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Hsieh MC, Ratnapradipa KL, Rozek L, Wen S, Chiu YW, Peters ES. Temporal trends and patterns for early- and late-onset adult liver cancer incidence vary by race/ethnicity, subsite, and histologic type in the United States from 2000 to 2019. Cancer Causes Control 2025; 36:551-560. [PMID: 39786651 PMCID: PMC11982089 DOI: 10.1007/s10552-024-01955-4] [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: 08/17/2024] [Accepted: 12/20/2024] [Indexed: 01/12/2025]
Abstract
PURPOSE To examine incidence trends and patterns for early- and late-onset liver cancer. METHODS Liver and intrahepatic bile duct (IBD) cancers diagnosed between 2000 and 2019 were acquired from 22 SEER registries. Variables included early-onset (20-49) vs. late-onset (50+), anatomic subsite, histologic type (hepatocellular carcinoma [HCC] and IBD cholangiocarcinoma [ICC]), sex, and race/ethnicity. Age-standardized incidence rates were calculated using SEER*Stat. Jointpoint regression analysis was employed to estimate the annual percent change (APC) and the average APC (AAPC) with pairwise comparisons for trend by sex and by race/ethnicity stratified by age and subsite. RESULTS Liver cancer incidence decreased among early-onset (AAPC [95% CI] - 2.39 [- 2.74, - 2.07]) but increased among late-onset patients (2.85 [2.71, 3.01]), primarily driven by HCC (3.60 [3.50, 3.71]). IBD incidence increased for both ages with ICC incidence annually increasing 7.92% (6.84, 9.26) for early-onset and 6.32% (5.46, 8.86) for late-onset patients. Early-onset liver cancer displayed comparable trends across racial/ethnic groups; however, late-onset liver cancer showed more variation, particularly among American Indian/Alaska Native/Asian Pacific Islander (AI/AN/API) populations, which experienced a significant decrease in incidence, thereby narrowing the gap with other racial/ethnic groups. For IBD, an identical pattern of early-onset IBD among non-Hispanic Blacks (NHBs) compared to Hispanics was showed with coincidence test p = 0.1522, and a parallel pattern was observed among late-onset patients for both sexes (p = 0.5087). CONCLUSION Late-onset HCC continues to rise, except for NHB and AI/AN/API, where incidence rates have started to decrease over the past 4-5 years. Early and late-onset ICC incidence continues to increase across all racial/ethnic groups.
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Affiliation(s)
- Mei-Chin Hsieh
- Epidemiology and Population Health Program, School of Public Health, Louisiana State University Health Sciences Center, 2020 Gravier St., 3Rd Floor, , New Orleans, LA, 70112, USA.
- Louisiana Tumor Registry, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA.
| | - Kendra L Ratnapradipa
- Epidemiology Department, College of Public Health, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Laura Rozek
- Oncology Academic Department, Georgetown University Medical Center, Washington, DC, 20057, USA
- Cancer Prevention and Control Program for Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA
| | - Shengdi Wen
- Epidemiology and Population Health Program, School of Public Health, Louisiana State University Health Sciences Center, 2020 Gravier St., 3Rd Floor, , New Orleans, LA, 70112, USA
| | - Yu-Wen Chiu
- Epidemiology and Population Health Program, School of Public Health, Louisiana State University Health Sciences Center, 2020 Gravier St., 3Rd Floor, , New Orleans, LA, 70112, USA
| | - Edward S Peters
- Epidemiology Department, College of Public Health, University of Nebraska Medical Center, Omaha, NE, 68198, USA
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Zhang Z, Zhao T, Meng W, Chen J, He C, Sun X, Huang H. DNA methylation-driven genes in hepatocellular carcinoma patients: insights into immune infiltration and prognostic implications. Front Med (Lausanne) 2025; 12:1520380. [PMID: 40357287 PMCID: PMC12066630 DOI: 10.3389/fmed.2025.1520380] [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: 10/31/2024] [Accepted: 04/09/2025] [Indexed: 05/15/2025] Open
Abstract
Background Hepatocellular carcinoma (HCC) poses a significant global burden as a highly prevalent and life-threatening malignant tumor that endangers human life and wellbeing. The purpose of this study was to examine how DNA methylation-driven genes impact the prognosis of HCC patients. Methods Differentially expressed genes from The Cancer Genome Atlas, GSE76427, GSE25097 and GSE14520 datasets were collected to perform differential expression analysis between HCC patients and controls. Weighted gene coexpression network analysis (WGCNA) was subsequently performed to create coexpression modules for the DEGs. Then, ssGSEA was employed to investigate the infiltration of immune cells in HCC. Enrichment analysis and methylation were carried out for the module genes. We utilized Kaplan-Meier survival analysis to assess patient prognosis. Results Eight coexpression modules were identified via WGCNA for 1927 upregulated and 1,231 downregulated DEGs, after which the hub genes of the modules were identified. Module 5 had high immune infiltration, and the hub gene SCAMP3 was positively associated with Tcm. Module 3 exhibited a low level of immune infiltration, and the expression of the hub gene HCLS1 was negatively correlated with T cells and dendritic cells. Furthermore, we obtained five hub genes (BOP1, BUB1B, NOTCH3, SCAMP3, and SNRPD2) as methylation-driven genes. BOP1 and BUB1B were found to be correlated with unfavorable overall survival in patients with HCC. Conclusion HCLS1 and SCAMP3 are associated with immunity, whereas BOP1 and BUB1B are modified by methylation and may serve as prognostic markers for HCC.
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Affiliation(s)
- Zhi Zhang
- Department of Hepatobiliary Surger, Guangxi Medical University Affliated Wuming Hospital, Nanning, China
| | - Tongling Zhao
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed by the Province and Ministry, Guangxi Medical University, Nanning, China
| | - Weida Meng
- Department of Hepatobiliary Surger, Guangxi Medical University Affliated Wuming Hospital, Nanning, China
| | - Jiahao Chen
- Department of Hepatobiliary Surger, Guangxi Medical University Affliated Wuming Hospital, Nanning, China
| | - Chengyi He
- Department of Hepatobiliary Surger, Guangxi Medical University Affliated Wuming Hospital, Nanning, China
| | - Xing Sun
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Hai Huang
- Department of Hepatobiliary Surger, Guangxi Medical University Affliated Wuming Hospital, Nanning, China
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Davis E, Ermi AG, Sarkar D. Astrocyte Elevated Gene-1/Metadherin (AEG-1/MTDH): A Promising Molecular Marker and Therapeutic Target for Hepatocellular Carcinoma. Cancers (Basel) 2025; 17:1375. [PMID: 40282551 PMCID: PMC12025727 DOI: 10.3390/cancers17081375] [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: 03/10/2025] [Revised: 04/16/2025] [Accepted: 04/17/2025] [Indexed: 04/29/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. The 5-year survival rate has been estimated to be less than 20% while its incidence rates have more than tripled since the 1980s. Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) has been demonstrated to have an influential role in HCC progression and the development of an aggressive phenotype. AEG-1 has been shown to be upregulated in many cancers, including HCC. Studies have shown that it plays a crucial role in the proliferation, invasion and metastasis, and evasion of apoptosis in HCC. Its relationship with proteins and pathways, such as MYC, SND1, PI3K/AKT, and other signaling pathways demonstrates its pertinent role in oncogenic development and relevance as a biomarker and therapeutic target. Recent studies have shown that AEG-1 is present in tumor tissues, and the anti-AEG-1 antibody is detected in the blood of cancer patients, demonstrating its viability as a diagnostic/prognostic marker. This review paper shines light on recent findings regarding the molecular implications of AEG-1, with emphasis on its role of regulating metabolic dysfunction-associated steatohepatitis (MASH), a key predisposing factor for HCC, new treatment strategies targeting AEG-1, and challenges associated with analyzing this intriguing molecule.
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Affiliation(s)
- Eva Davis
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Ali Gawi Ermi
- Department of Cellular, Molecular and Genetic Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Devanand Sarkar
- Department of Cellular, Molecular and Genetic Medicine, Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
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Sogbe M, Aliseda D, Sangro P, de la Torre-Aláez M, Sangro B, Argemi J. Prognostic value of circulating tumor DNA in different cancer types detected by ultra-low-pass whole-genome sequencing: a systematic review and patient-level survival data meta-analysis. Carcinogenesis 2025; 46:bgae073. [PMID: 39549302 PMCID: PMC11886806 DOI: 10.1093/carcin/bgae073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 10/23/2024] [Accepted: 11/14/2024] [Indexed: 11/18/2024] Open
Abstract
Ultra-low-pass whole-genome sequencing (ULP-WGS) (≤0.5 × coverage) of plasma cell-free DNA (cfDNA) has emerged as a low-cost, promising tool to assess the circulating tumor DNA (ctDNA) fraction. This meta-analysis aims to summarize the current findings and comprehensively investigate the prognostic value of baseline ctDNA detected by ULP-WGS in solid tumors. A systematic review was carried out by searching PubMed/MEDLINE and Scopus databases to identify eligible studies conducted between January 2014 and January 2024. Inclusion criteria comprised studies with reported overall survival and progression-free survival outcomes across therapy-naïve patients with different solid tumors. All patients underwent baseline ULP-WGS of plasma cfDNA and were categorized as ctDNA positive (tumor fraction ≥10%) or negative (tumor fraction <10%). A one-stage meta-analysis was performed using patient-level survival data reconstructed from published articles. A Cox proportional hazards model with shared frailty was used to assess the difference in survival between arms. A total of six studies, comprising 620 patients (367 negative ctDNA and 253 positive ctDNA), were included in the overall survival analysis, while five studies, involving 349 patients (212 negative ctDNA and 137 positive ctDNA), were included in the progression-free survival analysis. The meta-analysis showed that patients with baseline positive ctDNA had a significantly higher risk of death (HR = 2.60, 95% CI: 2.01-3.36) and disease progression (HR = 2.28, 95% CI: 1.71-3.05) compared to those with negative ctDNA. The presence of a positive ctDNA at baseline is associated with increased risk of death and progression in patients with same-stage cancer.
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Affiliation(s)
- Miguel Sogbe
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra, Av Pio XII 36, 31008, Pamplona, Spain
| | - Daniel Aliseda
- HPB and Liver Transplant Unit, Department of General Surgery and HPB Oncology Area, Clinica Universidad de Navarra, Av Pio XII 36, 31008, Pamplona, Spain
| | - Paloma Sangro
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra, Calle Marquesado de Santa Marta 1, 28027, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Av Monforte de Lemos 3-5, 28029, Madrid, Spain
| | - Manuel de la Torre-Aláez
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra, Calle Marquesado de Santa Marta 1, 28027, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Av Monforte de Lemos 3-5, 28029, Madrid, Spain
| | - Bruno Sangro
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra, Av Pio XII 36, 31008, Pamplona, Spain
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra, Calle Marquesado de Santa Marta 1, 28027, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Av Monforte de Lemos 3-5, 28029, Madrid, Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, 31008, Pamplona, Spain
| | - Josepmaria Argemi
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra, Av Pio XII 36, 31008, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Av Monforte de Lemos 3-5, 28029, Madrid, Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, 31008, Pamplona, Spain
- Center for Applied Medical Research (CIMA), RNA and DNA Medicine Program, University of Navarra, Av Pio XII 55, 31008, Pamplona, Spain
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Mollazadeh S, Saeedi N, Al-Asady AM, Ghorbani E, Khazaei M, Ryzhikov M, Avan A, Hassanian SM. Exploring Hepatocellular Carcinoma Pathogenesis: The Influence of Genetic Polymorphisms. Curr Pharm Des 2025; 31:432-442. [PMID: 39297458 DOI: 10.2174/0113816128327773240827062719] [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: 05/25/2024] [Accepted: 07/23/2024] [Indexed: 02/20/2025]
Abstract
Hepatocellular carcinoma (HCC) is influenced by several factors, among which genetic polymorphisms play a key role. Polymorphisms in various genes affect key pathways involved in HCC development, including metabolism, expression of inflammatory cytokines, cell proliferation, and apoptosis regulation. These polymorphisms induce differential effects on susceptibility to HCC, disease progression, and treatment outcomes. Understanding the effect of genetic variations on HCC pathogenesis is essential to elucidate underlying mechanisms and identify potential therapeutic targets. This review explores the diverse roles of genetic polymorphisms in HCC, providing insights into the complex interplay between genetic factors and disease development.
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Affiliation(s)
- Samaneh Mollazadeh
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Nikoo Saeedi
- Student Research Committee, Islamic Azad University, Mashhad Branch, Mashhad, Iran
| | | | - Elnaz Ghorbani
- Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mikhail Ryzhikov
- School of Medicine, Saint Louis University, Saint Louis, MO 63103, USA
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Human Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Zerrad C, Lkhider M, Bouqdayr M, Belkouchi A, Badre W, Tahiri M, Pineau P, Benjelloun S, Ezzikouri S. NOD1 and NOD2 genetic variants: Impact on hepatocellular carcinoma susceptibility and progression in Moroccan population. Gene 2024; 931:148847. [PMID: 39147112 DOI: 10.1016/j.gene.2024.148847] [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: 06/05/2024] [Revised: 07/25/2024] [Accepted: 08/12/2024] [Indexed: 08/17/2024]
Abstract
BACKGROUND Nucleotide-binding oligomerization domain 1 (NOD1) and NOD2 are involved in carcinogenic processes by recognizing bacterial cell wall components and triggering inflammation. This study explored the association between genetic variations in NOD1 and NOD2 and susceptibility to hepatocellular carcinoma (HCC) and its progression in a Moroccan population. METHODS Genotyping of NOD1 rs2075820 (C>T) and NOD2 rs718226 (A>G) was performed using the TaqMan allelic discrimination assay in 467 Moroccan individuals. The cohort included 156 patients with hepatocellular carcinoma (HCC), 155 patients with liver cirrhosis (LC) diagnosed with HBV, HCV, or MASLD, and 156 controls. RESULTS The NOD1 rs2075820 variant showed no association with HCC susceptibility or progression, which is consistent with in silico predictions. However, the NOD2 rs718226 G allele and GG genotype were more common in the HCC group compared to the cirrhosis and control groups. Individuals with the homozygous G variant had a 2-fold higher risk for HCC (ORad = 2.12; CI=1.01-4.44; Pad = 0.04). Those with the GG genotype also had an increased risk of HCC (GG vs. AG+AA ORad = 2.28; CI=1.15-4.54; Pad = 0.016). Furthermore, GG genotype carriers had a significantly higher risk of HCC progression (ORad = 2.58; CI=1.26-5.31; Pad = 0.031). Individuals with the rs718226 minor allele had a significantly elevated risk of progressing from LC to HCC (ORad = 1.50; CI=1.07-2.09; Pad = 0.016). Stratification analysis indicated that men had a higher risk of HCC progression compared to women (ORad = 4.63; CI=1.53-14.00 vs. ORad = 2.73; CI=1.05-7.09). CONCLUSION The NOD1 rs2075820 polymorphism does not appear to be a genetic risk factor for susceptibility to HCC. In contrast, the non-coding NOD2 rs718226 variant significantly increases HCC susceptibility and promotes liver cancer progression in the Moroccan population. Further studies involving larger cohorts are warranted to definitively confirm or refute the effects of NOD1 and NOD2 genetic variants on liver cancer susceptibility and progression.
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Affiliation(s)
- Chaimaa Zerrad
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco; Laboratoire de Virologie, Oncologie, Biosciences, Environnement et Énergies Nouvelles, Hassan II, Casablanca Faculté des Sciences et Techniques, Mohammedia, Morocco
| | - Mustapha Lkhider
- Laboratoire de Virologie, Oncologie, Biosciences, Environnement et Énergies Nouvelles, Hassan II, Casablanca Faculté des Sciences et Techniques, Mohammedia, Morocco
| | - Meryem Bouqdayr
- Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | | | - Wafaa Badre
- Service d'Hépato-Gastro-Entérologie, CHU Ibn Rochd, Casablanca, Morocco
| | - Mohamed Tahiri
- Service d'Hépato-Gastro-Entérologie, CHU Ibn Rochd, Casablanca, Morocco; Faculté de Médecine et de Pharmacie, Université Hassan II, Casablanca, Morocco
| | - Pascal Pineau
- Unité "Organisation Nucléaire et Oncogenèse", INSERM U993, Institut Pasteur, Paris, France
| | - Soumaya Benjelloun
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Sayeh Ezzikouri
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco.
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Shodry S, Hasan YTN, Ahdi IR, Ulhaq ZS. Gene targets with therapeutic potential in hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:4543-4547. [PMID: 39678796 PMCID: PMC11577361 DOI: 10.4251/wjgo.v16.i12.4543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/03/2024] [Accepted: 08/13/2024] [Indexed: 11/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Major treatments include liver transplantation, resection, and chemotherapy, but the 5-year recurrence rate remains high. Late diagnosis often prevents surgical intervention, contributing to poor patient survival rates. Carcinogenesis in HCC involves genetic alterations that drive the transformation of normal cells into malignant ones. Enhancer of zeste homolog 2 (EZH2), a key regulator of cell cycle progression, is frequently upregulated in HCC and is associated with advanced stages and poor prognosis, making it a potential biomarker. Additionally, signal transducer and activator of transcription 3, which binds to EZH2, affects disease staging and outcomes. Targeting EZH2 presents a promising therapeutic strategy. On the other hand, abnormal lipid metabolism is a hallmark of HCC and impacts prognosis. Fatty acid binding protein 5 is highly expressed in HCC tissues and correlates with key oncogenes, suggesting its potential as a biomarker. Other genes such as guanine monophosphate synthase, cell division cycle associated 5, and epidermal growth factor receptor provide insights into the molecular mechanisms of HCC, offering potential as biomarkers and therapeutic targets.
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Affiliation(s)
- Syifaus Shodry
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Yuliono Trika Nur Hasan
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Iwal Reza Ahdi
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Zulvikar Syambani Ulhaq
- Research Center for Preclinical and Clinical Medicine, National Research and Innovation Agency Republic of Indonesia, Cibinong 16911, Indonesia
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Meng L, Jiang Z, Shen G, Lin S, Gao F, Guo X, Lv B, Hu S, Ni Z, Chen S, Ji Y. Genetic alterations are related to clinicopathological features and risk of recurrence/metastasis of hepatocellular carcinoma. Eur J Cancer Prev 2024:00008469-990000000-00191. [PMID: 39642087 DOI: 10.1097/cej.0000000000000939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/08/2024]
Abstract
Lack of efficient biomarkers and clinical translation of molecular typing impedes the implementation of targeted therapy for hepatocellular carcinoma (HCC). High-throughput sequencing techniques represented by next-generation sequencing (NGS) are tools for detecting targetable genes. The objective of this study is to explore the genetic alterations associated with clinicopathological features and the risk of recurrence/metastasis in HCC. NGS analysis was conducted on formalin-fixed paraffin-embedded tissues from 164 resected liver samples obtained from Chinese patients. Morphologic subtypes were reviewed based on hematoxylin-eosin and immunohistochemistry staining, Correlation to the acquired molecular features were analyzed with clinicopathological information. We also retrieved follow-up information of the 123 transplanted cases from 2017 to 2019 to screen recurrence/metastasis-associated factors by univariate analysis. Generally, the most frequently mutated genes include TP53 and CTNNB1 which showed a trend of mutually exclusive mutation. Copy-number variant with the highest frequency was detected in TAF1 and CCND1 in 11q13.3 loci. Correlation analysis showed that various genetic alterations were associated with morphologic subtypes and other pathologic features. While gene signatures of proliferation/nonproliferation class were correlated with differentiation, satellite foci and other invasive morphological features. Macrotrabecular-massive subtype, TSC2 (tuberous sclerosis complex 2) mutation, Ki-67 expression, and other six factors were found to be associated with recurrence/metastasis after liver transplantation. Genetic alterations detected by NGS show correlation with not only pathological and clinical features, but also with recurrence/metastasis after liver transplantation. Further gene-level molecular typing will be practical for targeted therapy and individual recurrence risk assessment in HCC patients.
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Affiliation(s)
- Lili Meng
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai
| | - Zhenjian Jiang
- Department of Pathology, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen, China
| | - Guangyue Shen
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai
| | - Shulan Lin
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai
- Department of Pathology, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen, China
| | - Feng Gao
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai
| | - Xinxin Guo
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai
| | - Bin Lv
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai
| | - Shuying Hu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai
| | - Zheng Ni
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai
| | - Shanghua Chen
- Department of Pathology, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai
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Hung JH, Teng CF, Hung HC, Chen YL, Chen PJ, Ho CL, Chuang CH, Huang W. Genomic instabilities in hepatocellular carcinoma: biomarkers and application in immunotherapies. Ann Hepatol 2024; 29:101546. [PMID: 39147130 DOI: 10.1016/j.aohep.2024.101546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 05/16/2024] [Accepted: 06/18/2024] [Indexed: 08/17/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers. For patients with advanced HCC, liver function decompensation often occurs, which leads to poor tolerance to chemotherapies and other aggressive treatments. Therefore, it remains critical to develop effective therapeutic strategies for HCC. Etiological factors for HCC are complex and multifaceted, including hepatitis virus infection, alcohol, drug abuse, chronic metabolic abnormalities, and others. Thus, HCC has been categorized as a "genomically unstable" cancer due to the typical manifestation of chromosome breakage and aneuploidy, and oxidative DNA damage. In recent years, immunotherapy has provided a new option for cancer treatments, and the degree of genomic instability positively correlates with immunotherapy efficacies. This article reviews the endogenous and exogenous causes that affect the genomic stability of liver cells; it also updates the current biomarkers and their detection methods for genomic instabilities and relevant applications in cancer immunotherapies. Including genomic instability biomarkers in consideration of cancer treatment options shall increase the patients' well-being.
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Affiliation(s)
- Jui-Hsiang Hung
- Department of Biotechnology, Chia Nan University of Pharmacy & Science, Tainan, Taiwan
| | - Chiao-Feng Teng
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan; Program for Cancer Biology and Drug Development, China Medical University, Taichung, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
| | - Hsu-Chin Hung
- Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Lin Chen
- Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Pin-Jun Chen
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chung-Liang Ho
- Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan; Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Cheng-Hsiang Chuang
- Department of Life Science, College of Life Sciences and Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Wenya Huang
- Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan; Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center of Infectious Diseases and Signal Transduction, National Cheng Kung University, Tainan, Taiwan..
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Xiao Z, Yang F, Liu Z, Chen X, Ma S, Li H. An overview of risk assessment and monitoring of malignant transformation in cirrhotic nodules. Therap Adv Gastroenterol 2024; 17:17562848241293019. [PMID: 39493259 PMCID: PMC11528798 DOI: 10.1177/17562848241293019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 10/04/2024] [Indexed: 11/05/2024] Open
Abstract
Cirrhotic liver nodules can progress to hepatocellular carcinoma (HCC) through a multi-step carcinogenesis model, with dysplastic nodules being particularly high risk. Currently, monitoring the progression of non-HCC cirrhotic nodules is primarily through dynamic observation, but there is a lack of sensitive, efficient, and convenient methods. Dynamic monitoring and risk evaluation of malignant transformation are essential for timely treatment and improved patient survival rates. Routine liver biopsies are impractical for monitoring, and imaging techniques like ultrasound, computed tomography, and magnetic resonance imaging are not suitable for all patients or for accurately assessing subcentimeter nodules. Identifying serum biomarkers with high sensitivity, specificity, and stability, and developing a multi-index evaluation model, may provide a more convenient and efficient approach to monitoring pathological changes in cirrhotic nodules.
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Affiliation(s)
- Zhun Xiao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Fangming Yang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Zheng Liu
- Department of Combination of Traditional Chinese Medicine and Western Medicine, Medical College, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Xinju Chen
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Suping Ma
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, No. 19 Renmin Road, Zhengzhou 450000, China
| | - Heng Li
- Yong Loo Lin School of Medicine, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore
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11
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Jung YH, Lee YJ, Dao T, Jung KH, Yu J, Oh AR, Jeong Y, Gi H, Kim YU, Ryu D, Carrer M, Pajvani UB, Lee SB, Hong SS, Kim K. KCTD17-mediated Ras stabilization promotes hepatocellular carcinoma progression. Clin Mol Hepatol 2024; 30:895-913. [PMID: 39098817 PMCID: PMC11540369 DOI: 10.3350/cmh.2024.0364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/31/2024] [Accepted: 08/01/2024] [Indexed: 08/06/2024] Open
Abstract
BACKGROUND/AIMS Potassium channel tetramerization domain containing 17 (KCTD17) protein, an adaptor for the cullin3 (Cul3) ubiquitin ligase complex, has been implicated in various human diseases; however, its role in hepatocellular carcinoma (HCC) remains elusive. Here, we aimed to elucidate the clinical features of KCTD17, and investigate the mechanisms by which KCTD17 affects HCC progression. METHODS We analyzed transcriptomic data from patients with HCC. Hepatocyte-specific KCTD17 deficient mice were treated with diethylnitrosamine (DEN) to assess its effect on HCC progression. Additionally, we tested KCTD17-directed antisense oligonucleotides for their therapeutic potential in vivo. RESULTS Our investigation revealed the upregulation of KCTD17 expression in both tumors from patients with HCC and mouse models of HCC, in comparison to non-tumor controls. We identified the leucine zipper-like transcriptional regulator 1 (Lztr1) protein, a previously identified Ras destabilizer, as a substrate for KCTD17-Cul3 complex. KCTD17-mediated Lztr1 degradation led to Ras stabilization, resulting in increased proliferation, migration, and wound healing in liver cancer cells. Hepatocyte-specific KCTD17 deficient mice or liver cancer xenograft models were less susceptible to carcinogenesis or tumor growth. Similarly, treatment with KCTD17-directed antisense oligonucleotides (ASO) in a mouse model of HCC markedly lowered tumor volume as well as Ras protein levels, compared to those in control ASO-treated mice. CONCLUSION KCTD17 induces the stabilization of Ras and downstream signaling pathways and HCC progression and may represent a novel therapeutic target for HCC.
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Affiliation(s)
- Young Hoon Jung
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Yun Ji Lee
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Tam Dao
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Kyung Hee Jung
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Junjie Yu
- Department of Medicine, Columbia University, New York, NY, USA
- Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, China
| | - Ah-Reum Oh
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Yelin Jeong
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - HyunJoon Gi
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Young Un Kim
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Dongryeol Ryu
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | | | | | - Sang Bae Lee
- Division of Life Sciences, Jeonbuk National University, Jeonju, Korea
| | - Soon-Sun Hong
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - KyeongJin Kim
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
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12
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Kim SJ, Jung CW, Anh NH, Yoon YC, Long NP, Hong SS, Cho EJ, Kwon SW. Metabolic phenotyping combined with transcriptomics metadata fortifies the diagnosis of early-stage Hepatocellular carcinoma. J Adv Res 2024:S2090-1232(24)00391-6. [PMID: 39243943 DOI: 10.1016/j.jare.2024.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 07/31/2024] [Accepted: 09/03/2024] [Indexed: 09/09/2024] Open
Abstract
INTRODUCTION The low sensitivity of alpha-fetoprotein (AFP) renders it unsuitable as a stand-alone marker for early hepatocellular carcinoma (eHCC) surveillance. Therefore, additional blood-based biomarkers with enhanced sensitivities are required. OBJECTIVES In light of the metabolic changes that are distinctive to eHCC development, the current study presents a panel of serum metabolites that may serve as noninvasive diagnostic indicators for patients with eHCC. METHODS Serum samples obtained from normal control (NC), cirrhosis, and eHCC patients were analyzed by four different metabolomic platforms. A meta-analysis of very early-stage HCC transcriptomic datasets retrieved from public sources supports the integrated interpretation with metabolic changes. RESULTS A total of 94 metabolites were significantly correlated with a progressive disease status. Integrated analysis of the significant metabolites and differentially expressed genes from meta-analysis emphasized metabolic pathways including bile acid biosynthesis, phenylalanine and tyrosine metabolism, and butanoate metabolism. The 11 metabolites associated with these pathways were compiled into a metabolite panel for use as diagnostic signatures. With an accuracy of 81.8%, compared with 45.4% for a model trained solely on AFP, the model enhanced its ability to differentiate between the three groups by incorporating a metabolite panel and AFP. Upon examining the trained models using receiver operating characteristic curves, the AFP and metabolite panel combined model exhibited greater area under the curve values in comparisons between NC and eHCC (1.000 versus 0.810) and cirrhosis and eHCC (0.926 versus 0.556). The result was consistent in an independent validation cohort. CONCLUSION This study emphasizes the role of circulating metabolite markers in the diagnosis of eHCC.
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Affiliation(s)
- Sun Jo Kim
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Cheol Woon Jung
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Nguyen Hoang Anh
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Young Cheol Yoon
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Nguyen Phuoc Long
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 47392, Republic of Korea
| | - Soon-Sun Hong
- Department of Biomedical Science, College of Medicine, and Program in Biomedical Sciences and Engineering, Inha University, Incheon 22332, Republic of Korea
| | - Eun Ju Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Sung Won Kwon
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Plant Genomics and Breeding Institute, Seoul National University, Seoul 08826, Republic of Korea.
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13
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Jiang L, Meng Q, Liu L, Li W. A Comprehensive Review on Molecular Mechanisms, Treatments, and Brief Role of Natural Products in Hepatocellular Cancer. Nat Prod Commun 2024; 19. [DOI: 10.1177/1934578x241284873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Most initial liver cancers are hepatocellular carcinomas (HCC), which make up the vast majority of cases. Hepatitis B or C virus infection as well as alcohol consumption is among the key risk factors. The significance of the most intriguing soluble factors as indicators for early diagnosis and as suggested targets for therapy in light of the increasing challenges in precision medicine. The development of HCC is influenced by a complex combination between pro-inflammatory and anti-inflammatory cytokines and their signalling cascades. Recently,researchers are aims to assess the potential of a number of distinct molecular cascade/cascade including cytokines to function as key players with particular underlying etiologies. Increasing our knowledge of the signaling network that links retro differentiation and inflammationmay help us find novel therapeutic targets and develop combined therapies or treatments that work against tumors with a significant degree of heterogeneity. With nursing processes at its center, comprehensive nursing care is a new nursing paradigm that combines the benefits of primary and group nursin g as well as a perfect synthesis of many nursing metrics like nursing philosophy, nursing plan, and nursing quality evaluation. In order to treat patients with serious liver diseases like cancer, it can conduct nursing interventions item by item in accordance with the unique disease conditions of each patient and combine efficient therapeutic approaches with high-quality nursing modes. Dietary natural products, including fruits, vegetables, and spices, may prevent and treat liver cancer by inhibiting tumor growth, protecting the liver, and enhancing chemotherapy.
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Affiliation(s)
- Linlin Jiang
- Interventional Radiology, Harbin Medical University Cancer Hospital, Harbin Heilongjiang, China
| | - Qin Meng
- Department of Nursing, Huaian Hospital of Huaian City, Huaian Jiangsu,China
| | - Lixiu Liu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin Heilongjiang, China
| | - Weihang Li
- Interventional Radiology, Harbin Medical University Cancer Hospital, Harbin Heilongjiang, China
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14
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Moghimi A, Bani Hosseinian N, Mahdipour M, Ahmadpour E, Miranda‐Bedate A, Ghorbian S. Deciphering the Molecular Complexity of Hepatocellular Carcinoma: Unveiling Novel Biomarkers and Therapeutic Targets Through Advanced Bioinformatics Analysis. Cancer Rep (Hoboken) 2024; 7:e2152. [PMID: 39118438 PMCID: PMC11310554 DOI: 10.1002/cnr2.2152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/20/2024] [Accepted: 07/19/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) represents a primary liver tumor characterized by a bleak prognosis and elevated mortality rates, yet its precise molecular mechanisms have not been fully elucidated. This study uses advanced bioinformatics techniques to discern differentially expressed genes (DEGs) implicated in the pathogenesis of HCC. The primary objective is to discover novel biomarkers and potential therapeutic targets that can contribute to the advancement of HCC research. METHODS The bioinformatics analysis in this study primarily utilized the Gene Expression Omnibus (GEO) database as data source. Initially, the Transcriptome analysis console (TAC) screened for DEGs. Subsequently, we constructed a protein-protein interaction (PPI) network of the proteins associated to the identified DEGs with the STRING database. We obtained our hub genes using Cytoscape and confirmed the results through the GEPIA database. Furthermore, we assessed the prognostic significance of the identified hub genes using the GEPIA database. To explore the regulatory interactions, a miRNA-gene interaction network was also constructed, incorporating information from the miRDB database. For predicting the impact of gene overexpression on drug effects, we utilized CANCER DP. RESULTS A comprehensive analysis of HCC gene expression profiles revealed a total of 4716 DEGs, consisting of 2430 upregulated genes and 2313 downregulated genes in HCC sample compared to healthy control group. These DEGs exhibited significant enrichment in key pathways such as the PI3K-Akt signaling pathway, nuclear receptors meta-pathway, and various metabolism-related pathways. Further exploration of the PPI network unveiled the P53 signaling pathway and pyrimidine metabolism as the most prominent pathways. We identified 10 hub genes (ASPM, RRM2, CCNB1, KIF14, MKI67, SHCBP1, CENPF, ANLN, HMMR, and EZH2) that exhibited significant upregulation in HCC samples compared to healthy control group. Survival analysis indicated that elevated expression levels of these genes were strongly associated with changes in overall survival in HCC patients. Lastly, we identified specific miRNAs that were found to influence the expression of these genes, providing valuable insights into potential regulatory mechanisms underlying HCC progression. CONCLUSION The findings of this study have successfully identified pivotal genes and pathways implicated in the pathogenesis of HCC. These novel discoveries have the potential to significantly enhance our understanding of HCC at the molecular level, opening new ways for the development of targeted therapies and improved prognosis evaluation.
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Affiliation(s)
- Ata Moghimi
- Immunology Research Center, Tabriz University of Medical SciencesTabrizIran
| | | | - Mahdi Mahdipour
- Stem Cell Research Center, Tabriz University of Medical SciencesTabrizIran
- Department of Applied Cell Sciences, Faculty of Advanced Medical SciencesTabriz University of Medical SciencesTabrizIran
| | - Ehsan Ahmadpour
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical SciencesTabrizIran
| | | | - Saeid Ghorbian
- Department of Molecular GeneticsAhar Branch, Islamic Azad UniversityAharIran
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15
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Ucdal M, Burus A, Celtikci B. Cross talk between genetics and biochemistry in the pathogenesis of hepatocellular carcinoma. HEPATOLOGY FORUM 2024; 5:150-160. [PMID: 39006147 PMCID: PMC11237245 DOI: 10.14744/hf.2023.2023.0028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 09/21/2023] [Accepted: 11/15/2023] [Indexed: 07/16/2024]
Abstract
The liver is a crucial organ in the regulation of metabolism, signaling, and homeostasis. Using recent advanced sequencing technologies, several mutations of genes in major metabolic and signaling pathways have been discovered in the pathogenesis of hepatocellular carcinoma (HCC). These gene signatures alter expression and ultimately affect biochemical pathways by modifying enzyme/protein levels, resulting in numerous clinical outcomes related to HCC. It comes with varying forms of genetic and biochemical alterations, associated with carbohydrate, lipid, nucleic acid, and amino acid metabolism, as well as signaling pathways linked to tumorigenesis. Here, we aim to summarize the main components and mechanisms involved in the progression of HCC with a special focus on the metabolic regulation of key effectors of tumorigenesis, through the crosstalk between genetics and biochemistry. This paper provides an overview of hepatocellular carcinoma, underlying the fundamental effect of gene variations on metabolic and signaling pathways. Since there is still an unmet need for biomarkers and novel therapeutic targets, some of these signature genes or proteins can be used as novel biomarkers for diagnosis, prognosis, and novel potential therapeutic targets for the treatment of HCC.
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Affiliation(s)
- Mete Ucdal
- Department of Internal Medicine, Hacettepe University School of Medicine, Ankara, Turkiye
| | - Ayse Burus
- Department of Medical Biochemistry, Hacettepe University, School of Medicine, Ankara, Turkiye
| | - Basak Celtikci
- Department of Medical Biochemistry, Hacettepe University, School of Medicine, Ankara, Turkiye
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16
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Hao L, Li S, Chen G, Nie A, Zeng L, Xiao Z, Hu X. Study on the mechanism of quercetin in Sini Decoction Plus Ginseng Soup to inhibit liver cancer and HBV virus replication through CDK1. Chem Biol Drug Des 2024; 103:e14567. [PMID: 38858165 DOI: 10.1111/cbdd.14567] [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: 11/29/2023] [Revised: 03/18/2024] [Accepted: 06/03/2024] [Indexed: 06/12/2024]
Abstract
BACKGROUND To explore the anti-tumor and anti-virus key active ingredients of Sini Decoction Plus Ginseng Soup (SNRS) and their mechanisms. METHODS The main ingredients of SNRS were analyzed by network pharmacology, and quercetin was identified as the key active ingredient. Then, we obtained the targets of quercetin by using Drugbank, PharmMapper, and SwissTargetPrediction databases. Then, the targets of HBV-related hepatocellular carcinoma (HBV-related HCC) were obtained by using Genecards database. In addition, using the gene expression profiles of HBV-related HCC patients in GEO database and the genes with the greatest survival difference in GEPIA 2 database identified the potential targets of quercetin. In addition, the mechanism of potential genes was studied through GO, KEGG analysis, and PPI network. Using AUC and survival analysis to evaluate the diagnostic and prognostic value of cyclin-dependent kinase 1 (CDK1) and CCNB1. Finally, the effects of quercetin on proliferation of Hep3B and HepG2215 cells and the level of CDK1 and CCNB1 were verified in vitro. ELISA was used to measure the expression levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) after the intervention by quercetin for 24 h and 48 h in HepG2215 cell. RESULTS The first 10 key ingredients of SNRS were identified, and quercetin was the most key ingredient. The 101 potential quercetin targets were identified for the treatment of HBV-related HCC. GO and KEGG showed that 101 potential target enrichment in cancer and cell cycle regulation. By Venn analysis, CDK1 and CCNB1 were intersection targets, which could be used as potential targets for the action of quercetin on HBV-related HCC. Moreover, the expression of CDK1 and CCNB1 was highly expressed in the high-risk group, while the OS rate was low. The 1-year, 3-year and 5-year area under the curve (AUC) curves of CDK1 and CCNB1 were 0.724, 0.676, 0.622 and 0.745, 0.678, 0.634, respectively. Moreover, experimental results also showed that quercetin inhibited cell proliferation and reduced CDK1 expression in Hep3B and HepG2215 cells. The expressions of HBsAg and HBeAg in HepG2215 cell supernatant and cell gradually decreased with the increase of intervention time of quercetin and CDK1 inhibitor. CONCLUSIONS Quercetin is a key ingredient of anti-HBV-related HCC activity and inhibits HBV replication in SNRS by inhibiting CDK1.
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Affiliation(s)
- Liyuan Hao
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
| | - Shenghao Li
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
- Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei, P.R. China
| | - Guo Chen
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
| | - Aiyu Nie
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
| | - Liang Zeng
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
| | - Zhonghui Xiao
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
| | - Xiaoyu Hu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
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Marka S, Zografaki ME, Tsolomiti G, Kalliampakou KI, Tsolomitis A, Koumantou C, Smirlis D, Vassilaki N, Kintzios S. 2-(4-Nitrophenyl)isothiazol-3(2H)-one: A Promising Selective Agent against Hepatocellular Carcinoma Cells. Pharmaceuticals (Basel) 2024; 17:673. [PMID: 38931341 PMCID: PMC11206498 DOI: 10.3390/ph17060673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 05/10/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
Liver cancer ranks among the most prevalent malignancies globally and stands as a leading cause of cancer-related mortality. Numerous isothiazolone derivatives and analogues have been synthesized and investigated for their potential as anticancer agents; however, limited data exist regarding their efficacy against liver cancer. In the present study, two nitrophenyl-isothiazolones, the 5-benzoyl-2-(4-nitrophenyl)isothiazol-3(2H)-one (IsoA) and the 2-(4-nitrophenyl)isothiazol-3(2H)-one (IsoB), were preliminarily investigated for their cytotoxicity against hepatoma human (Huh7) cells as a liver cancer model and Immortalized Human Hepatocytes (IHHs) as a model of non-cancerous hepatocytes. IsoB, derived from IsoA after removal of the benzoyl moiety, demonstrated the highest cytotoxic effect against Huh7 cells with CC50 values of 19.3 μΜ at 24 h, 16.4 μΜ at 48 h, and 16.2 μΜ at 72 h of incubation, respectively. IsoB also exhibited selective toxicity against the liver cancerous Huh7 cells compared to IHH cells, reinforcing its role as a potent and selective anticancer agent. Remarkably, the cytotoxicity of IsoB was higher when compared with the standard chemotherapeutical agent 5-fluorouracil (5-FU), which also failed to exhibit higher toxicity against the liver cancerous cell lines. Moreover, IsoB-treated Huh7 cells presented a noteworthy reduction in mitochondrial membrane potential (ΔΨm) after 48 and 72 h, while mitochondrial superoxide levels showed an increase after 24 h of incubation. The molecular mechanism of the IsoB cytotoxic effect was also investigated using RT-qPCR, revealing an apoptosis-mediated cell death along with tumor suppressor TP53 overexpression and key-oncogene MYCN downregulation.
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Affiliation(s)
- Sofia Marka
- Laboratory of Cell Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece; (G.T.); (C.K.)
| | - Maria-Eleftheria Zografaki
- Laboratory of Molecular Biology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece; (M.-E.Z.); (K.I.K.)
| | - Georgia Tsolomiti
- Laboratory of Cell Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece; (G.T.); (C.K.)
| | - Katerina I. Kalliampakou
- Laboratory of Molecular Biology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece; (M.-E.Z.); (K.I.K.)
- Laboratory of Molecular Virology, Hellenic Pasteur Institute, 11521 Athens, Greece;
| | - Athanasios Tsolomitis
- School of Chemical Engineering, National Technical University, 15772 Athens, Greece;
| | - Christina Koumantou
- Laboratory of Cell Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece; (G.T.); (C.K.)
| | - Despina Smirlis
- Molecular Parasitology Laboratory, Microbiology Department, Hellenic Pasteur Institute, 11521 Athens, Greece;
| | - Niki Vassilaki
- Laboratory of Molecular Virology, Hellenic Pasteur Institute, 11521 Athens, Greece;
| | - Spyros Kintzios
- Laboratory of Cell Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece; (G.T.); (C.K.)
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18
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Sogbe M, Bilbao I, Marchese FP, Zazpe J, De Vito A, Pozuelo M, D’Avola D, Iñarrairaegui M, Berasain C, Arechederra M, Argemi J, Sangro B. Prognostic value of ultra-low-pass whole-genome sequencing of circulating tumor DNA in hepatocellular carcinoma under systemic treatment. Clin Mol Hepatol 2024; 30:177-190. [PMID: 38163441 PMCID: PMC11016491 DOI: 10.3350/cmh.2023.0426] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/14/2023] [Accepted: 12/27/2023] [Indexed: 01/03/2024] Open
Abstract
BACKGROUND/AIMS New prognostic markers are needed to identify patients with hepatocellular carcinoma (HCC) who carry a worse prognosis. Ultra-low-pass whole-genome sequencing (ULP-WGS) (≤0.5× coverage) of cell-free DNA (cfDNA) has emerged as a low-cost promising tool to assess both circulating tumor DNA (ctDNA) fraction and large structural genomic alterations. Here, we studied the performance of ULP-WGS of plasma cfDNA to infer prognosis in patients with HCC. METHODS Plasma samples were obtained from patients with HCC prior to surgery, locoregional or systemic therapy, and were analyzed by ULP-WGS of cfDNA to an average genome-wide fold coverage of 0.3x. ctDNA and copy number alterations (CNA) were estimated using the software package ichorCNA. RESULTS Samples were obtained from 73 HCC patients at different BCLC stages (BCLC 0/A: n=37, 50.7%; BCLC B/C: n=36, 49.3%). ctDNA was detected in 18 out of 31 patients who received systemic treatment. Patients with detectable ctDNA showed significantly worse overall survival (median, 13.96 months vs not reached). ctDNA remained an independent predictor of prognosis after adjustment by clinical-pathologic features and type of systemic treatment (hazard ratio 7.69; 95%, CI 2.09-28.27). Among ctDNA-positive patients under systemic treatments, the loss of large genomic regions in 5q and 16q arms was associated with worse prognosis after multivariate analysis. CONCLUSION ULP-WGS of cfDNA provides clinically relevant information about the tumor biology. The presence of ctDNA and the loss of 5q and 16q arms in ctDNA-positive patients are independent predictors of worse prognosis in patients with advanced HCC receiving systemic therapy.
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Affiliation(s)
- Miguel Sogbe
- Clinica Universidad de Navarra, Liver Unit, Pamplona, Spain
| | - Idoia Bilbao
- Clinica Universidad de Navarra, Liver Unit, Pamplona, Spain
| | - Francesco P. Marchese
- University of Navarra, Center for Applied Medical Research (CIMA), Computational Biology and Translational Genomics Program, Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Jon Zazpe
- University of Navarra, Center for Applied Medical Research (CIMA), Computational Biology and Translational Genomics Program, Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Annarosaria De Vito
- University of Navarra, Center for Applied Medical Research (CIMA), Computational Biology and Translational Genomics Program, Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Marta Pozuelo
- University of Navarra, Center for Applied Medical Research (CIMA), Computational Biology and Translational Genomics Program, Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Delia D’Avola
- Clinica Universidad de Navarra, Internal Medicine Department, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, Spain
| | - Mercedes Iñarrairaegui
- Clinica Universidad de Navarra, Liver Unit, Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, Spain
| | - Carmen Berasain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, Spain
- University of Navarra, Center for Applied Medical Research (CIMA), Hepatology Laboratory, Solid Tumors Program, Pamplona, Spain
| | - Maria Arechederra
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, Spain
- University of Navarra, Center for Applied Medical Research (CIMA), Hepatology Laboratory, Solid Tumors Program, Pamplona, Spain
| | - Josepmaria Argemi
- Clinica Universidad de Navarra, Liver Unit, Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, Spain
- University of Navarra, Center for Applied Medical Research (CIMA), Hepatology Laboratory, Solid Tumors Program, Pamplona, Spain
| | - Bruno Sangro
- Clinica Universidad de Navarra, Liver Unit, Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
- Clinica Universidad de Navarra, Liver Unit, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, Spain
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Ferreira B, Heredia A, Serpa J. An integrative view on glucagon function and putative role in the progression of pancreatic neuroendocrine tumours (pNETs) and hepatocellular carcinomas (HCC). Mol Cell Endocrinol 2023; 578:112063. [PMID: 37678603 DOI: 10.1016/j.mce.2023.112063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/16/2023] [Accepted: 09/02/2023] [Indexed: 09/09/2023]
Abstract
Cancer metabolism research area evolved greatly, however, is still unknown the impact of systemic metabolism control and diet on cancer. It makes sense that systemic regulators of metabolism can act directly on cancer cells and activate signalling, prompting metabolic remodelling needed to sustain cancer cell survival, tumour growth and disease progression. In the present review, we describe the main glucagon functions in the control of glycaemia and of metabolic pathways overall. Furthermore, an integrative view on how glucagon and related signalling pathways can contribute for pancreatic neuroendocrine tumours (pNETs) and hepatocellular carcinomas (HCC) progression, since pancreas and liver are the major organs exposed to higher levels of glucagon, pancreas as a producer and liver as a scavenger. The main objective is to bring to discussion some glucagon-dependent mechanisms by presenting an integrative view on microenvironmental and systemic aspects in pNETs and HCC biology.
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Affiliation(s)
- Bárbara Ferreira
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Campo Dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal; Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023, Lisboa, Portugal
| | - Adrián Heredia
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Campo Dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal; Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023, Lisboa, Portugal; Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz MB, 1649-028, Lisboa, Portugal
| | - Jacinta Serpa
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Campo Dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal; Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023, Lisboa, Portugal.
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20
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Abdelsattar S, Fahim SA, Kamel HFM, Al-Amodi H, Kasemy ZA, Khalil FO, Abdallah MS, Bedair HM, Gadallah ANAA, Sabry A, Sakr MA, Selim M, Gayed EMAE. The Potential Role of Circulating Long Miscellaneous RNAs in the Diagnosis and Prognosis of Hepatitis C Related Hepatocellular Carcinoma. Noncoding RNA 2023; 9:62. [PMID: 37888208 PMCID: PMC10609931 DOI: 10.3390/ncrna9050062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 10/04/2023] [Accepted: 10/08/2023] [Indexed: 10/28/2023] Open
Abstract
Ribonucleic acids (RNAs) are important regulators of gene expression and crucial for the progression of hepatocellular carcinoma (HCC). This study was designed to determine the diagnostic and prognostic utility of the circulating long miscellaneous RNAs; LINC01419, AK021443, and AF070632 in HCV-related HCC patients. Real-time PCR was used to measure their relative expression levels in the plasma of 194 HCV patients, 120 HCV-related HCC patients and 120 healthy controls. LINC01419 and AK021443 expression levels had significantly increasing linear trend estimates while AF070632 was dramatically downregulated in HCC compared to HCV. Interestingly, LINC01419 and AK021443 served as more significant diagnostic biomarkers for HCC than AF070632 and AFP. Multivariate analysis with cox regression revealed that the high expression of AK021443 [HR = 10.06, CI95%: 3.36-30.07], the high expression of LINC01419 [HR 4.13, CI95%: 1.32-12.86], and the low expression of AF070632 [HR = 2.70, CI95%: 1.07-6.81] were significant potential prognostic factors for HCC. Besides, the Kaplan-Meier analysis showed that HCC patients with high LIN01419 and AK021443 and low AF070632 expression levels had shorter OS. The circulating LINC01419 and AK021443 can be used as noninvasive potential biomarkers for diagnosis and prognosis of HCV-related HCC patients than AF070632 providing new targets for limiting the progression of the disease.
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Affiliation(s)
- Shimaa Abdelsattar
- Clinical Biochemistry and Molecular Diagnostics Department, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Sally A. Fahim
- Biochemistry Department, School of Pharmacy, Newgiza University (NGU), Cairo 94114, Egypt;
| | - Hala F. M. Kamel
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt;
- Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia;
| | - Hiba Al-Amodi
- Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia;
| | - Zeinab A. Kasemy
- Department of Public Health and Community Medicine, Faculty of Medicine, Menoufia University, Shebin El-Kom 32511, Egypt;
| | - Fatma O. Khalil
- Clinical Microbiology and Immunology Department, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt;
| | - Mahmoud S. Abdallah
- Clinical Pharmacy Department, Faculty of Pharmacy, University of Sadat City (USC), Sadat City 32897, Egypt;
| | - Hanan M. Bedair
- Clinical Pathology Department, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt;
| | | | - Aliaa Sabry
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt;
| | - Mohamed A. Sakr
- Medical Microbiology and Immunology Department, Faculty of Medicine, Suez University, Suez 43512, Egypt;
| | - Mahmoud Selim
- Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta 31111, Egypt;
| | - Eman M. Abd El Gayed
- Medical Biochemistry and Molecular Biology, Faculty of Medicine, Menoufia University, Shebin El-Kom 32511, Egypt;
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21
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Wang G, Qiao Y, Zhao Y, Song Y, Li M, Jin M, Yang D, Yin J, Li J, Liu W. Beauvericin exerts an anti-tumor effect on hepatocellular carcinoma by inducing PI3K/AKT-mediated apoptosis. Arch Biochem Biophys 2023; 745:109720. [PMID: 37611353 DOI: 10.1016/j.abb.2023.109720] [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: 05/27/2023] [Revised: 08/15/2023] [Accepted: 08/19/2023] [Indexed: 08/25/2023]
Abstract
Beauvericin is a world-spread mycotoxin isolated from the traditional Chinese medicine, Bombyx batryticatus (BB), which has been widely used to treat various neoplastic diseases. This study investigated the anti-hepatocellular carcinoma (HCC) activity of beauvericin and its potential mechanism. In this study, H22-bearing mice were intraperitoneally injected with 3, 5, 7 mg/kg of beauvericin once per-week over a three-week period. TUNEL staining determined the extent of tumor apoptosis induced by beauvericin. ELISA kits detected the level of IL-2, Perforin, and TNF-α, IFN-γ level in the serum. H22 hepatoma cells were exposed to beauvericin (5, 10, and 20 μmol/L) to investigate the underlying pathway. CCK-8 assay was used to observe the influence of beauvericin on the growth of H22 cells. Flow cytometry was used to detect the cell apoptosis and ROS level. Western blotting was performed to detect apoptotic and PI3K/AKT pathway protein production. The results showed that beauvericin could remarkably inhibit the growth of HCC in mice, combined with elevated TNF-α and IL-2. In vitro, beauvericin significantly promoted the generation of ROS, up-regulated Bax/Bcl-2 ratio and cleaved caspase-9, cleaved caspase-3 levels, down-regulated p-PI3K/PI3K ratio, p-AKT/AKT ratio, promoted the apoptosis of H22 cells, and inhibited the growth of H22 cells. Remarkably, treatment with PI3K/AKT activator (740Y-P and SC79) could prevent beauvericin-induced H22 cell apoptosis. These findings collectively indicate that beauvericin inhibits HCC growth by inducing apoptosis via the PI3K/AKT pathway.
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Affiliation(s)
- Gui Wang
- Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China.
| | - Yamei Qiao
- Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China.
| | - Yunyan Zhao
- Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China.
| | - Yuanyuan Song
- Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China.
| | - Mengyang Li
- Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China.
| | - Min Jin
- Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China.
| | - Dong Yang
- Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China.
| | - Jing Yin
- Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China.
| | - Junwen Li
- Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China.
| | - Weili Liu
- Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China.
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Hassanain M, Liu Y, Hussain W, Binowayn A, Barakeh D, Alsolme E, AlSaif F, Almasaad G, AlSwayyed M, Alaqel M, Aljunidel R, Abdelrahman S, Hauser CAE, Alqahtani S, Hoehndorf R, Abedalthagafi M. Genomic landscape in Saudi patients with hepatocellular carcinoma using whole-genome sequencing: a pilot study. FRONTIERS IN GASTROENTEROLOGY 2023; 2. [DOI: 10.3389/fgstr.2023.1205415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Background and aimsHepatocellular carcinoma (HCC) is the third most prevalent cancer in Saudi Arabia. HCC poses a significant clinical challenge due to the presence of resistance among certain patients to the standard therapeutic agent sorafenib. This study aims to unravel the genomic characteristics of HCC patients in Saudi Arabia, investigate the genetic makeup of tumors in both sorafenib-sensitive and sorafenib-resistant patients, and analyze the functional implications of genomic abnormalities observed in these individuals. The resistance displayed by some HCC patients toward sorafenib underscores the need for alternative treatment approaches to effectively combat this formidable disease burden.MethodsWhole-genome sequencing (WGS) was performed on 16 HCC samples and targeted sequencing was performed on seven additional tumors. We identified and validated somatic and germline genetic aberrations. Employing a prize-collecting Steiner tree algorithm, we identified important altered genetic modules and potential biomarkers for each patient. Furthermore, we analyzed non-synonymous germline and somatic mutations, specifically in patients who underwent sorafenib treatment.ResultsOut of the 13 patients who received sorafenib, three exhibited sorafenib sensitivity, while the others showed resistance to the drug. Notably, 3 out of 16 individuals carried cancer-predisposing mutations. Additionally, 8 out of 16 patients displayed non-synonymous somatic alterations in genes associated with cancer. In the targeted-sequencing samples, rare non-synonymous variants were observed across all seven cases. The study also revealed the presence of specific somatic aberrations, including TP53, PIK3CA, APOB, CTNNB1, DPYD, LRP1B, MYC, and NFE2L2, which were identified in two patients. Among the 42 genes linked to sorafenib treatment, 4 out of 10 resistant patients carried somatic non-synonymous variants. Furthermore, when analyzing the 5,000 genes most relevant to the 42 genes, 7 out of 10 resistant individuals exhibited rare non-synonymous germline variants. Interestingly, none of the three sorafenib-sensitive patients displayed any concerning variants in those genes.ConclusionOur findings indicate that most of the HCC patients possess cancer-related genetic variants, and the altered pathways in these patients exhibit similarities. Notably, resistant patients exhibit a higher frequency of aberrations in sorafenib-related genes than do sensitive patients. Specifically, 4 out of 10 resistant individuals demonstrated 13 somatic mutations, whereas none of the three sensitive patients exhibited any. Similarly, 7 out of 10 resistant patients possessed 30 germline mutations, while none were observed in the sensitive group (two-sided Fisher’s exact test; somatic: p=0.50, germline: 0.07). These results contribute to our understanding of the genetic landscape of HCC and highlight potential therapeutic targets that could aid in overcoming treatment resistance.
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Abdullah AD, Taher HJ, Alareer HS, Easa AM, Dakhil HA, Bustan RA. The Different MRI Features of Hepatocellular Adenoma and Hepatocellular Carcinoma. JOURNAL OF PHARMACY AND BIOALLIED SCIENCES 2023; 15:S1046-S1049. [PMID: 37693999 PMCID: PMC10485518 DOI: 10.4103/jpbs.jpbs_230_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 03/14/2023] [Accepted: 03/16/2023] [Indexed: 09/12/2023] Open
Abstract
Background Hepatocellular adenomas (HCAs) are benign tumours that may be broken down into three different molecular pathogenic categories: catenin activator, hepatic cell nuclear agent 1 (HNF- 1) that has been inactivated, and Inflammatory hepatic adenomas are a genetic and pathological subtype of hepatic adenoma. Methodology An analysis of 50 HCA cases was conducted to identify the magnetic resonance imaging characteristics that were specifically related to each HCA subtype IV. This method included 50 patients in total for the study, with 30 of them being new cases. Four cases involving medicine, pathology, surgery, and radiology were gathered and examined. Results As per these analyses for inactivated HNF-1, the sure predictive esteem about homogeneous indicator spillage on the compound shift pictures could have been as high as 100%, negative predictive quality could have been as high as 94.7%, affectability could have been as high as 86.7%, and specificity could have been as high as 100%. Enhancement of the solid blood vessels to support the ongoing and future stages of the portal vein change. It took a certain predictive quality of 88.5%, a negative predictive worth of about 84%, an affectability of about 85.2%, and more specificity of about 87.5% to diagnose incendiary HCA from the predominant signs seen for T2W successions linked with late constant upgrades. Conclusions Both HNF-1-mutated HCAs and incendiary HCAs need to be associated with specific magnetic resonance imaging phenotypes characterized independently as having diffused lipid repartition and sinusoidal expansion.
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Affiliation(s)
- Ayoob D Abdullah
- Department of Technology of Radiology and Radiotherapy, Tehran University of Medical Sciences, International Campus, Tehran, Iran
- Radiology Department, Al-Manara College for Medical Science, Missan, Iraq
| | - Hayder J. Taher
- Department of Technology of Radiology and Radiotherapy, Tehran University of Medical Sciences, International Campus, Tehran, Iran
- Department of Radiology, Hilla University College, Babylon, Iraq
| | - Hayder S. Alareer
- Department of Technology of Radiology and Radiotherapy, Tehran University of Medical Sciences, International Campus, Tehran, Iran
- Radiology Department, Collage of Health and Medical Technology, Al-Ayen University, Thi-Qar, Iraq
| | - Ahmed M. Easa
- Department of Technology of Radiology and Radiotherapy, Tehran University of Medical Sciences, International Campus, Tehran, Iran
- Radiology Department, Collage of Health and Medical Technology, Al-Ayen University, Thi-Qar, Iraq
| | - Hussein A. Dakhil
- Department of Technology of Radiology and Radiotherapy, Tehran University of Medical Sciences, International Campus, Tehran, Iran
- Radiology Department, Collage of Health and Medical Technology, Al-Ayen University, Thi-Qar, Iraq
| | - Raad A. Bustan
- Department of Technology of Radiology and Radiotherapy, Tehran University of Medical Sciences, International Campus, Tehran, Iran
- Radiology Department, Collage of Health and Medical Technology, Al-Ayen University, Thi-Qar, Iraq
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24
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Sohrab SS, Raj R, Nagar A, Hawthorne S, Paiva-Santos AC, Kamal MA, El-Daly MM, Azhar EI, Sharma A. Chronic Inflammation's Transformation to Cancer: A Nanotherapeutic Paradigm. Molecules 2023; 28:molecules28114413. [PMID: 37298889 DOI: 10.3390/molecules28114413] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/19/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
The body's normal immune response against any invading pathogen that causes infection in the body results in inflammation. The sudden transformation in inflammation leads to the rise of inflammatory diseases such as chronic inflammatory bowel disease, autoimmune disorders, and colorectal cancer (different types of cancer develop at the site of chronic infection and inflammation). Inflammation results in two ways: short-term inflammation i.e., non-specific, involves the action of various immune cells; the other results in long-term reactions lasting for months or years. It is specific and causes angiogenesis, fibrosis, tissue destruction, and cancer progression at the site of inflammation. Cancer progression relies on the interaction between the host microenvironment and tumor cells along with the inflammatory responses, fibroblast, and vascular cells. The two pathways that have been identified connecting inflammation and cancer are the extrinsic and intrinsic pathways. Both have their own specific role in linking inflammation to cancer, involving various transcription factors such as Nuclear factor kappa B, Activator of transcription, Single transducer, and Hypoxia-inducible factor, which in turn regulates the inflammatory responses via Soluble mediators cytokines (such as Interleukin-6, Hematopoietin-1/Erythropoietin, and tumor necrosis factor), chemokines (such as Cyclooxygenase-2, C-X-C Motif chemokines ligand-8, and IL-8), inflammatory cells, cellular components (such as suppressor cells derived from myeloid, tumor-associated macrophage, and acidophils), and promotes tumorigenesis. The treatment of these chronic inflammatory diseases is challenging and needs early detection and diagnosis. Nanotechnology is a booming field nowadays for its rapid action and easy penetration inside the infected destined cells. Nanoparticles are widely classified into different categories based on their different factors and properties such as size, shape, cytotoxicity, and others. Nanoparticles emerged as excellent with highly progressive medical inventions to cure diseases such as cancer, inflammatory diseases, and others. Nanoparticles have shown higher binding capacity with the biomolecules in inflammation reduction and lowers the oxidative stress inside tissue/cells. In this review, we have overall discussed inflammatory pathways that link inflammation to cancer, major inflammatory diseases, and the potent action of nanoparticles in chronic inflammation-related diseases.
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Affiliation(s)
- Sayed Sartaj Sohrab
- Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Riya Raj
- Department of Biochemistry, Bangalore University, Banglore 560056, India
| | - Amka Nagar
- Department of Life Science, School of Basic Science and Research, Sharda University, Greater Noida 201310, India
| | - Susan Hawthorne
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine BT52 1SA, UK
| | - Ana Cláudia Paiva-Santos
- Department of Pharmaceutical Technology, Faculty of Pharmacy of University of Coimbra, University of Coimbra, 3000-548 Coimbra, Portugal
- LAQV, REQUIMTE, Department of Pharmaceutical Technology, Faculty of Pharmacy of University of Coimbra, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Mohammad Amjad Kamal
- Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Enzymoics Inc., Hebersham, NSW 2770, Australia
- Novel Global Community Educational Foundation, Hebersham, NSW 2770, Australia
| | - Mai M El-Daly
- Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Esam I Azhar
- Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Ankur Sharma
- Strathclyde Institute of Pharmaceutical and Biomedical Sciences, University of Strathclyde, Glasgow G1 0RE, UK
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25
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The higher body mass index is associated with a lower somatic mutation dependency in hepatocellular carcinoma. INFORMATICS IN MEDICINE UNLOCKED 2023. [DOI: 10.1016/j.imu.2023.101187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023] Open
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Milana F, Polidoro MA, Famularo S, Lleo A, Boldorini R, Donadon M, Torzilli G. Surgical Strategies for Recurrent Hepatocellular Carcinoma after Resection: A Review of Current Evidence. Cancers (Basel) 2023; 15:508. [PMID: 36672457 PMCID: PMC9856445 DOI: 10.3390/cancers15020508] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/07/2023] [Accepted: 01/10/2023] [Indexed: 01/17/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and both liver resection and liver transplantation are considered potentially curative options. However, high recurrence rates affect the prognosis depending both on the primary HCC pathology characteristics or on the type and time of the relapse. While great attention has been usually posted on treatment algorithms for the first HCC, treatment algorithms for recurrent HCC (rHCC) are lacking. In these cases, surgery still represents a curative option with both redo hepatectomy and/or salvage liver transplantation, which are considered valid treatments in selected patients. In the current era of personalised medicine with promises of new systemic-targeted immuno-chemotherapies, we wished to perform a narrative review of the literature on the role of surgical strategies for rHCC.
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Affiliation(s)
- Flavio Milana
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, MI, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Michela Anna Polidoro
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Simone Famularo
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, MI, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, MI, Italy
- Department of Internal Medicine, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Renzo Boldorini
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, NO, Italy
- Department of Pathology, University Maggiore Hospital, 28100 Novara, NO, Italy
| | - Matteo Donadon
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, NO, Italy
- Department of General Surgery, University Maggiore Hospital, 28100 Novara, NO, Italy
| | - Guido Torzilli
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, MI, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
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Oura K, Morishita A, Tani J, Masaki T. Antitumor Effects and Mechanisms of Metabolic Syndrome Medications on Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022; 9:1279-1298. [PMID: 36545268 PMCID: PMC9760577 DOI: 10.2147/jhc.s392051] [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: 10/03/2022] [Accepted: 12/04/2022] [Indexed: 12/15/2022] Open
Abstract
Liver cancer has a high incidence and mortality rate worldwide, with hepatocellular carcinoma (HCC) being the most common histological type. With the decrease in the number of newly infected patients and the spread of antiviral therapy, hepatitis virus-negative chronic liver diseases including steatohepatitis are increasingly accounting for a large proportion of HCC, and an important clinical characteristic is the high prevalence of metabolic syndrome including hypertension, type 2 diabetes (T2D), dyslipidemia, and obesity. Since patients with steatohepatitis are less likely to undergo surveillance for early detection of HCC, they may be diagnosed at an advanced stage and have worse prognosis. Therefore, treatment strategies for patients with HCC caused by steatohepatitis, especially in advanced stages, become increasingly important. Further, hypertension, T2D, and dyslipidemia may occur as side effects during systemic treatment, and there will be increasing opportunities to prescribe metabolic syndrome medications, not only for originally comorbid diseases, but also for adverse events during HCC treatment. Interestingly, epidemiological studies have shown that patients taking some metabolic syndrome medications are less likely to develop various types of cancers, including HCC. Basic studies have also shown that these drugs have direct antitumor effects on HCC. In particular, angiotensin II receptor blockers (a drug group for treating hypertension), biguanides (a drug group for treating T2D), and statins (a drug group for treating dyslipidemia) have shown to elucidate antitumor effects against HCC. In this review, we focus on the antitumor effects of metabolic syndrome medications on HCC and their mechanisms based on recent literature. New therapeutic agents are also increasingly being reported. Analysis of the antitumor effects of metabolic syndrome medications on HCC and their mechanisms will be doubly beneficial for HCC patients with metabolic syndrome, and the use of these medications may be a potential strategy against HCC.
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Affiliation(s)
- Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan,Correspondence: Kyoko Oura, Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki, Kida, Kagawa, Japan, Tel +81-87-891-2156, Fax +81-87-891-2158, Email
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
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Carlsson MJ, Vollmer AS, Demuth P, Heylmann D, Reich D, Quarz C, Rasenberger B, Nikolova T, Hofmann TG, Christmann M, Fuhlbrueck JA, Stegmüller S, Richling E, Cartus AT, Fahrer J. p53 triggers mitochondrial apoptosis following DNA damage-dependent replication stress by the hepatotoxin methyleugenol. Cell Death Dis 2022; 13:1009. [PMID: 36446765 PMCID: PMC9708695 DOI: 10.1038/s41419-022-05446-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 11/15/2022] [Accepted: 11/16/2022] [Indexed: 12/03/2022]
Abstract
Liver cancer is one of the most frequent tumor entities worldwide, which is causally linked to viral infection, fatty liver disease, life-style factors and food-borne carcinogens, particularly aflatoxins. Moreover, genotoxic plant toxins including phenylpropenes are suspected human liver carcinogens. The phenylpropene methyleugenol (ME) is a constituent of essential oils in many plants and occurs in herbal medicines, food, and cosmetics. Following its uptake, ME undergoes Cytochrome P450 (CYP) and sulfotransferase 1A1 (SULT1A1)-dependent metabolic activation, giving rise to DNA damage. However, little is known about the cellular response to the induced DNA adducts. Here, we made use of different SULT1A1-proficient cell models including primary hepatocytes that were treated with 1'-hydroxymethyleugenol (OH-ME) as main phase I metabolite. Firstly, mass spectrometry showed a concentration-dependent formation of N2-MIE-dG as major DNA adduct, strongly correlating with SULT1A1 expression as attested in cells with and without human SULT1A1. ME-derived DNA damage activated mainly the ATR-mediated DNA damage response as shown by phosphorylation of CHK1 and histone 2AX, followed by p53 accumulation and CHK2 phosphorylation. Consistent with these findings, the DNA adducts decreased replication speed and caused replication fork stalling. OH-ME treatment reduced viability particularly in cell lines with wild-type p53 and triggered apoptotic cell death, which was rescued by pan-caspase-inhibition. Further experiments demonstrated mitochondrial apoptosis as major cell death pathway. ME-derived DNA damage caused upregulation of the p53-responsive genes NOXA and PUMA, Bax activation, and cytochrome c release followed by caspase-9 and caspase-3 cleavage. We finally demonstrated the crucial role of p53 for OH-ME triggered cell death as evidenced by reduced pro-apoptotic gene expression, strongly attenuated Bax activation and cell death inhibition upon genetic knockdown or pharmacological inhibition of p53. Taken together, our study demonstrates for the first time that ME-derived DNA damage causes replication stress and triggers mitochondrial apoptosis via the p53-Bax pathway.
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Affiliation(s)
- Max J. Carlsson
- grid.7645.00000 0001 2155 0333Division of Food Chemistry and Toxicology, Department of Chemistry, Technical University of Kaiserslautern, 67663 Kaiserslautern, Germany
| | - Anastasia S. Vollmer
- grid.8664.c0000 0001 2165 8627Rudolf Buchheim Institute of Pharmacology, Justus Liebig University Giessen, 35392 Giessen, Germany ,grid.411544.10000 0001 0196 8249Present Address: Department of Dermatology, University Medical Center, 69120 Heidelberg, Germany
| | - Philipp Demuth
- grid.7645.00000 0001 2155 0333Division of Food Chemistry and Toxicology, Department of Chemistry, Technical University of Kaiserslautern, 67663 Kaiserslautern, Germany
| | - Daniel Heylmann
- grid.8664.c0000 0001 2165 8627Rudolf Buchheim Institute of Pharmacology, Justus Liebig University Giessen, 35392 Giessen, Germany
| | - Diana Reich
- grid.410607.4Institute of Toxicology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany
| | - Caroline Quarz
- grid.7645.00000 0001 2155 0333Division of Food Chemistry and Toxicology, Department of Chemistry, Technical University of Kaiserslautern, 67663 Kaiserslautern, Germany
| | - Birgit Rasenberger
- grid.410607.4Institute of Toxicology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany
| | - Teodora Nikolova
- grid.410607.4Institute of Toxicology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany
| | - Thomas G. Hofmann
- grid.410607.4Institute of Toxicology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany
| | - Markus Christmann
- grid.410607.4Institute of Toxicology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany
| | - Julia A. Fuhlbrueck
- grid.7645.00000 0001 2155 0333Division of Food Chemistry and Toxicology, Department of Chemistry, Technical University of Kaiserslautern, 67663 Kaiserslautern, Germany
| | - Simone Stegmüller
- grid.7645.00000 0001 2155 0333Division of Food Chemistry and Toxicology, Department of Chemistry, Technical University of Kaiserslautern, 67663 Kaiserslautern, Germany
| | - Elke Richling
- grid.7645.00000 0001 2155 0333Division of Food Chemistry and Toxicology, Department of Chemistry, Technical University of Kaiserslautern, 67663 Kaiserslautern, Germany
| | - Alexander T. Cartus
- grid.7645.00000 0001 2155 0333Division of Food Chemistry and Toxicology, Department of Chemistry, Technical University of Kaiserslautern, 67663 Kaiserslautern, Germany
| | - Jörg Fahrer
- grid.7645.00000 0001 2155 0333Division of Food Chemistry and Toxicology, Department of Chemistry, Technical University of Kaiserslautern, 67663 Kaiserslautern, Germany ,grid.8664.c0000 0001 2165 8627Rudolf Buchheim Institute of Pharmacology, Justus Liebig University Giessen, 35392 Giessen, Germany ,grid.410607.4Institute of Toxicology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany
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29
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Pallerla SR, Hoan NX, Rachakonda S, Meyer CG, Van Tong H, Toan NL, Linh LTK, Giang DP, Kremsner PG, Bang MH, Song LH, Velavan TP. Custom gene expression panel for evaluation of potential molecular markers in hepatocellular carcinoma. BMC Med Genomics 2022; 15:235. [PMID: 36345011 PMCID: PMC9641913 DOI: 10.1186/s12920-022-01386-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 10/14/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. It is a highly heterogeneous disease with poor prognosis and limited treatment options, which highlights the need for reliable biomarkers. This study aims to explore molecular markers that allow stratification of HCC and may lead to better prognosis and treatment prediction. MATERIALS AND METHODS We studied 20 candidate genes (HCC hub genes, potential drug target genes, predominant somatic mutant genes) retrieved from literature and public databases with potential to be used as the molecular markers. We analysed expression of the genes by RT-qPCR in 30 HCC tumour and adjacent non-tumour paired samples from Vietnamese patients. Fold changes in expression were then determined using the 2-∆∆CT method, and unsupervised hierarchical clustering was generated using Cluster v3.0 software. RESULTS Clustering of expression data revealed two subtypes of tumours (proliferative and normal-like) and four clusters for genes. The expression profiles of the genes TOP2A, CDK1, BIRC5, GPC3, IGF2, and AFP were strongly correlated. Proliferative tumours were characterized by high expression of the c-MET, ARID1A, CTNNB1, RAF1, LGR5, and GLUL1 genes. TOP2A, CDK1, and BIRC5 HCC hub genes were highly expressed (> twofold) in 90% (27/30), 83% (25/30), and 83% (24/30) in the tissue samples, respectively. Among the drug target genes, high expression was observed in the GPC3, IGF2 and c-MET genes in 77% (23/30), 63% (19/30), and 37% (11/30), respectively. The somatic mutant Wnt/ß-catenin genes (CTNNB1, GLUL and LGR5) and TERT were highly expressed in 40% and 33% of HCCs, respectively. Among the HCC marker genes, a higher percentage of tumours showed GPC3 expression compared to AFP expression [73% (23/30) vs. 43% (13/30)]. CONCLUSION The custom panel and molecular markers from this study may be useful for diagnosis, prognosis, biomarker-guided clinical trial design, and prediction of treatment outcomes.
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Affiliation(s)
- Srinivas Reddy Pallerla
- Institute of Tropical Medicine, Universitätsklinikum Tübingen, Universität Tübingen, Wilhelmstr 27, 72074, Tübingen, Germany.
| | - Nghiem Xuan Hoan
- Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam.
- Department of Molecular Biology, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam.
| | - Sivaramakrishna Rachakonda
- Institute of Tropical Medicine, Universitätsklinikum Tübingen, Universität Tübingen, Wilhelmstr 27, 72074, Tübingen, Germany
| | - Christian G Meyer
- Institute of Tropical Medicine, Universitätsklinikum Tübingen, Universität Tübingen, Wilhelmstr 27, 72074, Tübingen, Germany
- Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam
| | | | | | - Le Thi Kieu Linh
- Institute of Tropical Medicine, Universitätsklinikum Tübingen, Universität Tübingen, Wilhelmstr 27, 72074, Tübingen, Germany
- Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam
| | - Dao Phuong Giang
- Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam
- Department of Molecular Biology, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam
| | - Peter G Kremsner
- Institute of Tropical Medicine, Universitätsklinikum Tübingen, Universität Tübingen, Wilhelmstr 27, 72074, Tübingen, Germany
- Centre de Recherches Medicales de Lambarene, Lambaréné, Gabon
| | - Mai Hong Bang
- Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam
- Faculty of Gastroenterology, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam
| | - Le Huu Song
- Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam
- Department of Molecular Biology, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam
| | - Thirumalaisamy P Velavan
- Institute of Tropical Medicine, Universitätsklinikum Tübingen, Universität Tübingen, Wilhelmstr 27, 72074, Tübingen, Germany
- Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam
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30
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Gárate-Rascón M, Recalde M, Rojo C, Fernández-Barrena MG, Ávila MA, Arechederra M, Berasain C. SLU7: A New Hub of Gene Expression Regulation—From Epigenetics to Protein Stability in Health and Disease. Int J Mol Sci 2022; 23:ijms232113411. [PMID: 36362191 PMCID: PMC9658179 DOI: 10.3390/ijms232113411] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 10/28/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
SLU7 (Splicing factor synergistic lethal with U5 snRNA 7) was first identified as a splicing factor necessary for the correct selection of 3′ splice sites, strongly impacting on the diversity of gene transcripts in a cell. More recent studies have uncovered new and non-redundant roles of SLU7 as an integrative hub of different levels of gene expression regulation, including epigenetic DNA remodeling, modulation of transcription and protein stability. Here we review those findings, the multiple factors and mechanisms implicated as well as the cellular functions affected. For instance, SLU7 is essential to secure liver differentiation, genome integrity acting at different levels and a correct cell cycle progression. Accordingly, the aberrant expression of SLU7 could be associated with human diseases including cancer, although strikingly, it is an essential survival factor for cancer cells. Finally, we discuss the implications of SLU7 in pathophysiology, with particular emphasis on the progression of liver disease and its possible role as a therapeutic target in human cancer.
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Affiliation(s)
- María Gárate-Rascón
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
| | - Miriam Recalde
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
| | - Carla Rojo
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
| | - Maite G. Fernández-Barrena
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Matías A. Ávila
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - María Arechederra
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Carmen Berasain
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-948-194700; Fax: +34-948-194717
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31
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Chen G, Liu ZP. Inferring causal gene regulatory network via GreyNet: From dynamic grey association to causation. Front Bioeng Biotechnol 2022; 10:954610. [PMID: 36237217 PMCID: PMC9551017 DOI: 10.3389/fbioe.2022.954610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 08/15/2022] [Indexed: 11/23/2022] Open
Abstract
Gene regulatory network (GRN) provides abundant information on gene interactions, which contributes to demonstrating pathology, predicting clinical outcomes, and identifying drug targets. Existing high-throughput experiments provide rich time-series gene expression data to reconstruct the GRN to further gain insights into the mechanism of organisms responding to external stimuli. Numerous machine-learning methods have been proposed to infer gene regulatory networks. Nevertheless, machine learning, especially deep learning, is generally a “black box,” which lacks interpretability. The causality has not been well recognized in GRN inference procedures. In this article, we introduce grey theory integrated with the adaptive sliding window technique to flexibly capture instant gene–gene interactions in the uncertain regulatory system. Then, we incorporate generalized multivariate Granger causality regression methods to transform the dynamic grey association into causation to generate directional regulatory links. We evaluate our model on the DREAM4 in silico benchmark dataset and real-world hepatocellular carcinoma (HCC) time-series data. We achieved competitive results on the DREAM4 compared with other state-of-the-art algorithms and gained meaningful GRN structure on HCC data respectively.
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Affiliation(s)
- Guangyi Chen
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong, China
| | - Zhi-Ping Liu
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong, China
- Center for Intelligent Medicine, Shandong University, Jinan, Shandong, China
- *Correspondence: Zhi-Ping Liu,
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32
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Nicolas CT, VanLith CJ, Hickey RD, Du Z, Hillin LG, Guthman RM, Cao WJ, Haugo B, Lillegard A, Roy D, Bhagwate A, O'Brien D, Kocher JP, Kaiser RA, Russell SJ, Lillegard JB. In vivo lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions. Nat Commun 2022; 13:5012. [PMID: 36008405 PMCID: PMC9411607 DOI: 10.1038/s41467-022-32576-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 08/08/2022] [Indexed: 11/23/2022] Open
Abstract
Conventional therapy for hereditary tyrosinemia type-1 (HT1) with 2-(2-nitro-4-trifluoromethylbenzoyl)−1,3-cyclohexanedione (NTBC) delays and in some cases fails to prevent disease progression to liver fibrosis, liver failure, and activation of tumorigenic pathways. Here we demonstrate cure of HT1 by direct, in vivo administration of a therapeutic lentiviral vector targeting the expression of a human fumarylacetoacetate hydrolase (FAH) transgene in the porcine model of HT1. This therapy is well tolerated and provides stable long-term expression of FAH in pigs with HT1. Genomic integration displays a benign profile, with subsequent fibrosis and tumorigenicity gene expression patterns similar to wild-type animals as compared to NTBC-treated or diseased untreated animals. Indeed, the phenotypic and genomic data following in vivo lentiviral vector administration demonstrate comparative superiority over other therapies including ex vivo cell therapy and therefore support clinical application of this approach. Hereditary tyrosinemia type 1 (HT1) is an inborn error of metabolism caused by a deficiency in fumarylacetoacetate hydrolase (FAH). Here, the authors show in an animal model that HT1 can be treated via in vivo portal vein administration of a lentiviral vector carrying the human FAH transgene.
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Affiliation(s)
- Clara T Nicolas
- Department of Surgery, Mayo Clinic, Rochester, MN, USA.,Faculty of Medicine, University of Barcelona, Barcelona, Spain.,Department of Surgery, University of Alabama Birmingham, Birmingham, AL, USA
| | | | - Raymond D Hickey
- Department of Surgery, Mayo Clinic, Rochester, MN, USA.,Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Zeji Du
- Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Lori G Hillin
- Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Rebekah M Guthman
- Department of Surgery, Mayo Clinic, Rochester, MN, USA.,Medical College of Wisconsin, Wausau, WI, USA
| | - William J Cao
- Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | | | | | - Diya Roy
- Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Aditya Bhagwate
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Daniel O'Brien
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Jean-Pierre Kocher
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Robert A Kaiser
- Department of Surgery, Mayo Clinic, Rochester, MN, USA.,Midwest Fetal Care Center, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA
| | | | - Joseph B Lillegard
- Department of Surgery, Mayo Clinic, Rochester, MN, USA. .,Midwest Fetal Care Center, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA. .,Pediatric Surgical Associates, Minneapolis, MN, USA.
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33
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Mahmood MS, Afzal M, Batool H, Saif A, Aqdas T, Ashraf NM, Saleem M. Screening of Pathogenic Missense Single Nucleotide Variants From LHPP Gene Associated With the Hepatocellular Carcinoma: An In silico Approach. Bioinform Biol Insights 2022; 16:11779322221115547. [PMID: 35966807 PMCID: PMC9373111 DOI: 10.1177/11779322221115547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 06/11/2022] [Indexed: 11/15/2022] Open
Abstract
LHPP gene encodes a phospholysine phosphohistidine inorganic pyrophosphate phosphatase, which functions as a tumor-suppressor protein. The tumor suppression by this protein has been confirmed in various cancers, including hepatocellular carcinoma (HCC). LHPP downregulation promotes cell growth and proliferation by modulating the PI3K/AKT signaling pathway. This study identifies potentially deleterious missense single nucleotide variants (SNVs) associated with the LHPP gene using multiple computational tools based on different algorithms. A total of 4 destabilizing mutants are identified as L22P, I212T, G227R, and G236R, from the conserved region of the phosphatase. The 3-dimensional (3D) modeling and structural comparison of variants with the native protein reveals significant structural and conformational variations after mutations, suggesting disruption in the function of phospholysine phosphohistidine inorganic pyrophosphate phosphatase. The identified mutations might, therefore, participate in the cause of HCC.
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Affiliation(s)
- Malik Siddique Mahmood
- School of Biochemistry & Biotechnology, University of the Punjab, Lahore, Pakistan.,Department of Biochemistry, NUR International University, Lahore, Pakistan
| | - Maryam Afzal
- School of Biochemistry & Biotechnology, University of the Punjab, Lahore, Pakistan
| | - Hina Batool
- Department of Life Sciences, University of Management and Technology, Lahore, Pakistan
| | - Amara Saif
- Department of Life Sciences, University of Management and Technology, Lahore, Pakistan
| | - Tahreem Aqdas
- School of Biochemistry & Biotechnology, University of the Punjab, Lahore, Pakistan
| | - Naeem Mahmood Ashraf
- Department of Biochemistry & Biotechnology, University of Gujrat, Gujrat, Pakistan
| | - Mahjabeen Saleem
- School of Biochemistry & Biotechnology, University of the Punjab, Lahore, Pakistan
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34
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Xi B, Luo FZ, He B, Wang F, Li ZK, Lai MC, Zheng SS. High nuclear ABCG1 expression is a poor predictor for hepatocellular carcinoma patient survival. Hepatobiliary Pancreat Dis Int 2022; 21:370-377. [PMID: 35778316 DOI: 10.1016/j.hbpd.2022.06.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 06/20/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND ATP-binding cassette transporter G1 (ABCG1) regulates cellular cholesterol homeostasis and plays a significant role in tumor immunity. But, for hepatocellular carcinoma (HCC), the role of ABCG1 has not been investigated. Thus, the aim of this study was to evaluate the prognostic value and clinicopathological significance of ABCG1 in HCC. METHODS One hundred and four adult patients with HCC were enrolled, and ABCG1 expression in paired HCC specimens was determined by immunohistochemistry. All these patients were stratified by ABCG1 expression, Kaplan-Meier analysis was used to compare the overall survival (OS) and recurrence-free survival (RFS), and Cox regression analysis was used to determine independent predictors of tumor recurrence. RESULTS Upregulation of ABCG1 was observed in HCC samples compared to matched tumor-adjacent tissues. Patients with high nuclear ABCG1 expression had lower OS and RFS (P = 0.012 and P = 0.020, respectively). High nuclear ABCG1 expression was related to larger tumor size (P = 0.004) and tumor recurrence (P = 0.027). Although ABCG1 was expressed in the cytoplasm, cytosolic expression could not predict the outcome in patients with HCC. A new stratification pattern was established based on the heterogenous ABCG1 expression pattern: high risk (Highnucleus/Lowcytosol), moderate risk (Highnucleus/Highcytosol or Lownucleus/Lowcytosol), and low risk (Lownucleus/Highcytosol). This ABCG1-based risk stratification could distinguish the different OS and RFS in patients with HCC. Multivariate Cox regression analysis indicated that ABCG1 high risk was an independent predictor of poor RFS (P = 0.015). CONCLUSIONS High nuclear ABCG1 expression indicates poor prognosis in patients with HCC. Asymmetric distribution of ABCG1 in the nucleus and cytoplasm may have an important role in tumor recurrence.
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Affiliation(s)
- Bin Xi
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Fang-Zhou Luo
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Bin He
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Fang Wang
- Department of Radiotherapy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Ze-Kuan Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Ming-Chun Lai
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Shu-Sen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Zhejiang University, Hangzhou 310003, China.
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35
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Kim HS, Yoon JS, Jeon Y, Park EJ, Lee JK, Chen S, Lee H, Park JY, Go H, Lee CW. Ssu72-HNF4α signaling axis classify the transition from steatohepatitis to hepatocellular carcinoma. Cell Death Differ 2022; 29:600-613. [PMID: 34616001 PMCID: PMC8901687 DOI: 10.1038/s41418-021-00877-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 09/08/2021] [Accepted: 09/15/2021] [Indexed: 11/09/2022] Open
Abstract
Growing evidence suggests a mechanistic link between steatohepatitis and hepatocellular carcinoma (HCC). However, the lack of representative animal models hampers efforts to understand pathophysiological mechanisms underlying steatohepatitis-related HCC. We found that liver-specific deletion of Ssu72 phosphatase in mice, leads to a high incidence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, but not HCC. However, loss of Ssu72 drastically increased the probability of HCC developing, as well as the population of hepatic progenitors, in various chemical and metabolic syndrome-induced HCC models. Importantly, hepatic Ssu72 loss resulted in the induction of mature hepatocyte-to-progenitor cell conversion, by dedifferentiation orchestrated by Ssu72-mediated hypo-phosphorylation of hepatocyte nuclear factor 4α (HNF4α), a master regulator of hepatocyte function. Our findings suggest that Ssu72-mediated HNF4α transcription contributes to the progression of steatohepatitis-associated HCC by regulating the dedifferentiation potential of hepatocytes. Thus, targeting the Ssu72-mediated HNF4α signaling that underlies the pathogenesis of steatohepatitis-associated HCC development could be a novel therapeutic intervention for steatohepatitis-associated HCC.
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Affiliation(s)
- Hyun-Soo Kim
- Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, South Korea.
| | - Joon-Sup Yoon
- Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, South Korea
| | - Yoon Jeon
- Research Institute, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, South Korea
| | - Eun-Ji Park
- Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, South Korea
| | - Jin-Kwan Lee
- Research Institute, Curogen Technology, Suwon, South Korea
| | - Si Chen
- Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, South Korea
| | - Ho Lee
- Research Institute, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, South Korea
| | - Jee Young Park
- Department of Pathology, Kyungpook National University Medical Center, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Heounjeong Go
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Chang-Woo Lee
- Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, South Korea.
- Research Institute, Curogen Technology, Suwon, South Korea.
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Identification of Immune-Related Prognostic mRNA and lncRNA in Patients with Hepatocellular Carcinoma. JOURNAL OF ONCOLOGY 2022; 2022:5313149. [PMID: 35027925 PMCID: PMC8752260 DOI: 10.1155/2022/5313149] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 11/19/2021] [Accepted: 11/30/2021] [Indexed: 12/18/2022]
Abstract
Background As the most common hepatic malignancy, hepatocellular carcinoma (HCC) has a high incidence; therefore, in this paper, the immune-related genes were sought as biomarkers in liver cancer. Methods In this study, a differential expression analysis of lncRNA and mRNA in The Cancer Genome Atlas (TCGA) dataset between the HCC group and the normal control group was performed. Enrichment analysis was used to screen immune-related differentially expressed genes. Cox regression analysis and survival analysis were used to determine prognostic genes of HCC, whose expression was detected by molecular experiments. Finally, important immune cells were identified by immune cell infiltration and detected by flow cytometry. Results Compared with the normal group, 1613 differentially expressed mRNAs (DEmRs) and 1237 differentially expressed lncRNAs (DElncRs) were found in HCC. Among them, 143 immune-related DEmRs and 39 immune-related DElncRs were screened out. These genes were mainly related to MAPK cascade, PI3K-AKT signaling pathway, and TGF-beta. Through Cox regression analysis and survival analysis, MMP9, SPP1, HAGLR, LINC02202, and RP11-598F7.3 were finally determined as the potential diagnostic biomarkers for HCC. The gene expression was verified by RT-qPCR and western blot. In addition, CD4 + memory resting T cells and CD8 + T cells were identified as protective factors for overall survival of HCC, and they were found highly expressed in HCC through flow cytometry. Conclusion The study explored the dysregulation mechanism and potential biomarkers of immune-related genes and further identified the influence of immune cells on the prognosis of HCC, providing a theoretical basis for the prognosis prediction and immunotherapy in HCC patients.
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Fanale D, Corsini LR, Scalia R, Brando C, Cucinella A, Madonia G, Dimino A, Filorizzo C, Barraco N, Bono M, Fiorino A, Magrin L, Sciacchitano R, Perez A, Russo TDB, Pantuso G, Russo A, Bazan V. Can the tumor-agnostic evaluation of MSI/MMR status be the common denominator for the immunotherapy treatment of patients with several solid tumors? Crit Rev Oncol Hematol 2022; 170:103597. [PMID: 35033663 DOI: 10.1016/j.critrevonc.2022.103597] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 01/11/2022] [Accepted: 01/11/2022] [Indexed: 12/24/2022] Open
Abstract
Alterations in short-repetitive DNA sequences, known as microsatellite instability (MSI), can reflect deficiencies in Mismatch Repair (MMR) system which represents a major player in DNA integrity maintenance. The incidence of MSI-H/dMMR has been shown to be variable depending on the tumor type. Several studies confirmed that dMMR/MSI status, although less frequent than PD-L1 expression, may better predict response to immune-checkpoint inhibitors (ICIs) in patients with solid tumors. In October 2016, the FDA granted pembrolizumab as breakthrough therapy for the treatment of non-CRC, MSI-H/dMMR tumors, providing, for the first time, a tumor-agnostic indication. In the next future, the tissue-agnostic evaluation of MSI-H/dMMR could become the common denominator for the immunotherapy treatment of patients with different advanced solid tumors, in order to select patient subgroups which may benefit from this therapy. In this Review we provided an overview of the main clinical studies describing the association between MSI-H/dMMR tumors and immunotherapy response.
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Affiliation(s)
- Daniele Fanale
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Lidia Rita Corsini
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Raimondo Scalia
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Chiara Brando
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Alessandra Cucinella
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Giorgio Madonia
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Alessandra Dimino
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Clarissa Filorizzo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Nadia Barraco
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Marco Bono
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Alessia Fiorino
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Luigi Magrin
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Roberta Sciacchitano
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Alessandro Perez
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Tancredi Didier Bazan Russo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Gianni Pantuso
- Unit of Oncological Surgery, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Antonio Russo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy.
| | - Viviana Bazan
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90127, Palermo, Italy
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Srivani Nagam L, Vadde R, Jinka R. Polymorphisms in hepatocellular carcinoma. THERANOSTICS AND PRECISION MEDICINE FOR THE MANAGEMENT OF HEPATOCELLULAR CARCINOMA 2022:125-133. [DOI: 10.1016/b978-0-323-98806-3.00013-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Shioi Y, Osakabe M, Yanagawa N, Nitta H, Sasaki A, Sugai T. Analysis of somatic copy number alterations in biliary tract carcinoma using a single nucleotide polymorphism array. Future Sci OA 2021; 8:FSO766. [PMID: 34900340 PMCID: PMC8656348 DOI: 10.2144/fsoa-2021-0057] [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: 05/02/2021] [Accepted: 10/19/2021] [Indexed: 11/23/2022] Open
Abstract
Aim: Biliary tract carcinoma (BTC), including gall bladder carcinoma (GBC) and biliary duct carcinoma (BDC), has a poor prognosis. Comprehensive genomic profiling has important roles in evaluation of the carcinogenesis of BTC. Materials & methods: We examined somatic copy number alterations (SCNAs) using a single nucleotide polymorphism array system to analyze 36 BTC samples (11 GBCs and 25 BDCs). Results: In hierarchical cluster analysis, two clusters were identified (subgroup 1 with low SCNAs and subgroup 2 with high SCNAs). GBC was predominant in subgroup 1, whereas BDC was predominant in subgroup 2, suggesting that GBC and BDC had different genetic backgrounds in terms of SCNAs. Conclusion: These findings could be helpful for establishing the molecular carcinogenesis of BTCs. Biliary tract carcinoma, including gall bladder carcinoma (GBC) and biliary duct carcinoma (BDC), has a poor prognosis. Comprehensive genomic (single nucleotide polymorphism-array) profiling plays important roles in evaluation of the carcinogenesis of biliary tract carcinoma. In the hierarchical cluster analysis, two clusters were identified (subgroup 1 with low somatic copy number alterations [SCNAs] and subgroup 2 with high SCNAs); GBC was found to be predominant in subgroup 1, whereas BDC was predominant in subgroup 2. These findings suggested that GBC and BDC had different genetic backgrounds in terms of SCNAs.
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Affiliation(s)
- Yoshihiro Shioi
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou, 0283695, Japan.,Department of Surgery, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou, 0283695, Japan
| | - Mitsumasa Osakabe
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou, 0283695, Japan
| | - Naoki Yanagawa
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou, 0283695, Japan
| | - Hiroyuki Nitta
- Department of Surgery, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou, 0283695, Japan
| | - Akira Sasaki
- Department of Surgery, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou, 0283695, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou, 0283695, Japan
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Wang T, Shao Z, Xiao Y, Zhang X, Chen Y, Shi B, Chen S, Wang Y, Peng J, Shang X. Predicting Hepatoma-Related Genes Based on Representation Learning of PPI network and Gene Ontology Annotations. 2021 IEEE INTERNATIONAL CONFERENCE ON BIOINFORMATICS AND BIOMEDICINE (BIBM) 2021:1892-1898. [DOI: 10.1109/bibm52615.2021.9669479] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Karakülah G, Yandim C. Identification of differentially expressed genomic repeats in primary hepatocellular carcinoma and their potential links to biological processes and survival. Turk J Biol 2021; 45:599-612. [PMID: 34803457 PMCID: PMC8574195 DOI: 10.3906/biy-2104-13] [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: 04/05/2021] [Accepted: 06/19/2021] [Indexed: 11/05/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers. Research on HCC so far primarily focused on genes and provided limited information on genomic repeats, which constitute more than half of the human genome and contribute to genomic stability. In line with this, repeat dysregulation was significantly shown to be pathological in various cancers and other diseases. In this study, we aimed to determine the full repeat expression profile of HCC for the first time. We utilised two independent RNA-seq datasets obtained from primary HCC tumours with matched normal tissues of 20 and 17 HCC patients, respectively. We quantified repeat expressions and analysed their differential expression. We also identified repeats that are cooperatively expressed with genes by constructing a gene coexpression network. Our results indicated that HCC tumours in both datasets harbour 24 differentially expressed repeats and even more elements were coexpressed with genes involved in various metabolic pathways. We discovered that two L1 elements (L1M3b, L1M3de) were downregulated and a handful of HERV subfamily repeats (HERV-Fc1-int, HERV3-int, HERVE_a-int, HERVK11D-int, HERVK14C-int, HERVL18-int) were upregulated with the exception of HERV1_LTRc, which was downregulated. Various LTR elements (LTR32, LTR9, LTR4, LTR52-int, LTR70) and MER elements (MER11C, MER11D, MER57C1, MER9a1, MER74C) were implicated along with few other subtypes including Charlie12, MLT2A2, Tigger15a, Tigger 17b. The only satellite repeat differentially expressed in both datasets was GSATII, whose expression was upregulated in 33 (>90%) out of 37 patients. Notably, GSATII expression correlated with HCC survival genes. Elements discovered here promise future studies to be considered for biomarker and HCC therapy research. The coexpression pattern of the GSATII satellite with HCC survival genes and the fact that it has been upregulated in the vast majority of patients make this repeat particularly stand out for HCC.
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Affiliation(s)
- Gökhan Karakülah
- İzmir Biomedicine and Genome Center (İBG), İzmir Turkey.,İzmir International Biomedicine and Genome Institute (İBG-İzmir), Dokuz Eylül University, İzmir Turkey
| | - Cihangir Yandim
- İzmir Biomedicine and Genome Center (İBG), İzmir Turkey.,Department of Genetics and Bioengineering, Faculty of Engineering, İzmir University of Economics, İzmir Turkey
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Si T, Huang Z, Jiang Y, Walker-Jacobs A, Gill S, Hegarty R, Hamza M, Khorsandi SE, Jassem W, Heaton N, Ma Y. Expression Levels of Three Key Genes CCNB1, CDC20, and CENPF in HCC Are Associated With Antitumor Immunity. Front Oncol 2021; 11:738841. [PMID: 34660300 PMCID: PMC8515852 DOI: 10.3389/fonc.2021.738841] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 09/13/2021] [Indexed: 12/11/2022] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a low 5-year survival rate. The heterogeneity of HCC makes monotherapy unlikely. The development of diagnostic programs and new treatments targeting common genetic events in the carcinogenic process are providing further insights into the management of HCC. The aim of this study was firstly to validate key genes that are involved in promoting HCC development and as biomarkers for early diagnosis and, secondly, to define their links with antitumor immunity including inhibitory checkpoints. Methods Multiple databases including Gene Expression Omnibus (GEO), Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier Plotter, UALCAN, and Oncomine were used for target gene screening and establishment of a co-expression network. Clinical data and RNAseq of 367 HCC patients were downloaded from the Cancer Genome Atlas (TCGA) database. The diagnostic and prognostic value of screened genes were tested by receiver operating characteristic (ROC) curve and correlation analysis. The links with the key genes in HCC and antitumor immunity were defined using both blood and liver tissue collected prospectively from HCC patients in our center. Results Upregulation of CCNB1, CDC20, and CENPF was commonly observed in HCC and are involved in the p53 signal pathway. The hepatic mRNA expression levels of these three genes were strongly associated with patients' prognosis and expressed high value of area under the ROC curve (AUC). Further analysis revealed that these three genes were positively correlated with the gene expression levels of IFN-γ, TNF-α, and IL-17 in peripheral blood. In addition, the expression of CENPF showed positive correlation with the percentage of CD8pos T cells and negative correlation with the percentage of CD4pos T cells in the peripheral blood. In the HCC microenvironment, the transcript levels of these three genes and inhibitory checkpoint molecules including PD-1, CTLA-4, and TIM-3 were positively correlated. Conclusion The upregulation of CCNB1, CDC20, and CENPF genes was a common event in hepatocarcinogenesis. Expression levels of CCNB1, CDC20, and CENPF showed potential for early diagnosis and prediction of prognosis in HCC patients. There is a close association between three genes and Th1/Th17 cytokines as well as the count of CD4pos and CD8pos T cells. The positive correlation between the three genes and inhibitory checkpoint genes, PD-1, CTLA-4, and TIM-3, indicates that these genes are linked with weakened antitumor immunity in HCC. Our findings may provide further insights into developing novel therapies for HCC.
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Affiliation(s)
- Tengfei Si
- Institute of Liver Studies, King's College Hospital, Department of Inflammation Biology, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom
| | - Zhenlin Huang
- The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuanhang Jiang
- Institute of Liver Studies, King's College Hospital, Department of Inflammation Biology, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom
| | - Abigail Walker-Jacobs
- Institute of Liver Studies, King's College Hospital, Department of Inflammation Biology, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom
| | - Shaqira Gill
- Institute of Liver Studies, King's College Hospital, Department of Inflammation Biology, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom
| | - Robert Hegarty
- Pediatric Liver, GI and Nutrition Centre, King's College Hospital, London, United Kingdom
| | - Mohammad Hamza
- Institute of Liver Studies, King's College Hospital, Department of Inflammation Biology, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom
| | - Shirin Elizabeth Khorsandi
- Institute of Liver Studies, King's College Hospital, Department of Inflammation Biology, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.,Transplant Service, King's College Hospital, London, United Kingdom.,The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, United Kingdom
| | - Wayel Jassem
- Institute of Liver Studies, King's College Hospital, Department of Inflammation Biology, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.,Transplant Service, King's College Hospital, London, United Kingdom
| | - Nigel Heaton
- Institute of Liver Studies, King's College Hospital, Department of Inflammation Biology, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.,Transplant Service, King's College Hospital, London, United Kingdom
| | - Yun Ma
- Institute of Liver Studies, King's College Hospital, Department of Inflammation Biology, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom
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Molecular classification of hepatocellular carcinoma: prognostic importance and clinical applications. J Cancer Res Clin Oncol 2021; 148:15-29. [PMID: 34623518 DOI: 10.1007/s00432-021-03826-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/03/2021] [Indexed: 01/17/2023]
Abstract
Hepatocellular carcinoma (HCC) is a lethal human malignancy with a very low overall and long-term survival rate. Poor prognostic outcomes are predominantly associated with HCC due to a huge landscape of heterogeneity found in the deadliest disease. However, molecular subtyping of HCC has significantly improved the knowledge of the underlying mechanisms that contribute towards the heterogeneity and progression of the disease. In this review, we have extensively summarized the current information available about molecular classification of HCC. This review can be of great significance for providing the insight information needed for development of novel, efficient and personalized therapeutic options for the treatment of HCC patients globally.
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44
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Murugesan K, Sharaf R, Montesion M, Moore JA, Pao J, Pavlick DC, Frampton GM, Upadhyay VA, Alexander BM, Miller VA, Javle MM, Bekaii Saab TS, Albacker LA, Ross JS, Ali SM. Genomic Profiling of Combined Hepatocellular Cholangiocarcinoma Reveals Genomics Similar to Either Hepatocellular Carcinoma or Cholangiocarcinoma. JCO Precis Oncol 2021; 5:PO.20.00397. [PMID: 34476330 PMCID: PMC8384404 DOI: 10.1200/po.20.00397] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 03/05/2021] [Accepted: 06/11/2021] [Indexed: 01/07/2023] Open
Abstract
PURPOSE Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a rare, aggressive primary liver carcinoma, with morphologic features of both hepatocellular carcinomas (HCC) and liver cholangiocarcinomas (CCA). METHODS The genomic profiles of 4,975 CCA, 1,470 HCC, and 73 cHCC-CCA cases arising from comprehensive genomic profiling in the course of clinical care were reviewed for genomic alterations (GA), tumor mutational burden, microsatellite instability status, genomic loss of heterozygosity, chromosomal aneuploidy, genomic ancestry, and hepatitis B virus status. RESULTS In cHCC-CCA, GA were most common in TP53 (65.8%), TERT (49.3%), and PTEN (9.6%), and 24.6% cHCC-CCA harbored potentially targetable GA. Other GA were predominantly associated with either HCC or CCA, including, but not limited to, TERT, FGFR2, IDH1, and presence of hepatitis B virus. On the basis of these features, a machine learning (ML) model was trained to classify a cHCC-CCA case as CCA-like or HCC-like. Of cHCC-CCA cases, 16% (12/73) were ML-classified as CCA-like and 58% (42/73) cHCC-CCA were ML-classified as HCC-like. The ML model classified more than 70% of cHCC-CCA as CCA-like or HCC-like on the basis of genomic profiles, without additional clinico-pathologic input. CONCLUSION These findings demonstrate the use of ML for classification as based on a targeted exome panel used during routine clinical care. Classification of cHCC-CCA by genomic features alone creates insights into the biology of the disease and warrants further investigation for relevance to clinical care.
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Affiliation(s)
| | | | | | | | - James Pao
- Foundation Medicine Inc, Cambridge, MA
| | | | | | - Vivek A Upadhyay
- Foundation Medicine Inc, Cambridge, MA.,Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA
| | | | | | - Milind M Javle
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
| | | | | | - Jeffrey S Ross
- Foundation Medicine Inc, Cambridge, MA.,Department of Pathology, State University of New York Upstate Medical University, Syracuse, NY
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Ge Y, Gu P, Wang W, Cao L, Zhang L, Li J, Mu W, Wang H. Benzo[a]pyrene stimulates miR-650 expression to promote the pathogenesis of fatty liver disease and hepatocellular carcinoma via SOCS3/JAK/STAT3 cascades. J Mol Cell Biol 2021; 13:mjab052. [PMID: 34450627 PMCID: PMC8697348 DOI: 10.1093/jmcb/mjab052] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 04/20/2021] [Accepted: 04/20/2021] [Indexed: 12/13/2022] Open
Abstract
Modern diets, which often feature high levels of fat and charcoal-grilled meat, contribute to the pathogenesis of obesity and nonalcoholic fatty liver disease (NAFLD), resulting in liver cancer progression. Benzo(a)pyrene (B[a]P) is a common environmental and foodborne pollutant found in smoke and fire-grilled foods, which can have an adverse effect on human health. Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer and the second leading cause of cancer-related deaths worldwide. The epidemiological studies suggest that both environmental risk factors and chronic liver injury including NAFL are important for HCC development, but the precise mechanisms linking eating habits to hepato-carcinogenesis remain unclear. In the present study, we demonstrated that various miRNAs in B[a]P-exposed tumor cells contribute to tumor metastasis, among which miR-650 could be the most potent inducer. Furthermore, we found that suppressor of cytokine signaling 3 (SOCS3) is directly regulated by miR-650 and its suppression regulates the activation of the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) cascade. Our findings reveal a possible adverse outcome pathway of SOCS3/JAK/STAT3 regulation in B[a]P-induced HCC progress. These results provide a better understanding of the adverse effects of chronic exposure to B[a]P on human health.
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Affiliation(s)
- Yang Ge
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-cell
Omics, School of Public Health, Shanghai Jiao Tong University School of
Medicine, Shanghai 200025, China
| | - Pengfei Gu
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-cell
Omics, School of Public Health, Shanghai Jiao Tong University School of
Medicine, Shanghai 200025, China
| | - Wenbo Wang
- Department of Oncology, Shanghai Tenth People's Hospital, School of Medicine,
Tongji University, Shanghai 200072, China
| | - Liyuan Cao
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-cell
Omics, School of Public Health, Shanghai Jiao Tong University School of
Medicine, Shanghai 200025, China
| | - Lulu Zhang
- Institute of Military Health Management, Second Military Medical
University, Shanghai 200433, China
| | - Jingquan Li
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-cell
Omics, School of Public Health, Shanghai Jiao Tong University School of
Medicine, Shanghai 200025, China
| | - Wei Mu
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-cell
Omics, School of Public Health, Shanghai Jiao Tong University School of
Medicine, Shanghai 200025, China
| | - Hui Wang
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-cell
Omics, School of Public Health, Shanghai Jiao Tong University School of
Medicine, Shanghai 200025, China
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of
Sciences, Shanghai 200031, China
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Hu G, Gao F, Wang G, Fang Y, Guo Y, Zhou J, Gu Y, Zhang C, Gao N, Wen Q, Qiao H. Use of proteomics to identify mechanisms of hepatocellular carcinoma with the CYP2D6*10 polymorphism and identification of ANGPTL6 as a new diagnostic and prognostic biomarker. J Transl Med 2021; 19:359. [PMID: 34412629 PMCID: PMC8375140 DOI: 10.1186/s12967-021-03038-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 08/10/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Although an association between the cytochrome P4502D6 (CYP2D6) *10 (100C>T) polymorphism and hepatocellular carcinoma (HCC) is known, the mechanism remains unclear. Here we aimed to explore mechanisms of CYP2D6*10 (100C>T) polymorphism conferring to HCC, and screen markers for HCC. METHODS Label-free global proteome profiling with 34 normal livers and peritumor tissue from 61 HCC patients was performed, and angiopoietin-like protein-6 (ANGPTL6) was evaluated in 2 liver samples validation cohorts and 2 blood specimens validation cohorts. RESULTS We found a significantly decreased frequency of TT in HCC patients which reduced HCC susceptibility by 69.2% and was accompanied by lowered enzymatic activity for CYP2D6. Proteomic analysis revealed 1342 differentially expressed proteins (DEPs) that were associated with HCC and 88 DEPs were identified as 100 TT-related proteins, likely underlying the susceptibility to HCC. Twenty-two upregulated DEPs and 66 downregulated DEPs were mainly related to lipid metabolism and the extracellular matrix, respectively. High ANGPTL6 was associated with a higher risk to HCC and worse prognosis. ANGPTL6 was both an independent risk factor and an independent prognostic factor for HCC and exhibited strong potential for predicting HCC occurrence, with comparable AUC values and higher sensitivity compared with alpha-fetoprotein. CONCLUSIONS The TT genotype-associated decreased risk of HCC appears to be related to lowered CYP2D6 activity and altered protein expression in the tumor microenvironment, and ANGPTL6 is a promising new diagnostic and prognostic biomarker for HCC. Our findings reveal new mechanistic insights for polymorphisms related to HCC risk and provide avenues for screening for HCC.
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Affiliation(s)
- Guiming Hu
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Fei Gao
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Guanzhe Wang
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yan Fang
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yuanyuan Guo
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Jun Zhou
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, 450052, Henan, China.,Affiliated People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuhan Gu
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Cunzhen Zhang
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Na Gao
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Qiang Wen
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Hailing Qiao
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, 450052, Henan, China.
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Blidisel A, Marcovici I, Coricovac D, Hut F, Dehelean CA, Cretu OM. Experimental Models of Hepatocellular Carcinoma-A Preclinical Perspective. Cancers (Basel) 2021; 13:3651. [PMID: 34359553 PMCID: PMC8344976 DOI: 10.3390/cancers13153651] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 07/16/2021] [Accepted: 07/17/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the most frequent form of primary liver carcinoma, is a heterogenous and complex tumor type with increased incidence, poor prognosis, and high mortality. The actual therapeutic arsenal is narrow and poorly effective, rendering this disease a global health concern. Although considerable progress has been made in terms of understanding the pathogenesis, molecular mechanisms, genetics, and therapeutical approaches, several facets of human HCC remain undiscovered. A valuable and prompt approach to acquire further knowledge about the unrevealed aspects of HCC and novel therapeutic candidates is represented by the application of experimental models. Experimental models (in vivo and in vitro 2D and 3D models) are considered reliable tools to gather data for clinical usability. This review offers an overview of the currently available preclinical models frequently applied for the study of hepatocellular carcinoma in terms of initiation, development, and progression, as well as for the discovery of efficient treatments, highlighting the advantages and the limitations of each model. Furthermore, we also focus on the role played by computational studies (in silico models and artificial intelligence-based prediction models) as promising novel tools in liver cancer research.
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Affiliation(s)
- Alexandru Blidisel
- Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania; (A.B.); (F.H.); (O.M.C.)
| | - Iasmina Marcovici
- Faculty of Pharmacy, “Victor Babeș” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania;
- Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania
| | - Dorina Coricovac
- Faculty of Pharmacy, “Victor Babeș” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania;
- Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania
| | - Florin Hut
- Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania; (A.B.); (F.H.); (O.M.C.)
| | - Cristina Adriana Dehelean
- Faculty of Pharmacy, “Victor Babeș” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania;
- Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania
| | - Octavian Marius Cretu
- Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania; (A.B.); (F.H.); (O.M.C.)
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Metallomic profile in non-cirrhotic hepatocellular carcinoma supports a phenomenon of metal metabolism adaptation in tumor cells. Sci Rep 2021; 11:14195. [PMID: 34244548 PMCID: PMC8271004 DOI: 10.1038/s41598-021-93369-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 06/18/2021] [Indexed: 01/31/2023] Open
Abstract
We have previously described a form of hepatocellular carcinoma (HCC) in non-cirrhotic liver (HCC-NC) developed by Peruvian patients. We analyzed the metallomic profile in hepatic tissues from two independent cohorts exhibiting HCC-NC. Clinical, histopathological data, and HCC and non-tumoral liver (NTL) samples of 38 Peruvian and 38 French HCC-NC patients, were studied. Twelve metals were quantified using ICP/MS: Mn, Fe, Cu, Co, Zn, As, Se, Rb, Mo, Cd, Pb, and Sn. Associations between metals and survival were assessed. Our data showed significant differences between cohorts. Mean ages were 40.6 ± 20, 67.5 ± 9 years old for Peruvians and French, respectively. Fifty percent of the Peruvian patients were positive for the HBsAg, versus 3% in French patients. Mn, Cu, Zn, As, Se, Rb, Mo, Cd, Sn metal concentrations were higher in NTL of Peruvians. Importantly, metal concentrations were lower in HCC areas compared to NTL tissues in both cohorts, except for Cu for which mean concentration was higher in HCC (p < 0.05). Se concentration in HCC was associated with extended survival only in Peruvians. Our data, obtained in Peruvian and French HCC-NC cohorts, highlights similarity in the metallomic profile of HCC compared to NTL during the hepatic tumorigenesis in these specific groups of patients.
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Morshedi K, Borran S, Ebrahimi MS, Masoud Khooy MJ, Seyedi ZS, Amiri A, Abbasi-Kolli M, Fallah M, Khan H, Sahebkar A, Mirzaei H. Therapeutic effect of curcumin in gastrointestinal cancers: A comprehensive review. Phytother Res 2021; 35:4834-4897. [PMID: 34173992 DOI: 10.1002/ptr.7119] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/18/2021] [Accepted: 03/26/2021] [Indexed: 12/11/2022]
Abstract
Gastrointestinal (GI) cancers with a high global prevalence are a leading cause of morbidity and mortality. Accordingly, there is a great need to develop efficient therapeutic approaches. Curcumin, a naturally occurring agent, is a promising compound with documented safety and anticancer activities. Recent studies have demonstrated the activity of curcumin in the prevention and treatment of different cancers. According to systematic studies on curcumin use in various diseases, it can be particularly effective in GI cancers because of its high bioavailability in the gastrointestinal tract. Nevertheless, the clinical applications of curcumin are largely limited because of its low solubility and low chemical stability in water. These limitations may be addressed by the use of relevant analogues or novel delivery systems. Herein, we summarize the pharmacological effects of curcumin against GI cancers. Moreover, we highlight the application of curcumin's analogues and novel delivery systems in the treatment of GI cancers.
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Affiliation(s)
- Korosh Morshedi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Sarina Borran
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | | | - Zeynab Sadat Seyedi
- Department of Cell and Molecular Biology, Faculty of Chemistry, University of Kashan, Kashan, Iran
| | - Atefeh Amiri
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Abbasi-Kolli
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Maryam Fallah
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakistan
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Tumor-Associated Neutrophils in Hepatocellular Carcinoma Pathogenesis, Prognosis, and Therapy. Cancers (Basel) 2021; 13:cancers13122899. [PMID: 34200529 PMCID: PMC8228651 DOI: 10.3390/cancers13122899] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 05/31/2021] [Accepted: 06/06/2021] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma represents the most prevalent primary liver cancer worldwide, and it is either caused by intrinsic genetic mutations or by a multitude of extrinsic risk factors. Even though the interplay between chronic inflammatory changes and hepatocarcinogenesis has been at the forefront of clinical investigation for the past few decades, the role of tumor-associated neutrophils (TANs) in HCC development still remains ambiguous. On the one hand, N1 TANs exhibit an anti-tumorigenic activity, mediated by direct or indirect tumor cell lysis, whereas on the other hand, N2 TANs have been correlated with increased HCC growth, invasiveness, and metastasis. The association of an elevated Neutrophil-to-Lymphocyte Ratio (NLR) with poor prognosis in patients with HCC, has been recently brought into spotlight, consolidating its widespread use as a reliable biomarker. Due to the decisive involvement of TANs in HCC pathogenesis and development, the utilization of various neutrophil-centered anticancer treatment modalities has been under clinical experimentation, selectively targeting and modulating the processes of neutrophil recruitment, activation, and migration. This review summarizes current evidence on the role of TANs in HCC pathogenesis and progression, as well as in their potential involvement in tumor therapy, shedding light on emerging anticancer treatment methods targeting neutrophils.
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