review. Int J Mol Sci 2022; 23:14117. [PMID: 36430594 PMCID: PMC9698799 DOI: 10.3390/ijms232214117] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/10/2022] [Accepted: 11/11/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most common malignancies and the third cause of cancer-related death worldwide, with surgery being the best prognostic tool. Among the well-known causative factors of HCC are chronic liver virus infections, chronic virus hepatitis B (HBV) and chronic hepatitis virus C (HCV), aflatoxins, tobacco consumption, and non-alcoholic liver disease (NAFLD). There is a need for the development of efficient molecular markers and alternative therapeutic targets of great significance. In this review, we describe the general characteristics of HCC and present a variety of targeted therapies that resulted in progress in HCC therapy.
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Affiliation(s)
- Christos Damaskos
- Renal Transplantation Unit, Laiko General Hospital, 11527 Athens, Greece
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Nikolaos Garmpis
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Dimitrios Dimitroulis
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Anna Garmpi
- First Department of Propedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Iason Psilopatis
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Prodromos Kanavidis
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | | | - Gregory Kouraklis
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michail V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Georgios Marinos
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Konstantinos Kontzoglou
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Efstathios A. Antoniou
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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13
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Xu W, Nie C, Lv H, Chen B, Wang J, Wang S, Zhao J, He Y, Chen X. Molecular subtypes based on Wnt-signaling gene expression predict prognosis and tumor microenvironment in hepatocellular carcinoma. Front Immunol 2022; 13:1010554. [PMID: 36275697 PMCID: PMC9582750 DOI: 10.3389/fimmu.2022.1010554] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/26/2022] [Indexed: 11/16/2022] Open
Abstract
Based on increasing research evidence, hepatocellular carcinoma (HCC) is heterogeneous, and genetic profiling has led to the identification of multiple subtypes of this disease. To advance our knowledge and the ability to use individualized medicine in the treatment of HCC, it is essential to perform a complete and methodical characterization of various molecular subtypes. The canonical Wnt/β-catenin pathway is an evolutionarily conserved complicated signaling mechanism that plays a role in carcinogenesis and progression of HCC. In this study, we acquired RNA sequencing, somatic mutation, and clinical data from 701 patients from The Cancer Genome Atlas and Gene Expression Omnibus databases and stratified patients into two subgroups: WNT-high and WNT-low. In general, the WNT-high subtype is associated with an immunosuppressive microenvironment, poor prognosis, cancer-related pathways, and a low response to immune checkpoint therapy. We also found that WNT3 is negatively linked to CD8+ T-cell infiltration using multiple immunofluorescence assays. Finally, we developed a WNT-related prognostic model to predict the survival time of patients with HCC. In summary, we developed a new classification scheme for HCC based on Wnt signaling signatures. This classification produced substantial clinical effects, both in terms of assessing patient prognosis and immunotherapy administered to patients with HCC.
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Affiliation(s)
- Weifeng Xu
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, China
| | - Caiyun Nie
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Huifang Lv
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - BeiBei Chen
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jianzheng Wang
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Saiqi Wang
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jing Zhao
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yunduan He
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Xiaobing Chen
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, China
- *Correspondence: Xiaobing Chen,
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14
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Zhu Y, Li Z, Zhang J, Liu M, Jiang X, Li B. Identification of crucial lncRNAs and mRNAs in liver regeneration after portal vein ligation through weighted gene correlation network analysis. BMC Genomics 2022; 23:665. [PMID: 36131263 PMCID: PMC9490934 DOI: 10.1186/s12864-022-08891-0] [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: 04/22/2022] [Accepted: 09/12/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Portal vein ligation (PVL)-induced liver hypertrophy increases future liver remnant (FLR) volume and improves resectability of large hepatic carcinoma. However, the molecular mechanism by which PVL facilitates liver hypertrophy remains poorly understood. METHODS To gain mechanistic insight, we established a rat PVL model and carried out a comprehensive transcriptome analyses of hepatic lobes preserving portal blood supply at 0, 1, 7, and 14-day after PVL. The differentially expressed (DE) long-non coding RNAs (lncRNAs) and mRNAs were applied to conduct weighted gene co-expression network analysis (WGCNA). LncRNA-mRNA co-expression network was constructed in the most significant module. The modules and genes associated with PVL-induced liver hypertrophy were assessed through quantitative real-time PCR. RESULTS A total of 4213 DElncRNAs and 6809 DEmRNAs probesets, identified by transcriptome analyses, were used to carry out WGCNA, by which 10 modules were generated. The largest and most significant module (marked in black_M6) was selected for further analysis. Gene Ontology (GO) analysis of the module exhibited several key biological processes associated with liver regeneration such as complement activation, IL-6 production, Wnt signaling pathway, autophagy, etc. Sixteen mRNAs (Notch1, Grb2, IL-4, Cops4, Stxbp1, Khdrbs2, Hdac2, Gnb3, Gng10, Tlr2, Sod1, Gosr2, Rbbp5, Map3k3, Golga2, and Rev3l) and ten lncRNAs (BC092620, AB190508, EF076772, BC088302, BC158675, BC100646, BC089934, L20987, BC091187, and M23890) were identified as hub genes in accordance with gene significance value, module membership value, protein-protein interaction (PPI) and lncRNA-mRNA co-expression network. Furthermore, the overexpression of 3 mRNAs (Notch1, Grb2 and IL-4) and 4 lncRNAs (BC089934, EF076772, BC092620, and BC088302) was validated in hypertrophic liver lobe tissues from PVL rats and patients undergoing hepatectomy after portal vein embolization (PVE). CONCLUSIONS Microarray and WGCNA analysis revealed that the 3 mRNAs (Notch1, Grb2 and IL-4) and the 4 lncRNAs (BC089934, EF076772, BC092620 and BC088302) may be promising targets for accelerating liver regeneration before extensive hepatectomy.
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Affiliation(s)
- Yan Zhu
- Department of Pathology, Changhai Hospital, Secondary Military Medicine University, Shanghai, 200433, China
| | - Zhishuai Li
- Biliary Tract Surgery Department I, Eastern Hepatobiliary Surgery Hospital, Secondary Military Medicine University, 225 Changhai Road, Yangpu, Shanghai, 200438, People's Republic of China
| | - Jixiang Zhang
- Biliary Tract Surgery Department I, Eastern Hepatobiliary Surgery Hospital, Secondary Military Medicine University, 225 Changhai Road, Yangpu, Shanghai, 200438, People's Republic of China
| | - Mingqi Liu
- Biliary Tract Surgery Department I, Eastern Hepatobiliary Surgery Hospital, Secondary Military Medicine University, 225 Changhai Road, Yangpu, Shanghai, 200438, People's Republic of China
| | - Xiaoqing Jiang
- Biliary Tract Surgery Department I, Eastern Hepatobiliary Surgery Hospital, Secondary Military Medicine University, 225 Changhai Road, Yangpu, Shanghai, 200438, People's Republic of China.
| | - Bin Li
- Biliary Tract Surgery Department I, Eastern Hepatobiliary Surgery Hospital, Secondary Military Medicine University, 225 Changhai Road, Yangpu, Shanghai, 200438, People's Republic of China.
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15
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Zhang L, Chen C, Chai D, Li C, Guan Y, Liu L, Kuang T, Deng W, Wang W. The association between antibiotic use and outcomes of HCC patients treated with immune checkpoint inhibitors. Front Immunol 2022; 13:956533. [PMID: 36059512 PMCID: PMC9429218 DOI: 10.3389/fimmu.2022.956533] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 08/02/2022] [Indexed: 11/13/2022] Open
Abstract
Objective Recently, immune checkpoint inhibitor (ICI) treatment has shown encouraging performance in improving the prognosis of hepatocellular carcinoma (HCC) patients. The gut microbiome plays a vital role in altering the efficacy of ICIs, which may be impacted by antibiotics. The aim of the meta-analysis is to estimate the influence of antibiotic use on the survival of HCC patients treated with ICIs. Methods The literature review was conducted using databases like PubMed, EMBASE, Cochrane Library, CNKI, WANFANG DATA, VIP, Google Scholar, and ClinicalTrials.gov before May 15, 2022. The primary endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Results A total of six retrospective studies met the inclusion criteria. 1056 patients were included in the study, of which 352 (33.33%) received antibiotic treatment. The meta-analysis results revealed antibiotic use did not affect the OS (HR: 1.41, 95% CI: 0.96-2.08, P = 0.088) and PFS (HR: 1.21, 95% CI: 0.73-2.00, P = 0.459) in HCC patients treated with ICIs. Besides, the use of antibiotics did not reduce the ORR (OR: 1.06, 95% CI: 0.69-1.64, P = 0.784) and DCR (OR: 0.42, 95% CI: 0.09-2.06, P = 0.286) in HCC patients treated with ICIs. Conclusion Current evidence reveals that antibiotic use does alter the therapeutic efficacy of ICIs in HCC patients. Systematic Review Registration https://www.crd.york.ac.uk/, identifier CRD42022311948.
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Affiliation(s)
- Lilong Zhang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, China
| | - Chen Chen
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Dongqi Chai
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, China
| | - Chunlei Li
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, China
| | - Yongjun Guan
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, China
| | - Li Liu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, China
| | - Tianrui Kuang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, China
| | - Wenhong Deng
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Wenhong Deng, ; Weixing Wang,
| | - Weixing Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Wenhong Deng, ; Weixing Wang,
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16
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Zhou J, Zhang B, Wang H, Wang D, Zhang M, Zhang M, Wang X, Fan S, Xu Y, Zeng Q, Jia Y, Xi J, Nan X, He L, Zhou X, Li S, Zhong W, Yue W, Pei X. A Functional Screening Identifies a New Organic Selenium Compound Targeting Cancer Stem Cells: Role of c-Myc Transcription Activity Inhibition in Liver Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2201166. [PMID: 35652264 PMCID: PMC9353477 DOI: 10.1002/advs.202201166] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/05/2022] [Indexed: 05/04/2023]
Abstract
Cancer stem cells (CSCs) are reported to play essential roles in chemoresistance and metastasis. Pathways regulating CSC self-renewal and proliferation, such as Hedgehog, Notch, Wnt/β-catenin, TGF-β, and Myc, may be potential therapeutic targets. Here, a functional screening from the focused library with 365 compounds is performed by a step-by-step strategy. Among these candidate molecules, phenyl-2-pyrimidinyl ketone 4-allyl-3-amino selenourea (CU27) is chosen for further identification because it proves to be the most effective compound over others on CSC inhibition. Through ingenuity pathway analysis, it is shown CU27 may inhibit CSC through a well-known stemness-related transcription factor c-Myc. Gene set enrichment analysis, dual-luciferase reporter assays, expression levels of typical c-Myc targets, molecular docking, surface plasmon resonance, immunoprecipitation, and chromatin immunoprecipitation are conducted. These results together suggest CU27 binds c-Myc bHLH/LZ domains, inhibits c-Myc-Max complex formation, and prevents its occupancy on target gene promoters. In mouse models, CU27 significantly sensitizes sorafenib-resistant tumor to sorafenib, reduces the primary tumor size, and inhibits CSC generation, showing a dramatic anti-metastasis potential. Taken together, CU27 exerts inhibitory effects on CSC and CSC-associated traits in hepatocellular carcinoma (HCC) via c-Myc transcription activity inhibition. CU27 may be a promising therapeutic to treat sorafenib-resistant HCC.
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Affiliation(s)
- Jun‐Nian Zhou
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Biao Zhang
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Hai‐Yang Wang
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Dong‐Xing Wang
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
| | - Ming‐Ming Zhang
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
| | - Min Zhang
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijing100850P. R. China
| | - Xiao‐Kui Wang
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijing100850P. R. China
| | - Shi‐Yong Fan
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijing100850P. R. China
| | - Ying‐Chen Xu
- Department of Hepatobiliary SurgeryBeijing Tongren HospitalBeijing100730P. R. China
| | - Quan Zeng
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Ya‐Li Jia
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Jia‐Fei Xi
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Xue Nan
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Li‐Juan He
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Xin‐Bo Zhou
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijing100850P. R. China
| | - Song Li
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijing100850P. R. China
| | - Wu Zhong
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijing100850P. R. China
| | - Wen Yue
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Xue‐Tao Pei
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
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17
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Kalimuthu AK, Parasuraman P, Sivakumar P, Murugesan S, Arunachalam S, Pandian SRK, Ravishankar V, Ammunje DN, Sampath M, Panneerselvam T, Kunjiappan S. In silico, in vitro screening of antioxidant and anticancer potentials of bioactive secondary metabolites from an endophytic fungus (Curvularia sp.) from Phyllanthus niruri L. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:48908-48925. [PMID: 35201581 DOI: 10.1007/s11356-022-19249-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 02/11/2022] [Indexed: 06/14/2023]
Abstract
The main objective of this research work is to discover novel and efficient phytochemical substances from endophytic fungus found in medicinal plants. Curvularia geniculata L. (C. geniculata L.), an endophytic fungus isolated from Phyllanthus niruri L. (P. niruri L.), was tested against hepatoma cell lines (HepG2) in order to screen their antioxidant and anticancer potentials. The profiling of phytochemicals from the fungal extract was characterized using gas chromatography-mass spectrometry (GC-MS), and molecular docking was done for the identified compounds against one of the potential receptors predominantly present in the hepatocellular carcinoma cell lines. Among the phytochemicals found, 2-methyl-7-phenylindole had the highest binding affinity (- 8.8 kcal mol-1) for the epidermal growth factor receptor (EGFR). The stability of 2-methyl-7-phenylindole in the EGFR-binding pockets was tested using in silico molecular dynamics simulation. The fungal extract showed the highest antioxidant activity as measured by DPPH, ABTS radical scavenging, and FRAP assays. In vitro cytotoxicity assay of fungal extract demonstrated the concentration-dependent cytotoxicity against HepG2 cells after 24 h, and the IC50 (50% cell death) value was estimated to be 62.23 μg mL-1. Typical morphological changes such as condensation of nuclei and deformed membrane structures are indicative of ongoing apoptosis. The mitochondria of HepG2 cells were also targeted by the endophytic fungal extract, which resulted in substantial generation of reactive oxygen species (ROS) leading to the destruction of mitochondrial transmembrane potential integrity. These outcomes suggest that the ethyl acetate extract of C. geniculata L. has the potential to be an antioxidant agent and further to be exploited in developing potential anticancer agents.
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Affiliation(s)
- Arjun Kumar Kalimuthu
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil, Srivilliputhur, 626126, Tamil Nadu, India
| | - Pavadai Parasuraman
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, 560054, Karnataka, India
| | - Pandian Sivakumar
- School of Petroleum Technology, Pandit Deendayal Energy University, Gandhinagar, 382426, Gujarat, India
| | - Sankaranarayanan Murugesan
- Department of Pharmacy, Birla Institute of Technology & Science Pilani, Pilani Campus, Pilani, 333031, Rajasthan, India
| | - Sankarganesh Arunachalam
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil, Srivilliputhur, 626126, Tamil Nadu, India
| | - Sureshbabu Ram Kumar Pandian
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil, Srivilliputhur, 626126, Tamil Nadu, India
| | - Vigneshwaran Ravishankar
- Department of Biotechnology, Mepco Schlenk Engineering College, Sivakasi, 626005, Tamil Nadu, India
| | - Damodar Nayak Ammunje
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, 560054, Karnataka, India
| | - Muthukumar Sampath
- Department of Bioengineering, Birla Institute of Technology Mesra, Ranchi-835215, Mesra, Jharkhand, India
| | - Theivendran Panneerselvam
- Department of Pharmaceutical Chemistry, Swamy Vivekanandha College of Pharmacy, Tiruchengodu, 637205, Tamil Nadu, India
| | - Selvaraj Kunjiappan
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil, Srivilliputhur, 626126, Tamil Nadu, India.
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18
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Li L, Xu L, Zhou S, Wang P, Zhang M, Li B. Tumour site is a risk factor for hepatocellular carcinoma after hepatectomy: a 1:2 propensity score matching analysis. BMC Surg 2022; 22:104. [PMID: 35313888 PMCID: PMC8935716 DOI: 10.1186/s12893-022-01564-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 03/15/2022] [Indexed: 02/08/2023] Open
Abstract
Background The effect of the anatomic location of HCC on the prognosis of patients after hepatectomy is currently unclear. Methods Patients who underwent hepatectomy were retrospectively enrolled and divided into the right tumour resection group (R group) and the left tumour resection group (L group) according to the tumour anatomic location. To avoid bias, 1:2 propensity score matching (PSM) analysis was used. Based on the survival data, disease-free survival (DFS) and overall survival (OS) were evaluated by the Kaplan–Meier method, and long-term survival analysis was performed. Cox proportional hazards regression was used to analyse the risk factors associated with postoperative prognosis. Results A total of 700 patients were enrolled in our study. After 1:2 PSM, 354 and 177 patients were enrolled in the R group and the L group, respectively, with comparable baseline characteristics. Survival analysis showed that patients in the L group had a significantly higher recurrence rate than patients in the R group (P = 0.036), but there was no significant difference in the survival rate (P = 0.99). Long-term survival analysis showed that the survival rate of the L group was lower than that of the R group (P < 0.01). Multivariate analysis showed that tumour location in the left liver was an independent risk factor for tumour recurrence (hazard ratio, 1.263; 95% CI, 1.005–1.587) and long-term survival (hazard ratio, 3.232; 95% CI, 1.284–8.134). Conclusion For HCC patients, the recurrence rate and long-term survival rate of left liver tumours were significantly higher than those of right liver tumours, indicating that the anatomical location of the tumour has a significant effect on the survival of HCC patients. Trial registration Chinese Clinical Trial Registry, ChiCTR2100052407. Registered 25 October 2021, http://www.chictr.org.cn/showproj.aspx?proj=135500.
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Affiliation(s)
- Lian Li
- Department of Liver Surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan Province, China
| | - Liangliang Xu
- Department of Liver Surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan Province, China
| | - Siqi Zhou
- Department of Liver Surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan Province, China
| | - Peng Wang
- Department of Liver Surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan Province, China
| | - Ming Zhang
- Department of Liver Surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan Province, China.
| | - Bo Li
- Department of Liver Surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan Province, China.
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19
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Dat VHX, Nhung BTH, Chau NNB, Cuong PH, Hieu VD, Linh NTM, Quoc NB. Identification of potential microRNA groups for the diagnosis of hepatocellular carcinoma (HCC) using microarray datasets and bioinformatics tools. Heliyon 2022; 8:e08987. [PMID: 35243101 PMCID: PMC8873536 DOI: 10.1016/j.heliyon.2022.e08987] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/19/2021] [Accepted: 02/15/2022] [Indexed: 11/30/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third cause of cancer-related death worldwide. Potential microRNAs have been reported as biomarkers for early detection of HCC as well as novel molecular targets for HCC treatment. Various tissue expression profiles of miRNAs using three microarray datasets from groups in Asia (2), Europe, America (GSE147892, GSE21362, GSE74618, GSE40744) and multiple bioinformatics tools were integrated to determine the most significant miRNA groups to assist in the diagnosis of HCC. Statistical analyses identified at least 30 miRNAs with 17 up-regulated and 13 down-regulated in HCC-related tumor tissues. All the miRNAs also showed relevance to the hallmarks of cancer such as cell proliferation, invasion, metastasis, angiogenesis, metabolism, epithelial-mesenchymal transition and apoptosis. Expression levels of miRNAs observed in the European group showed up-regulation at 5–37% compared to both Asian and American groups. Interestingly, four miRNAs divided into two groups as miR-182-5p/miR-1269a and miR-199a/miR-422a were the most promising for diagnosis of HCC patients from healthy controls, with AUC values of 0.902 and 0.892, respectively. Results provided evidence of the correlation between potential miRNAs and HCC that could be useful for disease diagnosis based on in-depth analyses of large case numbers and cohort studies.
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Affiliation(s)
- Vo Hoang Xuan Dat
- Faculty of Biological Sciences, Nong Lam University, Ho Chi Minh City, Viet Nam
| | - Bui Thi Huyen Nhung
- Faculty of Biological Sciences, Nong Lam University, Ho Chi Minh City, Viet Nam
| | | | | | - Vo Duc Hieu
- Ho Chi Minh City Oncology Hospital, Viet Nam
| | | | - Nguyen Bao Quoc
- Faculty of Biological Sciences, Nong Lam University, Ho Chi Minh City, Viet Nam.,Research Institute of Biotechnology and Environment, Nong Lam University, Ho Chi Minh City, Viet Nam
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20
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Tawfik SM, Abdollah MRA, Elmazar MM, El-Fawal HAN, Abdelnaser A. Effects of Metformin Combined With Antifolates on HepG2 Cell Metabolism and Cellular Proliferation. Front Oncol 2022; 12:828988. [PMID: 35186762 PMCID: PMC8851913 DOI: 10.3389/fonc.2022.828988] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 01/11/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC), one of the most prevalent types of cancers worldwide, continues to maintain high levels of resistance to standard therapy. As clinical data revealed poor response rates, the need for developing new methods has increased to improve the overall wellbeing of patients with HCC. Furthermore, a growing body of evidence shows that cancer metabolic changes are a key feature of many types of human malignancies. Metabolic reprogramming refers to cancer cells’ ability to change their metabolism in order to meet the increased energy demand caused by continuous growth, rapid proliferation, and other neoplastic cell characteristics. For these reasons, metabolic pathways may become new therapeutic and chemopreventive targets. The aim of this study was to investigate the metabolic alterations associated with metformin (MET), an anti-diabetic agent when combined with two antifolate drugs: trimethoprim (TMP) or methotrexate (MTX), and how metabolic changes within the cancer cell may be used to increase cellular death. In this study, single drugs and combinations were investigated using in vitro assays including cytotoxicity assay (MTT), RT-qPCR, annexin V/PI apoptosis assay, scratch wound assay and Seahorse XF analysis, on a human HCC cell line, HepG2. The cytotoxicity assay showed that the IC50 of MET as single therapy was 44.08 mM that was reduced to 22.73 mM and 29.29 mM when combined with TMP and MTX, respectively. The co-treatment of both drugs increased p53 and Bax apoptotic markers, while decreased the anti-apoptotic marker; Bcl-2. Both combinations increased the percentage of apoptotic cells and halted cancer cell migration when compared to MET alone. Furthermore, both combinations decreased the MET-induced increase in glycolysis, while also inducing mitochondrial damage, altering cancer cell bioenergetics. These findings provide an exciting insight into the anti-proliferative and apoptotic effects of MET and anti-folates on HepG2 cells, and how in combination, may potentially combat the aggressiveness of HCC.
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Affiliation(s)
- Sherouk M Tawfik
- Department of Chemistry, School of Sciences and Engineering, The American University in Cairo, Cairo, Egypt.,Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt.,The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt
| | - Maha R A Abdollah
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt.,The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt
| | - Mohey M Elmazar
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt
| | - Hassan A N El-Fawal
- Institute of Global Public Health, School of Sciences and Engineering, The American University in Cairo, Cairo, Egypt
| | - Anwar Abdelnaser
- Institute of Global Public Health, School of Sciences and Engineering, The American University in Cairo, Cairo, Egypt
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21
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Bakrania A, Zheng G, Bhat M. Nanomedicine in Hepatocellular Carcinoma: A New Frontier in Targeted Cancer Treatment. Pharmaceutics 2021; 14:41. [PMID: 35056937 PMCID: PMC8779722 DOI: 10.3390/pharmaceutics14010041] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/17/2021] [Accepted: 12/22/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and is associated with a dismal median survival of 2-9 months. The fundamental limitations and ineffectiveness of current HCC treatments have led to the development of a vast range of nanotechnologies with the goal of improving the safety and efficacy of treatment for HCC. Although remarkable success has been achieved in nanomedicine research, there are unique considerations such as molecular heterogeneity and concomitant liver dysfunction that complicate the translation of nanotheranostics in HCC. This review highlights the progress, challenges, and targeting opportunities in HCC nanomedicine based on the growing literature in recent years.
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Affiliation(s)
- Anita Bakrania
- Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada;
- Ajmera Transplant Program, University Health Network, Toronto, ON M5G 2N2, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada;
| | - Gang Zheng
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada;
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Mamatha Bhat
- Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada;
- Ajmera Transplant Program, University Health Network, Toronto, ON M5G 2N2, Canada
- Division of Gastroenterology, Department of Medicine, University Health Network, Toronto, ON M5G 2C4, Canada
- Department of Medical Sciences, University of Toronto, Toronto, ON M5S 1A1, Canada
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22
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Chisari A, Golán I, Campisano S, Gélabert C, Moustakas A, Sancho P, Caja L. Glucose and Amino Acid Metabolic Dependencies Linked to Stemness and Metastasis in Different Aggressive Cancer Types. Front Pharmacol 2021; 12:723798. [PMID: 34588983 PMCID: PMC8473699 DOI: 10.3389/fphar.2021.723798] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 08/20/2021] [Indexed: 12/26/2022] Open
Abstract
Malignant cells are commonly characterised by being capable of invading tissue, growing self-sufficiently and uncontrollably, being insensitive to apoptosis induction and controlling their environment, for example inducing angiogenesis. Amongst them, a subpopulation of cancer cells, called cancer stem cells (CSCs) shows sustained replicative potential, tumor-initiating properties and chemoresistance. These characteristics make CSCs responsible for therapy resistance, tumor relapse and growth in distant organs, causing metastatic dissemination. For these reasons, eliminating CSCs is necessary in order to achieve long-term survival of cancer patients. New insights in cancer metabolism have revealed that cellular metabolism in tumors is highly heterogeneous and that CSCs show specific metabolic traits supporting their unique functionality. Indeed, CSCs adapt differently to the deprivation of specific nutrients that represent potentially targetable vulnerabilities. This review focuses on three of the most aggressive tumor types: pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC) and glioblastoma (GBM). The aim is to prove whether CSCs from different tumour types share common metabolic requirements and responses to nutrient starvation, by outlining the diverse roles of glucose and amino acids within tumour cells and in the tumour microenvironment, as well as the consequences of their deprivation. Beyond their role in biosynthesis, they serve as energy sources and help maintain redox balance. In addition, glucose and amino acid derivatives contribute to immune responses linked to tumourigenesis and metastasis. Furthermore, potential metabolic liabilities are identified and discussed as targets for therapeutic intervention.
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Affiliation(s)
- Andrea Chisari
- Department of Chemistry, School of Sciences, National University of Mar del Plata, Mar del Plata, Argentina
| | - Irene Golán
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Sabrina Campisano
- Department of Chemistry, School of Sciences, National University of Mar del Plata, Mar del Plata, Argentina
| | - Caroline Gélabert
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Aristidis Moustakas
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Patricia Sancho
- Translational Research Unit, Hospital Universitario Miguel Servet, IIS Aragon, Zaragoza, Spain
| | - Laia Caja
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden
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23
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Tonon F, Farra R, Zennaro C, Pozzato G, Truong N, Parisi S, Rizzolio F, Grassi M, Scaggiante B, Zanconati F, Bonazza D, Grassi G, Dapas B. Xenograft Zebrafish Models for the Development of Novel Anti-Hepatocellular Carcinoma Molecules. Pharmaceuticals (Basel) 2021; 14:803. [PMID: 34451900 PMCID: PMC8400454 DOI: 10.3390/ph14080803] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/02/2021] [Accepted: 08/03/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common type of tumor and the second leading cause of tumor-related death worldwide. Liver cirrhosis is the most important predisposing factor for HCC. Available therapeutic approaches are not very effective, especially for advanced HCC, which is the most common form of the disease at diagnosis. New therapeutic strategies are therefore urgently needed. The use of animal models represents a relevant tool for preclinical screening of new molecules/strategies against HCC. However, several issues, including animal husbandry, limit the use of current models (rodent/pig). One animal model that has attracted the attention of the scientific community in the last 15 years is the zebrafish. This freshwater fish has several attractive features, such as short reproductive time, limited space and cost requirements for husbandry, body transparency and the fact that embryos do not show immune response to transplanted cells. To date, two different types of zebrafish models for HCC have been developed: the transgenic zebrafish and the zebrafish xenograft models. Since transgenic zebrafish models for HCC have been described elsewhere, in this review, we focus on the description of zebrafish xenograft models that have been used in the last five years to test new molecules/strategies against HCC.
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Affiliation(s)
- Federica Tonon
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I 34149 Trieste, Italy; (F.T.); (R.F.); (C.Z.); (G.P.); (F.Z.); (D.B.)
| | - Rossella Farra
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I 34149 Trieste, Italy; (F.T.); (R.F.); (C.Z.); (G.P.); (F.Z.); (D.B.)
| | - Cristina Zennaro
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I 34149 Trieste, Italy; (F.T.); (R.F.); (C.Z.); (G.P.); (F.Z.); (D.B.)
| | - Gabriele Pozzato
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I 34149 Trieste, Italy; (F.T.); (R.F.); (C.Z.); (G.P.); (F.Z.); (D.B.)
| | - Nhung Truong
- Stem Cell Research and Application Laboratory, VNUHCM, University of Science, Ho Chi Minh City 72711, Vietnam;
| | - Salvatore Parisi
- Pathology Unit, CRO Aviano, National Cancer Institute, IRCCS, I 33081 Aviano, Italy; (S.P.); (F.R.)
- Doctoral School in Molecular Biomedicine, University of Trieste, I 34127 Trieste, Italy
| | - Flavio Rizzolio
- Pathology Unit, CRO Aviano, National Cancer Institute, IRCCS, I 33081 Aviano, Italy; (S.P.); (F.R.)
- Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, I 30170 Mestre, Italy
| | - Mario Grassi
- Department of Engineering and Architecture, University of Trieste, Via Valerio 6/A, I 34127 Trieste, Italy;
| | - Bruna Scaggiante
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I 34149 Trieste, Italy; (B.S.); (B.D.)
| | - Fabrizio Zanconati
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I 34149 Trieste, Italy; (F.T.); (R.F.); (C.Z.); (G.P.); (F.Z.); (D.B.)
| | - Deborah Bonazza
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I 34149 Trieste, Italy; (F.T.); (R.F.); (C.Z.); (G.P.); (F.Z.); (D.B.)
| | - Gabriele Grassi
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I 34149 Trieste, Italy; (F.T.); (R.F.); (C.Z.); (G.P.); (F.Z.); (D.B.)
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I 34149 Trieste, Italy; (B.S.); (B.D.)
| | - Barbara Dapas
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I 34149 Trieste, Italy; (B.S.); (B.D.)
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24
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Huang NC, Huang RL, Huang XF, Chang KF, Lee CJ, Hsiao CY, Lee SC, Tsai NM. Evaluation of anticancer effects of Juniperus communis extract on hepatocellular carcinoma cells in vitro and in vivo. Biosci Rep 2021; 41:BSR20211143. [PMID: 34151367 PMCID: PMC8276093 DOI: 10.1042/bsr20211143] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/10/2021] [Accepted: 06/15/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and accounts for the fourth leading cause of all cancer deaths. Scientific evidence has found that plant extracts seem to be a reliable choice due to their multitarget effects against HCC. Juniperus communis has been used for centuries in traditional medicine and its anticancer properties have been reported. As a result, the purpose of the study was to investigate the anticancer effect and mechanism of J. communis extract (JCo extract) on HCC in vitro and in vivo. In the present study, we found that JCo extract inhibited the growth of human HCC cells by inducing cell cycle arrest at the G0/G1 phase, extensive apoptosis and suppressing metastatic protein expressions in HCC cells. Moreover, the combinational treatment of JCo and VP-16 was found to enhance the anticancer effect, revealing that JCo extract might have the potential to be utilized as an adjuvant to promote HCC treatment. Furthermore, in vivo study, JCo extract significantly suppressed HCC tumor growth and extended the lifespan with no or low systemic and pathological toxicity. JCo extract significantly up-regulated the expression of pro-apoptotic proteins and tumor suppressor p53, suppressed VEGF/VEGFR autocrine signaling, down-regulated cell cycle regulatory proteins and MMP2/MMP9 proteins. Overall, our results provide a basis for exploiting JCo extract as a potential anticancer agent against HCC.
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Affiliation(s)
- Nan-Chieh Huang
- Department of Information Engineering, I-Shou University, Kaohsiung 84001, Taiwan, R.O.C
- Division of Family Medicine, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 81342, Taiwan, R.O.C
| | - Ru-Lai Huang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi 60002, Taiwan, R.O.C
| | - Xiao-Fan Huang
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C
| | - Kai-Fu Chang
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C
| | - Chien-Ju Lee
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C
| | - Chih-Yen Hsiao
- Division of Nephrology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi 60002, Taiwan, R.O.C
- Department of Hospital and Health Care Administration, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan, R.O.C
| | - Shan-Chih Lee
- Department of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C
- Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung 40201, Taiwan, R.O.C
| | - Nu-Man Tsai
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 40201, Taiwan, R.O.C
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25
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Romano F, Chiarelli M, Garancini M, Scotti M, Zago M, Cioffi G, De Simone M, Cioffi U. Rethinking the Barcelona clinic liver cancer guidelines: Intermediate stage and Child-Pugh B patients are suitable for surgery? World J Gastroenterol 2021; 27:2784-2794. [PMID: 34135554 PMCID: PMC8173387 DOI: 10.3748/wjg.v27.i21.2784] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 02/24/2021] [Accepted: 04/29/2021] [Indexed: 02/06/2023] Open
Abstract
According to Barcelona Clinic Liver Cancer recommendations, intermediate stage hepatocellular carcinomas (stage B) are excluded from liver resection and are referred to palliative treatment. Moreover, Child-Pugh B patients are not usually candidates for liver resection. However, many hepatobiliary centers in the world manage patients with intermediate stage hepatocellular carcinoma or Child-Pugh B cirrhosis with liver resection, maintaining that hepatic resection is not contraindicated in selected patients with non-early-stage hepatocellular carcinoma and without normal liver function. Several studies demonstrate that resection provides the best survival benefit for selected patients in very early/early and even in intermediate stages of Barcelona Clinic Liver Cancer classification, and this treatment gives good results in the setting of multinodular, large tumors in patients with portal hypertension and/or Child-Pugh B cirrhosis. In this review we explore this controversial topic, and we show through the literature analysis how liver resection may improve the short- and long-term survival rate of carefully selected Barcelona Clinic Liver Cancer B and Child-Pugh B hepatocellular carcinoma patients. However, other large clinical studies are needed to clarify which patients with intermediate stage hepatocellular carcinoma are most likely to benefit from liver resection.
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Affiliation(s)
- Fabrizio Romano
- Department of Surgery, School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
| | - Marco Chiarelli
- Emergency and Robotic Surgery, A. Manzoni Hospital, ASST Lecco, Lecco 23900, Italy
| | - Mattia Garancini
- Department of General Surgery, San Gerardo Hospital, Monza 20900, Italy
| | - Mauro Scotti
- Department of General Surgery, San Gerardo Hospital, Monza 20900, Italy
| | - Mauro Zago
- Emergency and Robotic Surgery, A. Manzoni Hospital, ASST Lecco, Lecco 23900, Italy
| | - Gerardo Cioffi
- Department of Sciences and Technologies, Università degli Studi del Sannio di Benevento, Benevento 82100, Italy
| | | | - Ugo Cioffi
- Department of Surgery, University of Milan, Milano 20122, Italy
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Vogl TJ, Langenbach MC, Hammerstingl R, Albrecht MH, Chatterjee AR, Gruber-Rouh T. Evaluation of two different transarterial chemoembolization protocols using Lipiodol and degradable starch microspheres in therapy of hepatocellular carcinoma: a prospective trial. Hepatol Int 2021; 15:685-694. [PMID: 34043158 PMCID: PMC8286929 DOI: 10.1007/s12072-021-10193-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 04/17/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND This prospective randomized trial is designed to compare the performance of conventional transarterial chemoembolization (cTACE) using Lipiodol-only with additional use of degradable starch microspheres (DSM) for hepatocellular carcinoma (HCC) in BCLC-stage-B based on metric tumor response. METHODS Sixty-one patients (44 men; 17 women; range 44-85) with HCC were evaluated in this IRB-approved HIPPA compliant study. The treatment protocol included three TACE-sessions in 4-week intervals, in all cases with Mitomycin C as a chemotherapeutic agent. Multiparametric magnetic resonance imaging (MRI) was performed prior to the first and 4 weeks after the last TACE. Two treatment groups were determined using a randomization sheet: In 30 patients, TACE was performed using Lipiodol only (group 1). In 31 cases Lipiodol was combined with DSMs (group 2). Response according to tumor volume, diameter, mRECIST criteria, and the development of necrotic areas were analyzed and compared using the Mann-Whitney-U, Kruskal-Wallis-H-test, and Spearman-Rho. Survival data were analyzed using the Kaplan-Meier estimator. RESULTS A mean overall tumor volume reduction of 21.45% (± 62.34%) was observed with an average tumor volume reduction of 19.95% in group 1 vs. 22.95% in group 2 (p = 0.653). Mean diameter reduction was measured with 6.26% (± 34.75%), for group 1 with 11.86% vs. 4.06% in group 2 (p = 0.678). Regarding mRECIST criteria, group 1 versus group 2 showed complete response in 0 versus 3 cases, partial response in 2 versus 7 cases, stable disease in 21 versus 17 cases, and progressive disease in 3 versus 1 cases (p = 0.010). Estimated overall survival was in mean 33.4 months (95% CI 25.5-41.4) for cTACE with Lipiosol plus DSM, and 32.5 months (95% CI 26.6-38.4), for cTACE with Lipiodol-only (p = 0.844), respectively. CONCLUSIONS The additional application of DSM during cTACE showed a significant benefit in tumor response according to mRECIST compared to cTACE with Lipiodol-only. No benefit in survival time was observed.
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Affiliation(s)
- T J Vogl
- Institute for Diagnostic and Interventional Radiology, Johann Wolfgang Goethe University, Theodor-Stern-Kai, 760590, Frankfurt am Main, Germany
| | - M C Langenbach
- Institute for Diagnostic and Interventional Radiology, Johann Wolfgang Goethe University, Theodor-Stern-Kai, 760590, Frankfurt am Main, Germany
| | - R Hammerstingl
- Institute for Diagnostic and Interventional Radiology, Johann Wolfgang Goethe University, Theodor-Stern-Kai, 760590, Frankfurt am Main, Germany
| | - M H Albrecht
- Institute for Diagnostic and Interventional Radiology, Johann Wolfgang Goethe University, Theodor-Stern-Kai, 760590, Frankfurt am Main, Germany
| | - A R Chatterjee
- Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC, USA
| | - T Gruber-Rouh
- Institute for Diagnostic and Interventional Radiology, Johann Wolfgang Goethe University, Theodor-Stern-Kai, 760590, Frankfurt am Main, Germany.
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MicroRNA-4651 represses hepatocellular carcinoma cell growth and facilitates apoptosis via targeting FOXP4. Biosci Rep 2021; 40:224903. [PMID: 32436934 PMCID: PMC7286879 DOI: 10.1042/bsr20194011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 04/16/2020] [Accepted: 04/17/2020] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) belong to the subgroup of small noncoding RNAs, which typically serve as important gene regulators to participate in different biological events, such as tumor cell growth and apoptosis. Recent studies indicated microRNA-4651 (miR-4651) was involved in hepatocellular carcinoma (HCC) progression. The certain role of miRNA-4651 during the progression of HCC, however, remains unclear. Herein, we investigated the mRNA expression level of miR-4651 in HCC tissues and HCC cell lines and found miR-4651 was noticeably down-regulated compared with the normal liver tissues and QSG-7701 cell line, respectively. Then, miR-4561 overexpression obviously repressed the proliferation and promoted apoptosis in two HCC cell lines. Interestingly, we further identified that miR-4561 could directly interact with FOXP4 in HCC cells by using bio-informatic method and report assay. Moreover, forced expression of FOXP4 showed an opposite effect compared with miR-4561 in HCC cell lines. Hence, our findings strongly indicated that miR-4561 regulated the HCC cell growth and apoptosis mainly through targeting the FOXP4 genes. Clinically, the miR-4561/FOXP4 axis might be a potential target for therapeutic application of HCC patient treatment.
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28
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Peng Z, Gong Y, Liang X. Role of FAT1 in health and disease. Oncol Lett 2021; 21:398. [PMID: 33777221 PMCID: PMC7988705 DOI: 10.3892/ol.2021.12659] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 02/25/2021] [Indexed: 01/15/2023] Open
Abstract
FAT atypical cadherin 1 (FAT1), which encodes a protocadherin, is one of the most frequently mutated genes in human cancer. Over the past 20 years, the role of FAT1 in tissue growth and in the development of diseases has been extensively studied. There is definitive evidence that FAT1 serves a substantial role in the maintenance of organs and development, and its expression appears to be tissue-specific. FAT1 activates a variety of signaling pathways through protein-protein interactions, including the Wnt/β-catenin, Hippo and MAPK/ERK signaling pathways, which affect cell proliferation, migration and invasion. Abnormal FAT1 expression may lead to the development of tumors and may affect prognosis. Therefore, FAT1 may have potential in tumor therapy. The structural and functional changes mediated by FAT1, its tissue distribution and changes in FAT1 expression in human diseases are described in the present review, which provides further insight for understanding the role of FAT1 in development and disease.
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Affiliation(s)
- Zizhen Peng
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang School of Medicine, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yanyu Gong
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang School of Medicine, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xiaoqiu Liang
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang School of Medicine, University of South China, Hengyang, Hunan 421001, P.R. China
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Liu Z, Ding F, Shen X. Total flavonoids of Radix Tetrastigma suppress inflammation-related hepatocellular carcinoma cell metastasis. Mol Genet Genomics 2021; 296:571-579. [PMID: 33576897 PMCID: PMC8144124 DOI: 10.1007/s00438-020-01759-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 12/21/2020] [Indexed: 11/30/2022]
Abstract
This study aimed to investigate the effects of the total flavonoids of Radix Tetrastigma (RTF) on inflammation-related hepatocellular carcinoma (HCC) development. Extracted RTF was diluted to different concentrations for subsequent experiments. HCC cells were cotreated with lipopolysaccharide (LPS) and RTF to investigate the effects of RTF on LPS-stimulated HCC cells. A CCK-8 kit was used to measure cell proliferation. Apoptosis was detected with a flow cytometer. Cell migration and invasion were quantified by wound healing and Transwell assays, respectively. The expression of TLR4 and COX-2 and activation of the NF-κB pathway were determined by Western blotting. Treatment with LPS significantly enhanced cell proliferation and decreased the apoptosis rate, while cell migration and invasion were notably upregulated. RTF suppressed the proliferation and invasion induced by LPS stimulation and promoted HCC cell apoptosis. The protein levels of Bax and cleaved caspase-3 were decreased and that of Bcl-2 was increased by LPS in HCC cells, which could be rescued by RTF. RTF significantly inhibited the LPS-induced expression of the proinflammatory mediators IL-6 and IL-8 in HCC cells. Mechanistically, with RTF treatment, the upregulated expression of TLR4 and COX-2 induced by LPS was obviously downregulated. Furthermore, the phosphorylation of NF-κB/p65 was significantly decreased in LPS-stimulated cells after supplementation with RTF. Our study suggests that RTF exerts a significant inhibitory effect on the LPS-induced enhancement of the malignant behaviors of HCC cells via inactivation of TLR4/NF-κB signaling. RTF may be a promising chemotherapeutic agent to limit HCC development and inflammation-mediated metastasis.
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Affiliation(s)
- Zhendong Liu
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of TCM), Hangzhou, 310006, China
| | - Fangmi Ding
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of TCM), Hangzhou, 310006, China
| | - Xingyong Shen
- Department of Oncology, Xijing Hospital, Air Force Military Medical University, 15 Changle West Road, Xian, 710032, Shaanxi, China.
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Deng J, Zhong F, Gu W, Qiu F. Exploration of Prognostic Biomarkers among Replication Factor C Family in the Hepatocellular Carcinoma. Evol Bioinform Online 2021; 17:1176934321994109. [PMID: 33628006 PMCID: PMC7885030 DOI: 10.1177/1176934321994109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 01/19/2021] [Indexed: 01/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the common cancers with a high incidence and mortality. The human replication factor C (RFC) family contains 5 subunits that play an important role in DNA replication and DNA damage repair. RFCs are abnormally expressed in a variety of cancers; some of them are differentially expressed in HCC tissues and related to tumor growth. However, the expression, prognostic value, and effect targets of the whole RFC family in HCC are still unclear. To address these issues, we performed a multidimensional analysis of RFCs in HCC patients by Oncomine, UALCAN, GEPIA, Human protein atlas, Kaplan-Meier plotter, cBioPortal, GeneMANIA, String, and LinkedOmics. mRNA expression of RFCs was significantly increased in HCC tissues. There was a significant correlation between the expression of RFC2/3/4/5 and tumor stage of HCC patients. Besides, high mRNA expression of RFC2/4 was associated with worse overall survival (OS). Moreover, genetic alterations of RFCs were associated with worse OS in HCC patients. We found that genes co-expressed with RFC2/4 were mainly involved in biological processes, such as chromosome segregation, mitotic cell cycle phase transition, and telomere organization and they activated the cell cycle and spliceosome pathways. The gene set is mainly enriched in cancer-related kinases AURKA, ATR, CDK1, PLK1, and CHEK1. E2F family members were the key transcription factors for RFCs. Our results suggest that differentially expressed RFC2 and RFC4 are potential prognostic biomarkers in HCC and may act on E2F transcription factors and some kinase targets to dysregulate the cell cycle pathway. These efforts may provide new research directions for prognostic biomarkers and therapeutic targets in HCC.
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Affiliation(s)
- Jianxiong Deng
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Fangyan Zhong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Weiguo Gu
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Feng Qiu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R. China
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Fukuyama K, Asagiri M, Sugimoto M, Tsushima H, Seo S, Taura K, Uemoto S, Iwaisako K. Gene expression profiles of liver cancer cell lines reveal two hepatocyte-like and fibroblast-like clusters. PLoS One 2021; 16:e0245939. [PMID: 33539378 PMCID: PMC7861371 DOI: 10.1371/journal.pone.0245939] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 01/08/2021] [Indexed: 12/19/2022] Open
Abstract
Cancer cell lines are widely used in basic research to study cancer development, growth, invasion, or metastasis. They are also used for the development and screening of anticancer drugs. However, there are no clear criteria for choosing the most suitable cell lines among the wide variety of cancer cell lines commercially available for research, and the choice is often based on previously published reports. Here, we investigated the characteristics of liver cancer cell lines by analyzing the gene expression data available in the Cancer Cell Line Encyclopedia. Unsupervised clustering analysis of 28 liver cancer cell lines yielded two main clusters. One cluster showed a gene expression pattern similar to that of hepatocytes, and the other showed a pattern similar to that of fibroblasts. Analysis of hepatocellular carcinoma gene expression profiles available in The Cancer Genome Atlas showed that the gene expression patterns in most hepatoma tissues were similar to those in the hepatocyte-like cluster. With respect to liver cancer research, our findings may be useful for selecting an appropriate cell line for a specific study objective. Furthermore, our approach of utilizing a public database for comparing the properties of cell lines could be an attractive cell line selection strategy that can be applied to other fields of research.
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Affiliation(s)
- Keita Fukuyama
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masataka Asagiri
- Department of Pharmacology, Yamaguchi University Graduate School of Medicine, Ube, Japan
- Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Masahiro Sugimoto
- Research and Development Center for Minimally Invasive Therapies Health Promotion and Preemptive Medicine, Tokyo Medical University, Shinjuku, Japan
| | - Hiraki Tsushima
- Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan
| | - Satoru Seo
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kojiro Taura
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Keiko Iwaisako
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan
- Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan
- * E-mail:
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Moniaux N, Lacaze L, Gothland A, Deshayes A, Samuel D, Faivre J. Cyclin-dependent kinase inhibitors p21 and p27 function as critical regulators of liver regeneration following 90% hepatectomy in the rat. World J Hepatol 2020; 12:1198-1210. [PMID: 33442448 PMCID: PMC7772727 DOI: 10.4254/wjh.v12.i12.1198] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/26/2020] [Accepted: 10/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver reduction is the main curative treatment for primary liver cancer, but its use remains limited as liver regeneration requires a minimum of 30% functional parenchyma.
AIM To study the dynamics of the liver regeneration process and consequent behavior of cell cycle regulators in rats after extended hepatectomy (90%) and postoperative glucose infusions.
METHODS Post-hepatectomy liver failure was triggered in 84 Wistar rats by reducing their liver mass by 90%. The animals received a post-operative glucose infusion and were randomly assigned to two groups: One to investigate the survival rate and the other for biochemical analyses. Animals that underwent laparotomy or 70% hepatectomy were used as controls. Blood and liver samples were collected on postoperative days 1 to 7. Liver morphology, function, and regeneration were studied with histology, immunohistochemistry, and western blotting.
RESULTS Postoperative mortality after major resection reached 20% and 55% in the first 24 h and 48 h, respectively, with an overall total of 70% 7 d after surgery. No apparent signs of apoptotic cell death were detected in the extended hepatectomy rat livers, but hepatocytes displaying a clear cytoplasm and an accumulation of hyaline material testified to changes affecting their functional activities. Liver regeneration started properly, as early events initiating cell proliferation occurred within the first 3 h, and the G1 to S transition was detected in less than 12 h. However, a rise in p27 (Kip1) followed by p21 (Waf1/Cip1) cell cycle inhibitor levels led to a delayed S phase progression and mitosis. Overall, liver regeneration in rats with a 90% hepatectomy was delayed by 24 h and associated with a delayed onset and lower peak magnitude of hepatocellular deoxyribonucleic acid synthesis.
CONCLUSION This work highlights the critical importance of the cyclin/cyclin-dependent kinase inhibitors of the Cip/Kip family in regulating the liver regeneration timeline following extended hepatectomy.
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Affiliation(s)
- Nicolas Moniaux
- INSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, Villejuif 94800, France
- Université Paris-Saclay, Faculté de Médecine Le Kremlin, Bicêtre 94270, France
| | - Laurence Lacaze
- INSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, Villejuif 94800, France
- Université Paris-Saclay, Faculté de Médecine Le Kremlin, Bicêtre 94270, France
| | - Adélie Gothland
- INSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, Villejuif 94800, France
- Université Paris-Saclay, Faculté de Médecine Le Kremlin, Bicêtre 94270, France
| | - Alice Deshayes
- INSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, Villejuif 94800, France
- Université Paris-Saclay, Faculté de Médecine Le Kremlin, Bicêtre 94270, France
| | - Didier Samuel
- INSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, Villejuif 94800, France
- Université Paris-Saclay, Faculté de Médecine Le Kremlin, Bicêtre 94270, France
| | - Jamila Faivre
- INSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, Villejuif 94800, France
- Université Paris-Saclay, Faculté de Médecine Le Kremlin, Bicêtre 94270, France
- Department of Pôle de Biologie Médicale, Laboratoire d’Onco-Hématologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Paul-Brousse University Hospital, Villejuif 94800, France
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Setayesh T, Colquhoun SD, Wan YJY. Overexpression of Galectin-1 and Galectin-3 in hepatocellular carcinoma. LIVER RESEARCH 2020; 4:173-179. [PMID: 34567824 PMCID: PMC8460053 DOI: 10.1016/j.livres.2020.11.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Galectins (Gals) are evolutionarily conserved proteins that bind to β-galactoside containing glycans. Abnormal expression of Gals is associated with the development, progression, and metastasis of different types of cancer. Among the 11 Gals identified in humans, the roles of Gal-1 and Gal-3 have been extensively investigated in various tumors. Here, we summarize the roles of overly expressed Gal-1 and Gal-3 in the pathogenesis of hepatocellular carcinoma (HCC). The overexpression of Gal-1 and Gal-3 correlates with tumor growth, HCC cell migration and invasion, tumor aggressiveness, metastasis, and poor prognosis. A potentially promising future treatment strategy for HCC may include the combination of immunotherapy with Gal-1 inhibition. Additional research is warranted to investigate targeting Gal-1 and Gal-3 for HCC treatment.
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Affiliation(s)
- Tahereh Setayesh
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, USA
| | | | - Yu-Jui Yvonne Wan
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, USA,Corresponding author. Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, USA. (Y.-J.Y. Wan)
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Chai NX, Chapiro J. Therapy of Intermediate-Stage Hepatocellular Carcinoma: Current Evidence and Clinical Practice. Semin Intervent Radiol 2020; 37:456-465. [PMID: 33328701 PMCID: PMC7732559 DOI: 10.1055/s-0040-1719186] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Intermediate-stage Hepatocellular Carcinoma (HCC) represents a wide range of disease burden. Patients with different levels of liver function, tumor size, and number of lesions may all have intermediate-stage disease according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Several minimally invasive image-guided locoregional therapies are available for the treatment of intermediate-stage HCC, including conventional transarterial chemoembolization (cTACE), drug-eluting bead TACE (DEB-TACE), yttrium-90 radioembolization (Y-90 RE), thermal ablation, bland embolization, and combination therapy. Available clinical evidence points to cTACE as the current gold standard for the locoregional treatment of intermediate-stage HCC. DEB-TACE is at best non-inferior to cTACE in terms of survival benefit. Y-90 RE is a maturing therapy, and some institutions have adopted it as first-line therapy for intermediate-stage HCC. Thermal ablation combined with TACE may be used in select patients, while bland embolization has only limited evidence for its use. The combination of locoregional therapy with VEGF inhibitors or immune checkpoint inhibitors has also been explored. This article will examine in detail the clinical evidence supporting available locoregional treatment options for intermediate-stage HCC.
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Affiliation(s)
- Nathan X. Chai
- Division of Vascular and Interventional Radiology, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut
| | - Julius Chapiro
- Division of Vascular and Interventional Radiology, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut
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Abyadeh M, Meyfour A, Gupta V, Zabet Moghaddam M, Fitzhenry MJ, Shahbazian S, Hosseini Salekdeh G, Mirzaei M. Recent Advances of Functional Proteomics in Gastrointestinal Cancers- a Path towards the Identification of Candidate Diagnostic, Prognostic, and Therapeutic Molecular Biomarkers. Int J Mol Sci 2020; 21:ijms21228532. [PMID: 33198323 PMCID: PMC7697099 DOI: 10.3390/ijms21228532] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/02/2020] [Accepted: 11/11/2020] [Indexed: 02/07/2023] Open
Abstract
Gastrointestinal (GI) cancer remains one of the common causes of morbidity and mortality. A high number of cases are diagnosed at an advanced stage, leading to a poor survival rate. This is primarily attributed to the lack of reliable diagnostic biomarkers and limited treatment options. Therefore, more sensitive, specific biomarkers and curative treatments are desirable. Functional proteomics as a research area in the proteomic field aims to elucidate the biological function of unknown proteins and unravel the cellular mechanisms at the molecular level. Phosphoproteomic and glycoproteomic studies have emerged as two efficient functional proteomics approaches used to identify diagnostic biomarkers, therapeutic targets, the molecular basis of disease and mechanisms underlying drug resistance in GI cancers. In this review, we present an overview on how functional proteomics may contribute to the understanding of GI cancers, namely colorectal, gastric, hepatocellular carcinoma and pancreatic cancers. Moreover, we have summarized recent methodological developments in phosphoproteomics and glycoproteomics for GI cancer studies.
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Affiliation(s)
- Morteza Abyadeh
- Cell Science Research Center, Department of Molecular Systems Biology, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 1665659911, Iran; (M.A.); (G.H.S.)
| | - Anna Meyfour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
- Cell Science Research Center, Department of Stem Cells and Developmental Biology, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 1665659911, Iran
- Correspondence: (A.M.); (M.M.)
| | - Vivek Gupta
- Department of Clinical Medicine, Macquarie University, Macquarie Park, NSW 2113, Australia;
| | | | - Matthew J. Fitzhenry
- Australian Proteome Analysis Facility, Macquarie University, Macquarie Park, NSW 2113, Australia;
| | - Shila Shahbazian
- Department of Molecular Sciences, Macquarie University, Macquarie Park, NSW 2113, Australia;
| | - Ghasem Hosseini Salekdeh
- Cell Science Research Center, Department of Molecular Systems Biology, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 1665659911, Iran; (M.A.); (G.H.S.)
- Department of Molecular Sciences, Macquarie University, Macquarie Park, NSW 2113, Australia;
| | - Mehdi Mirzaei
- Department of Clinical Medicine, Macquarie University, Macquarie Park, NSW 2113, Australia;
- Correspondence: (A.M.); (M.M.)
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Song H, Liu Y, Li X, Chen S, Xie R, Chen D, Gao H, Wang G, Cai B, Yang X. Long noncoding RNA CASC11 promotes hepatocarcinogenesis and HCC progression through EIF4A3-mediated E2F1 activation. Clin Transl Med 2020; 10:e220. [PMID: 33252856 PMCID: PMC7643871 DOI: 10.1002/ctm2.220] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 10/13/2020] [Accepted: 10/14/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Growing evidences have been revealing that long noncoding RNAs are vital factors in oncogenesis and tumor development. Among them, cancer susceptibility candidate 11 (CASC11) has displayed an impressively essential role in various kinds of cancers including hepatocellular carcinoma (HCC). Nevertheless, its role and potential mechanism in HCC still remain to be fully investigated. METHODS CASC11 expression level was evaluated by real-time polymerase chain reaction, western blotting, and in situ hybridization staining in HCC patients, and its prognostic effect was analyzed. The role of CASC11 in HCC tumorigenesis and progression was investigated by cell proliferation assay, transwell assay, extracellular acidification rate, western blotting, flow cytometry, and an in vivo xenograft model. The interactions among CASC11, E2F transcription factor 1 (E2F1), and eukaryotic translation initiation factor 4A3 (EIF4A3) were explored by using quantitative reverse transcriptase polymerase chain reaction, western blotting, RNA-binding protein immunoprecipitation assay, and chromatin immunoprecipitation assays. RESULTS Upregulation of CASC11 was confirmed in HCC tissues and associated with poor prognosis. Loss of function assays showed inhibition of CASC11 expression suppressed HCC cells proliferation, mobility, and glucose metabolism and promoted apoptosis. E2F1 expression significantly decreased after inhibition of CASC11. Rescue experiments illustrated that E2F1 overexpression alleviated the suppression of CASC11 inhibition on HCC progression in vitro and in vivo. Mechanistically, CASC11 recruited EIF4A3 to enhance the stability of E2F1 mRNA. CASC11 and E2F1 impacted the activation of the NF-κB signaling and PI3K/AKT/mTOR pathway and further regulated the expression PD-L1 that is an important target of immunotherapy. In addition, we identified YY1 could modulate CASC11 expression by binding to its promoter. CONCLUSIONS Our data revealed that CASC11 promoted the progression of HCC by means of EIF4A3-mediated E2F1 upregulation, indicating CASC11 is a promising diagnostic biomarker and therapeutic target for HCC.
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Affiliation(s)
- Hang Song
- School of Integrated Chinese and Western MedicineAnhui University of Chinese MedicineHefeiChina
| | - Yan Liu
- Department of Interventional RadiologyBeijing Chao‐yang Hospital Affiliated with Capital Medical UniversityBeijingChina
- The Key Laboratory of Bio‐Medical DiagnosticsSuzhou Institute of Biomedical Engineering and Technology, Chinese Academy of SciencesSuzhouChina
| | - Xinquan Li
- School of Integrated Chinese and Western MedicineAnhui University of Chinese MedicineHefeiChina
| | - Shuhua Chen
- Department of laboratory medicine, Yunfu People's HospitalSouthern Medical UniversityYunfuChina
| | - Rongzhang Xie
- Department of laboratory medicine, Yunfu People's HospitalSouthern Medical UniversityYunfuChina
| | - Dabao Chen
- School of Integrated Chinese and Western MedicineAnhui University of Chinese MedicineHefeiChina
| | - Huawu Gao
- School of Integrated Chinese and Western MedicineAnhui University of Chinese MedicineHefeiChina
| | - Guoquan Wang
- School of Integrated Chinese and Western MedicineAnhui University of Chinese MedicineHefeiChina
| | - Biao Cai
- School of Integrated Chinese and Western MedicineAnhui University of Chinese MedicineHefeiChina
- Anhui Academy of Chinese MedicineInstitute of Integrated Chinese and Western MedicineHefeiChina
- Anhui Province Key Laboratory of Chinese Medicinal FormulaAnhui University of Chinese MedicineHefeiChina
| | - Xiangyu Yang
- Department of Interventional RadiologyBeijing Chao‐yang Hospital Affiliated with Capital Medical UniversityBeijingChina
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Al-Naamani K, Al-Hashami Z, Al-Siyabi O, Al-Moundri M, Al-Bahrani B, Al-Sinani S, Al-Zakwani I, Omar H, Al-Busafi SA, Al-Zuhaibi H, AlMamari A, Kamath BR, Al-Kalbani A, Burney IA. Hepatocellular Carcinoma in Oman: An analysis of 284 cases. Sultan Qaboos Univ Med J 2020; 20:e316-e322. [PMID: 33110647 PMCID: PMC7574808 DOI: 10.18295/squmj.2020.20.03.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 01/21/2020] [Accepted: 02/19/2020] [Indexed: 12/16/2022] Open
Abstract
Objectives Hepatocellular carcinoma (HCC) is the most common type of primary liver tumour worldwide and is increasing in incidence. This study aimed to describe the clinical characteristics of HCC among Omani patients, along with its major risk factors, outcomes and the role of surveillance. Methods This retrospective case-series study was conducted between January 2008 and December 2015 at the three main tertiary care hospitals in Oman. All adult Omani patients diagnosed with HCC and visited these hospitals during the study period were included. Relevant data were collected from the patients’ electronic medical records. Results A total of 284 HCC patients were included in the analysis. The mean age was 61.02 ± 11.41 years and 67.6% were male. The majority had liver cirrhosis (79.9%), with the most common aetiologies being chronic hepatitis C (46.5%) and B (43.2%). Only 13.7% of cases were detected by the HCC surveillance programme. Approximately half of the patients (48.5%) had a single liver lesion and 31.9% had a liver tumour of >5 cm in size. Approximately half (49.2%) had alpha-fetoprotein levels of ≥200 ng/mL. The majority (72.5%) were diagnosed using multiphase computed tomography alone. Less than half of the patients (48.9%) were offered one or more HCC treatment modalities. Conclusion The majority of Omani HCC patients were male and had cirrhosis due to viral hepatitis. In addition, few patients were identified by the national surveillance programme and presented with advanced disease precluding therapeutic or even palliative treatment.
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Affiliation(s)
- Khalid Al-Naamani
- Department of Internal Medicine, Armed Forces Hospital, Muscat, Oman
| | - Zamzam Al-Hashami
- Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman
| | | | | | | | - Siham Al-Sinani
- Department of Child Health, Sultan Qaboos University Hospital, Muscat, Oman
| | - Ibrahim Al-Zakwani
- Departments of Pharmacology & Clinical Pharmacy, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Heba Omar
- Department of Endemic Medicine & Hepatology, Faculty of Medicine, Cairo University, Egypt
| | - Said A Al-Busafi
- Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman
| | - Haifa Al-Zuhaibi
- Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman
| | | | - Bola R Kamath
- Department of Internal Medicine, Armed Forces Hospital, Muscat, Oman
| | | | - Ikram Ali Burney
- Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman
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Loosen SH, Wirtz TH, Roy S, Vucur M, Castoldi M, Schneider AT, Koppe C, Ulmer TF, Roeth AA, Bednarsch J, Alizai PH, Paffenholz P, Demir M, Trautwein C, Tacke F, Neumann UP, Roderburg C, Luedde T. Circulating levels of microRNA193a-5p predict outcome in early stage hepatocellular carcinoma. PLoS One 2020; 15:e0239386. [PMID: 32960907 PMCID: PMC7508360 DOI: 10.1371/journal.pone.0239386] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 09/04/2020] [Indexed: 02/08/2023] Open
Abstract
While tumor resection and liver transplantation (LT) represent potentially curative therapeutic options for patients with early-stage hepatocellular carcinoma (HCC), the identification of the ideal surgical candidates has remained challenging. Just recently, miRNA-193a-5p was described as a tumor suppressor in murine and human HCC but only little is known about circulating miRNA-193a-5p in HCC patients. Here, we evaluated serum levels of miR-193a-5p by qPCR in 41 HCC patients undergoing tumor resection (n = 33) or LT (n = 8) and 20 controls. Circulating relative miR-193a-5p levels were significantly elevated in HCC patients compared to healthy controls. While relative miR-193a-5p levels were comparable between patients of different underlying disease etiology and tumor size, high relative miR-193a-5p levels were predictive for the patients' postoperative outcome, which was confirmed in uni- and multivariate Cox-regression analysis. As such, HCC patients with a preoperative relative miR-193a-5p level above the ideal cut-off value (3.57) had a median overall survival (OS) of only 451 days compared to 1158 days in patients with a relative miR-193a-5p level below this cut-off value. Our data support a novel function of miR-193a-5p as a biomarker in early-stage HCC patients that might help to identify the best surgical candidates in terms of postoperative outcome.
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Affiliation(s)
- Sven H. Loosen
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Theresa H. Wirtz
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Sanchari Roy
- Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen, Germany
| | - Mihael Vucur
- Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen, Germany
| | - Mirco Castoldi
- Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen, Germany
| | - Anne T. Schneider
- Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen, Germany
| | - Christiane Koppe
- Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen, Germany
| | - Tom F. Ulmer
- Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Anjali A. Roeth
- Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Jan Bednarsch
- Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Patrick H. Alizai
- Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Pia Paffenholz
- Department of Urology, University Hospital Cologne, Cologne, Germany
| | - Münevver Demir
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Ulf P. Neumann
- Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Christoph Roderburg
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Tom Luedde
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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Burenina OY, Lazarevich NL, Kustova IF, Shavochkina DA, Moroz EA, Kudashkin NE, Patyutko YI, Metelin AV, Kim EF, Skvortsov DA, Zatsepin TS, Rubtsova MP, Dontsova OA. Panel of potential lncRNA biomarkers can distinguish various types of liver malignant and benign tumors. J Cancer Res Clin Oncol 2020; 147:49-59. [PMID: 32918630 DOI: 10.1007/s00432-020-03378-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 09/01/2020] [Indexed: 02/06/2023]
Abstract
PURPOSE Liver cancers are among the deadliest malignancies due to a limited efficacy of early diagnostics, the lack of appropriate biomarkers and insufficient discrimination of different types of tumors by classic and molecular methods. In this study, we searched for novel long non-coding RNA (lncRNA) as well as validated several known candidates suitable as probable biomarkers for primary liver tumors of various etiology. METHODS We described a novel lncRNA HELIS (aka "HEalthy LIver Specific") and estimated its expression by RT-qPCR in 82 paired tissue samples from patients with hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), combined HCC-CCA, pediatric hepatoblastoma (HBL) and non-malignant hepatocellular adenoma (HCA) and focal nodular hyperplasia (FNH). Additionally, we examined expression of cancer-associated lncRNAs HULC, MALAT1, UCA1, CYTOR, LINC01093 and H19, which were previously studied mainly in HCC. RESULTS We demonstrated that down-regulation of HELIS strongly correlates with carcinogenesis; whereas in tumors with non-hepatocyte origin (HBL, CCA) or in a number of poorly differentiated HCC, this lncRNA is not expressed. We showed that recently discovered LINC01093 is dramatically down-regulated in all malignant liver cancers; while in benign tumors LINC01093 expression is just twice decreased in comparison to adjacent samples. CONCLUSION Our study revealed that among all measured biomarkers only down-regulated HELIS and LINC01093, up-regulated CYTOR and dysregulated HULC are perspective for differential diagnostics of liver cancers; whereas others demonstrated discordant results and cannot be considered as potential universal biomarkers for this purpose.
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Affiliation(s)
- Olga Y Burenina
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Skolkovo, Moscow, Russia, 143026.
| | - Natalia L Lazarevich
- Institute of Carcinogenesis, FSBI "N.N. Blokhin National Medical Research Center of Oncology" of the Ministry of Health of the Russian Federation, Moscow, Russia, 115478
- Biology Department, Lomonosov Moscow State University, Moscow, Russia, 119234
| | - Inna F Kustova
- Institute of Carcinogenesis, FSBI "N.N. Blokhin National Medical Research Center of Oncology" of the Ministry of Health of the Russian Federation, Moscow, Russia, 115478
| | - Daria A Shavochkina
- Institute of Carcinogenesis, FSBI "N.N. Blokhin National Medical Research Center of Oncology" of the Ministry of Health of the Russian Federation, Moscow, Russia, 115478
| | - Ekaterina A Moroz
- Institute of Clinical Oncology, FSBI "N.N. Blokhin National Medical Research Center of Oncology" of the Ministry of Health of the Russian Federation, Moscow, Russia, 115478
| | - Nikolay E Kudashkin
- Institute of Clinical Oncology, FSBI "N.N. Blokhin National Medical Research Center of Oncology" of the Ministry of Health of the Russian Federation, Moscow, Russia, 115478
| | - Yuriy I Patyutko
- Institute of Clinical Oncology, FSBI "N.N. Blokhin National Medical Research Center of Oncology" of the Ministry of Health of the Russian Federation, Moscow, Russia, 115478
| | - Alexey V Metelin
- Petrovsky National Research Centre of Surgery, Moscow, Russia, 119991
| | - Eduard F Kim
- Petrovsky National Research Centre of Surgery, Moscow, Russia, 119991
| | - Dmitry A Skvortsov
- Lomonosov Moscow State University, Chemistry Department and A.N. Belozersky Institute of Physico-Chemical Biology, Moscow, Russia, 119992
- Faculty of Biology and Biotechnologies, Higher School of Economics, Moscow, Russia, 101000
| | - Timofei S Zatsepin
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Skolkovo, Moscow, Russia, 143026
- Lomonosov Moscow State University, Chemistry Department and A.N. Belozersky Institute of Physico-Chemical Biology, Moscow, Russia, 119992
| | - Maria P Rubtsova
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Skolkovo, Moscow, Russia, 143026
- Lomonosov Moscow State University, Chemistry Department and A.N. Belozersky Institute of Physico-Chemical Biology, Moscow, Russia, 119992
| | - Olga A Dontsova
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Skolkovo, Moscow, Russia, 143026
- Lomonosov Moscow State University, Chemistry Department and A.N. Belozersky Institute of Physico-Chemical Biology, Moscow, Russia, 119992
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Gan-Qing-Ning Formula Inhibits the Growth of Hepatocellular Carcinoma by Promoting Apoptosis and Inhibiting Angiogenesis in H 22 Tumor-Bearing Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:6376912. [PMID: 32831873 PMCID: PMC7428871 DOI: 10.1155/2020/6376912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/24/2020] [Accepted: 07/23/2020] [Indexed: 11/17/2022]
Abstract
Objective Gang-Qing-Ning (GQN) is a traditional Chinese medicine formula that has been used in the treatment of hepatocellular carcinoma (HCC) in the folk population for decades. However, scientific validation is still necessary to lend credibility to the traditional use of GQN against HCC. This study investigates the antitumor effect of GQN on H22 tumor-bearing mice and its possible mechanism. Methods Fifty H22 tumor-bearing mice were randomly assigned to five groups. Three groups were treated with high, medium, and low dosages of GQN (27.68, 13.84, and 6.92 g/kg, respectively); the positive control group was treated with cytoxan (CTX) (20 mg/kg) and the model group was treated with normal saline. After 10 days' treatment, the tumor inhibitory rates were calculated. Pathological changes in tumor tissue were observed, and the key proteins and genes of the mitochondrial apoptosis pathway were measured, as well as the mRNA expression levels of VEGF in tumor tissue. Results The tumor inhibitory rates of high, medium, and low dosages of GQN groups were 47.39%, 38.26%, and 22.17%, respectively. The high dosage of the GQN group significantly increased the protein and mRNA expression levels of Bax, Cyt-C, and cleaved Caspase 3 (or Caspase 3) (P < 0.01) but decreased the expression levels of Bcl-2, VEGF, and microvessel density (MVD) (P < 0.01). Conclusions The high dosage of GQN can significantly inhibit the tumor growth in H22 tumor-bearing mice. It exerts the antitumor effect by enhancing proapoptotic factors and inhibiting the antiapoptotic factor of the mitochondrial apoptosis pathway and inhibiting tumor angiogenesis.
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Wang J, Pu J, Zhang Y, Yao T, Luo Z, Li W, Xu G, Liu J, Wei W, Deng Y. Exosome-transmitted long non-coding RNA SENP3-EIF4A1 suppresses the progression of hepatocellular carcinoma. Aging (Albany NY) 2020; 12:11550-11567. [PMID: 32602848 PMCID: PMC7343467 DOI: 10.18632/aging.103302] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 04/27/2020] [Indexed: 06/11/2023]
Abstract
Extracellular communication mediated by exosomes in a tumor microenvironment can substantially affect tumor progression. However, the effect of exosomal long non-coding RNA SENP3-EIF4A1 on hepatocellular carcinoma (HCC) is still unclear. In this study, SENP3-EIF4A1 expressions in patients with HCC and healthy controls were detected and compared. Results showed that SENP3-EIF4A1 was significantly reduced in HCC tissues and exosomes from the plasma of patients with HCC (P<0.05) and was primarily encapsulated by exosomes. The patients with HCC and the healthy controls could be distinguished using exosomal SENP3-EIF4A1 (AUC=0.8028). The transfer of exosomal SENP3-EIF4A1 secreted by normal cells to HCC cells stimulated apoptosis and weakened the invasion and migration abilities of HCC cells to suppress their malignant biological behavior (P<0.05). Additionally, exosomal SENP3-EIF4A1 was capable of inhibiting tumor growth in vivo and modulating the expression of ZFP36 by competitively binding to miR-9-5p. In conclusion, exosomal SENP3-EIF4A1 is a new favorable biomarker for clinically detecting HCC, and SENP3-EIF4A1 can be transmitted by exosomes from normal cells to HCC cells to inhibit the in vitro and in vivo development of HCC. Thus, exosomal SENP3-EIF4A1 is involved in the communication between normal cells and HCC cells during the onset of HCC.
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MESH Headings
- Animals
- Apoptosis
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Case-Control Studies
- Cell Line, Tumor
- Cell Proliferation
- Disease Progression
- Exosomes/metabolism
- Female
- Gene Expression Regulation, Neoplastic
- Healthy Volunteers
- Humans
- Liver/pathology
- Liver Neoplasms/blood
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Male
- Mice
- MicroRNAs/metabolism
- Middle Aged
- RNA, Long Noncoding/blood
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Tristetraprolin/genetics
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Jianchu Wang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
- Clinic Medicine Research Center of Hepatobiliary Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
| | - Jian Pu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
- Clinic Medicine Research Center of Hepatobiliary Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
| | - Ying Zhang
- Clinic Medicine Research Center of Hepatobiliary Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
- Library of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
| | - Tianwei Yao
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
- Clinic Medicine Research Center of Hepatobiliary Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
| | - Zongjiang Luo
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
- Clinic Medicine Research Center of Hepatobiliary Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
| | - Wenchuan Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
- Clinic Medicine Research Center of Hepatobiliary Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
| | - Guidan Xu
- Clinic Medicine Research Center of Hepatobiliary Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
- Department of Infectious Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
| | - Juan Liu
- Clinic Medicine Research Center of Hepatobiliary Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
| | - Wujun Wei
- Clinic Medicine Research Center of Hepatobiliary Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
- Department of Infectious Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
| | - Yibin Deng
- Clinic Medicine Research Center of Hepatobiliary Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
- Department of Infectious Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
- Centre for Medical Laboratory Science, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Zhuang Autonomous Region, Baise 533000, China
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Cheng X, Tian P, Zheng W, Yan X. Piplartine attenuates the proliferation of hepatocellular carcinoma cells via regulating hsa_circ_100338 expression. Cancer Med 2020; 9:4265-4273. [PMID: 32281302 PMCID: PMC7300402 DOI: 10.1002/cam4.3043] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 02/12/2020] [Accepted: 03/01/2020] [Indexed: 12/11/2022] Open
Abstract
Researches have pointed that piplartine inhibits the proliferation of hepatocellular carcinoma (HCC) cells, however, the underlying mechanisms has not been well defined. Currently, more and more studies have pointed out that circRNAs can regulate tumor cell proliferation, involve in the tumorigenesis mechanism of various tumors. In this study, we explored whether piplartine may participate in the development of HCC through the regulation of ability of HCC cell proliferation by circRNA. Based on the chip analysis, we selected candidate circRNAs that are highly correlated with HCC. CircRNA expression in OSCC cells treated with piplartine was detected by qRT-PCR. We found that only the expression of hsa_circ_100338 (circ-100338) was observably reduced. The expression characteristics of circ-100338 in HCC cell lines were also verified by qRT-PCR. Subsequently, whether or notcirc-100338 can regulate ZEB1 via competitively binding to miR-141-3p was determined by the RIP assay and dual luciferase reporter gene assay. The effect of the circ-100338/miR-141-3p/ZEB1 axis on the proliferation of HCC cell was tested by EdU and CCK-8 assay. Results showed that circ-100338 expression was observably increased in HCC cell lines. Simultaneously, circ-100338 can regulate the expression of ZEB1by competitively binding to miR-141-3p. Moreover high expression of circ-100338 can stimulate the proliferation of HCC cells. Our current study revealed that circ-100338 played as a ceRNA in promoting the progression of HCC by sponging miR-141-3p, while piplartine can participate in the development of HCC by inhibiting the expression of circ-100338.
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Affiliation(s)
- Xiaoli Cheng
- Department of PharmacyBao'an Maternal and Child Health HospitalJinan UniversityShenzhenChina
| | - Pan Tian
- Department of PharmacyBao'an Maternal and Child Health HospitalJinan UniversityShenzhenChina
| | - Wengzhong Zheng
- Department of AnesthesiologyBao'an Maternal and Child Health HospitalJinan UniversityShenzhenChina
| | - Xuetao Yan
- Department of AnesthesiologyBao'an Maternal and Child Health HospitalJinan UniversityShenzhenChina
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Zhang F, Zhu Y, Wu S, Hou G, Wu N, Qian L, Yang D. MLK3 is a newly identified microRNA-520b target that regulates liver cancer cell migration. PLoS One 2020; 15:e0230716. [PMID: 32214367 PMCID: PMC7098554 DOI: 10.1371/journal.pone.0230716] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 03/06/2020] [Indexed: 12/15/2022] Open
Abstract
The roles of microRNAs (miRNAs) in liver cancer have attracted much attention in recent years. In this study, we demonstrate that miR-520b is downregulated in MHCC-97H cells, a liver cancer cell line with high potential of metastasis, compared with MHCC-97L cells which has a low potential of metastasis. Furthermore, the enhanced expression of miR-520b could inhibit liver cancer cell migration, while silencing its expression resulted in increased migration. Mixed lineage kinase 3 (MLK3) was identified as a direct and functional new target of miR-520b. This regulation was also confirmed by luciferase reporter assays. In addition, our results showed that overexpression of the MLK3 expression partially reversed the effect of miR-520b on liver cancer cell migration, indicating that MLK3 contributes to the migration in liver cancer. The newly identified miR-520b/MLK3 axis partially elucidates the molecular mechanism of liver cancer cell migration and represents a new potential therapeutic target for liver cancer treatment.
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Affiliation(s)
- Fei Zhang
- Anhui Vocational College of Defense Technology, Lu'an, Anhui, China
| | - Yu Zhu
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Shuhua Wu
- Anhui Provincial Children's Hospital, Hefei, Anhui, China
| | - Guodong Hou
- Anhui Vocational College of Defense Technology, Lu'an, Anhui, China
| | - Nianxiang Wu
- Anhui Vocational College of Defense Technology, Lu'an, Anhui, China
| | - Lirun Qian
- Anhui Vocational College of Defense Technology, Lu'an, Anhui, China
| | - Dong Yang
- Department of Hepatobiliary Surgery, Zhuji People's Hospital of Zhejiang Province, Zhuji, Zhejiang, China
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Laroia ST, Yadav K, Rastogi A, Kumar G, Kumar S, Sarin SK. Diagnostic efficacy of dynamic liver imaging using qualitative diagnostic algorithm versus LI-RADS v2018 lexicon for atypical versus classical HCC lesions: A decade of experience from a tertiary liver institute. Eur J Radiol Open 2020; 7:100219. [PMID: 32083152 PMCID: PMC7016378 DOI: 10.1016/j.ejro.2020.100219] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 01/20/2020] [Accepted: 01/22/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE To analyze and evaluate the diagnostic performance of conventional diagnostic (qualitative) imaging features versus LI-RADSv2018 lexicon for indeterminate and atypical Hepatocellular carcinoma (HCC) on dynamic liver imaging with reference to histopathology. PATIENTS AND METHODS This retrospective study (June 2009-June 2019) evaluated the performance characteristics of conventional imaging findings, versus the Liver Imaging Reporting and Data System (LIRADS) v2018, for interpretation of indeterminate and atypical HCC, in patients who underwent subsequent histopathological analysis (gold standard). A total of 100,457 dynamic hepatobiliary CT and MR examinations were performed over ten years at our institute. Using current international imaging guidelines, 3218 patients were found to have suspected liver cancer lesions on imaging. Classical enhancement pattern of typical HCC was seen in 2916 of these patients. These patients did not require further biopsy. We enrolled, the remaining (n = 302) patients, who underwent biopsy, into our study group. Two radiologists, blinded to pathology findings, reviewed and classified these lesions, in consensus, according to LI-RADS® lexicon and as per 'conventional' (Indeterminate, Atypical HCC, Classical HCC, other malignancies) imaging. The histopathology diagnosis was considered as the final diagnosis. Alpha feto protein (AFP) levels amongst various subgroups were compared. Statistical analysis was performed to calculate the efficacy of LIRADS versus qualitative imaging parameters in comparison with histopathology. RESULTS A total of n = 302 patients, [89 % men (n = 269), mean age 57.08 ± 12.43 years] underwent biopsy for suspected liver lesions. Qualitative imaging had 92.3 % (CI 88.53-94.91) sensitivity, 41.4 % (CI 25.51-59.26) specificity, positive predictive value (PPV) of 93.7 % (CI 90.11-96.02), negative predictive value (NPV) of 36.4 % (CI 22.19-53.38), positive likelihood ratio (PLHR) of 1.575 (CI 1.40-1.77) and negative likelihood ratio of (NLHR) 0.19 (CI 0.13-0.26). It correctly classified 87.4 % of lesions diagnosed on pathology. In comparison, LI-RADS was found to have 92 % sensitivity, 55.5 % specificity, 97 % PPV, 30.3 %, NPV, PLHR 2.068 (CI 1.62-2.64), NLHR 0.15 (CI 0.11-0.18) and 89.7 % diagnostic accuracy. A total of 38 patients (17 false negative, 21 false positive lesions) had discordant diagnoses on imaging versus histopathology. The kappa agreement between LIRADs and qualitative Imaging was found to be 0.77 ± .07 (p < 0.001). LIRADS and qualitative imaging collectively had 97 % sensitivity, 30 % specificity, 91.9 % PPV, 55.6 % NPV, PLHR of 1.39 (CI 1.27-1.51) and NLHR of 0.09 (0.048-0.19) which was better than, either reporting system, independently. CONCLUSION It was observed that the LI-RADS v2018 lexicon with qualitative imaging as a combination technique added extra value in interpretation of atypical HCC or indeterminate lesions on dynamic CT and MRI compared to either as 'stand- alone' reporting systems.
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Affiliation(s)
- Shalini Thapar Laroia
- Department of Radiology, Institute of Liver and Biliary Sciences, Sector D-1, Vasant Kunj, New Delhi, 110070, India
| | - Komal Yadav
- Department of Radiology, Institute of Liver and Biliary Sciences, Sector D-1, Vasant Kunj, New Delhi, 110070, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver & Biliary Sciences, Sector D-1, Vasant Kunj, New Delhi, 110070, India
| | - Guresh Kumar
- Department of Research, Institute of Liver & Biliary Sciences, Sector D-1, Vasant Kunj, New Delhi, 110 070, India
| | - Senthil Kumar
- Department of HPB Surgery and Liver Transplantation, Institute of Liver & Biliary Sciences, Sector D-1, Vasant Kunj, New Delhi, 110 070, India
| | - Shiv Kumar Sarin
- Chair of Department of Hepatology, Institute of Liver & Biliary Sciences, Sector D-1, Vasant Kunj, New Delhi, 110070, India
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Sridhar S, Sharma I, Sankpal UT, Ghabach B, Narra K, Neerukonda L, Basha R. Targeted Molecular Therapeutic Options for Hepatocellular Carcinoma. Crit Rev Oncog 2020; 25:47-55. [PMID: 32865910 PMCID: PMC11079775 DOI: 10.1615/critrevoncog.2020034985] [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] [Indexed: 11/13/2022]
Abstract
Liver cancer is the 6th leading cause of cancer related deaths in the US even though it ranks 14th in incidence. More men are diagnosed with liver cancer than women, and the number of projected deaths among men (20,020) is almost double that among women (10,140) in the US. Infections like hepatitis and metabolic conditions like obesity are believed to be major risk factors for the onset of liver cancer. Hepatocellular carcinoma (HCC), the most common type of liver cancer, accounts for 75% of all cases. Chemotherapy has not been effective in treating HCC. Targeted therapies are being used in advanced HCC patients due to a better survival and less side effects when compared to traditional chemotherapy. Therapeutic agents targeting the regulators of growth factor signaling pathways and the mediators of downstream signaling-for example, inhibitors of the tyrosine kinase receptor-are used as targeted molecular therapies. Kinase inhibitors that modulate growth signals, such as sorafenib and lenvatinib, are commonly employed in targeted molecular therapy for HCC patients. This review covers these agents, highlighting modes of action and providing details on clinical trials.
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Affiliation(s)
- Swathi Sridhar
- Texas College of Osteopathic Medicine, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas
| | - Ishna Sharma
- Texas College of Osteopathic Medicine, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas
| | - Umesh T. Sankpal
- Texas College of Osteopathic Medicine, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas
| | | | | | | | - Riyaz Basha
- Texas College of Osteopathic Medicine, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas
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Koo BW, Lim DJ, Oh AY, Na HS. Retrospective Comparison between the Effects of Propofol and Inhalation Anesthetics on Postoperative Recurrence of Early- and Intermediate-Stage Hepatocellular Carcinoma. Med Princ Pract 2020; 29:422-428. [PMID: 32074612 PMCID: PMC7511682 DOI: 10.1159/000506637] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 02/17/2020] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Previous studies have reported that propofol has antitumor, anti-inflammatory, and antioxidant effects in addition to its anesthetic properties. To confirm this, a retrospective investigation was conducted to determine whether different anesthetic agents, particularly propofol and inhalation anesthetics, have an effect on the recurrence of hepatocellular carcinoma (HCC) in patients who were diagnosed with primary HCC and underwent laparoscopic hepatectomy. SUBJECTS AND METHODS Patients with Barcelona Clinic Liver Cancer stages 0, A, and B HCC, who underwent laparoscopic hepatic resection, were enrolled in this study. Post-operative HCC recurrence, which was determined from postoperative liver CT, was evaluated 24 months postoperatively with respect to the main anesthetic agents. The characteristics of HCC and other patient-related or surgery-related variables were evaluated together. RESULTS AND CONCLUSION During the 24-month period after hepatic resection, less HCC patients in the propofol group than in the inhalation group recurred (p = 0.046). The mean time to recurrence was 20.8 months (95% CI, 19.7-22.0) and 19.1 months (95% CI, 17.8-20.4) in the propofol group and the inhalation group, respectively. In addition, multivariable Cox proportional regression analysis revealed that the propofol group showed significantly decreased recurrence versus the inhalation group (hazard ratio, 0.57; 95% CI, 0.47-0.69; p = 0.029). When propofol was used as the main general anesthetic agent for laparoscopic hepatic resection, the postoperative 2-year recurrence rate decreased in early- and intermediate-stage HCC.
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Affiliation(s)
- Bon-Wook Koo
- Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Dae-Jin Lim
- Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Ah-Young Oh
- Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Hyo-Seok Na
- Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea,
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Yu H, Han R, Su J, Chen H, Li D. Multi-marker diagnosis method for early Hepatocellular Carcinoma based on surface plasmon resonance. Clin Chim Acta 2019; 502:9-14. [PMID: 31837298 DOI: 10.1016/j.cca.2019.12.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 11/21/2019] [Accepted: 12/08/2019] [Indexed: 12/30/2022]
Abstract
Early diagnosis of Hepatocellular Carcinoma (HCC) is an important means to raise the survival rate of patients. Multi-marker combined detection is a powerful tool of early HCC diagnosis. Traditional detection methods are not effective and accurate because it is difficult to achieve combined detection of multiple markers. In this paper, we selected Alpha Fetoprotein (AFP) and miRNA-125b as the combined detection markers to improve the simultaneously diagnostic sensitivity and specificity. The anti-AFP monoclonal antibody and the DNA probes paired with the miRNA-125b were modified on the surface of surface plasmon resonance (SPR) sensor respectively to specifically recognize AFP and miRNA-125b in serum. In order to enhance the SPR response signal and detection sensitivity, Double Antibody Sandwich Method (DASM) and S9.6 antibody enhanced method were applied to achieve low detection limit of the two markers. Experimental results showed that AFP (25-400 ng/mL) was accurately detected by DASM and the detection limit of miRNA-125b by S9.6 antibody enhanced method reached 123.044 pM. These results verified the feasibility of the multi-marker detection method in early diagnosis of HCC.
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Affiliation(s)
- Haixia Yu
- Tianjin Key Laboratory of Biomedical Detecting Techniques and Instruments, Tianjin University, 300072, China
| | - Ruixue Han
- Tianjin Key Laboratory of Biomedical Detecting Techniques and Instruments, Tianjin University, 300072, China
| | - Jie Su
- State Key Laboratory of Precision Measuring Technology and Instruments, Tianjin University, 300072, China
| | - Hailong Chen
- State Key Laboratory of Precision Measuring Technology and Instruments, Tianjin University, 300072, China
| | - Dachao Li
- State Key Laboratory of Precision Measuring Technology and Instruments, Tianjin University, 300072, China.
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The Pre- and Postoperative FIB-4 Indexes Are Good Predictors to the Outcomes of HBV-Related HCC Patients after Resection. Gastroenterol Res Pract 2019; 2019:8945798. [PMID: 31885547 PMCID: PMC6914978 DOI: 10.1155/2019/8945798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 09/24/2019] [Indexed: 12/21/2022] Open
Abstract
Background and Aim Liver fibrosis is associated with the prognosis of patients with hepatocellular carcinoma (HCC) after resection. The fibrosis-4 (FIB-4) index is an accurate and noninvasive marker to determine the degree of liver fibrosis. Here, we evaluated the effect of pre- and postoperative FIB-4 index in predicting the outcomes after resection of HCC in patients who have chronic hepatitis B (CHB) infection. Methods A total of 534 CHB patients with HCC who received curative hepatectomy between 2001 and 2016 at Kaohsiung Chang Gung Memorial Hospital, Taiwan, were enrolled in this study. The impact of the FIB-4 index (preoperative and the 1st year after operation) on overall survival (OS) and recurrence-free survival (RFS) was evaluated. Results There was a significant association between the preoperative FIB-4 index and Metavir fibrosis stage (p < 0.01). The multivariate analysis showed that preoperative FIB‐4 > 2 is an independent risk factor for RFS and OS after HCC curative resection [hazard ratio (HR), 1.902; 95% CI, 1.491–2.460; p < 0.001, and HR, 2.207; 95% CI, 1.420–3.429; p < 0.001, respectively]. Notably, preoperative FIB-4 is also an independent risk factor for RFS (HR, 1.219; p = 0.035) in noncirrhotic patients. Furthermore, patients had deteriorated FIB-4 1 year after operation [definition: the value (the 1st year FIB‐4 after operation minus preoperative FIB‐4) > 1] and had an adverse outcome in RFS and OS (p < 0.001, both). Conclusion The pre and postoperative FIB-4 indexes are useful clinical markers to predict the prognosis in HBV-HCC patients after curative hepatectomy.
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El-Hamouly MS, Azzam AA, Ghanem SE, El-Bassal FI, Shebl N, Shehata AMF. Circulating microRNA-301 as a promising diagnostic biomarker of hepatitis C virus-related hepatocellular carcinoma. Mol Biol Rep 2019; 46:5759-5765. [PMID: 31471732 DOI: 10.1007/s11033-019-05009-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 07/30/2019] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is a serious consequence of persistent hepatitis C virus (HCV) infection and represents one of the most aggressive neoplasms globally. The implication of microRNA-301 (miR-301) in the initiation and progression of different types of cancers has been proved. We aimed to assess circulating microRNA-301 as possible biomarker for the early detection of HCC in patients with chronic HCV infection. miR-301 expression levels were estimated in plasma samples of 42 patients with newly diagnosed HCV-related HCC, 48 chronically HCV infected patients with liver cirrhosis and 40 healthy individuals by reverse transcription-quantitative polymerase chain reaction technique. In comparison with chronically HCV infected patients and healthy controls, miR-301 expression levels were significantly increased in HCC patients (P < 0.001). miR-301 levels distinguished HCC patients from chronic HCV patients, with area under the receiver-operating characteristic curve of 0.89 (95% CI 0.82-0.96), the sensitivity and the specificity were 78.57% and 89.58% respectively. Moreover, miR-301 levels were significantly linked with tumor size (P = 0.014), serum levels of alpha-fetoprotein (AFP) (P = 0.028) and Barcelona Clinic Liver Cancer (BCLC) score (P = 0.003). These results reveal that miR-301 can serve as a promising non-invasive biomarker for diagnosis of HCC in chronically HCV infected patients.
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Affiliation(s)
- Moamena S El-Hamouly
- Tropical Medicine Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, 32511, Egypt.
| | - Ayman A Azzam
- Clinical Biochemistry and Molecular Diagnostics, National Liver Institute, Shebin El-Kom, Menoufia, Egypt
| | - Samar E Ghanem
- Clinical Biochemistry and Molecular Diagnostics, National Liver Institute, Shebin El-Kom, Menoufia, Egypt
| | - Fathia I El-Bassal
- Clinical Pathology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Nashwa Shebl
- Hepatology Department, National Liver Institute, Shebin El-Kom, Menoufia, Egypt
| | - Amira M F Shehata
- Clinical Pathology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, Egypt
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Downregulation of LncRNA GAS5 promotes liver cancer proliferation and drug resistance by decreasing PTEN expression. Mol Genet Genomics 2019; 295:251-260. [PMID: 31705194 DOI: 10.1007/s00438-019-01620-5] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 10/29/2019] [Indexed: 12/31/2022]
Abstract
Accumulating evidence has shown that the long noncoding RNAs (lncRNAs) play a crucial role in the regulation of hepatocellular carcinoma (HCC) progression and drug resistance. In this study, we aimed to investigate the biological function roles of lncRNAs growth arrest-specific 5 (GAS5) and its underlying molecular mechanism in the development of HCC. qRT-PCR was used to detect GAS5, miR-21, and PTEN levels. MTT, cell counting assays, and xenograft mouse model were applied to measure cell proliferation rate in vitro and in vivo. The luciferase reporter assay and RNA immune-precipitation assay were introduced to evaluate the relationship between GAS5 and miR-21. We found that GAS5 was downregulated in HCC cell lines and tumor tissues. Knockdown of GAS5 enhanced HCC cell proliferation in vitro and in vivo and increased HCC cell resistance to doxorubicin. GAS5 acted as a sponge for miR-21 silencing and consequently led to the elevation of PTEN expression. Our data demonstrated that GAS5 functioned as a tumor suppressor role in HCC through regulation of miR-21-PTEN singling pathways, suggesting a potential application of GAS5 in HCC therapy.
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