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Shinde S, Bigogno CM, Simmons A, Kathuria N, Ghose A, Apte V, Lapitan P, Makker S, Caglayan A, Boussios S. Precision oncology through next generation sequencing in hepatocellular carcinoma. Heliyon 2025; 11:e42054. [PMID: 39927143 PMCID: PMC11804570 DOI: 10.1016/j.heliyon.2025.e42054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 01/08/2025] [Accepted: 01/15/2025] [Indexed: 02/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer that originates from underlying inflammation, often associated with Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infections. Despite the availability of treatments, there are high rates of tumour relapse due to the development of drug resistance in infected cells. Next-Generation Sequencing (NGS) plays a crucial role in overcoming this issue by sequencing both viral and host genomes to identify mutations and genetic heterogeneity. The knowledge gained from sequencing is then utilised to develop countermeasures against these mutants through different combination therapies. Advances in NGS have led to sequencing with higher accuracy and throughput, thereby enabling personalized and effective treatments. The purpose of this article is to highlight how NGS has contributed to precision medicine in HCC and the possible integration of artificial intelligence (AI) to bolster the advancement.
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Affiliation(s)
- Sayali Shinde
- Barts Cancer Institute, Queen Mary University of London, Cancer Research UK Barts Centre, London, UK
| | - Carola Maria Bigogno
- Department of Medical Oncology, St. Bartholomew's Hospital, Barts Health NHS Trust, London, UK
- British Oncology Network for Undergraduate Societies (BONUS), UK
| | - Ana Simmons
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- QIAGEN Manchester, Manchester, UK
| | - Nikita Kathuria
- Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Aruni Ghose
- Department of Medical Oncology, St. Bartholomew's Hospital, Barts Health NHS Trust, London, UK
- Department of Medical Oncology, Medway NHS Foundation Trust, Kent, UK
- Department of Medical Oncology, Mount Vernon Cancer Centre, East and North Hertfordshire NHS Trust, London, UK
| | - Vedika Apte
- University College London Medical School, London, UK
- University College London Oncology Society, London, UK
| | - Patricia Lapitan
- School of Medical Sciences, The University of Manchester, Manchester, UK
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey, UK
- University College London Cancer Institute, London, UK
| | - Shania Makker
- University College London Cancer Institute, London, UK
- Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Barts and the London Oncology Society, London, UK
| | - Aydin Caglayan
- Department of Medical Oncology, Medway NHS Foundation Trust, Kent, UK
| | - Stergios Boussios
- Department of Medical Oncology, Medway NHS Foundation Trust, Kent, UK
- Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, King's College London, Strand, London, UK
- Kent and Medway Medical School, University of Kent, Canterbury, UK
- Faculty of Medicine, Health, and Social Care, Canterbury Christ Church University, Canterbury, UK
- AELIA Organization, 9th Km Thessaloniki–Thermi, 57001 Thessaloniki, Greece
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Huang H, Wu Q, Qiao H, Chen S, Hu S, Wen Q, Zhou G. P53 status combined with MRI findings for prognosis prediction of single hepatocellular carcinoma. Magn Reson Imaging 2025; 116:110293. [PMID: 39631483 DOI: 10.1016/j.mri.2024.110293] [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: 04/11/2024] [Revised: 10/17/2024] [Accepted: 11/30/2024] [Indexed: 12/07/2024]
Abstract
OBJECT To develop and validate a nomogram for predicting recurrence in individuals suffering single hepatocellular carcinoma (HCC) after curative hepatectomy. MATERIAL AND METHODS A retrospective analysis was conducted on 189 patients with single HCC undergoing curative resection in our center were randomized into training and validation cohorts. P53 status was determined using immunohistochemistry. Clinical data, such as age, and gender were collected. MRI findings, such as tumor size, intratumoral arteries, the presence of peritumoral enhancement and intratumoral necrosis were also recorded. Nomograms were established based on the predictors selected in the training cohort, and receiver operating characteristic (ROC) curve analyses were used to compare the predictive ability among single predictors and nomogram model. The Kaplan-Meier method was used to assess the impact of each predictor and nomogram model on HCC recurrence. The results were validated in the validation cohort. RESULTS Multivariate Cox regression analysis showed that P53 (P < 0.001), tumor size (P = 0.009), and intratumoral artery (P = 0.026) were the independent risk factors for HCC recurrence. The nomogram model demonstrated favorable C-index of 0.740 (95 %CI:0.653-0.826) and 0.767 (95 %CI: 0.633-0.900) in the training and validation cohorts, and the areas under the curve was 0.740 and 0.752, which was better than the performance of P53 and MR factors alone. Calibration curves indicated a good agreement between observed actual outcomes and predicted values. Kaplan-Meier curves indicated that nomogram model was powerful in discrimination and clinical usefulness. CONCLUSIONS The integrated nomogram combining P53 status and MRI findings can be a valuable prognostic tool for predicting postoperative recurrence of single HCC.
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Affiliation(s)
- Hong Huang
- Department of Radiology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214122, China; Department of Radiology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
| | - Qinghua Wu
- Department of Interventional Radiology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Hongyan Qiao
- Department of Radiology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Sujing Chen
- Department of Radiology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Shudong Hu
- Department of Radiology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Qingqing Wen
- GE Healthcare, MR Research China, Beijing, China
| | - Guofeng Zhou
- Department of Radiology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China; Shanghai Institute of Medical Imaging, 180 Fenglin Road, Shanghai 200032, China.
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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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Daniel N, Genua F, Jenab M, Mayén AL, Chrysovalantou Chatziioannou A, Keski-Rahkonen P, Hughes DJ. The role of the gut microbiome in the development of hepatobiliary cancers. Hepatology 2024; 80:1252-1269. [PMID: 37055022 PMCID: PMC11487028 DOI: 10.1097/hep.0000000000000406] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/31/2023] [Accepted: 04/03/2023] [Indexed: 04/15/2023]
Abstract
Hepatobiliary cancers, including hepatocellular carcinoma and cancers of the biliary tract, share high mortality and rising incidence rates. They may also share several risk factors related to unhealthy western-type dietary and lifestyle patterns as well as increasing body weights and rates of obesity. Recent data also suggest a role for the gut microbiome in the development of hepatobiliary cancer and other liver pathologies. The gut microbiome and the liver interact bidirectionally through the "gut-liver axis," which describes the interactive relationship between the gut, its microbiota, and the liver. Here, we review the gut-liver interactions within the context of hepatobiliary carcinogenesis by outlining the experimental and observational evidence for the roles of gut microbiome dysbiosis, reduced gut barrier function, and exposure to inflammatory compounds as well as metabolic dysfunction as contributors to hepatobiliary cancer development. We also outline the latest findings regarding the impact of dietary and lifestyle factors on liver pathologies as mediated by the gut microbiome. Finally, we highlight some emerging gut microbiome editing techniques currently being investigated in the context of hepatobiliary diseases. Although much work remains to be done in determining the relationships between the gut microbiome and hepatobiliary cancers, emerging mechanistic insights are informing treatments, such as potential microbiota manipulation strategies and guiding public health advice on dietary/lifestyle patterns for the prevention of these lethal tumors.
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Affiliation(s)
- Neil Daniel
- Cancer Biology and Therapeutics Laboratory, Conway Institute, School of Biomedical and Biomolecular Sciences, University College Dublin, Dublin, Ireland
| | - Flavia Genua
- Cancer Biology and Therapeutics Laboratory, Conway Institute, School of Biomedical and Biomolecular Sciences, University College Dublin, Dublin, Ireland
| | - Mazda Jenab
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - Ana-Lucia Mayén
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | | | - Pekka Keski-Rahkonen
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - David J. Hughes
- Cancer Biology and Therapeutics Laboratory, Conway Institute, School of Biomedical and Biomolecular Sciences, University College Dublin, Dublin, Ireland
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Ming Y, Gong Y, Fu X, Ouyang X, Peng Y, Pu W. Small-molecule-based targeted therapy in liver cancer. Mol Ther 2024; 32:3260-3287. [PMID: 39113358 PMCID: PMC11489561 DOI: 10.1016/j.ymthe.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 03/13/2024] [Accepted: 08/02/2024] [Indexed: 08/23/2024] Open
Abstract
Liver cancer is one of the most prevalent malignant tumors worldwide. According to the Barcelona Clinic Liver Cancer staging criteria, clinical guidelines provide tutorials to clinical management of liver cancer at their individual stages. However, most patients diagnosed with liver cancer are at advanced stage; therefore, many researchers conduct investigations on targeted therapy, aiming to improve the overall survival of these patients. To date, small-molecule-based targeted therapies are highly recommended (first line: sorafenib and lenvatinib; second line: regorafenib and cabozantinib) by current the clinical guidelines of the American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network. Herein, we summarize the small-molecule-based targeted therapies in liver cancer, including the approved and preclinical therapies as well as the therapies under clinical trials, and introduce their history of discovery, clinical trials, indications, and molecular mechanisms. For drug resistance, the revealed mechanisms of action and the combination therapies are also discussed. In fact, the known small-molecule-based therapies still have limited clinical benefits to liver cancer patients. Therefore, we analyze the current status and give our ideas for the urgent issues and future directions in this field, suggesting clues for novel techniques in liver cancer treatment.
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Affiliation(s)
- Yue Ming
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Yanqiu Gong
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xuewen Fu
- Jinhua Huanke Environmental Technology Co., Ltd., Jinhua 321000, China
| | - Xinyu Ouyang
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yong Peng
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China.
| | - Wenchen Pu
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
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6
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Li D, Bao Q, Ren S, Ding H, Guo C, Gao K, Wan J, Wang Y, Zhu M, Xiong Y. Comprehensive Analysis of the Mechanism of Anoikis in Hepatocellular Carcinoma. Genet Res (Camb) 2024; 2024:8217215. [PMID: 39297018 PMCID: PMC11410409 DOI: 10.1155/2024/8217215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 06/25/2024] [Accepted: 08/10/2024] [Indexed: 09/21/2024] Open
Abstract
Background Hepatocellular carcinoma (HCC), ranking as the second-leading cause of global mortality among malignancies, poses a substantial burden on public health worldwide. Anoikis, a type of programmed cell death, serves as a barrier against the dissemination of cancer cells to distant organs, thereby constraining the progression of cancer. Nevertheless, the mechanism of genes related to anoikis in HCC is yet to be elucidated. Methods This paper's data (TCGA-HCC) were retrieved from the database of the Cancer Genome Atlas (TCGA). Differential gene expression with prognostic implications for anoikis was identified by performing both the univariate Cox and differential expression analyses. Through unsupervised cluster analysis, we clustered the samples according to these DEGs. By employing the least absolute shrinkage and selection operator Cox regression analysis (CRA), a clinical predictive gene signature was generated from the DEGs. The Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to determine the proportions of immune cell types. The external validation data (GSE76427) were procured from Gene Expression Omnibus (GEO) to verify the performance of the clinical prognosis gene signature. Western blotting and immunohistochemistry (IHC) analysis confirmed the expression of risk genes. Results In total, 23 prognostic DEGs were identified. Based on these 23 DEGs, the samples were categorized into four distinct subgroups (clusters 1, 2, 3, and 4). In addition, a clinical predictive gene signature was constructed utilizing ETV4, PBK, and SLC2A1. The gene signature efficiently distinguished individuals into two risk groups, specifically low and high, demonstrating markedly higher survival rates in the former group. Significant correlations were observed between the expression of these risk genes and a variety of immune cells. Moreover, the outcomes from the validation cohort analysis aligned consistently with those obtained from the training cohort analysis. The results of Western blotting and IHC showed that ETV4, PBK, and SLC2A1 were upregulated in HCC samples. Conclusion The outcomes of this paper underscore the effectiveness of the clinical prognostic gene signature, established utilizing anoikis-related genes, in accurately stratifying patients. This signature holds promise in advancing the development of personalized therapy for HCC.
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Affiliation(s)
- Dongqian Li
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Nantong University Medical School of Nantong University, Nantong 226001, Jiangsu, China
- Nantong University Medical School, Nantong 226001, Jiangsu, China
| | - Qian Bao
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Nantong University Medical School of Nantong University, Nantong 226001, Jiangsu, China
- Nantong University Medical School, Nantong 226001, Jiangsu, China
| | - Shiqi Ren
- Nantong University Medical School, Nantong 226001, Jiangsu, China
| | - Haoxiang Ding
- Nantong University Medical School, Nantong 226001, Jiangsu, China
| | - Chengfeng Guo
- Nantong University Medical School, Nantong 226001, Jiangsu, China
| | - Kai Gao
- Nantong University Medical School, Nantong 226001, Jiangsu, China
| | - Jian Wan
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Nantong University Medical School of Nantong University, Nantong 226001, Jiangsu, China
| | - Yao Wang
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Nantong University Medical School of Nantong University, Nantong 226001, Jiangsu, China
| | - MingYan Zhu
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Nantong University Medical School of Nantong University, Nantong 226001, Jiangsu, China
| | - Yicheng Xiong
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Nantong University Medical School of Nantong University, Nantong 226001, Jiangsu, China
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Dawoud A, Elmasri RA, Mohamed AH, Mahmoud A, Rostom MM, Youness RA. Involvement of CircRNAs in regulating The "New Generation of Cancer Hallmarks": A Special Depiction on Hepatocellular Carcinoma. Crit Rev Oncol Hematol 2024; 196:104312. [PMID: 38428701 DOI: 10.1016/j.critrevonc.2024.104312] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 02/01/2024] [Accepted: 02/26/2024] [Indexed: 03/03/2024] Open
Abstract
The concept of 'Hallmarks of Cancer' is an approach of reducing the enormous complexity of cancer to a set of guiding principles. As the underlying mechanism of cancer are portrayed, we find that we gain insight and additional aspects of the disease arise. The understanding of the tumor microenvironment (TME) brought a new dimension and led to the discovery of novel hallmarks such as senescent cells, non-mutational epigenetic reprogramming, polymorphic microbiomes and unlocked phenotypic plasticity. Circular RNAs (circRNAs) are single-stranded, covalently closed RNA molecules that are ubiquitous across all species. Recent studies on the circRNAs have highlighted their crucial function in regulating the formation of human malignancies through a range of biological processes. The primary goal of this review is to clarify the role of circRNAs in the most common form of liver cancer, hepatocellular carcinoma (HCC). This review also addressed the topic of how circRNAs affect HCC hallmarks, including the new generation hallmarks. Finally, the enormous applications that these rapidly expanding ncRNA molecules serve in the functional and molecular development of effective HCC diagnostic biomarkers and therapeutic targets.
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Affiliation(s)
- A Dawoud
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, New Administrative Capital, Egypt; School of Medicine, University of North California, Chapel Hill, NC 27599, USA
| | - R A Elmasri
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, New Administrative Capital, Egypt
| | - A H Mohamed
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, New Administrative Capital, Egypt; Department of Chemistry, Faculty of Science, Cairo University, Cairo, Egypt
| | - A Mahmoud
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, New Administrative Capital, Egypt; Biotechnology School, Nile University, Giza 12677, Egypt
| | - M M Rostom
- Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
| | - R A Youness
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, New Administrative Capital, Egypt.
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Duan BT, Zhao XK, Cui YY, Liu DZ, Wang L, Zhou L, Zhang XY. Construction and validation of somatic mutation-derived long non-coding RNAs signatures of genomic instability to predict prognosis of hepatocellular carcinoma. World J Gastrointest Surg 2024; 16:842-859. [PMID: 38577085 PMCID: PMC10989333 DOI: 10.4240/wjgs.v16.i3.842] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/20/2023] [Accepted: 02/19/2024] [Indexed: 03/22/2024] Open
Abstract
BACKGROUND Long non-coding RNAs (LncRNAs) have been found to be a potential prognostic factor for cancers, including hepatocellular carcinoma (HCC). Some LncRNAs have been confirmed as potential indicators to quantify genomic instability (GI). Nevertheless, GI-LncRNAs remain largely unexplored. This study established a GI-derived LncRNA signature (GILncSig) that can predict the prognosis of HCC patients. AIM To establish a GILncSig that can predict the prognosis of HCC patients. METHODS Identification of GI-LncRNAs was conducted by combining LncRNA expression and somatic mutation profiles. The GI-LncRNAs were then analyzed for functional enrichment. The GILncSig was established in the training set by Cox regression analysis, and its predictive ability was verified in the testing set and TCGA set. In addition, we explored the effects of the GILncSig and TP53 on prognosis. RESULTS A total of 88 GI-LncRNAs were found, and functional enrichment analysis showed that their functions were mainly involved in small molecule metabolism and GI. The GILncSig was constructed by 5 LncRNAs (miR210HG, AC016735.1, AC116351.1, AC010643.1, LUCAT1). In the training set, the prognosis of high-risk patients was significantly worse than that of low-risk patients, and similar results were verified in the testing set and TCGA set. Multivariate Cox regression analysis and stratified analysis confirmed that the GILncSig could be used as an independent prognostic factor. Receiver operating characteristic curve analysis of the GILncSig showed that the area under the curve (0.773) was higher than the two LncRNA signatures published recently. Furthermore, the GILncSig may have a better predictive performance than TP53 mutation status alone. CONCLUSION We established a GILncSig that can predict the prognosis of HCC patients, which will help to guide prognostic evaluation and treatment decisions.
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Affiliation(s)
- Bo-Tao Duan
- Department of Hepatobiliary Surgery, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Xue-Kai Zhao
- Department of Hepatobiliary Surgery, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Yang-Yang Cui
- Department of Hepatobiliary Surgery, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - De-Zheng Liu
- Department of Hepatobiliary Surgery, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Lin Wang
- Department of Ophthalmology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Lei Zhou
- Department of Hepatobiliary Surgery, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Xing-Yuan Zhang
- Department of Hepatobiliary Surgery, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
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Hu W, Ma SL, Qiong L, Du Y, Gong LP, Pan YH, Sun LP, Wen JY, Chen JN, Guan XY, Shao CK. PPM1G promotes cell proliferation via modulating mutant GOF p53 protein expression in hepatocellular carcinoma. iScience 2024; 27:109116. [PMID: 38384839 PMCID: PMC10879691 DOI: 10.1016/j.isci.2024.109116] [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: 09/01/2023] [Revised: 11/25/2023] [Accepted: 01/31/2024] [Indexed: 02/23/2024] Open
Abstract
The serine/threonine protein phosphatase family involves series of cellular processes, such as pre-mRNA splicing. The function of one of its members, protein phosphatase, Mg2+/Mn2+ dependent 1G (PPM1G), remains unclear in hepatocellular carcinoma (HCC). Our results demonstrated that PPM1G was significantly overexpressed in HCC cells and tumor tissues compared with the normal liver tissues at both protein and RNA levels. High PPM1G expression is associated with shorter overall survival (p < 0.0001) and disease-free survival (p = 0.004) in HCC patients. Enhanced expression of PPM1G increases the cell proliferation rate, and knockdown of PPM1G led to a significant reduction in tumor volume in vivo. Further experiments illustrated that upregulated-PPM1G expression increased the protein expression of gain-of-function (GOF) mutant p53. Besides, the immunoprecipitation analysis revealed a direct interaction between PPM1G and GOF mutant p53. Collectively, PPM1G can be a powerful prognostic predictor and potential drug-target molecule.
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Affiliation(s)
- Wen Hu
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Shao-Lin Ma
- Department of Gynecological Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China
| | - Liang Qiong
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Yu Du
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Li-Ping Gong
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Yu-Hang Pan
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Li-Ping Sun
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Jing-Yun Wen
- Department of Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Jian-Ning Chen
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Xin-Yuan Guan
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
- Department of Clinical Oncology, the University of Hong Kong, Hong Kong, China
| | - Chun-Kui Shao
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
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Phoolchund AGS, Khakoo SI. MASLD and the Development of HCC: Pathogenesis and Therapeutic Challenges. Cancers (Basel) 2024; 16:259. [PMID: 38254750 PMCID: PMC10814413 DOI: 10.3390/cancers16020259] [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: 11/27/2023] [Revised: 12/29/2023] [Accepted: 01/02/2024] [Indexed: 01/24/2024] Open
Abstract
Metabolic-dysfunction-associated steatotic liver disease (MASLD, previously known as non-alcoholic fatty liver disease (NAFLD)) represents a rapidly increasing cause of chronic liver disease and hepatocellular carcinoma (HCC), mirroring increasing rates of obesity and metabolic syndrome in the Western world. MASLD-HCC can develop at an earlier stage of fibrosis compared to other causes of chronic liver disease, presenting challenges in how to risk-stratify patients to set up effective screening programmes. Therapeutic decision making for MASLD-HCC is also complicated by medical comorbidities and disease presentation at a later stage. The response to treatment, particularly immune checkpoint inhibitors, may vary by the aetiology of the disease, and, in the future, patient stratification will be key to optimizing the therapeutic pathways.
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Affiliation(s)
- Anju G. S. Phoolchund
- Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK
| | - Salim I. Khakoo
- Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK
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11
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Iourov IY, Vorsanova SG, Yurov YB. A Paradoxical Role for Somatic Chromosomal Mosaicism and Chromosome Instability in Cancer: Theoretical and Technological Aspects. Methods Mol Biol 2024; 2825:67-78. [PMID: 38913303 DOI: 10.1007/978-1-0716-3946-7_3] [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] [Indexed: 06/25/2024]
Abstract
Somatic chromosomal mosaicism, chromosome instability, and cancer are intimately linked together. Addressing the role of somatic genome variations (encompassing chromosomal mosaicism and instability) in cancer yields paradoxical results. Firstly, somatic mosaicism for specific chromosomal rearrangement causes cancer per se. Secondly, chromosomal mosaicism and instability are associated with a variety of diseases (chromosomal disorders demonstrating less severe phenotypes, complex diseases), which exhibit cancer predisposition. Chromosome instability syndromes may be considered the best examples of these diseases. Thirdly, chromosomal mosaicism and instability are able to result not only in cancerous diseases but also in non-cancerous disorders (brain diseases, autoimmune diseases, etc.). Currently, the molecular basis for these three outcomes of somatic chromosomal mosaicism and chromosome instability remains incompletely understood. Here, we address possible mechanisms for the aforementioned scenarios using a system analysis model. A number of theoretical models based on studies dedicated to chromosomal mosaicism and chromosome instability seem to be valuable for disentangling and understanding molecular pathways to cancer-causing genome chaos. In addition, technological aspects of uncovering causes and consequences of somatic chromosomal mosaicism and chromosome instability are discussed. In total, molecular cytogenetics, cytogenomics, and system analysis are likely to form a powerful technological alliance for successful research against cancer.
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Affiliation(s)
- Ivan Y Iourov
- Yurov's Laboratory of Molecular Genetics and Cytogenomics of the Brain, Mental Health Research Center, Moscow, Russia
- Vorsanova's Laboratory of Molecular Cytogenetics of Neuropsychiatric Diseases, Veltischev Research and Clinical Institute for Pediatrics and Pediatric Surgery of the Pirogov Russian National Research Medical University of the Russian Ministry of Health, Moscow, Russia
| | - Svetlana G Vorsanova
- Yurov's Laboratory of Molecular Genetics and Cytogenomics of the Brain, Mental Health Research Center, Moscow, Russia
- Vorsanova's Laboratory of Molecular Cytogenetics of Neuropsychiatric Diseases, Veltischev Research and Clinical Institute for Pediatrics and Pediatric Surgery of the Pirogov Russian National Research Medical University of the Russian Ministry of Health, Moscow, Russia
| | - Yuri B Yurov
- Yurov's Laboratory of Molecular Genetics and Cytogenomics of the Brain, Mental Health Research Center, Moscow, Russia
- Vorsanova's Laboratory of Molecular Cytogenetics of Neuropsychiatric Diseases, Veltischev Research and Clinical Institute for Pediatrics and Pediatric Surgery of the Pirogov Russian National Research Medical University of the Russian Ministry of Health, Moscow, Russia
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12
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Zhu HX, Zheng WC, Chen H, Chen JY, Lin F, Chen SH, Xue XY, Zheng QS, Liang M, Xu N, Chen DN, Sun XL. Exploring Novel Genome Instability-associated lncRNAs and their Potential Function in Pan-Renal Cell Carcinoma. Comb Chem High Throughput Screen 2024; 27:1788-1807. [PMID: 37957851 DOI: 10.2174/0113862073258779231020052115] [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: 06/01/2023] [Revised: 09/14/2023] [Accepted: 09/21/2023] [Indexed: 11/15/2023]
Abstract
OBJECTIVE Genomic instability can drive clonal evolution, continuous modification of tumor genomes, and tumor genomic heterogeneity. The molecular mechanism of genomic instability still needs further investigation. This study aims to identify novel genome instabilityassociated lncRNAs (GI-lncRNAs) and investigate the role of genome instability in pan-Renal cell carcinoma (RCC). MATERIALS AND METHODS A mutator hypothesis was employed, combining the TCGA database of somatic mutation (SM) information, to identify GI-lncRNAs. Subsequently, a training cohort (n = 442) and a testing cohort (n = 439) were formed by randomly dividing all RCC patients. Based on the training cohort dataset, a multivariate Cox regression analysis lncRNAs risk model was created. Further validations were performed in the testing cohort, TCGA cohort, and different RCC subtypes. To confirm the relative expression levels of lncRNAs in HK-2, 786-O, and 769-P cells, qPCR was carried out. Functional pathway enrichment analyses were performed for further investigation. RESULTS A total of 170 novel GI-lncRNAs were identified. The lncRNA prognostic risk model was constructed based on LINC00460, AC073218.1, AC010789.1, and COLCA1. This risk model successfully differentiated patients into distinct risk groups with significantly different clinical outcomes. The model was further validated in multiple independent patient cohorts. Additionally, functional and pathway enrichment analyses revealed that GI-lncRNAs play a crucial role in GI. Furthermore, the assessments of immune response, drug sensitivity, and cancer stemness revealed a significant relationship between GI-lncRNAs and tumor microenvironment infiltration, mutational burden, microsatellite instability, and drug resistance. CONCLUSIONS In this study, we discovered four novel GI-lncRNAs and developed a novel signature that effectively predicted clinical outcomes in pan-RCC. The findings provide valuable insights for pan-RCC immunotherapy and shed light on potential underlying mechanisms.
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Affiliation(s)
- Hui-Xin Zhu
- Department of Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Wen-Cai Zheng
- Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Hang Chen
- Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Jia-Yin Chen
- Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Fei Lin
- Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Shao-Hao Chen
- Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Xue-Yi Xue
- Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
- Fujian Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Qing-Shui Zheng
- Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Min Liang
- Department of Anesthesiology, Anesthesiology Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Ning Xu
- Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
- Fujian Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Dong-Ning Chen
- Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Xiong-Lin Sun
- Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
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Song Z, Zhang J, Sun Y, Jiang Z, Liu X. Establishment and validation of an immune infiltration predictive model for ovarian cancer. BMC Med Genomics 2023; 16:227. [PMID: 37759229 PMCID: PMC10538244 DOI: 10.1186/s12920-023-01657-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND The most prevalent mutation in ovarian cancer is the TP53 mutation, which impacts the development and prognosis of the disease. We looked at how the TP53 mutation associates the immunophenotype of ovarian cancer and the prognosis of the disease. METHODS We investigated the state of TP53 mutations and expression profiles in culturally diverse groups and datasets and developed an immune infiltration predictive model relying on immune-associated genes differently expressed between TP53 WT and TP53 MUT ovarian cancer cases. We aimed to construct an immune infiltration predictive model (IPM) to enhance the prognosis of ovarian cancer and investigate the impact of the IPM on the immunological microenvironment. RESULTS TP53 mutagenesis affected the expression of seventy-seven immune response-associated genes. An IPM was implemented and evaluated on ovarian cancer patients to distinguish individuals with low- and high-IPM subgroups of poor survival. For diagnostic and therapeutic use, a nomogram is thus created. According to pathway enrichment analysis, the pathways of the human immune response and immune function abnormalities were the most associated functions and pathways with the IPM genes. Furthermore, patients in the high-risk group showed low proportions of macrophages M1, activated NK cells, CD8+ T cells, and higher CTLA-4, PD-1, PD-L1, and TIM-3 than patients in the low-risk group. CONCLUSIONS The IPM model may identify high-risk patients and integrate other clinical parameters to predict their overall survival, suggesting it is a potential methodology for optimizing ovarian cancer prognosis.
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Affiliation(s)
- Zhenxia Song
- Department of Obstetrics, Qingdao women and childeren's hospital, #6 Tongfu Road, Shibei District, Qingdao, Shandong, 266000, P. R. China
| | - Jingwen Zhang
- Department of Obstetrics, Qingdao women and childeren's hospital, #6 Tongfu Road, Shibei District, Qingdao, Shandong, 266000, P. R. China
| | - Yue Sun
- Department of Obstetrics, Qingdao women and childeren's hospital, #6 Tongfu Road, Shibei District, Qingdao, Shandong, 266000, P. R. China
| | - Zhongmin Jiang
- Department of Pathology, Tian Jin Fifth's Central Hospital, #41 Zhejiang Road, Binhai District, Tianjin, 300450, P. R. China
| | - Xiaoning Liu
- Department of Obstetrics, Qingdao women and childeren's hospital, #6 Tongfu Road, Shibei District, Qingdao, Shandong, 266000, P. R. China.
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14
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Wei Y, Lan C, Wang X, Zhou X, Liao X, Huang H, Wei Z, Li T, Peng T, Zhu G. RAD51AP1 as an Immune-Related Prognostic Biomarker and Therapeutic Response Predictor in Hepatocellular Carcinoma. Int J Gen Med 2023; 16:4377-4392. [PMID: 37789880 PMCID: PMC10543100 DOI: 10.2147/ijgm.s431206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 09/19/2023] [Indexed: 10/05/2023] Open
Abstract
Background RAD51 associated protein 1 (RAD51AP1) is shown to regulate cell proliferation and cancer progression. However, the immune-infiltrating correlation and the therapeutics guidance of RAD51AP1 in hepatocellular carcinoma (HCC) still need further investigation. Methods In this study, comprehensive bioinformatic analysis of RAD51AP1 on differential expression, clinicopathologic correlation, prognostic value, and function enrichment were performed in The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO; GSE14520 and GSE76427), and International Cancer Genome Consortium (ICGC) datasets. Besides, the Guangxi cohort containing 50 pairs HCC and adjacent non-cancerous samples from First Affiliated Hospital of Guangxi Medical University was served as validation cohort. Moreover, we explored the predictive value of RAD51AP1 to therapeutics response and its underlying correlation with HCC immunoinfiltration. Results RAD51AP1 was significantly overexpressed in HCC tissues and had a high diagnostic value of HCC. The shorter survival time and poorer clinical features were showed when RAD51AP1 upregulated, and then a nomogram featuring RAD51AP1 expression and other clinicopathologic factors was established to predict prognosis. In CIBERSORT analysis, higher T cells follicular helper but lower T cells CD4+ memory resting infiltration levels were exhibited when RAD51AP1 upregulated. The ssGSEA analysis demonstrated that high-RAD51AP1 expression subgroup had higher macrophages, Th2 and Treg cells infiltration levels, but lower type II IFN response function. Furthermore, high-RAD51AP1 expression subgroup exhibited the upregulated expression levels of immune-related checkpoint genes, but lower IPS and TIDE scores which suggested a possibly better immunotherapy response. The drug sensitivity analysis showed the high-expression subgroup may be more susceptible to Bexarotene, Doxorubicin, Gemcitabine and Tipifarnib. Conclusion Taken together, RAD51AP1 is a potential diagnostic and prognostic biomarker. It may be related to the immunosuppressive microenvironment and could be an underlying HCC treatment strategy. However, the conclusions still require further validation studies.
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Affiliation(s)
- Yongguang Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, 530021, People’s Republic of China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, 530021, People’s Republic of China
| | - Chenlu Lan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, 530021, People’s Republic of China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, 530021, People’s Republic of China
| | - Xiangkun Wang
- Departments of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, 530021, People’s Republic of China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, 530021, People’s Republic of China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, 530021, People’s Republic of China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, 530021, People’s Republic of China
| | - Huasheng Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, 530021, People’s Republic of China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, 530021, People’s Republic of China
| | - Zhongliu Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, 530021, People’s Republic of China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, 530021, People’s Republic of China
| | - Tianman Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, 530021, People’s Republic of China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, 530021, People’s Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, 530021, People’s Republic of China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, 530021, People’s Republic of China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, 530021, People’s Republic of China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, 530021, People’s Republic of China
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15
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Schmidt M, Foster GR, Coppens M, Thomsen H, Dolmetsch R, Heijink L, Monahan PE, Pipe SW. Molecular evaluation and vector integration analysis of HCC complicating AAV gene therapy for hemophilia B. Blood Adv 2023; 7:4966-4969. [PMID: 37352263 PMCID: PMC10463188 DOI: 10.1182/bloodadvances.2023009876] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 05/23/2023] [Accepted: 06/13/2023] [Indexed: 06/25/2023] Open
Affiliation(s)
| | - Graham R. Foster
- Barts Liver Centre, Queen Mary University of London, London, United Kingdom
| | - Michiel Coppens
- Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Cardiovascular Sciences, Pulmonary Hypertension & Thrombosis, Amsterdam, The Netherlands
| | | | | | | | | | - Steven W. Pipe
- Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, MI
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Xu J, Wu X, Chen J, Cheng Y, Zhang X. A TP53-associated metabolic gene signature for the prediction of overall survival and therapeutic responses in hepatocellular carcinoma. JOURNAL OF RADIATION RESEARCH AND APPLIED SCIENCES 2023. [DOI: 10.1016/j.jrras.2023.100552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
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Yuan J, Abdurahman A, Cui N, Hao T, Zou J, Liu L, Wu Y. Adjuvant therapy with Huatan Sanjie Granules improves the prognosis of patients with primary liver cancer: a cohort study and the investigation of its mechanism of action based on network pharmacology. Front Pharmacol 2023; 14:1091177. [PMID: 37324453 PMCID: PMC10267985 DOI: 10.3389/fphar.2023.1091177] [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: 01/16/2023] [Accepted: 05/18/2023] [Indexed: 06/17/2023] Open
Abstract
Objective: Nowadays, primary liver carcinoma (PLC) is one of the major contributors to the global cancer burden, and China has the highest morbidity and mortality rates in the world. As a well-known Chinese herbal medicine (CHM) prescription, Huatan Sanjie Granules (HSG) has been used clinically for many years to treat PLC with remarkable efficacy, but the underlying mechanism of action remains unclear. Methods: A clinical cohort study was conducted to observe the overall survival of PLC patients with vs. without oral administration of HSG. Meanwhile, the BATMAN-TCM database was used to retrieve the potential active ingredients in the six herbs of HSG and their corresponding drug targets. PLC-related targets were then screened through the Gene Expression Omnibus (GEO) database. The protein-protein interaction (PPI) network of targets of HSG against PLC was constructed using Cytoscape software. The cell function assays were further carried out for verification. Results: The results of the cohort study showed that the median survival time of PLC patients exposed to HSG was 269 days, which was 23 days longer than that of the control group (HR, 0.62; 95% CI, 0.38-0.99; p = 0.047). In particular, the median survival time of Barcelona Clinic Liver Cancer stage C patients was 411 days in the exposure group, which was 137 days longer than that in the control group (HR, 0.59; 95% CI, 0.35-0.96; p = 0.036). Meanwhile, the enrichment analysis result for the obtained PPI network consisting of 362 potential core therapeutic targets suggest that HSG may inhibit the growth of liver cancer (LC) cells by blocking the PI3K-Akt/MAPK signaling pathways. Furthermore, the above prediction results were verified by a series of in vitro assays. Specifically, we found that the expressions TP53 and YWHA2, the targets of the hepatitis B virus signaling pathway, were significantly affected by HSG. Conclusion: HSG shows promising therapeutic efficacy in the adjuvant treatment of PLC.
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Affiliation(s)
- Juhua Yuan
- Beijing Hospital of Integrated Traditional Chinese and Western Medicine, Beijing, China
| | - Abdusami Abdurahman
- Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Department of Molecular Pharmacology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Ning Cui
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Tengteng Hao
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jianhua Zou
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Liren Liu
- Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Department of Molecular Pharmacology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yu Wu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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18
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Chen Y, Zhu Z, Ma T, Zhang L, Chen J, Jiang J, Lu C, Ding Y, Guan W, Yi N, Ren H. TP53 mutation-related senescence is an indicator of hepatocellular carcinoma patient outcomes from multiomics profiles. SMART MEDICINE 2023; 2:e20230005. [PMID: 39188277 PMCID: PMC11235654 DOI: 10.1002/smmd.20230005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/13/2023] [Indexed: 08/28/2024]
Abstract
TP53 mutation frequently occurs in hepatocellular carcinoma (HCC). Senescence also plays a vital role in the ongoing process of HCC. P53 is believed to regulate the advancement of senescence in HCC. However, the exact mechanism of TP53 mutation-related senescence remains unclear. In this study, we found the TP53 mutation was positively correlated with senescence in HCC, and the differential expressed genes were primarily located in macrophages. Our results proved that the risk score could have an independent and vital role in predicting the prognosis of HCC patients. In addition, HCC patients with a high risk score may most probably benefit from immune checkpoint block therapy. We also found the risk score is elevated in chemotherapy-treated HCC samples, with a high level of senescence-associated secretory phenotype. Finally, we validated the risk-score genes in the protein level and noticed the risk score is positively related with M2 polarization. Of note, we considered that the risk score under the TP53 mutation and senescence is a promising biomarker with the potential to aid in predicting prognosis, defining tumor environment characteristics, and assessing the benefits of immunotherapy for HCC patients.
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Affiliation(s)
- Yu‐Yan Chen
- Department of Hepatobiliary SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Zheng‐Yi Zhu
- Department of Hepatobiliary SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Tao Ma
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Lu Zhang
- Nanjing Drum Tower Hospital Clinical College of Jiangsu UniversityNanjingChina
| | - Jing Chen
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Jia‐Wei Jiang
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Cui‐Hua Lu
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Yi‐Tao Ding
- Department of Hepatobiliary SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
- Department of General SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Wen‐Xian Guan
- Department of General SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Nan Yi
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Hao‐Zhen Ren
- Department of Hepatobiliary SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
- Department of General SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
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19
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Tan X, Xu L, Jian X, Ouyang J, Hu B, Yang X, Wang T, Xie L. PGNneo: A Proteogenomics-Based Neoantigen Prediction Pipeline in Noncoding Regions. Cells 2023; 12:782. [PMID: 36899918 PMCID: PMC10000440 DOI: 10.3390/cells12050782] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/26/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
The development of a neoantigen-based personalized vaccine has promise in the hunt for cancer immunotherapy. The challenge in neoantigen vaccine design is the need to rapidly and accurately identify, in patients, those neoantigens with vaccine potential. Evidence shows that neoantigens can be derived from noncoding sequences, but there are few specific tools for identifying neoantigens in noncoding regions. In this work, we describe a proteogenomics-based pipeline, namely PGNneo, for use in discovering neoantigens derived from the noncoding region of the human genome with reliability. In PGNneo, four modules are included: (1) noncoding somatic variant calling and HLA typing; (2) peptide extraction and customized database construction; (3) variant peptide identification; (4) neoantigen prediction and selection. We have demonstrated the effectiveness of PGNneo and applied and validated our methodology in two real-world hepatocellular carcinoma (HCC) cohorts. TP53, WWP1, ATM, KMT2C, and NFE2L2, which are frequently mutating genes associated with HCC, were identified in two cohorts and corresponded to 107 neoantigens from non-coding regions. In addition, we applied PGNneo to a colorectal cancer (CRC) cohort, demonstrating that the tool can be extended and verified in other tumor types. In summary, PGNneo can specifically detect neoantigens generated by noncoding regions in tumors, providing additional immune targets for cancer types with a low tumor mutational burden (TMB) in coding regions. PGNneo, together with our previous tool, can identify coding and noncoding region-derived neoantigens and, thus, will contribute to a complete understanding of the tumor immune target landscape. PGNneo source code and documentation are available at Github. To facilitate the installation and use of PGNneo, we provide a Docker container and a GUI.
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Affiliation(s)
- Xiaoxiu Tan
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
- Shanghai-MOST Key Laboratory of Health and Disease Genomics & Institute of Genome and Bioinformatics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200237, China
| | - Linfeng Xu
- Shanghai-MOST Key Laboratory of Health and Disease Genomics & Institute of Genome and Bioinformatics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200237, China
| | - Xingxing Jian
- Shanghai-MOST Key Laboratory of Health and Disease Genomics & Institute of Genome and Bioinformatics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200237, China
| | - Jian Ouyang
- Shanghai-MOST Key Laboratory of Health and Disease Genomics & Institute of Genome and Bioinformatics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200237, China
| | - Bo Hu
- Liver Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xinrong Yang
- Liver Cancer Institute, Fudan University, Shanghai 200032, China
| | - Tao Wang
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Lu Xie
- Shanghai-MOST Key Laboratory of Health and Disease Genomics & Institute of Genome and Bioinformatics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200237, China
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Xun Z, Wang Y, Long J, Li Y, Yang X, Sun H, Zhao H. Development and validation of a genomic instability-related lncRNA prognostic model for hepatocellular carcinoma. Front Genet 2023; 13:1034979. [PMID: 36712850 PMCID: PMC9877230 DOI: 10.3389/fgene.2022.1034979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 12/22/2022] [Indexed: 01/15/2023] Open
Abstract
Genomic instability is a characteristic of tumors, and recent studies have shown that it is related to a poor prognosis of multiple cancers. Long non-coding RNAs (lncRNAs) have become a research hotspot in recent years, and many unknown biological functions are being explored. For example, some lncRNAs play a critical role in the initiation and progression of multiple cancer types by modulating genomic instability. However, the role of genomic instability-related lncRNAs in liver cancer remains unclear. Therefore, we screened genomic instability-related lncRNAs by combining somatic mutation data and RNA-Seq data in The Cancer Genome Atlas (TCGA) database. We established a genomic instability-related lncRNA model (GLncM) involving ZFPM2-AS1 and MIR210HG to predict the hepatocellular carcinoma (HCC) prognosis and further explore the clinical significance of these lncRNAs, and the robustness of the model was validated in the verification set. Thereafter, we calculated the immune score for each patient and explored the relationship between genome instability and the immune microenvironment. The analysis indicated that this model was better than the immune microenvironment in predicting the prognosis of HCC patients, suggesting that the GLncM may be an effective indicator of HCC prognosis and providing a new direction and strategy for estimating the prognosis of HCC patients.
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Hepatocellular Carcinoma: Current Therapeutic Algorithm for Localized and Advanced Disease. JOURNAL OF ONCOLOGY 2022; 2022:3817724. [PMID: 36624801 PMCID: PMC9825221 DOI: 10.1155/2022/3817724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 01/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer in patients with liver cirrhosis of various etiologies. In recent years, there has been an advance in the knowledge of molecular mechanisms and a better staging definition of patients which has allowed the development of new therapies that have entered the therapeutic workup of these patients. Deep information on molecular drivers of HCC contributed to the development of targeted therapies with remarkable benefits. The novel strategies of targeting immune evasion using immune checkpoint inhibitors and CAR-T and TCR-T therapeutics have also shown promising results. For advanced diseases, the therapeutic algorithm has been recently updated, thanks to the efficacy of combining immunotherapy and antiangiogenic therapy in the first-line setting, and new drugs, both as single-agents or combinations, are currently under investigation.
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22
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Bispo IMC, Granger HP, Almeida PP, Nishiyama PB, de Freitas LM. Systems biology and OMIC data integration to understand gastrointestinal cancers. World J Clin Oncol 2022; 13:762-778. [PMID: 36337313 PMCID: PMC9630993 DOI: 10.5306/wjco.v13.i10.762] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/22/2021] [Accepted: 10/02/2022] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancers are a set of diverse diseases affecting many parts/ organs. The five most frequent GI cancer types are esophageal, gastric cancer (GC), liver cancer, pancreatic cancer, and colorectal cancer (CRC); together, they give rise to 5 million new cases and cause the death of 3.5 million people annually. We provide information about molecular changes crucial to tumorigenesis and the behavior and prognosis. During the formation of cancer cells, the genomic changes are microsatellite instability with multiple chromosomal arrangements in GC and CRC. The genomically stable subtype is observed in GC and pancreatic cancer. Besides these genomic subtypes, CRC has epigenetic modification (hypermethylation) associated with a poor prognosis. The pathway information highlights the functions shared by GI cancers such as apoptosis; focal adhesion; and the p21-activated kinase, phosphoinositide 3-kinase/Akt, transforming growth factor beta, and Toll-like receptor signaling pathways. These pathways show survival, cell proliferation, and cell motility. In addition, the immune response and inflammation are also essential elements in the shared functions. We also retrieved information on protein-protein interaction from the STRING database, and found that proteins Akt1, catenin beta 1 (CTNNB1), E1A binding protein P300, tumor protein p53 (TP53), and TP53 binding protein 1 (TP53BP1) are central nodes in the network. The protein expression of these genes is associated with overall survival in some GI cancers. The low TP53BP1 expression in CRC, high EP300 expression in esophageal cancer, and increased expression of Akt1/TP53 or low CTNNB1 expression in GC are associated with a poor prognosis. The Kaplan Meier plotter database also confirmed the association between expression of the five central genes and GC survival rates. In conclusion, GI cancers are very diverse at the molecular level. However, the shared mutations and protein pathways might be used to understand better and reveal diagnostic/prognostic or drug targets.
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Affiliation(s)
- Iasmin Moreira Costa Bispo
- Núcleo de Biointegração, Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45.029-094, Bahia, Brazil
| | - Henry Paul Granger
- Núcleo de Biointegração, Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45.029-094, Bahia, Brazil
| | - Palloma Porto Almeida
- Division of Experimental and Translational Research, Brazilian National Cancer Institute, Rio de Janeiro 20231-050, Brazil
| | - Patricia Belini Nishiyama
- Núcleo de Biointegração, Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45.029-094, Bahia, Brazil
| | - Leandro Martins de Freitas
- Núcleo de Biointegração, Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45.029-094, Bahia, Brazil
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Molecular Classification of Hepatocellular Carcinoma Using Wnt-Hippo Signaling Pathway-Related Genes. Cancers (Basel) 2022; 14:cancers14194580. [PMID: 36230503 PMCID: PMC9559216 DOI: 10.3390/cancers14194580] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/14/2022] [Accepted: 09/19/2022] [Indexed: 12/05/2022] Open
Abstract
Simple Summary The characters of Taiwanese hepatocellular carcinoma (HCC) are different from other parts of the world. We characterized the molecular features of HCC using a newly developed classification system based on the expression of the Wnt–Hippo signaling pathway-related genes. We analyzed the data in terms of prognostic value, transcriptome features, immune infiltration, and clinical characteristics, and compared the resulting subclasses with previously published classifications. A new molecular classification method based on a 272 gene panel of Wnt–Hippo pathways that may provide a new target for the treatment. Abstract In Taiwan, a combination of hepatitis B and C infection, economic boom-related food and alcohol overconsumption, and Chinese medicine prescriptions has led to a high rate of hepatocellular carcinoma (HCC). However, the causative factors and underlying tumor biology for this unique HCC environment have not been identified. Wnt and Hippo signaling pathways play an important regulatory role in HCC development, and their functions are generally considered as positive and negative regulators of cell proliferation, respectively. In this study, we characterized the molecular features of HCC using a newly developed classification system based on the expression of the Wnt–Hippo signaling pathway-related genes. RNA sequencing (RNA-Seq) was performed on liver tumor tissues from 100 patients with liver cancer. RNA-Seq data for 272 previously characterized Wnt–Hippo signaling pathway-related genes were used for hierarchical clustering. We analyzed the data in terms of prognostic value, transcriptome features, immune infiltration, and clinical characteristics, and compared the resulting subclasses with previously published classifications. Four subclasses of HCC (HCCW1–4) were identified. Subclass HCCW1 displayed the highest PCDHB4 expression. Subclass HCCW2 displayed lower Edmondson–Steiner grades (I and II) and CTNNB1 mutation frequencies. Subclass HCCW3 was associated with a good prognosis, the highest PCDHGB7 expression, high CD8+ naïve T cells abundance, and relatively low TP53 mutation rates. Subclass HCCW4 was associated with a poor prognosis, the highest PCDHB2 and PCDHB6 expression, a relatively high abundance of Th1 cells, NKT and class-switched memory B cells, relatively low enrichment of cDC, iDC, and CD4+ memory T cells, and high Edmondson–Steiner grades (III and IV). We also identified Wnt–Hippo signaling pathway-related genes that may influence immune cell infiltration. We developed a panel of 272 Wnt–Hippo signaling pathway-related genes to classify HCC into four groups based on Taiwanese HCC and The Cancer Genome Atlas Liver Hepatocellular Carcinoma datasets. This novel molecular classification system may aid the treatment of HCC.
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Prognostic Value of MUC16 Mutation and Its Correlation with Immunity in Hepatocellular Carcinoma Patients. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:3478861. [PMID: 36034941 PMCID: PMC9410786 DOI: 10.1155/2022/3478861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 07/18/2022] [Accepted: 07/20/2022] [Indexed: 12/24/2022]
Abstract
Objective Identifying gene mutation signatures will enable a better understanding for the occurrence, development, and prognosis of hepatocellular carcinoma (HCC) and provide some potential biomarkers for clinical practice. This study investigated the mutated genes in HCC patients and assessed their relationship with tumor mutation burden (TMB) and prognosis. Methods The somatic mutation annotation format (MAF) document, mRNA expression matrix, and clinical information of HCC patients were obtained from the International Cancer Genome Consortium (ICGC) and the Cancer Genome Atlas (TCGA) database. The differences of TMB between the mutant type and the wild-type genes were detected using the Mann–Whitney U test. The link of gene mutations with prognosis was explored by the Kaplan–Meier analysis. The proportion of 22 immune cells' composition was measured using CIBERSORT algorithm. Results The two databases screened 16 common mutated genes, which included TP53, TTN, LRP1B, ZFHX4, MUC16, OBSCN, CSMD3, FLG, CSMD1, SYNE1, SPTA1, USH2A, KMT2C, PCLO, HMCN1, and FAT3. After a series of analysis, MUC16 mutation was found to be highly correlated with TMB and was regarded as an independent factor predicting HCC. Furthermore, gene set enrichment analysis (GSEA) indicated that the MUC16 mutation was significantly involved in HCC cell metabolism. Conclusions MUC16 mutation seems to be a valuable potential biomarker for HCC development and its overall survival.
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Ye T, Lin L, Cao L, Huang W, Wei S, Shan Y, Zhang Z. Novel Prognostic Signatures of Hepatocellular Carcinoma Based on Metabolic Pathway Phenotypes. Front Oncol 2022; 12:863266. [PMID: 35677150 PMCID: PMC9168273 DOI: 10.3389/fonc.2022.863266] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 04/06/2022] [Indexed: 12/03/2022] Open
Abstract
Hepatocellular carcinoma is a disastrous cancer with an aberrant metabolism. In this study, we aimed to assess the role of metabolism in the prognosis of hepatocellular carcinoma. Ten metabolism-related pathways were identified to classify the hepatocellular carcinoma into two clusters: Metabolism_H and Metabolism_L. Compared with Metabolism_L, patients in Metabolism_H had lower survival rates with more mutated TP53 genes and more immune infiltration. Moreover, risk scores for predicting overall survival based on eleven differentially expressed metabolic genes were developed by the least absolute shrinkage and selection operator (LASSO)-Cox regression model in The Cancer Genome Atlas (TCGA) dataset, which was validated in the International Cancer Genome Consortium (ICGC) dataset. The immunohistochemistry staining of liver cancer patient specimens also identified that the 11 genes were associated with the prognosis of liver cancer patients. Multivariate Cox regression analyses indicated that the differentially expressed metabolic gene-based risk score was also an independent prognostic factor for overall survival. Furthermore, the risk score (AUC = 0.767) outperformed other clinical variables in predicting overall survival. Therefore, the metabolism-related survival-predictor model may predict overall survival excellently for HCC patients.
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Affiliation(s)
- Tingbo Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Leilei Lin
- Department of Ultrasound, Wenzhou People's Hospital, Wenzhou, China
| | - Lulu Cao
- Department of Pathology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
| | - Weiguo Huang
- Department of Vascular Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shengzhe Wei
- Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yunfeng Shan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhongjing Zhang
- Department of Vascular Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Yang Y, Qu Y, Li Z, Tan Z, Lei Y, Bai S. Identification of Novel Characteristics in TP53-Mutant Hepatocellular Carcinoma Using Bioinformatics. Front Genet 2022; 13:874805. [PMID: 35651938 PMCID: PMC9149291 DOI: 10.3389/fgene.2022.874805] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 04/20/2022] [Indexed: 11/29/2022] Open
Abstract
Background: TP53 mutations are the most frequent mutations in hepatocellular carcinoma (HCC) and affect the occurrence and development of this cancer type. Therefore, it is essential to clarify the function and mechanism of TP53 mutations in HCC. Methods: We performed a sequence of bioinformatic analyses to elucidate the characteristics of TP53 mutations in HCC. We downloaded the data of hepatocellular carcinoma from The Cancer Genome Atlas database and used different R packages for serial analyses, including gene mutation analysis, copy number variation analysis, analysis of the tumor mutational burden and microsatellite instability, differential gene expression analysis, and functional enrichment analysis of TP53 mutations, and performed gene set enrichment analysis. We established a protein-protein interaction network using the STRING online database and used the Cytoscape software for network visualization, and hub gene screening. In addition, we performed anticancer drug sensitivity analysis using data from the Genomics of Drug Sensitivity in Cancer. Immune infiltration and prognosis analyses were also performed. Results: Missense mutations accounted for a great proportion of HCC mutations, the frequency of single nucleotide polymorphisms was high, and C > T was the most common form of single nucleotide variations. TP53 had a mutation rate of 30% and was the most commonly mutated gene in HCC. In the TP53 mutant group, the tumor mutational burden (p < 0.001), drug sensitivity (p < 0.05), ESTIMATE score (p = 0.038), and stromal score (p < 0.001) dramatically decreased. The Cytoscape software screened ten hub genes, including CT45A1, XAGE1B, CT55, GAGE2A, PASD1, MAGEA4, CTAG2, MAGEA10, MAGEC1, and SAGE1. The prognostic model showed a poor prognosis in the TP53 mutation group compared with that in the wild-type group (overall survival, p = 0.023). Univariate and multivariate cox regression analyses revealed that TP53 mutation was an independent risk factor for the prognosis of HCC patients (p <0.05). The constructed prognostic model had a favorable forecast value for the prognosis of HCC patients at 1 and 3 years (1-year AUC = 0.752, 3-years AUC = 0.702). Conclusion: This study further deepened our understanding of TP53-mutated HCC, provided new insights into a precise individualized therapy for HCC, and has particular significance for prognosis prediction.
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Affiliation(s)
- Yang Yang
- The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yajuan Qu
- Department of Rehabilitation Medicine, Qujing Second People's Hospital, Qujing, China
| | - Zhaopeng Li
- The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zhiyong Tan
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Youming Lei
- The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Song Bai
- The First Affiliated Hospital of Kunming Medical University, Kunming, China
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Zou JY, Huang YJ, He J, Tang ZX, Qin L. Glycolytic and fatty acid oxidation genes affect the treatment and prognosis of liver cancer. World J Clin Cases 2022; 10:4737-4760. [PMID: 35801051 PMCID: PMC9198879 DOI: 10.12998/wjcc.v10.i15.4737] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 02/02/2022] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Metabolic reprogramming is a feature of tumour cells and is essential to support their rapid proliferation. The glycolytic activity of liver cancer cells is significantly higher than that of normal liver cells, and the rapidly proliferating tumour cells are powered by aerobic glycolysis. Lipid metabolism reprogramming enables tumour cells to meet their needs for highly proliferative growth and is an important driving force for the development of hepatocellular carcinoma (HCC).
AIM To explore the influence of different metabolic subtypes of HCC and analyse their significance in guiding prognosis and treatment based on the molecular mechanism of glycolysis and fatty acid oxidation (FAO).
METHODS By downloading related data from public databases including the Cancer Genome Atlas (TCGA), the Molecular Signatures Database, and International Cancer Genome Consortium, we utilised unsupervised consensus clustering to divide TCGA Liver Hepatocellular Carcinoma samples into four metabolic subgroups and compared single nucleotide polymorphism, copy number variation, tumour microenvironment, and Genomics of Drug Sensitivity in Cancer and Tumour Immune Dysfunction and Exclusion between different metabolites. The differences and causes of survival and the clinical characteristics between them were analysed, and a prognostic model was established based on glycolysis and FAO genes. Combined with the clinical features, a Norman diagram was created to compare the pros and cons of each model.
RESULTS In the four metabolic subgroups, with the increase in glycolytic expression, the median survival of patients showed the worst results, while FAO showed the best. When comparing the follow-up analysis of each group, we considered that the differences between them might be related to reactive oxygen species, somatic copy number variation of key genes, and immune microenvironment. It was also found that the FAO group and the low-risk group had better efficacy and response to immune checkpoint blockade treatment and anti-tumour drugs.
CONCLUSION There are obvious differences in genes, chromosomes, and clinical characteristics between metabolic subgroups. The establishment of a prognostic model could predict patient prognosis and guide clinical treatment.
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Affiliation(s)
- Jia-Yue Zou
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Yu-Jie Huang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Jun He
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Zu-Xiong Tang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Lei Qin
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
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Lau JF, Vokuhl C. [Epithelial childhood liver tumors : An overview of the new WHO classification for pediatric tumors]. DER PATHOLOGE 2022; 43:202-209. [PMID: 35384506 DOI: 10.1007/s00292-022-01067-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/24/2022] [Indexed: 06/14/2023]
Abstract
Pediatric liver tumors are very rare tumors and account for less than 1% of all childhood malignancies. By far the most common tumors are hepatoblastomas. This review discusses epithelial malignant childhood liver tumors, with particular attention to the morphology of the different hepatoblastoma subtypes. In addition, other malignant liver tumors such as the so-called hepatocellular tumor NOS and the second-most common childhood liver tumor, the hepatocellular carcinoma, are discussed. In addition to the typical morphological characteristics, the immunohistochemical and molecular aspects are also be presented, which can help to distinguish these entities with often overlapping morphology.
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Affiliation(s)
- J F Lau
- Sektion Kinderpathologie, Institut für Pathologie, Universitätsklinikum Bonn, Venusberg-Campus 1, 53127, Bonn, Deutschland
| | - C Vokuhl
- Sektion Kinderpathologie, Institut für Pathologie, Universitätsklinikum Bonn, Venusberg-Campus 1, 53127, Bonn, Deutschland.
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Kim T, Issa D, Onyshchenko M. Analyzing TCGA Data to Identify Gene Mutations Linked to Hepatocellular Carcinoma in Asians. Gastrointest Tumors 2022; 9:43-58. [PMID: 36590851 PMCID: PMC9801391 DOI: 10.1159/000524576] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 03/13/2022] [Indexed: 01/04/2023] Open
Abstract
Introduction Liver cancer is the sixth most common and second most fatal type of cancer worldwide. Few treatment options are available as patients with liver cancer are often diagnosed in an advanced stage due to a lack of clinical symptoms. Effectively preventing and treating liver cancer relies heavily on early diagnosis; early diagnosis results from identifying and monitoring high-risk patients. Epigenetic risk factors, such as hepatitis B, hepatitis C, cirrhosis, nonalcoholic fatty liver disease, and alcohol/tobacco abuse, are highly prevalent in Asia and likely cause Asians to have a higher incidence and mortality rate of liver cancer. While these acquired risk factors are relatively well understood, the underlying genetic background of liver cancer in Asians has not been well established or correlated with clinical outcomes. Methods In this study, we accessed The Cancer Genome Atlas (TCGA) hepatocellular carcinoma clinical and mutation data through TCGAbiolinksGUI. Results We found that mutations in five genes (TP53, TTN, OBSCN, MUC5B, CSMD1) were statistically linked with increased mortality in Asians compared to non-Asians, four of which (TTN, OBSCN, MUC5B, CSMD1) were also more prevalent in the Asian population. Within the Asian cohort, two gene mutations (TTN, HMCN1) were statistically linked with worse outcomes. We also found that the TP53 mutation predicts worse outcomes within the non-Asian cohort but not within the Asian cohort. Discussion/Conclusion Our findings can improve cancer care in the Asian population through better disease prognostication, evaluations for potential targeted therapy, and a deeper understanding of liver cancer pathogenesis.
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Affiliation(s)
- Tane Kim
- Orange County School of the Arts, Santa Ana, California, USA
| | - Danny Issa
- Division of Digestive Diseases, Department of Medicine, UCLA School of Medicine, Los Angeles, California, USA
| | - Mykola Onyshchenko
- Hematology-Oncology Division, Department of Medicine, Harbor-UCLA/Lundquist Institute, Torrance, California, USA,*Mykola Onyshchenko,
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Jiang Z, Zhao Q, Chen L, Luo Y, Shen L, Cao Z, Wang Q. UBR3 promotes inflammation and apoptosis via DUSP1/p38 pathway in the nucleus pulposus cells of patients with intervertebral disc degeneration. Hum Cell 2022; 35:792-802. [PMID: 35332432 DOI: 10.1007/s13577-022-00693-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 03/15/2022] [Indexed: 11/04/2022]
Abstract
Intervertebral disc disease (IDD) is a primary cause of low back pain, affecting 5% of individuals. Previous study have shown that dual-specificity (Thr/Tyr) phosphatase 1 (DUSP1) regulates p38 MAPK activity and DUSP1 level is regulated by ubiquitination. As an E3 ubiquitin-protein ligase, UBR3 has been shown to regulate a variety of biological processes through ubiquitination. However, the role of UBR3/DUSP1/p38 in IDD remains to be elucidated. In the current study, we found that UBR3 was significantly increased in the nucleus pulposus tissues of IDD patients and was correlated with IDD severity. Silencing UBR3 promoted the growth, inhibited apoptosis, and inhibited inflammation in primary NPCs. Mechanism study suggested that UBR3 exerted its effects through p38. Co-immunoprecipitation assay indicated that UBR3 promoted DUSP1 ubiquitination. Overexpression of DUSP1 reversed the effect of UBR3 overexpression. Our data also supported that UBR3 was positively correlated with p-p38, but negatively correlated with DUSP1 in IDD. In summary, UBR3 promotes inflammation and apoptosis via inhibiting the p38 signaling pathway by DUSP1 ubiquitination in the NPCs of IDD patients. These findings highlight the importance of UBR3/DUSP1/p38 signaling pathway in IDD and provide new insights for the prevention and treatment of IDD.
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Affiliation(s)
- Zhenhuan Jiang
- Department of Orthopaedics, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Qinghua Zhao
- Department of Orthopaedics, School of Medicine, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Liang Chen
- Department of Orthopaedics, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Yifeng Luo
- Department of Radiology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Lei Shen
- Department of Orthopaedics, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Zhihong Cao
- Department of Radiology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China.
| | - Qiang Wang
- Department of Orthopaedics, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China.
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Oncogenic Mutation BRAF V600E Changes Phenotypic Behavior of THLE-2 Liver Cells through Alteration of Gene Expression. Int J Mol Sci 2022; 23:ijms23031548. [PMID: 35163468 PMCID: PMC8836259 DOI: 10.3390/ijms23031548] [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: 11/22/2021] [Revised: 01/12/2022] [Accepted: 01/17/2022] [Indexed: 12/10/2022] Open
Abstract
The accumulation of mutations in cancer driver genes, such as tumor suppressors or proto-oncogenes, affects cellular homeostasis. Disturbances in the mechanism controlling proliferation cause significant augmentation of cell growth and division due to the loss of sensitivity to the regulatory signals. Nowadays, an increasing number of cases of liver cancer are observed worldwide. Data provided by the International Cancer Genome Consortium (ICGC) have indicated many alterations within gene sequences, whose roles in tumor development are not well understood. A comprehensive analysis of liver cancer (virus-associated hepatocellular carcinoma) samples has identified new and rare mutations in B-Raf proto-oncogene (BRAF) in Japanese HCC patients, as well as BRAF V600E mutations in French HCC patients. However, their function in liver cancer has never been investigated. Here, using functional analysis and next generation sequencing, we demonstrate the tumorigenic effect of BRAF V600E on hepatocytes (THLE-2 cell line). Moreover, we identified genes such as BMP6, CXCL11, IL1B, TBX21, RSAD2, MMP10, and SERPIND1, which are possibly regulated by the BRAF V600E-mediated, mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) signaling pathway. Through several functional assays, we demonstrate that BRAF L537M, D594A, and E648G mutations alone are not pathogenic in liver cancer. The investigation of genome mutations and the determination of their impact on cellular processes and functions is crucial to unraveling the molecular mechanisms of liver cancer development.
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Guz M, Jeleniewicz W, Cybulski M. An Insight into miR-1290: An Oncogenic miRNA with Diagnostic Potential. Int J Mol Sci 2022; 23:1234. [PMID: 35163157 PMCID: PMC8835968 DOI: 10.3390/ijms23031234] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/11/2022] [Accepted: 01/19/2022] [Indexed: 12/12/2022] Open
Abstract
For more than two decades, the view of the roles of non-coding RNAs (ncRNAs) has been radically changing. These RNA molecules that are transcribed from our genome do not have the capacity to encode proteins, but are critical regulators of gene expression at different levels. Our knowledge is constantly enriched by new reports revealing the role of these new molecular players in the development of many pathological conditions, including cancer. One of the ncRNA classes includes short RNA molecules called microRNAs (miRNAs), which are involved in the post-transcriptional control of gene expression affecting various cellular processes. The aberrant expression of miRNAs with oncogenic and tumor-suppressive function is associated with cancer initiation, promotion, malignant transformation, progression and metastasis. Oncogenic miRNAs, also known as oncomirs, mediate the downregulation of tumor-suppressor genes and their expression is upregulated in cancer. Nowadays, miRNAs show promising application in diagnosis, prediction, disease monitoring and therapy response. Our review presents a current view of the oncogenic role of miR-1290 with emphasis on its properties as a cancer biomarker in clinical medicine.
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Affiliation(s)
- Małgorzata Guz
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (W.J.); (M.C.)
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Da BB, Luo S, Huang M, Song F, Ding R, Xiao Y, Fu Y, Yang YS, Wang HL. Prediction of Hepatocellular Carcinoma Prognosis and Immune Cell Infiltration Using Gene Signature Associated with Inflammatory Response. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:2415129. [PMID: 35035517 PMCID: PMC8759924 DOI: 10.1155/2022/2415129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/05/2021] [Accepted: 12/09/2021] [Indexed: 12/24/2022]
Abstract
It has been demonstrated that the inflammatory response influences cancer development and can be used as a prognostic biomarker in various tumors. However, the relevance of genes associated with inflammatory responses in hepatocellular carcinoma (HCC) remains unknown. The Cancer Genome Atlas (TCGA) database was analyzed using weighted gene coexpression network analysis (WGCNA) and differential analysis to discover essential inflammatory response-related genes (IFRGs). Cox regression studies, both univariate and multivariate, were employed to develop a prognostic IFRGs signature. Additionally, Gene Set Enrichment Analysis (GSEA) was used to deduce the biological function of the IFRGs signature. Finally, we estimated immune cell infiltration using a single sample GSEA (ssGSEA) and x-cell. Our results revealed that, among the major HCC IFRGs, two (DNASE1L3 and KLKB1) were employed to create a predictive IFRG signature. The IFRG signature could correctly predict overall survival (O.S) as per Kaplan-Meier time-dependent roc curves analysis. It was also linked to pathological tumor stage and T stage and might be used as a prognostic predictor in HCC. GSEA analysis concluded that the IFRG signature might influence the immune response in HCC. Immunological cell infiltration and immune checkpoint molecule expression differed in the high-risk and low-risk groups. As a result of our findings, DNASILE may play a role in the tumor microenvironment. However, more research is necessary to confirm the role of DNASE1L3 and KLKB1.
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Affiliation(s)
- Bin-Bin Da
- Department of Minimally Invasive Interventional Medicine Yunnan Cancer Hospital, Kunming 650118, China
| | - Shuai Luo
- Department of Minimally Invasive Interventional Medicine Yunnan Cancer Hospital, Kunming 650118, China
| | - Ming Huang
- Department of Minimally Invasive Interventional Medicine Yunnan Cancer Hospital, Kunming 650118, China
| | - Fei Song
- Department of Minimally Invasive Interventional Medicine Yunnan Cancer Hospital, Kunming 650118, China
| | - Rong Ding
- Department of Minimally Invasive Interventional Medicine Yunnan Cancer Hospital, Kunming 650118, China
| | - Yao Xiao
- Department of Minimally Invasive Interventional Medicine Yunnan Cancer Hospital, Kunming 650118, China
| | - Yang Fu
- CT Room, Kunming First People's Hospital, Kunming 650000, China
| | - Yin-Shan Yang
- Department of Minimally Invasive Interventional Medicine Yunnan Cancer Hospital, Kunming 650118, China
| | - Hai-Lei Wang
- Hepatobiliary Pancreatic Vascular Surgery, Kunming First People's Hospital, Kunming 650031, China
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Khatib SA, Wang XW. Causes and functional intricacies of inter- and intratumor heterogeneity of primary liver cancers. Adv Cancer Res 2022; 156:75-102. [DOI: 10.1016/bs.acr.2022.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Pavani G, Amendola M. Targeted Gene Delivery: Where to Land. Front Genome Ed 2021; 2:609650. [PMID: 34713234 PMCID: PMC8525409 DOI: 10.3389/fgeed.2020.609650] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 12/16/2020] [Indexed: 12/12/2022] Open
Abstract
Genome-editing technologies have the potential to correct most genetic defects involved in blood disorders. In contrast to mutation-specific editing, targeted gene insertion can correct most of the mutations affecting the same gene with a single therapeutic strategy (gene replacement) or provide novel functions to edited cells (gene addition). Targeting a selected genomic harbor can reduce insertional mutagenesis risk, while enabling the exploitation of endogenous promoters, or selected chromatin contexts, to achieve specific transgene expression levels/patterns and the modulation of disease-modifier genes. In this review, we will discuss targeted gene insertion and the advantages and limitations of different genomic harbors currently under investigation for various gene therapy applications.
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Affiliation(s)
- Giulia Pavani
- INTEGRARE, UMR_S951, Genethon, Inserm, Univ Evry, Univ Paris-Saclay, Evry, France
| | - Mario Amendola
- INTEGRARE, UMR_S951, Genethon, Inserm, Univ Evry, Univ Paris-Saclay, Evry, France
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Yang CL, Qiu X, Lin JY, Chen XY, Zhang YM, Hu XY, Zhong JH, Tang S, Li XY, Xiang BD, Zhang ZM. Potential Role and Clinical Value of PPP2CA in Hepatocellular Carcinoma. J Clin Transl Hepatol 2021; 9:661-671. [PMID: 34722181 PMCID: PMC8516843 DOI: 10.14218/jcth.2020.00168] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 02/25/2021] [Accepted: 04/05/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND AND AIMS Protein phosphatase 2A (PP2A) is associated with many cancers. This study aimed to clarify whether PPP2CA, which encodes the alpha isoform of the catalytic subunit of PP2A, plays a role in hepatocellular carcinoma (HCC) and to identify the potential underlying molecular pathways. METHODS Based on bioinformatics, public databases and our in-house RNA-Seq database, we analyzed the clinical value and molecular mechanism of PPP2CA in HCC. RESULTS Data were analyzed from 2,545 patients with HCC and 1,993 controls without HCC indexed in The Cancer Genome Atlas database, the Gene Expression Omnibus database and our in-house RNA-Seq database. PPP2CA expression was significantly higher in HCC tissue than in non-cancerous tissues (standardized mean difference: 0.69, 95% confidence interval [CI]: 0.50-0.89). PPP2CA expression was able to differentiate HCC from non-HCC, with an area under the summary receiver operator characteristic curve of 0.79 (95% CI: 0.75-0.83). Immunohistochemistry of tissue sections confirmed that PPP2CA protein was up-regulated in HCC tissues. High PPP2CA expression in HCC patients was associated with shorter overall, progression-free and disease-free survival. Potential molecular pathways through which PPP2CA may be involved in HCC were determined using miRWalk 2.0 as well as analysis of Gene Ontology categories, Kyoto Encyclopedia of Genes and Genomes pathways, and protein-protein interaction networks. CONCLUSIONS PPP2CA is up-regulated in HCC and higher expression correlates with worse prognosis. PPP2CA shows potential as a diagnostic marker for HCC. Future studies should examine whether PPP2CA contributes to HCC through the candidate microRNAs, pathways and hub genes identified in this study.
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Affiliation(s)
- Cheng-Lei Yang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Xue Qiu
- The First Clinical Medical School, Guangxi Medical University, Nanning, Guangxi, China
| | - Jin-Yan Lin
- The First Clinical Medical School, Guangxi Medical University, Nanning, Guangxi, China
| | - Xiao-Yu Chen
- Department of Pathology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Yu-Mei Zhang
- Department of Medical Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xiao-Yin Hu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Jian-Hong Zhong
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Shen Tang
- School of Basic Medical Sciences, Guangxi Medical University, Nanning, Guangxi, China
| | - Xi-Yi Li
- School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Bang-De Xiang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Zhi-Ming Zhang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
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Zhang G, Su L, Lv X, Yang Q. A novel tumor doubling time-related immune gene signature for prognosis prediction in hepatocellular carcinoma. Cancer Cell Int 2021; 21:522. [PMID: 34627241 PMCID: PMC8502295 DOI: 10.1186/s12935-021-02227-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 09/24/2021] [Indexed: 12/30/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) has become a global health issue of wide concern due to its high prevalence and poor therapeutic efficacy. Both tumor doubling time (TDT) and immune status are closely related to the prognosis of HCC patients. However, the association between TDT-related genes (TDTRGs) and immune-related genes (IRGs) and the value of their combination in predicting the prognosis of HCC patients remains unclear. The current study aimed to discover reliable biomarkers for anticipating the future prognosis of HCC patients based on the relationship between TDTRGs and IRGs. Methods Tumor doubling time-related genes (TDTRGs) were acquired from GSE54236 by using Pearson correlation test and immune-related genes (IRGs) were available from ImmPort. Prognostic TDTRGs and IRGs in TCGA-LIHC dataset were determined to create a prognostic model by the LASSO-Cox regression and stepwise Cox regression analysis. International Cancer Genome Consortium (ICGC) and another cohort of individual clinical samples acted as external validations. Additionally, significant impacts of the signature on HCC immune microenvironment and reaction to immune checkpoint inhibitors were observed. Results Among the 68 overlapping genes identified as TDTRG and IRG, a total of 29 genes had significant prognostic relevance and were further selected by performing a LASSO-Cox regression model based on the minimum value of λ. Subsequently, a prognostic three-gene signature including HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), C-type lectin domain family 1 member B (CLEC1B), and Collectin sub-family member 12 (COLEC12) was finally identified by stepwise Cox proportional modeling. The signature exhibited superior accuracy in forecasting the survival outcomes of HCC patients in TCGA, ICGC and the independent clinical cohorts. Patients in high-risk subgroup had significantly increased levels of immune checkpoint molecules including PD-L1, CD276, CTLA4, CXCR4, IL1A, PD-L2, TGFB1, OX40 and CD137, and are therefore more sensitive to immune checkpoint inhibitors (ICIs) treatment. Finally, we first found that overexpression of CLEC1B inhibited the proliferation and migration ability of HuH7 cells. Conclusions In summary, the prognostic signature based on TDTRGs and IRGs could effectively help clinicians classify HCC patients for prognosis prediction and individualized immunotherapies. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02227-w.
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Affiliation(s)
- Genhao Zhang
- Department of Blood Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Lisa Su
- Department of Genetic and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xianping Lv
- Department of Blood Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qiankun Yang
- Department of Blood Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Huang T, Yan T, Chen G, Zhang C. Development and Validation of a Gene Mutation-Associated Nomogram for Hepatocellular Carcinoma Patients From Four Countries. Front Genet 2021; 12:714639. [PMID: 34621291 PMCID: PMC8490742 DOI: 10.3389/fgene.2021.714639] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 09/03/2021] [Indexed: 01/07/2023] Open
Abstract
Background: Genomic alteration is the basis of occurrence and development of carcinoma. Specific gene mutation may be associated with the prognosis of hepatocellular carcinoma (HCC) patients without distant or lymphatic metastases. Hence, we developed a nomogram based on prognostic gene mutations that could predict the overall survival of HCC patients at early stage and provide reference for immunotherapy. Methods: HCC cohorts were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. The total patient was randomly assigned to training and validation sets. Univariate and multivariate cox analysis were used to select significant variables for construction of nomogram. The support vector machine (SVM) and principal component analysis (PCA) were used to assess the distinguished effect of significant genes. Besides, the nomogram model was evaluated by concordance index, time-dependent receiver operating characteristics (ROC) curve, calibration curve and decision curve analysis (DCA). Gene Set Enrichment Analysis (GSEA), CIBERSORT, Tumor Immune Dysfunction and Exclusion (TIDE) and Immunophenoscore (IPS) were utilized to explore the potential mechanism of immune-related process and immunotherapy. Results: A total of 695 HCC patients were selected in the process including 495 training patients and 200 validation patients. Nomogram was constructed based on T stage, age, country, mutation status of DOCK2, EYS, MACF1 and TP53. The assessment showed the nomogram has good discrimination and high consistence between predicted and actual data. Furthermore, we found T cell exclusion was the potential mechanism of malignant progression in high-risk group. Meanwhile, low-risk group might be sensitive to immunotherapy and benefit from CTLA-4 blocker treatment. Conclusion: Our research established a nomogram based on mutant genes and clinical parameters, and revealed the underlying association between these risk factors and immune-related process.
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Affiliation(s)
- Tingping Huang
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tao Yan
- Department of Thoracic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Gonghai Chen
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chunqing Zhang
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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Saha J, Bae J, Wang SY, Lu H, Chappell LJ, Gopal P, Davis AJ. Ablating putative Ku70 phosphorylation sites results in defective DNA damage repair and spontaneous induction of hepatocellular carcinoma. Nucleic Acids Res 2021; 49:9836-9850. [PMID: 34428289 PMCID: PMC8464062 DOI: 10.1093/nar/gkab743] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 12/31/2022] Open
Abstract
Multiple pathways mediate the repair of DNA double-strand breaks (DSBs), with numerous mechanisms responsible for driving choice between the pathways. Previously, we reported that mutating five putative phosphorylation sites on the non-homologous end joining (NHEJ) factor, Ku70, results in sustained retention of human Ku70/80 at DSB ends and attenuation of DSB repair via homologous recombination (HR). In this study, we generated a knock-in mouse, in which the three conserved putative phosphorylation sites of Ku70 were mutated to alanine to ablate potential phosphorylation (Ku703A/3A), in order to examine if disrupting DSB repair pathway choice by modulating Ku70/80 dynamics at DSB ends results in enhanced genomic instability and tumorigenesis. The Ku703A/3A mice developed spontaneous and have accelerated chemical-induced hepatocellular carcinoma (HCC) compared to wild-type (Ku70+/+) littermates. The HCC tumors from the Ku703A/3A mice have increased γH2AX and 8-oxo-G staining, suggesting decreased DNA repair. Spontaneous transformed cell lines from Ku703A/3A mice are more radiosensitive, have a significant decrease in DNA end resection, and are more sensitive to the DNA cross-linking agent mitomycin C compared to cells from Ku70+/+ littermates. Collectively, these findings demonstrate that mutating the putative Ku70 phosphorylation sites results in defective DNA damage repair and disruption of this process drives genomic instability and accelerated development of HCC.
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Affiliation(s)
- Janapriya Saha
- Division of Molecular Radiation Biology, Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Jinsung Bae
- Division of Molecular Radiation Biology, Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Shih-Ya Wang
- Division of Molecular Radiation Biology, Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Huiming Lu
- Division of Molecular Radiation Biology, Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA
| | | | - Purva Gopal
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Anthony J Davis
- Division of Molecular Radiation Biology, Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA
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Patil S, Jahagirdar S, Khot M, Sengupta K. Studying the Role of Chromosomal Instability (CIN) in GI Cancers Using Patient-derived Organoids. J Mol Biol 2021; 434:167256. [PMID: 34547328 DOI: 10.1016/j.jmb.2021.167256] [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: 05/01/2021] [Revised: 08/28/2021] [Accepted: 09/13/2021] [Indexed: 01/10/2023]
Abstract
Chromosomal instability (CIN) is associated with the initiation and progression of gastrointestinal (GI) tract cancers. Cancers of the GI tract are typically characterized by altered chromosome numbers. While the dynamics of CIN have been extensively characterized in 2D monolayer cell cultures derived from GI tumors, the tumor microenvironment and 3D tumor architecture also contribute to the progression of CIN, which is not captured in 2D cell culture systems. To overcome these limitations, self-organizing cellular structures that retain organ-specific 3D architecture, namely organoids, have been derived from various tissues of the GI tract. Organoids derived from normal tissue and patient tumors serve as a useful paradigm to study the crosstalk between tumor cells in the context of a tissue microenvironment and its impact on chromosomal stability. Such a paradigm, therefore, has a considerable advantage over 2D cell culture systems in drug screening and personalized medicine. Here, we review the importance of patient-derived tumor organoids (PDTOs) as a model to study CIN in cancers of the GI tract.
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Affiliation(s)
- Shalaka Patil
- Chromosome Biology Lab (CBL), Indian Institute of Science Education and Research (IISER), Pune 411008, India. https://twitter.com/@ShalakaPatil11
| | - Sanika Jahagirdar
- Chromosome Biology Lab (CBL), Indian Institute of Science Education and Research (IISER), Pune 411008, India. https://twitter.com/@SanikaJag
| | - Maithilee Khot
- Chromosome Biology Lab (CBL), Indian Institute of Science Education and Research (IISER), Pune 411008, India. https://twitter.com/@MaithileeKhot
| | - Kundan Sengupta
- Chromosome Biology Lab (CBL), Indian Institute of Science Education and Research (IISER), Pune 411008, India.
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Guo C, Zhou J, Ma B, Wang R, Ge Y, Wang Z, Ji B, Wang W, Zhang J, Wang Z. A Somatic Mutation-Derived LncRNA Signature of Genomic Instability Predicts Prognosis for Patients With Liver Cancer. Front Surg 2021; 8:724792. [PMID: 34504866 PMCID: PMC8421795 DOI: 10.3389/fsurg.2021.724792] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 07/26/2021] [Indexed: 12/11/2022] Open
Abstract
Background: Genomic instability is considered as one of the hallmarks of hepatocellular carcinoma (HCC) and poses a significant challenge to the clinical treatment. The emerging evidence has revealed the roles of long non-coding RNAs (lncRNAs) in the maintenance of genomic instability. This study is aimed to develop a genomic instability-related lncRNA signature for determining HCC prognosis and the suitability of patients for immunotherapy. Methods: In this study, data related to transcriptome profiling, clinical features, and the somatic mutations of patients with HCC were downloaded from The Cancer Genomic Atlas (TCGA). Bioinformatics analysis was performed to identify and construct a somatic mutation-derived genomic instability-associated lncRNA signature (GILncSig). Single-sample gene set enrichment analysis (ssGSEA) was applied to estimate the levels of immune cell infiltration. A nomogram was constructed, and calibration was performed to assess the effectiveness of the model. Results: In the study, seven genomic instability-related lncRNAs were identified and used to define a prognostic signature. Patients with HCC were stratified into high- and low-risk groups with significant differences in the survival (median survival time = 1.489, 1.748 year; p = 0.006) based on the optimal cutoff value (risk score = 1.010) of the risk score in the training group. In addition, GILncSig was demonstrated to be an independent risk factor for the patients with HCC when compared to the clinical parameters (p < 0.001). According to the receiver operating characteristic (ROC) curve, nomogram, and calibration plot, the signature could predict the survival rate for the patients with HCC in the 1st, 3rd, and 5th years. Furthermore, ssGSEA revealed the potential of the signature in guiding decisions for administering clinical treatment. Conclusions: In this study, we developed a novel prognostic model based on the somatic mutation-derived lncRNAs and validated it using an internal dataset. The independence of the GILncSig was estimated using univariate and follow-up multivariate analyses. Immunologic analysis was used to evaluate the complex factors involved in the HCC progression.
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Affiliation(s)
- Cheng Guo
- Department of Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jie Zhou
- Department of Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Boyu Ma
- Department of Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Rui Wang
- Department of Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yanli Ge
- Department of Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhe Wang
- Department of Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Bing Ji
- Department of Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wei Wang
- Department of Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Junjie Zhang
- Department of Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhirong Wang
- Department of Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
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Chen CC, Chen CY, Cheng SF, Shieh TM, Leu YL, Chuang WY, Liu KT, Ueng SH, Shih YH, Chou LF, Wang TH. Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models. Int J Mol Sci 2021; 22:ijms22189766. [PMID: 34575923 PMCID: PMC8471855 DOI: 10.3390/ijms22189766] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/01/2021] [Accepted: 09/07/2021] [Indexed: 12/21/2022] Open
Abstract
Molecules involved in DNA damage response (DDR) are often overexpressed in cancer cells, resulting in poor responses to chemotherapy and radiotherapy. Although treatment efficacy can be improved with the concomitant use of DNA repair inhibitors, the accompanying side effects can compromise the quality of life of patients. Therefore, in this study, we identified a natural compound that could inhibit DDR, using the single-strand annealing yeast-cell analysis system, and explored its mechanisms of action and potential as a chemotherapy adjuvant in hepatocellular carcinoma (HCC) cell lines using comet assay, flow cytometry, Western blotting, immunofluorescence staining, and functional analyses. We developed a mouse model to verify the in vitro findings. We found that hydroxygenkwanin (HGK) inhibited the expression of RAD51 and progression of homologous recombination, thereby suppressing the ability of the HCC cell lines to repair DNA damage and enhancing their sensitivity to doxorubicin. HGK inhibited the phosphorylation of DNA damage checkpoint proteins, leading to apoptosis in the HCC cell lines. In the mouse xenograft model, HGK enhanced the sensitivity of liver cancer cells to doxorubicin without any physiological toxicity. Thus, HGK can inhibit DDR in liver cancer cells and mouse models, making it suitable for use as a chemotherapy adjuvant.
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Affiliation(s)
- Chin-Chuan Chen
- Tissue Bank, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan; (C.-C.C.); (C.-Y.C.); (Y.-L.L.)
- Graduate Institute of Natural Products, Chang Gung University, Taoyuan 33303, Taiwan;
| | - Chi-Yuan Chen
- Tissue Bank, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan; (C.-C.C.); (C.-Y.C.); (Y.-L.L.)
- Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan
| | - Shu-Fang Cheng
- Graduate Institute of Natural Products, Chang Gung University, Taoyuan 33303, Taiwan;
| | - Tzong-Ming Shieh
- School of Dentistry, College of Dentistry, China Medical University, Taichung 40402, Taiwan;
| | - Yann-Lii Leu
- Tissue Bank, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan; (C.-C.C.); (C.-Y.C.); (Y.-L.L.)
- Graduate Institute of Natural Products, Chang Gung University, Taoyuan 33303, Taiwan;
| | - Wen-Yu Chuang
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan; (W.-Y.C.); (S.-H.U.)
- College of Medicine, Chang Gung University, Taoyuan 33303, Taiwan
| | - Kuang-Ting Liu
- Department of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan;
- Department of Pathology & Laboratory Medicine, Taoyuan Armed Forces General Hospital, Taoyuan 32551, Taiwan
| | - Shir-Hwa Ueng
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan; (W.-Y.C.); (S.-H.U.)
- College of Medicine, Chang Gung University, Taoyuan 33303, Taiwan
| | - Yin-Hwa Shih
- Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung 41354, Taiwan;
| | - Li-Fang Chou
- Kidney Research Center, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
- Correspondence: (L.-F.C.); (T.-H.W.)
| | - Tong-Hong Wang
- Tissue Bank, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan; (C.-C.C.); (C.-Y.C.); (Y.-L.L.)
- Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan
- Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
- Correspondence: (L.-F.C.); (T.-H.W.)
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Amendola M, Bedel A, Buj-Bello A, Carrara M, Concordet JP, Frati G, Gilot D, Giovannangeli C, Gutierrez-Guerrero A, Laurent M, Miccio A, Moreau-Gaudry F, Sourd C, Valton J, Verhoeyen E. Recent Progress in Genome Editing for Gene Therapy Applications: The French Perspective. Hum Gene Ther 2021; 32:1059-1075. [PMID: 34494480 DOI: 10.1089/hum.2021.191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Recent advances in genome editing tools, especially novel developments in the clustered regularly interspaced short palindromic repeats associated to Cas9 nucleases (CRISPR/Cas9)-derived editing machinery, have revolutionized not only basic science but, importantly, also the gene therapy field. Their flexibility and ability to introduce precise modifications in the genome to disrupt or correct genes or insert expression cassettes in safe harbors in the genome underline their potential applications as a medicine of the future to cure many genetic diseases. In this review, we give an overview of the recent progress made by French researchers in the field of therapeutic genome editing, while putting their work in the general context of advances made in the field. We focus on recent hematopoietic stem cell gene editing strategies for blood diseases affecting the red blood cells or blood coagulation as well as lysosomal storage diseases. We report on a genome editing-based therapy for muscular dystrophy and the potency of T cell gene editing to increase anticancer activity of chimeric antigen receptor T cells to combat cancer. We will also discuss technical obstacles and side effects such as unwanted editing activity that need to be surmounted on the way toward a clinical implementation of genome editing. We propose here improvements developed today, including by French researchers to overcome the editing-related genotoxicity and improve editing precision by the use of novel recombinant nuclease-based systems such as nickases, base editors, and prime editors. Finally, a solution is proposed to resolve the cellular toxicity induced by the systems employed for gene editing machinery delivery.
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Affiliation(s)
- Mario Amendola
- Genethon, Evry, France.,Université Paris-Saclay, Univ Evry, Inserm, Genethon, Integrare Research Unit UMR_S951, Evry, France
| | - Aurélie Bedel
- Bordeaux University, Bordeaux, France.,INSERM U1035, Biotherapy of Genetic Diseases, Inflammatory Disorders and Cancers, Bordeaux, France.,Biochemistry Laboratory, University Hospital Bordeaux, Bordeaux, France
| | - Ana Buj-Bello
- Genethon, Evry, France.,Université Paris-Saclay, Univ Evry, Inserm, Genethon, Integrare Research Unit UMR_S951, Evry, France
| | - Mathieu Carrara
- Museum National d'Histoire Naturelle, Inserm U1154, CNRS UMR 7196, Sorbonne Universités, Paris, France
| | - Jean-Paul Concordet
- Museum National d'Histoire Naturelle, Inserm U1154, CNRS UMR 7196, Sorbonne Universités, Paris, France
| | - Giacomo Frati
- Laboratory of Chromatin and Gene Regulation During Development, Imagine Institute, INSERM UMR1163, Paris, France.,Université de Paris, Paris, France
| | - David Gilot
- Inserm U1242, Université de Rennes, Centre de lutte contre le cancer Eugène Marquis, Rennes, France
| | - Carine Giovannangeli
- Museum National d'Histoire Naturelle, Inserm U1154, CNRS UMR 7196, Sorbonne Universités, Paris, France
| | - Alejandra Gutierrez-Guerrero
- CIRI-International Center for Infectiology Research, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université Lyon, Lyon, France
| | - Marine Laurent
- Genethon, Evry, France.,Université Paris-Saclay, Univ Evry, Inserm, Genethon, Integrare Research Unit UMR_S951, Evry, France
| | - Annarita Miccio
- Laboratory of Chromatin and Gene Regulation During Development, Imagine Institute, INSERM UMR1163, Paris, France.,Université de Paris, Paris, France
| | - François Moreau-Gaudry
- Bordeaux University, Bordeaux, France.,INSERM U1035, Biotherapy of Genetic Diseases, Inflammatory Disorders and Cancers, Bordeaux, France.,Biochemistry Laboratory, University Hospital Bordeaux, Bordeaux, France
| | - Célia Sourd
- Genethon, Evry, France.,Université Paris-Saclay, Univ Evry, Inserm, Genethon, Integrare Research Unit UMR_S951, Evry, France
| | | | - Els Verhoeyen
- CIRI-International Center for Infectiology Research, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université Lyon, Lyon, France.,Université Côte d'Azur, INSERM, C3M, Nice, France
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Zhao Z, Gad H, Benitez-Buelga C, Sanjiv K, Xiangwei H, Kang H, Feng M, Zhao Z, Berglund UW, Xia Q, Helleday T. NEIL3 Prevents Senescence in Hepatocellular Carcinoma by Repairing Oxidative Lesions at Telomeres during Mitosis. Cancer Res 2021; 81:4079-4093. [PMID: 34045188 PMCID: PMC9398161 DOI: 10.1158/0008-5472.can-20-1028] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 01/06/2021] [Accepted: 05/25/2021] [Indexed: 01/07/2023]
Abstract
Patients with hepatocellular carcinoma (HCC) suffer from few treatment options and poor survival rates. Here we report that endonuclease VIII-like protein 3 (NEIL3) is overexpressed in HCC and correlates with poor survival. All six HCC cell lines investigated were dependent on NEIL3 catalytic activity for survival and prevention of senescence, while NEIL3 was dispensable for nontransformed cells. NEIL3-depleted HCC cell lines accumulated oxidative DNA lesions specifically at telomeres, resulting in telomere dysfunctional foci and 53BP1 foci formation. Following oxidative DNA damage during mitosis, NEIL3 relocated to telomeres and recruited apurinic endonuclease 1 (APE1), indicating activation of base excision repair. META-FISH revealed that NEIL3, but not NEIL1 or NEIL2, is required to initiate APE1 and polymerase beta (POLB)-dependent base excision repair at oxidized telomeres. Repeated exposure of NEIL3-depleted cells to oxidizing damage induced chromatin bridges and damaged telomeres. These results demonstrate a novel function for NEIL3 in repair of oxidative DNA damage at telomeres in mitosis, which is important to prevent senescence of HCC cells. Furthermore, these data suggest that NEIL3 could be a target for therapeutic intervention for HCC. SIGNIFICANCE: This study describes compartmentalization of base excision repair during mitosis that is dependent on NEIL3, APE1, and POLB to repair oxidative damage accumulating at telomeres in hepatocellular carcinoma.
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Affiliation(s)
- Zhenjun Zhao
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.,Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Helge Gad
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.,Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
| | - Carlos Benitez-Buelga
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Kumar Sanjiv
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Hua Xiangwei
- Organ Transplantation Center, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - He Kang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Mingxuan Feng
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhicong Zhao
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ulrika Warpman Berglund
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Corresponding Authors: Thomas Helleday, Karolinska Institutet, Tomtebodavägen 23B, Stockholm S-171 65, Sweden. E-mail: ; and Xia Qiang, Renji Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200001, China. E-mail:
| | - Thomas Helleday
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.,Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.,Corresponding Authors: Thomas Helleday, Karolinska Institutet, Tomtebodavägen 23B, Stockholm S-171 65, Sweden. E-mail: ; and Xia Qiang, Renji Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200001, China. E-mail:
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Su L, Zhang G, Kong X. A Novel Five-Gene Signature for Prognosis Prediction in Hepatocellular Carcinoma. Front Oncol 2021; 11:642563. [PMID: 34336648 PMCID: PMC8322700 DOI: 10.3389/fonc.2021.642563] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 04/06/2021] [Indexed: 01/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has been a global health issue and attracted wide attention due to its high incidence and poor outcomes. In this study, our purpose was to explore an effective prognostic marker for HCC. Five cohort profile datasets from GEO (GSE25097, GSE36376, GSE62232, GSE76427 and GSE101685) were integrated with TCGA-LIHC and GTEx dataset to identify differentially expressed genes (DEGs) between normal and cancer tissues in HCC patients, then 5 upregulated differentially expressed genes and 32 downregulated DEGs were identified as common DEGs in total. Next, we systematically explored the relationship between the expression of 37 common DEGs in tumor tissues and overall survival (OS) rate of HCC patients in TCGA and constructed a novel prognostic model composed of five genes (AURKA, PZP, RACGAP1, ACOT12 and LCAT). Furthermore, the predicted performance of the five-gene signature was verified in ICGC and another independent clinical samples cohort, and the results demonstrated that the signature performed well in predicting the OS rate of patients with HCC. What is more, the signature was an independent hazard factor for HCC patients when considering other clinical factors in the three cohorts. Finally, we found the signature was significantly associated with HCC immune microenvironment. In conclusion, the prognostic five-gene signature identified in our present study could efficiently classify patients with HCC into subgroups with low and high risk of longer overall survival time and help clinicians make decisions for individualized treatment.
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Affiliation(s)
- Lisa Su
- Department of Genetic and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Genhao Zhang
- Department of Blood Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiangdong Kong
- Department of Genetic and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Guo M, Wang SM. Genome Instability-Derived Genes Are Novel Prognostic Biomarkers for Triple-Negative Breast Cancer. Front Cell Dev Biol 2021; 9:701073. [PMID: 34322487 PMCID: PMC8312551 DOI: 10.3389/fcell.2021.701073] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 06/10/2021] [Indexed: 12/31/2022] Open
Abstract
Background Triple-negative breast cancer (TNBC) is an aggressive disease. Recent studies have identified genome instability-derived genes for patient outcomes. However, most of the studies mainly focused on only one or a few genome instability-related genes. Prognostic potential and clinical significance of genome instability-associated genes in TNBC have not been well explored. Methods In this study, we developed a computational approach to identify TNBC prognostic signature. It consisted of (1) using somatic mutations and copy number variations (CNVs) in TNBC to build a binary matrix and identifying the top and bottom 25% mutated samples, (2) comparing the gene expression between the top and bottom 25% samples to identify genome instability-related genes, and (3) performing univariate Cox proportional hazards regression analysis to identify survival-associated gene signature, and Kaplan–Meier, log-rank test, and multivariate Cox regression analyses to obtain overall survival (OS) information for TNBC outcome prediction. Results From the identified 111 genome instability-related genes, we extracted a genome instability-derived gene signature (GIGenSig) of 11 genes. Through survival analysis, we were able to classify TNBC cases into high- and low-risk groups by the signature in the training dataset (log-rank test p = 2.66e−04), validated its prognostic performance in the testing (log-rank test p = 2.45e−02) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (log-rank test p = 2.57e−05) datasets, and further validated the predictive power of the signature in five independent datasets. Conclusion The identified novel signature provides a better understanding of genome instability in TNBC and can be applied as prognostic markers for clinical TNBC management.
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Affiliation(s)
- Maoni Guo
- Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China
| | - San Ming Wang
- Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China
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Huo J, Wu L, Zang Y. Construction and Validation of a Reliable Six-Gene Prognostic Signature Based on the TP53 Alteration for Hepatocellular Carcinoma. Front Oncol 2021; 11:618976. [PMID: 34178618 PMCID: PMC8222811 DOI: 10.3389/fonc.2021.618976] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 04/14/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The high mutation rate of TP53 in hepatocellular carcinoma (HCC) makes it an attractive potential therapeutic target. However, the mechanism by which TP53 mutation affects the prognosis of HCC is not fully understood. MATERIAL AND APPROACH This study downloaded a gene expression profile and clinical-related information from The Cancer Genome Atlas (TCGA) database and the international genome consortium (ICGC) database. We used Gene Set Enrichment Analysis (GSEA) to determine the difference in gene expression patterns between HCC samples with wild-type TP53 (n=258) and mutant TP53 (n=116) in the TCGA cohort. We screened prognosis-related genes by univariate Cox regression analysis and Kaplan-Meier (KM) survival analysis. We constructed a six-gene prognostic signature in the TCGA training group (n=184) by Lasso and multivariate Cox regression analysis. To assess the predictive capability and applicability of the signature in HCC, we conducted internal validation, external validation, integrated analysis and subgroup analysis. RESULTS A prognostic signature consisting of six genes (EIF2S1, SEC61A1, CDC42EP2, SRM, GRM8, and TBCD) showed good performance in predicting the prognosis of HCC. The area under the curve (AUC) values of the ROC curve of 1-, 2-, and 3-year survival of the model were all greater than 0.7 in each independent cohort (internal testing cohort, n = 181; TCGA cohort, n = 365; ICGC cohort, n = 229; whole cohort, n = 594; subgroup, n = 9). Importantly, by gene set variation analysis (GSVA) and the single sample gene set enrichment analysis (ssGSEA) method, we found three possible causes that may lead to poor prognosis of HCC: high proliferative activity, low metabolic activity and immunosuppression. CONCLUSION Our study provides a reliable method for the prognostic risk assessment of HCC and has great potential for clinical transformation.
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Affiliation(s)
- Junyu Huo
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Liqun Wu
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yunjin Zang
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
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Cell-Free DNA Analysis by Whole-Exome Sequencing for Hepatocellular Carcinoma: A Pilot Study in Thailand. Cancers (Basel) 2021; 13:cancers13092229. [PMID: 34066484 PMCID: PMC8125351 DOI: 10.3390/cancers13092229] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/28/2021] [Accepted: 04/29/2021] [Indexed: 01/05/2023] Open
Abstract
Simple Summary Liquid biopsy for cell-free DNA (cfDNA) is a non-invasive technique to characterize the genetic profile of a tumor. Despite being a valuable tool, there is no mutational profile of cfDNA from hepatocellular carcinoma (HCC) in patients from Thailand, where HCC is prevalent. The present study aimed to demonstrate the utility of using whole-exome sequencing of cfDNA to define the somatic mutation profiles of HCC in Thai patients who underwent nonoperative therapies. The level of cfDNA was higher in HCC patients than in chronic hepatitis patients. Single nucleotide variations were present in somatic genes in cfDNA, including in ZNF814, HRNR, ZNF492, ADAMTS12, FLG, OBSCN, TP53, and TTN. The co-occurrence of HRNR and TTN mutations in cfDNA was associated with shorter overall survival. These findings indicate that the mutational profiles of cfDNA reflected those of HCC tissue, and cfDNA could serve as a useful biomarker for diagnosis and prognosis in HCC patients. Abstract Cell-free DNA (cfDNA) has been used as a non-invasive biomarker for detecting cancer-specific mutations. However, the mutational profile of cfDNA in Thai patients with hepatocellular carcinoma (HCC) has not been investigated. Here, we demonstrated the utility of using whole-exome sequencing (WES) of cfDNA to define the somatic mutation profiles of HCC in Thai patients. The comprehensive profile of cfDNA was determined with WES to identify variants in matched cfDNA and germline DNA from 30 HCC patients in Thailand who underwent nonoperative therapies. The level of cfDNA was higher in HCC patients compared with chronic hepatitis patients (p-value < 0.001). Single nucleotide variants were present in somatic genes in cfDNA, including in ZNF814 (27%), HRNR (20%), ZNF492 (20%), ADAMTS12 (17%), FLG (17%), OBSCN (17%), TP53 (17%), and TTN (17%). These same mutations were matched to HCC mutation data from The Cancer Genome Atlas (TCGA) and a previous Thai HCC study. The co-occurrence of HRNR and TTN mutations in cfDNA was associated with shorter overall survival in HCC patients (hazard ratio = 1.60, p-value = 0.0196). These findings indicate that the mutational profile of cfDNA accurately reflected that of HCC tissue and suggest that cfDNA could serve as a useful biomarker for diagnosis and prognosis in Thai HCC patients. In addition, we demonstrated the use of the pocket-sized sequencer of Oxford Nanopore Technology to detect copy-number variants in HCC tissues that could be applied for onsite clinical detection/monitoring of HCC.
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Wang M, Tao H, Huang P. Clinical significance of LARGE1 in progression of liver cancer and the underlying mechanism. Gene 2021; 779:145493. [PMID: 33588034 DOI: 10.1016/j.gene.2021.145493] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 01/31/2021] [Accepted: 02/03/2021] [Indexed: 12/26/2022]
Abstract
Liver cancer is a malignant disease and causes thousands of death each year. The prognosis is dismal for patients with metastasis and recurrence. It is urgent to disclose the cause and mechanism underlying liver cancer. LARGE1 encodes a glycosyltransferase and was reported to promote progression in cancer. But its role in liver cancer is unknown. In this study, LARGE1 displayed upregulated expression in liver cancer cells. When LARGE1 was knocked down in SMMC-7721 and Huh-7 cells, the ability of cell proliferation and colony formation were decreased significantly. Cell migration and invasion were suppressed. The number of cells in G1 phase increased but decreased in S phase. Cell apoptosis was not affected. Tumor growth in vivo was also inhibited. Tumor volume was decreased from 1270 mm3 to 721 mm3 (p < 0.05) and tumor weight from 0.95 g to 0.63 g (p < 0.05). Furthermore, the expression of β-catenin, TCF and Cyclin D1 was reduced when LARGE1 was knocked down but increased in LARGE1-overexpressed cells. LGK-974, a specific inhibitor in canonical Wnt signaling, inhibited cell proliferation even when LARGE1 was over-expressed. In tumor tissues, LARGE1 was increased by 4.8 folds compared to paratumoral tissues. And higher LARGE1 expression caused shorter survival. Clinicopathological analysis demonstrated that LARGE1 was associated with TNM stage (Ⅰ/Ⅱ vs III/IV, p = 0.005). Therefore, LARGE1 promotes progression and regulates Wnt/β-catenin signaling pathway in liver cancer.
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Affiliation(s)
- Min Wang
- Medical Research & Laboratory Diagnostic Center, Central Hospital affiliated to Shandong First Medical University, Jinan 250013, China
| | - Haiyan Tao
- Department of Acupuncture & Massage, Central Hospital affiliated to Shandong First Medical University, Jinan 250013, China
| | - Ping Huang
- Medical Research & Laboratory Diagnostic Center, Central Hospital affiliated to Shandong First Medical University, Jinan 250013, China.
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Zhao Z, He K, Zhang Y, Hua X, Feng M, Zhao Z, Sun Y, Jiang Y, Xia Q. XRCC2 repairs mitochondrial DNA damage and fuels malignant behavior in hepatocellular carcinoma. Cancer Lett 2021; 512:1-14. [PMID: 33964350 DOI: 10.1016/j.canlet.2021.04.026] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 01/03/2023]
Abstract
The effects of DNA damage repair (DDR) and mitochondrial dysfunction associated with HCC have been investigated, but the functional role of mitochondrial DDR in HCC remains elusive. We studied the DDR genes and identified XRCC2 as a potential prognostic marker for HCC. XRCC2 overexpression was detected in HCC cells and shown to promote the malignant behavior of cancer cells. XRCC2 depletion in HCC cells led to DNA damage accumulation at the replication site in the nucleus. Additionally, XRCC2-depleted HCC cells exhibited impaired mitochondrial respiration and reduced complex I (CI) activity as XRCC2 was responsible for elimination of mitochondrial DNA (mtDNA) damage and maintenance of mtDNA-encoded CI-related genes' transcription in a RAD51-dependent manner. We showed that tunicamycin (Tm)-activated sXBP1 bound to the TGTCAT domain and suppressed XRCC2 expression. In HCC patients, we observed a negative correlation between XBP1 and XRCC2 expression. Moreover, XRCC2 inhibition by Tm led to genomic and mtDNA damage, which impaired the transcription of mtDNA-encoded CI-related genes and prevented tumor proliferation in vivo. We described the role of XRCC2 in mtDNA damage repair and HCC progression while unveiling the potential anti-tumor effect of Tm.
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Affiliation(s)
- Zhenjun Zhao
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kang He
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yu Zhang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiangwei Hua
- Center of Organ Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Mingxuan Feng
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhichong Zhao
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yuan Sun
- SJTU-Yale Joint Centre for Biostatistics, School of Mathematical Sciences, Shanghai Jiao Tong University, Shanghai, China
| | - Yuhui Jiang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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