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1
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Jen IA, Kuo TBJ, Liaw YP. Sex-specific associations of Notch signaling with chronic HBV infection: a study from Taiwan Biobank. Biol Sex Differ 2024; 15:69. [PMID: 39237981 PMCID: PMC11378497 DOI: 10.1186/s13293-024-00641-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 08/15/2024] [Indexed: 09/07/2024] Open
Abstract
BACKGROUND Hepatitis B, a liver infection caused by the hepatitis B virus (HBV), can develop into a chronic infection that puts patients at high risk of death from cirrhosis and liver cancer. In this study, we aimed to investigate the difference of reactome pre-Notch expression and processing between males and females by using gene to function analysis in FUMA. METHODS We analyzed Taiwan Biobank (TWB) data pertaining to 48,874 women and 23,178 men individuals which were collected from 2008 to 2019. According to hepatitis B surface antigen (HBsAg) status in hematology, positive and negative were classified into case and control in the genome-wide association study (GWAS) analysis. RESULTS We found 4715 women and 2656 men HBV cases. The genomic risk loci were different between males and females. In male, three risk loci (rs3732421, rs1884575 and Affx-28516147) were detected while eight risk loci (Affx-4564106, rs932745, rs7574865, rs34050244, rs77041685, rs107822, rs2296651 and rs12599402) were found in female. In addition, sex also presented different results. In females, the most significant SNPs are gathered in chromosome 6. However, except for chromosome 6, significant HBV infection SNPs also could be found in chromosome 3 among males. We further investigated gene function in FUMA to identify the difference in reactome pre-Notch expression and processing between males and females. We found that POGLUT1 and HIST1H2BC only appeared in men but not in women. CONCLUSION According to our study, the reactome pre-Notch expression including POGLUT1 and HIST1H2BC was associated with a risk of Hepatitis B in Taiwanese men when compared to women.
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Affiliation(s)
- I-An Jen
- Institute of Public Health, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Brain Science, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Li-Nong St., Beitou, Taipei, 11221, Taiwan
- Sleep Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Terry B J Kuo
- Institute of Brain Science, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Li-Nong St., Beitou, Taipei, 11221, Taiwan.
- Sleep Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
| | - Yung-Po Liaw
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, No. 110 Sec. 1 Jianguo N. Road, Taichung, 40201, Taiwan.
- Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City, 40201, Taiwan.
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2
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Yan W, Rao D, Fan F, Liang H, Zhang Z, Dong H. Hepatitis B virus X protein and TGF-β: partners in the carcinogenic journey of hepatocellular carcinoma. Front Oncol 2024; 14:1407434. [PMID: 38962270 PMCID: PMC11220127 DOI: 10.3389/fonc.2024.1407434] [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: 03/26/2024] [Accepted: 05/21/2024] [Indexed: 07/05/2024] Open
Abstract
Hepatitis B infection is substantially associated with the development of liver cancer globally, with the prevalence of hepatocellular carcinoma (HCC) cases exceeding 50%. Hepatitis B virus (HBV) encodes the Hepatitis B virus X (HBx) protein, a pleiotropic regulatory protein necessary for the transcription of the HBV covalently closed circular DNA (cccDNA) microchromosome. In previous studies, HBV-associated HCC was revealed to be affected by HBx in multiple signaling pathways, resulting in genetic mutations and epigenetic modifications in proto-oncogenes and tumor suppressor genes. In addition, transforming growth factor-β (TGF-β) has dichotomous potentials at various phases of malignancy as it is a crucial signaling pathway that regulates multiple cellular and physiological processes. In early HCC, TGF-β has a significant antitumor effect, whereas in advanced HCC, it promotes malignant progression. TGF-β interacts with the HBx protein in HCC, regulating the pathogenesis of HCC. This review summarizes the respective and combined functions of HBx and TGB-β in HCC occurrence and development.
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Affiliation(s)
- Wei Yan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| | - Dean Rao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| | - Feimu Fan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Zunyi Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| | - Hanhua Dong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
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Chan T, Cheng L, Hsu C, Yang P, Liao T, Hsieh H, Lin P, HuangFu W, Chuu C, Tsai KK. ASPM stabilizes the NOTCH intracellular domain 1 and promotes oncogenesis by blocking FBXW7 binding in hepatocellular carcinoma cells. Mol Oncol 2024; 18:562-579. [PMID: 38279565 PMCID: PMC10920086 DOI: 10.1002/1878-0261.13589] [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: 04/01/2023] [Revised: 12/03/2023] [Accepted: 01/15/2024] [Indexed: 01/28/2024] Open
Abstract
Notch signaling is aberrantly activated in approximately 30% of hepatocellular carcinoma (HCC), significantly contributing to tumorigenesis and disease progression. Expression of the major Notch receptor, NOTCH1, is upregulated in HCC cells and correlates with advanced disease stages, although the molecular mechanisms underlying its overexpression remain unclear. Here, we report that expression of the intracellular domain of NOTCH1 (NICD1) is upregulated in HCC cells due to antagonism between the E3-ubiquitin ligase F-box/WD repeat-containing protein 7 (FBXW7) and the large scaffold protein abnormal spindle-like microcephaly-associated protein (ASPM) isoform 1 (ASPM-i1). Mechanistically, FBXW7-mediated polyubiquitination and the subsequent proteasomal degradation of NICD1 are hampered by the interaction of NICD1 with ASPM-i1, thereby stabilizing NICD1 and rendering HCC cells responsive to stimulation by Notch ligands. Consistently, downregulating ASPM-i1 expression reduced the protein abundance of NICD1 but not its FBXW7-binding-deficient mutant. Reinforcing the oncogenic function of this regulatory module, the forced expression of NICD1 significantly restored the tumorigenic potential of ASPM-i1-deficient HCC cells. Echoing these findings, NICD1 was found to be strongly co-expressed with ASPM-i1 in cancer cells in human HCC tissues (P < 0.001). In conclusion, our study identifies a novel Notch signaling regulatory mechanism mediated by protein-protein interaction between NICD1, FBXW7, and ASPM-i1 in HCC cells, representing a targetable vulnerability in human HCC.
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Affiliation(s)
- Tze‐Sian Chan
- Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of MedicineTaipei Medical UniversityTaiwan
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang HospitalTaipei Medical UniversityTaiwan
- School of Medicine, College of MedicineTaipei Medical UniversityTaiwan
- Pancreatic Cancer Group, Taipei Cancer CenterTaipei Medical UniversityTaiwan
| | - Li‐Hsin Cheng
- Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of MedicineTaipei Medical UniversityTaiwan
- Core Laboratory of Organoids Technology, Office of R&DTaipei Medical UniversityTaiwan
| | - Chung‐Chi Hsu
- School of Medicine, College of MedicineI‐Shou UniversityKaohsiung CityTaiwan
| | - Pei‐Ming Yang
- Master Program in Graduate Institute of Cancer Biology and Drug DiscoveryTaipei Medical UniversityTaiwan
| | - Tai‐Yan Liao
- Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of MedicineTaipei Medical UniversityTaiwan
| | - Hsiao‐Yen Hsieh
- Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of MedicineTaipei Medical UniversityTaiwan
| | - Pei‐Chun Lin
- Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of MedicineTaipei Medical UniversityTaiwan
| | - Wei‐Chun HuangFu
- Master Program in Graduate Institute of Cancer Biology and Drug DiscoveryTaipei Medical UniversityTaiwan
| | - Chih‐Pin Chuu
- Institute of Cellular and System MedicineNational Health Research InstitutesMiaoliTaiwan
| | - Kelvin K. Tsai
- Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of MedicineTaipei Medical UniversityTaiwan
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang HospitalTaipei Medical UniversityTaiwan
- Pancreatic Cancer Group, Taipei Cancer CenterTaipei Medical UniversityTaiwan
- Core Laboratory of Organoids Technology, Office of R&DTaipei Medical UniversityTaiwan
- TMU Research Center of Cancer Translational MedicineTaipei Medical UniversityTaiwan
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Ahmad A, Tiwari RK, Siddiqui S, Chadha M, Shukla R, Srivastava V. Emerging trends in gastrointestinal cancers: Targeting developmental pathways in carcinogenesis and tumor progression. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 385:41-99. [PMID: 38663962 DOI: 10.1016/bs.ircmb.2023.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
Gastrointestinal carcinomas are a group of cancers associated with the digestive system and its accessory organs. The most prevalent cancers related to the gastrointestinal tract are colorectal, gall bladder, gastric, hepatocellular, and esophageal cancers, respectively. Molecular aberrations in different signaling pathways, such as signal transduction systems or developmental pathways are the chief triggering mechanisms in different cancers Though a massive advancement in diagnostic and therapeutic interventions results in improved survival of patients with gastrointestinal cancer; the lower malignancy stages of these carcinomas are comparatively asymptomatic. Various gastrointestinal-related cancers are detected at advanced stages, leading to deplorable prognoses and increased rates of recurrence. Recent molecular studies have elucidated the imperative roles of several signaling pathways, namely Wnt, Hedgehog, and Notch signaling pathways, play in the progression, therapeutic responsiveness, and metastasis of gastrointestinal-related cancers. This book chapter gives an interesting update on recent findings on the involvement of developmental signaling pathways their mechanistic insight in gastrointestinalcancer. Subsequently, evidences supporting the exploration of gastrointestinal cancer related molecular mechanisms have also been discussed for developing novel therapeutic strategies against these debilitating carcinomas.
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Affiliation(s)
- Afza Ahmad
- Department of Biosciences, Integral University, Lucknow, Uttar Pradesh, India
| | - Rohit Kumar Tiwari
- Department of Clinical Research, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Saleha Siddiqui
- Department of Biotechnology, Delhi Technological University, Delhi, India
| | - Muskan Chadha
- Department of Nutrition and Dietetics, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Ratnakar Shukla
- Department of Clinical Research, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Vivek Srivastava
- Department of Chemistry & Biochemistry, Sharda School of Basic Sciences & Research, Sharda University, Greater Noida, Uttar Pradesh, India.
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5
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Bianca C, Sidhartha E, Tiribelli C, El-Khobar KE, Sukowati CHC. Role of hepatitis B virus in development of hepatocellular carcinoma: Focus on covalently closed circular DNA. World J Hepatol 2022; 14:866-884. [PMID: 35721287 PMCID: PMC9157711 DOI: 10.4254/wjh.v14.i5.866] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/31/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with hepatitis B virus (HBV) remains a major global health problem, especially in developing countries. It may lead to prolonged liver damage, fibrosis, cirrhosis, and hepatocellular carcinoma. Persistent chronic HBV infection is related to host immune response and the stability of the covalently closed circular DNA (cccDNA) in human hepatocytes. In addition to being essential for viral transcription and replication, cccDNA is also suspected to play a role in persistent HBV infections or hepatitis relapses since cccDNA is very stable in non-dividing human hepatocytes. Understanding the pathogenicity and oncogenicity of HBV components would be essential in the development of new diagnostic tools and treatment strategies. This review summarizes the role and molecular mechanisms of HBV cccDNA in hepatocyte transformation and hepatocarcinogenesis and current efforts to its detection and targeting.
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Affiliation(s)
- Claryssa Bianca
- Department of Biomedicine, Indonesia International Institute for Life Sciences, Jakarta 13210, Indonesia
| | - Elizabeth Sidhartha
- Department of Biomedicine, Indonesia International Institute for Life Sciences, Jakarta 13210, Indonesia
| | - Claudio Tiribelli
- Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
| | - Korri Elvanita El-Khobar
- Eijkman Center for Molecular Biology, National Research and Innovation Agency (BRIN), Jakarta 10340, Indonesia
| | - Caecilia H C Sukowati
- Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
- Eijkman Center for Molecular Biology, National Research and Innovation Agency (BRIN), Jakarta 10340, Indonesia.
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6
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Gouda G, Gupta MK, Donde R, Behera L, Vadde R. Metabolic pathway-based target therapy to hepatocellular carcinoma: a computational approach. THERANOSTICS AND PRECISION MEDICINE FOR THE MANAGEMENT OF HEPATOCELLULAR CARCINOMA, VOLUME 2 2022:83-103. [DOI: 10.1016/b978-0-323-98807-0.00003-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/06/2023]
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7
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Sekiba K, Otsuka M, Koike K. Potential of HBx Gene for Hepatocarcinogenesis in Noncirrhotic Liver. Semin Liver Dis 2021; 41:142-149. [PMID: 33984871 DOI: 10.1055/s-0041-1723033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Current treatments for hepatitis B virus (HBV) using nucleos(t)ide analogs cannot eliminate the risk of hepatocellular carcinoma (HCC) development. As HBV-associated HCC can develop even in the absence of liver cirrhosis, HBV is regarded to possess direct oncogenic potential. HBV regulatory protein X (HBx) has been identified as a primary mediator of HBV-mediated hepatocarcinogenesis. A fragment of the HBV genome that contains the coding region of HBx is commonly integrated into the host genome, resulting in the production of aberrant proteins and subsequent hepatocarcinogenesis. Besides, HBx interferes with the host DNA or deoxyribonucleic acid damage repair pathways, signal transduction, epigenetic regulation of gene expression, and cancer immunity, thereby promoting carcinogenesis in the noncirrhotic liver. However, numerous molecules and pathways have been implicated in the development of HBx-associated HCC, suggesting that the mechanisms underlying HBx-mediated hepatocarcinogenesis remain to be elucidated.
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Affiliation(s)
- Kazuma Sekiba
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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8
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Chow AKM, Yau SWL, Ng L. Novel molecular targets in hepatocellular carcinoma. World J Clin Oncol 2020; 11:589-605. [PMID: 32879846 PMCID: PMC7443834 DOI: 10.5306/wjco.v11.i8.589] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 06/04/2020] [Accepted: 06/20/2020] [Indexed: 02/06/2023] Open
Abstract
Globally, hepatocellular carcinoma (HCC) is a leading cause of cancer and cancer-related deaths. The therapeutic efficacy of locoregional and systemic treatment in patients with advanced HCC remains low, which results in a poor prognosis. The development of sorafenib for the treatment of HCC has resulted in a new era of molecular targeted therapy for this disease. However, the median overall survival was reported to be barely higher in the sorafenib treatment group than in the control group. Hence, in this review we describe the importance of developing more effective targeted therapies for the management of advanced HCC. Recent investigations of molecular signaling pathways in several cancers have provided some insights into developing molecular therapies that target critical members of these signaling pathways. Proteins involved in the Hedgehog and Notch signaling pathways, Polo-like kinase 1, arginine, histone deacetylases and Glypican-3 can be potential targets in the treatment of HCC. Monotherapy has limited therapeutic efficacy due to the development of inhibitory feedback mechanisms and induction of chemoresistance. Thus, emphasis is now on the development of personalized and combination molecular targeted therapies that can serve as ideal therapeutic strategies for improved management of HCC.
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Affiliation(s)
- Ariel Ka-Man Chow
- School of Nursing and Health Studies, The Open University of Hong Kong, Hong Kong, China
| | - Simon Wing-Lung Yau
- School of Nursing and Health Studies, The Open University of Hong Kong, Hong Kong, China
| | - Lui Ng
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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9
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Salama YA, El-karef A, El Gayyar AM, Abdel-Rahman N. Beyond its antioxidant properties: Quercetin targets multiple signalling pathways in hepatocellular carcinoma in rats. Life Sci 2019; 236:116933. [DOI: 10.1016/j.lfs.2019.116933] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 10/01/2019] [Accepted: 10/03/2019] [Indexed: 12/19/2022]
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10
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Huang Q, Li J, Zheng J, Wei A. The Carcinogenic Role of the Notch Signaling Pathway in the Development of Hepatocellular Carcinoma. J Cancer 2019; 10:1570-1579. [PMID: 31031867 PMCID: PMC6485212 DOI: 10.7150/jca.26847] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 01/12/2019] [Indexed: 12/11/2022] Open
Abstract
The Notch signaling pathway, known to be a highly conserved signaling pathway in embryonic development and adult tissue homeostasis, participates in cell fate decisions that include cellular differentiation, cell survival and cell death. However, other studies have shown that aberrant in Notch signaling is pro-tumorigenic, particularly in hepatocellular carcinoma (HCC). HCC is one of the most common malignant tumors in the world and has a high mortality rate. Growing evidence supports that Notch signaling plays a critical role in the development of HCC by regulating the tumor microenvironment, tumorigenesis, progression, angiogenesis, invasion and metastasis. Accordingly, overexpression of Notch is closely associated with poor prognosis in HCC. In this review, we focus on the pro-tumorigenic role of Notch signaling in HCC, summarize the current knowledge of Notch signaling and its role in HCC development, and outline the therapeutic potential of targeting Notch signaling in HCC.
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Affiliation(s)
- Qinfeng Huang
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
| | - Junhong Li
- The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning 530023, Guangxi, China
| | - Jinghui Zheng
- Discipline Construction Office, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi, China
| | - Ailing Wei
- The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning 530023, Guangxi, China
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Plasma Level of miR-5193 As a Novel Biomarker for Diagnosis of HBV-Related Hepatocellular Carcinoma. HEPATITIS MONTHLY 2019. [DOI: 10.5812/hepatmon.84455] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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12
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Hany H, Shalaby A, Al Kashef W, Kandil W, Shahin RA, El-Alfy H, Besheer T, Farag R, Mohamed M. Evaluation of the role of Notch1 expression in hepatic carcinogenesis with clinico-pathological correlation. Pathology 2018; 50:730-736. [PMID: 30389219 DOI: 10.1016/j.pathol.2018.08.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 08/14/2018] [Accepted: 08/22/2018] [Indexed: 02/07/2023]
Abstract
The role of Notch pathway in hepatocarcinogenesis is unclear with conflicting results reported from different researchers. This study aimed to investigate the exact role of Notch1 in hepatocarcinogenesis and its influence on survival and to determine the possibility of it being a target therapy. Differential immunohistochemical expression of Notch1 in 100 cases of hepatocellular carcinoma (HCC) and adjacent non-neoplastic liver tissue was performed. The results showed that expression of Notch1 was significantly higher in the non-neoplastic hepatic tissues than in HCC tissues (p < 0.001), but there was no significant difference in Notch1 expression between cirrhotic and non-cirrhotic liver tissue (p = 0.197). Notch1 expression was higher in low grade than in high grade HCC (p = 0.036). Notch1 expression showed reverse correlation with mitotic count (p = 0.008), and necrosis (p = 0.005). The disease free survival was shorter in patients displaying low levels of Notch1 expression (p = 0.045). The overall survival showed no significant difference between high and low levels of Notch1 expression; however, it was somewhat longer in patients with high Notch1 expression (p = 0.220). In conclusion, the tumour suppressor role of Notch1 was supported and the use of Notch1 agonists may have a role in improving the prognosis of HCC.
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Affiliation(s)
- Heba Hany
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt
| | - Asem Shalaby
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt; Pathology Department, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.
| | - Wagdi Al Kashef
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt
| | - Wageha Kandil
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt
| | - Rehab-Allah Shahin
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt
| | - Hatem El-Alfy
- Tropical Disease Department, Mansoura University Hospital, Mansoura University, Mansoura, Egypt
| | - Tarek Besheer
- Tropical Disease Department, Mansoura University Hospital, Mansoura University, Mansoura, Egypt
| | - Raghda Farag
- Tropical Disease Department, Mansoura University Hospital, Mansoura University, Mansoura, Egypt
| | - Mie Mohamed
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt
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Kongkavitoon P, Butta P, Sanpavat A, Bhattarakosol P, Tangtanatakul P, Wongprom B, Tangkijvanich P, Hirankarn N, Palaga T. Regulation of periostin expression by Notch signaling in hepatocytes and liver cancer cell lines. Biochem Biophys Res Commun 2018; 506:739-745. [PMID: 30384995 DOI: 10.1016/j.bbrc.2018.10.144] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 10/23/2018] [Indexed: 12/29/2022]
Abstract
Notch signaling is involved in both differentiation of hepatocyte progenitors and hepatocellular carcinoma (HCC). The mechanism whereby Notch signaling regulates cellular transformation in hepatocytes is still controversial. This study investigated the impact of overexpressing truncated intracellular Notch1 (NICD1) on transcriptomic profiles of immortalized human hepatocytes. RNA sequencing and gene ontology enrichment analysis revealed that extracellular matrix organization and hyaluronan biosynthesis process gene sets are among those affected by Notch hyperactivation. The relationship between Notch signaling and periostin, an extracellular matrix protein highly expressed in HCC, were further studied. Modulating Notch signaling through NICD1 overexpression or treatment with a gamma secretase inhibitor resulted in increased or decreased periostin expression, respectively, in HCC and liver bile duct carcinoma cell lines. Based on The Cancer Genome Atlas database, mRNA levels of NOTCH1 and POSTN are positively correlated in tumor tissues but not in nontumor tissues. Two consensus RBPJ binding motifs were identified in the -3932/-3921 and + 2522/+2533 bp of POSTN regulatory regions, and NOTCH1 is associated with these binding sites in a liver bile duct carcinoma cell line. Taken together, these results indicate that Notch signaling directly regulates transcription of POSTN in hepatocytes and liver cancer cell lines and may be a candidate for drug targeting in liver cancer.
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Affiliation(s)
- Pornrat Kongkavitoon
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Phayathai Road, Pathumwan, Bangkok, 10330, Thailand; Center of Excellence in Immunology and Immune-mediated Diseases, Phayathai Road, Pathumwan, Bangkok, 10330, Thailand
| | - Patcharavadee Butta
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Phayathai Road, Pathumwan, Bangkok, 10330, Thailand; Center of Excellence in Immunology and Immune-mediated Diseases, Phayathai Road, Pathumwan, Bangkok, 10330, Thailand
| | - Anapat Sanpavat
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, Phayathai Road, Pathumwan, Bangkok, 10330, Thailand
| | - Pattarasinee Bhattarakosol
- Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Phayathai Road, Pathumwan, Bangkok, 10330, Thailand
| | - Pattarin Tangtanatakul
- Center of Excellence in Immunology and Immune-mediated Diseases, Phayathai Road, Pathumwan, Bangkok, 10330, Thailand; Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Phayathai Road, Pathumwan, Bangkok, 10330, Thailand
| | - Benjawan Wongprom
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Phayathai Road, Pathumwan, Bangkok, 10330, Thailand; Center of Excellence in Immunology and Immune-mediated Diseases, Phayathai Road, Pathumwan, Bangkok, 10330, Thailand
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Phayathai Road, Pathumwan, Bangkok, 10330, Thailand
| | - Nattiya Hirankarn
- Center of Excellence in Immunology and Immune-mediated Diseases, Phayathai Road, Pathumwan, Bangkok, 10330, Thailand; Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Phayathai Road, Pathumwan, Bangkok, 10330, Thailand
| | - Tanapat Palaga
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Phayathai Road, Pathumwan, Bangkok, 10330, Thailand; Center of Excellence in Immunology and Immune-mediated Diseases, Phayathai Road, Pathumwan, Bangkok, 10330, Thailand.
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Kunanopparat A, Issara-Amphorn J, Leelahavanichkul A, Sanpavat A, Patumraj S, Tangkijvanich P, Palaga T, Hirankarn N. Delta-like ligand 4 in hepatocellular carcinoma intrinsically promotes tumour growth and suppresses hepatitis B virus replication. World J Gastroenterol 2018; 24:3861-3870. [PMID: 30228780 PMCID: PMC6141339 DOI: 10.3748/wjg.v24.i34.3861] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 07/05/2018] [Accepted: 07/16/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the role of Delta-like ligand 4 (DLL4) on tumour growth in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) in vivo.
METHODS We suppressed DLL4 expression in an HBV expressing HCC cell line, HepG2.2.15 and analysed the growth ability of cells as subcutaneous tumours in nude mice. The expression of tumour angiogenesis regulators, VEGF-A and VEGF-R2 in tumour xenografts were examined by western blotting. The tumour proliferation and neovasculature were examined by immunohistochemistry. The viral replication and viral protein expression were measured by quantitative PCR and western blotting, respectively.
RESULTS Eighteen days after implantation, tumour volume in mice implanted with shDLL4 HepG2.2.15 was significantly smaller than in mice implanted with control HepG2.2.15 (P < 0.0001). The levels of angiogenesis regulators, VEGF-A and VEGF-R2 were significantly decreased in implanted tumours with suppressed DLL4 compared with the control group (P < 0.001 and P < 0.05, respectively). Furthermore, the suppression of DLL4 expression in tumour cells reduced cell proliferation and the formation of new blood vessels in tumours. Unexpectedly, increased viral replication was observed after suppression of DLL4 in the tumours.
CONCLUSION This study demonstrates that DLL4 is important in regulating the tumour growth of HBV-associated HCC as well as the neovascularization and suppression of HBV replication.
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Affiliation(s)
- Areerat Kunanopparat
- Center of Excellence in Immunology and Immune Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Jiraphorn Issara-Amphorn
- Center of Excellence in Immunology and Immune Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Asada Leelahavanichkul
- Center of Excellence in Immunology and Immune Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Anapat Sanpavat
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Suthiluk Patumraj
- Center of Excellence for Microcirculation, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Pisit Tangkijvanich
- Research Unit of Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Tanapat Palaga
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
| | - Nattiya Hirankarn
- Center of Excellence in Immunology and Immune Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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Wu IC, Liu WC, Chang TT. Applications of next-generation sequencing analysis for the detection of hepatocellular carcinoma-associated hepatitis B virus mutations. J Biomed Sci 2018; 25:51. [PMID: 29859540 PMCID: PMC5984823 DOI: 10.1186/s12929-018-0442-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 04/30/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Next-generation sequencing (NGS) is a powerful and high-throughput method for the detection of viral mutations. This article provides a brief overview about optimization of NGS analysis for hepatocellular carcinoma (HCC)-associated hepatitis B virus (HBV) mutations, and hepatocarcinogenesis of relevant mutations. MAIN BODY For the application of NGS analysis in the genome of HBV, four noteworthy steps were discovered in testing. First, a sample-specific reference sequence was the most effective mapping reference for NGS. Second, elongating the end of reference sequence improved mapping performance at the end of the genome. Third, resetting the origin of mapping reference sequence could probed deletion mutations and variants at a certain location with common mutations. Fourth, using a platform-specific cut-off value to distinguish authentic minority variants from technical artifacts was found to be highly effective. One hundred and sixty-seven HBV single nucleotide variants (SNVs) were found to be studied previously through a systematic literature review, and 12 SNVs were determined to be associated with HCC by meta-analysis. From comprehensive research using a HBV genome-wide NGS analysis, 60 NGS-defined HCC-associated SNVs with their pathogenic frequencies were identified, with 19 reported previously. All the 12 HCC-associated SNVs proved by meta-analysis were confirmed by NGS analysis, except for C1766T and T1768A which were mainly expressed in genotypes A and D, but including the subgroup analysis of A1762T. In the 41 novel NGS-defined HCC-associated SNVs, 31.7% (13/41) had cut-off values of SNV frequency lower than 20%. This showed that NGS could be used to detect HCC-associated SNVs with low SNV frequency. Most SNV II (the minor strains in the majority of non-HCC patients) had either low (< 20%) or high (> 80%) SNV frequencies in HCC patients, a characteristic U-shaped distribution pattern. The cut-off values of SNV frequency for HCC-associated SNVs represent their pathogenic frequencies. The pathogenic frequencies of HCC-associated SNV II also showed a U-shaped distribution. Hepatocarcinogenesis induced by HBV mutated proteins through cellular pathways was reviewed. CONCLUSION NGS analysis is useful to discover novel HCC-associated HBV SNVs, especially those with low SNV frequency. The hepatocarcinogenetic mechanisms of novel HCC-associated HBV SNVs defined by NGS analysis deserve further investigation.
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Affiliation(s)
- I-Chin Wu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan, Republic of China.,Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan, Republic of China
| | - Wen-Chun Liu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan, Republic of China.,Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan, Republic of China
| | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan, Republic of China.
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Liao B, Zhou H, Liang H, Li C. Regulation of ERK and AKT pathways by hepatitis B virus X protein via the Notch1 pathway in hepatocellular carcinoma. Int J Oncol 2017; 51:1449-1459. [PMID: 29048612 PMCID: PMC5643068 DOI: 10.3892/ijo.2017.4126] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Accepted: 07/18/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) is the dominant risk factor for hepatocellular carcinoma (HCC). HBV X protein (HBx) plays crucial roles in HCC carcinogenesis. HBx interferes with several signaling pathways including the Notch1 pathway in HCC. In this study, we found that Notch1 was highly expressed in HCC, especially in large HCCs. Notch1 and HBx co-localized in HCC and their levels were positively correlated with each other. Notch1 expression was more elevated in HepG2.2.15 cells than that in HepG2 cells. HBx activated the Notch1 pathway in HepG2.2.15 cells. Suppression of HBx and the Notch1 pathway attenuated the growth of HepG2.2.15 cells. Notch1, ERK, and AKT pathways were inhibited after γ-secretase inhibitor treatment. Dual-specificity phosphatase 1 (DUSP1) and phosphatase and tensin homolog (PTEN) were upregulated after γ-secretase inhibitor treatment and Hes1 inhibition. Luciferase reporter assays showed that Hes1 suppressed the promoters of DUSP1 and PTEN genes, which was reversed by γ-secretase inhibitor treatment. Western blotting demonstrated that DUSP1 dephosphorylated pERK and PTEN dephosphorylated pAKT. Collectively, we found a link among HBx, the Notch1 pathway, DUSP1/PTEN, and ERK/AKT pathways, which influenced HCC cell survival and could be a therapeutic target for HCC treatment.
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Affiliation(s)
- Bo Liao
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei 430030, P.R. China
| | - Honghao Zhou
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei 430030, P.R. China
| | - Huifang Liang
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei 430030, P.R. China
| | - Changhai Li
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei 430030, P.R. China
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17
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Kunanopparat A, Kimkong I, Palaga T, Tangkijvanich P, Sirichindakul B, Hirankarn N. Increased ATG5-ATG12 in hepatitis B virus-associated hepatocellular carcinoma and their role in apoptosis. World J Gastroenterol 2016; 22:8361-8374. [PMID: 27729742 PMCID: PMC5055866 DOI: 10.3748/wjg.v22.i37.8361] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2016] [Revised: 07/04/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate autophagy-related genes, particularly ATG12, in apoptosis and cell cycle in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and non-HBV-HCC cell lines.
METHODS The expression of autophagy-related genes in HBV-associated hepatocellular carcinoma and non-HBV-HCC cell lines and human liver tissues was examined by quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blotting. The silencing of target genes was used to examine the function of various genes in apoptosis and cell cycle progression.
RESULTS The expression of autophagy related genes ATG5, ATG12, ATG9A and ATG4B expression was analyzed in HepG2.2.15 cells and compared with HepG2 and THLE cells. We found that ATG5 and ATG12 mRNA expression was significantly increased in HepG2.2.15 cells compared to HepG2 cells (P < 0.005). Moreover, ATG5-ATG12 protein levels were increased in tumor liver tissues compared to adjacent non-tumor tissues mainly from HCC patients with HBV infection. We also analyzed the function of ATG12 in cell apoptosis and cell cycle progression. The percentage of apoptotic cells increased by 11.4% in ATG12-silenced HepG2.2.15 cells (P < 0.005) but did not change in ATG12-silenced HepG2 cells under starvation with Earle’s balanced salt solution. However, the combination blockade of Notch signaling and ATG12 decreased the apoptotic rate of HepG2.2.15 cells from 55.6% to 50.4% (P < 0.05).
CONCLUSION ATG12 is important for HBV-associated apoptosis and a potential drug target for HBV-HCC. Combination inhibition of ATG12/Notch signaling had no additional effect on HepG2.2.15 apoptosis.
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18
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Tu KS, Yao YM. Epithelial-mesenchymal transition and related signaling pathways in hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2016; 24:2131-2142. [DOI: 10.11569/wcjd.v24.i14.2131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common forms of liver cancer and the third leading cause of cancer-related mortality in the world. Although numerous therapeutic strategies have been employed to treat this fatal disease, the prognosis of HCC patients remains dismal with a low 5-year survival rate of approximately 30%. Postoperative recurrence and metastasis of HCC are the leading cause of poor prognosis. Metastasis has been thought to rely on non-motile epithelial tumor cells acquiring characteristics of mesenchymal cells, which are more migratory. This change is known as the epithelial-to-mesenchymal transition (EMT). EMT has been considered one of the main reasons for the invasion and metastasis of HCC. Notably, increasing evidence indicates that several signaling pathways participate in the regulation of EMT in HCC. In the current review, we will discuss the current progress in research of EMT and its related signaling pathways in HCC.
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19
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Kongkavitoon P, Tangkijvanich P, Hirankarn N, Palaga T. Hepatitis B Virus HBx Activates Notch Signaling via Delta-Like 4/Notch1 in Hepatocellular Carcinoma. PLoS One 2016; 11:e0146696. [PMID: 26766040 PMCID: PMC4713073 DOI: 10.1371/journal.pone.0146696] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 12/20/2015] [Indexed: 12/12/2022] Open
Abstract
Hepatitis virus B (HBV) infection is one of the major causes of hepatocellular carcinomas (HCC). HBx protein encoded in HBV genome is one of the key viral factors leading to malignant transformation of infected cells. HBx functions by interfering with cellular functions, causing aberration in cellular behaviour and transformation. Notch signalling is a well-conserved pathway involved in cellular differentiation, cell survival and cell death operating in various types of cells. Aberration in the Notch signalling pathways is linked to various tumors, including HCC. The role of HBx on the Notch signalling in HCC, however, is still controversial. In this study, we reported that HBV genome-containing HCC cell line HepG2 (HepG2.2.15) expressed higher Notch1 and Delta-like 4 (Dll4), compared to the control HepG2 without HBV genome. This upregulation coincided with increased appearance of the cleavage of Notch1, indicating constitutively activated Notch signalling. Silencing of HBx specifically reduced the level of Dll4 and cleaved Notch1. The increase in Dll4 level was confirmed in clinical specimens of HCC lesion, in comparison with non-tumor lesions. Using specific signalling pathway inhibitors, we found that MEK1/2, PI3K/AKT and NF-κB pathways are critical for HBx-mediated Dll4 upregulation. Silencing of HBx clearly decreased the level of phosphorylation of Akt and Erk1/2. Upon silencing of Dll4 in HepG2.2.15, decreased cleaved Notch1, increased apoptosis and cell cycle arrest were observed, suggesting a critical role of HBx-Dll4-Notch1 axis in regulating cell survival in HCC. Furthermore, clonogenic assay confirmed the important role of Dll4 in regulating cell survival of HBV-genome containing HCC cell line. Taken together, we reported a link between HBx and the Notch signalling in HCC that affects cell survival of HCC, which can be a potential target for therapy.
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Affiliation(s)
- Pornrat Kongkavitoon
- Center of Excellence in Immunology and Immune-mediated Diseases, Chulalongkorn University, Bangkok, Thailand
- Interdisciplinary Graduate Program in Medical Microbiology, Graduate School, Chulalongkorn University, Bangkok, Thailand
| | - Pisit Tangkijvanich
- Research Unit of Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Nattiya Hirankarn
- Center of Excellence in Immunology and Immune-mediated Diseases, Chulalongkorn University, Bangkok, Thailand
- Interdisciplinary Graduate Program in Medical Microbiology, Graduate School, Chulalongkorn University, Bangkok, Thailand
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- * E-mail: (TP); (NH)
| | - Tanapat Palaga
- Center of Excellence in Immunology and Immune-mediated Diseases, Chulalongkorn University, Bangkok, Thailand
- Interdisciplinary Graduate Program in Medical Microbiology, Graduate School, Chulalongkorn University, Bangkok, Thailand
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
- * E-mail: (TP); (NH)
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20
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Gil-García B, Baladrón V. The complex role of NOTCH receptors and their ligands in the development of hepatoblastoma, cholangiocarcinoma and hepatocellular carcinoma. Biol Cell 2015; 108:29-40. [DOI: 10.1111/boc.201500029] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 11/24/2015] [Indexed: 12/12/2022]
Affiliation(s)
- Borja Gil-García
- Laboratory of Biochemistry and Molecular Biology; Department of Inorganic and Organic Chemistry and Biochemistry; Medical School/CRIB/Biomedicine Unit; University of Castilla-La Mancha (UCLM)/CSIC; 02008, Albacete Spain
| | - Victoriano Baladrón
- Laboratory of Biochemistry and Molecular Biology; Department of Inorganic and Organic Chemistry and Biochemistry; Medical School/CRIB/Biomedicine Unit; University of Castilla-La Mancha (UCLM)/CSIC; 02008, Albacete Spain
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21
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Gao J, Xiong Y, Wang Y, Wang Y, Zheng G, Xu H. Hepatitis B virus X protein activates Notch signaling by its effects on Notch1 and Notch4 in human hepatocellular carcinoma. Int J Oncol 2015; 48:329-37. [PMID: 26530164 DOI: 10.3892/ijo.2015.3221] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 10/01/2015] [Indexed: 12/17/2022] Open
Abstract
Deregulated expression of Notch receptors and abnormal activity of Notch signaling have been observed in a growing number of malignant tumors, however, the expression and activity of Notch in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and their relationship with HBV X protein (HBx) are still not fully elucidated. To address this, we examined the overall expression of Notch receptors in HBV-associated HCC tissues, analyzed their relationship with HBx, and further investigated the role of Notch signaling in HBx stable transfected HepG2 cells (HepG2X). The results showed that Notch signaling could be activated by HBx in HepG2 cells. The expression of cytoplasmic Notch1 or nuclear Notch4 was correlated with the expression of HBx in HBV-associated HCC tissues. The expression of cytoplasmic Notch1 or nuclear Notch4 could also be upregulated by HBx in HepG2X cells. The upregulation of Notch1 by HBx was through p38 MAPK pathway. Moreover, HBx was found to directly interact with Notch1, whereas, not with Notch4 in HepG2X cells. Suppression of Notch signaling by γ-secretase inhibitor (GSI) decreased cell growth, blocked cell cycle progression and induced cell apoptosis in HepG2X cells. The present study indicates that HBx activates Notch signaling by its effects on Notch1 and Notch4, and therefore, recruits Notch signaling as a downstream pathway contributing to its carcinogenic role in HBV-associated HCC.
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Affiliation(s)
- Juan Gao
- Department of Digestive Diseases, Wuhan General Hospital of Guangzhou Command PLA, Wuhan, Hubei 430070, P.R. China
| | - Yimin Xiong
- Department of Digestive Diseases, Wuhan General Hospital of Guangzhou Command PLA, Wuhan, Hubei 430070, P.R. China
| | - Yan Wang
- Department of Digestive Diseases, Wuhan General Hospital of Guangzhou Command PLA, Wuhan, Hubei 430070, P.R. China
| | - Yiming Wang
- Department of Digestive Diseases, Wuhan General Hospital of Guangzhou Command PLA, Wuhan, Hubei 430070, P.R. China
| | - Guorong Zheng
- Department of Digestive Diseases, Wuhan General Hospital of Guangzhou Command PLA, Wuhan, Hubei 430070, P.R. China
| | - Hualin Xu
- Department of Digestive Diseases, Wuhan General Hospital of Guangzhou Command PLA, Wuhan, Hubei 430070, P.R. China
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22
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Sun G, Mackey LV, Coy DH, Yu CY, Sun L. The Histone Deacetylase Inhibitor Vaproic Acid Induces Cell Growth Arrest in Hepatocellular Carcinoma Cells via Suppressing Notch Signaling. J Cancer 2015; 6:996-1004. [PMID: 26366213 PMCID: PMC4565849 DOI: 10.7150/jca.12135] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Accepted: 07/19/2015] [Indexed: 12/29/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a type of malignant cancer. Notch signaling is aberrantly expressed in HCC tissues with more evidence showing that this signaling plays a critical role in HCCs. In the present study, we investigate the effects of the anti-convulsant drug valproic acid (VPA) in HCC cells and its involvement in modulating Notch signaling. We found that VPA, acting as a histone deacetylase (HDAC) inhibitor, induced a decrease in HDAC4 and an increase in acetylated histone 4 (AcH4) and suppressed HCC cell growth. VPA also induced down-regulation of Notch signaling via suppressing the expression of Notch1 and its target gene HES1, with an increase of tumor suppressor p21 and p63. Furthermore, Notch1 activation via overexpressing Notch1 active form ICN1 induced HCC cell proliferation and anti-apoptosis, indicating Notch signaling played an oncogenic role in HCC cells. Meanwhile, VPA could reverse Notch1-induced increase of cell proliferation. Interestingly, VPA was also observed to stimulate the expression of G protein-coupled somatostatin receptor type 2 (SSTR2) that has been used in receptor-targeting therapies. This discovery supports a combination therapy of VPA with the SSTR2-targeting agents. Our in vitro assay did show that the combination of VPA and the peptide-drug conjugate camptothecin-somatostatin (CPT-SST) displayed more potent anti-proliferative effects on HCC cells than did each alone. VPA may be a potential drug candidate in the development of anti-HCC drugs via targeting Notch signaling, especially in combination with receptor-targeting cytotoxic agents.
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Affiliation(s)
- Guangchun Sun
- 1. Department of Pharmacy, The Fifth People's Hospital of Shanghai, Fudan University; 801 He-Qing Rd., Shanghai 200240, China
| | - Lily V Mackey
- 3. Department of Medicine, School of Medicine, Tulane Health Sciences Center, New Orleans, LA 70112-2699, USA
| | - David H Coy
- 3. Department of Medicine, School of Medicine, Tulane Health Sciences Center, New Orleans, LA 70112-2699, USA
| | - Cui-Yun Yu
- 2. Institute of Pharmacy & Pharmacology, Department of Pharmacy, University of South China, Hengyang 421001, China ; 3. Department of Medicine, School of Medicine, Tulane Health Sciences Center, New Orleans, LA 70112-2699, USA
| | - Lichun Sun
- 1. Department of Pharmacy, The Fifth People's Hospital of Shanghai, Fudan University; 801 He-Qing Rd., Shanghai 200240, China ; 2. Institute of Pharmacy & Pharmacology, Department of Pharmacy, University of South China, Hengyang 421001, China ; 3. Department of Medicine, School of Medicine, Tulane Health Sciences Center, New Orleans, LA 70112-2699, USA
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Su BH, Qu J, Song M, Huang XY, Hu XM, Xie J, Zhao Y, Ding LC, She L, Chen J, Lin LS, Lin X, Zheng DL, Lu YG. NOTCH1 signaling contributes to cell growth, anti-apoptosis and metastasis in salivary adenoid cystic carcinoma. Oncotarget 2015; 5:6885-95. [PMID: 25149541 PMCID: PMC4196170 DOI: 10.18632/oncotarget.2321] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background: Numerous studies have reported both the tumor-suppressive and oncogenic roles of the Notch pathway, indicating that Notch activity regulates tumor biology in a complex, context-dependent manner. The aim of the present study was to identify the role of NOTCH1 in the cell growth and metastasis of SACC. Methods: We analyzed the expression of NOTCH1 in clinical SACC samples using immunohistochemical staining. We silenced the expression of NOTCH1 and overexpressed activated NOTCH1 to elucidate the effects of NOTCH1 on proliferation, migration and invasion. NOTCH1 target genes were validated by real-time PCR. Results: Our results showed that NOTCH1 was upregulated in SACC tissues when compared with normal tissues, and this upregulation was further enhanced in SACC tissues with metastasis and recurrence when compared with SACC tissues without metastasis. Overexpression of NOTCH1 in SACC cells promoted cell growth, migration and invasion, and knockdown of NOTCH1 inhibited cell proliferation in vitro and tumorigenicity in vivo by inducing cell apoptosis. Conclusions:The results of this study suggest that NOTCH1 plays a key role in the cell growth, anti-apoptosis, and metastasis of SACC. NOTCH1 inhibitors might therefore have potential therapeutic applications in treating SACC patients by inhibiting cancer cell growth and metastasis.
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Affiliation(s)
- Bo-Hua Su
- Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, Fuzhou, China. These authors contributed equally to this work
| | - Jing Qu
- Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, Fuzhou, China. These authors contributed equally to this work
| | - Min Song
- Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, Fuzhou, China. These authors contributed equally to this work
| | - Xiao-Yu Huang
- Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, Fuzhou, China
| | - Xiao-Meng Hu
- Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, Fuzhou, China
| | - Jian Xie
- Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, Fuzhou, China
| | - Yong Zhao
- Department of Pathology, Affiliated Stomatological Hospital, Fujian Medical University, Fuzhou, China
| | - Lin-Can Ding
- Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, Fuzhou, China
| | - Lin She
- Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, Fuzhou, China
| | - Jiang Chen
- Center of Dental Implant, Affiliated Stomatological Hospital, Fujian Medical University, Fuzhou, China
| | - Li-Song Lin
- Department of Oral and Maxillofacial Surgery, Affiliated First Hospital of Fujian Medical University, Fuzhou, China
| | - Xu Lin
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Da-Li Zheng
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. Molecular Oncology, Moffitt Cancer Center, Tampa, FL, United States
| | - You-Guang Lu
- Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, Fuzhou, China
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Ryu SH, Jang MK, Kim WJ, Lee D, Chung YH. Metastatic tumor antigen in hepatocellular carcinoma: golden roads toward personalized medicine. Cancer Metastasis Rev 2014; 33:965-80. [PMID: 25325987 DOI: 10.1007/s10555-014-9522-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC), a prototype of hypervascular tumors, is one of the most common malignancies in the world, especially hyperendemic in the Far East where chronic hepatitis B virus (HBV) infection is highly prevalent. It is characterized by the clinical feature of a poor prognosis or a high mortality due to its already far advanced stages at diagnosis. It is so multifactorial that hepatocarcinogenesis cannot be explained by a single molecular mechanism. To date, a number of pathways have been known to contribute to the development, growth, angiogenesis, and even metastasis of HCC. Among the various factors, metastatic tumor antigens (MTAs) or metastasis-associated proteins have been vigorously investigated as an intriguing target in the field of hepatocarcinogenesis. According to recent studies including ours, MTAs are not only involved in the HCC development and growth (molecular carcinogenesis), but also closely associated with the post-operative recurrence and a poor prognosis or a worse response to post-operative anti-cancer therapy (clinical significance). Herein, we review MTAs in light of their essential structure, functions, and molecular mechanism in hepatocarcinogenesis. We will also focus in detail on the interaction between hepatitis B x protein (HBx) of HBV and MTA in order to clarify the HBV-associated HCC development. Finally, we will discuss the prognostic significance and clinical application of MTA in HCC. We believe that this review will help clinicians to understand the meaning and use of the detection of MTA in order to more effectively manage their HCC patients.
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Affiliation(s)
- Soo Hyung Ryu
- Department of Internal Medicine, Inje University College of Medicine, Seoul Paik Hospital, Seoul, South Korea
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Sun Q, Wang R, Luo J, Wang P, Xiong S, Liu M, Cheng B. Notch1 promotes hepatitis B virus X protein-induced hepatocarcinogenesis via Wnt/β-catenin pathway. Int J Oncol 2014; 45:1638-48. [PMID: 25017705 DOI: 10.3892/ijo.2014.2537] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Accepted: 06/24/2014] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus X protein (HBx) is implicated in the pathogenesis of hepatocellular carcinoma (HCC) via a network of signaling pathways. Notch pathway is a major member of the network. Notch signaling may generate opposing effect in different steps of carcinogenesis, depending on the tumor cell type and the status of other signaling pathways, such as Wnt signaling pathway. Our previous studies have shown that activated Notch1 signaling is required for HBx to promote proliferation and survival of human hepatic cell line L02. However, the exact mechanisms remain vague. Here, we used L02/HBx cell lines as a cell model to study the relationship between Notch and Wnt/β-catenin pathways in promoting proliferation. We observed that activated Notch1 and Wnt/β-catenin signaling pathways and L02 cell malignant transformation were induced by HBx. Inhibition of the Notch1 pathway decreased the activation of Wnt/β-catenin pathway and cell proliferation, while inhibition of the Wnt/β-catenin pathway impaired cell proliferation, but did not significantly affect Notch1 signaling pathway in L02/HBx cells. Furthermore, inhibition of the Wnt/β-catenin pathway overcame the inhibition effect of knockdown Notch1 on proliferation and survival in L02/HBx cells. Additionally, the activity of Wnt/β-catenin signaling appears to be consistent with Fzd10 expression. Therefore, we demonstrate that Wnt signaling is downstream of the Notch pathway in regulating proliferation of L02/HBx cells, and which may be related to Fzd10 instead of Fzd7. These data suggest a new model of HBx-related HCC via cooperation between Wnt and Notch pathways.
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Affiliation(s)
- Qian Sun
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Ronghua Wang
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Jing Luo
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Peng Wang
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Si Xiong
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Man Liu
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Bin Cheng
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
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26
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Liu Y, Xing ZB, Wang SQ, Chen S, Liu YK, Li YH, Li YF, Wang YQ, Lu Y, Hu WN, Zhang JH. MDM2-MOF-H4K16ac axis contributes to tumorigenesis induced by Notch. FEBS J 2014; 281:3315-24. [PMID: 24898892 DOI: 10.1111/febs.12863] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Revised: 05/29/2014] [Accepted: 05/30/2014] [Indexed: 12/17/2022]
Affiliation(s)
- Yan Liu
- College of Life Sciences; Hebei United University; Tangshan China
- Central Laboratory; Cancer Institute; Tangshan People's Hospital; China
| | - Zhao-Bin Xing
- College of Life Sciences; Hebei United University; Tangshan China
| | - Shu-Qing Wang
- Department of Nephrology; Kailuan General Hospital; Tangshan Hebei China
| | - Su Chen
- School of Life Sciences; Tongji University; Shanghai China
| | - Yan-Kun Liu
- Central Laboratory; Cancer Institute; Tangshan People's Hospital; China
| | - Yu-Hui Li
- Central Laboratory; Cancer Institute; Tangshan People's Hospital; China
| | - Yu-Feng Li
- Central Laboratory; Cancer Institute; Tangshan People's Hospital; China
| | - Ya-Qi Wang
- College of Life Sciences; Hebei United University; Tangshan China
- Central Laboratory; Cancer Institute; Tangshan People's Hospital; China
| | - Yang Lu
- First Hospital of Shi-Jia Zhuang City; China
| | - Wan-Ning Hu
- Central Laboratory; Cancer Institute; Tangshan People's Hospital; China
| | - Jing-Hua Zhang
- Central Laboratory; Cancer Institute; Tangshan People's Hospital; China
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27
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Abstract
Signaling pathways have become a major source of targets for novel therapies in hepatocellular carcinoma (HCC). Survival benefits achieved with sorafenib, a multikinase inhibitor, are unprecedented and underscore the importance of improving our understanding of how signaling networks interact in transformed cells. Numerous signaling modules are de-regulated in HCC, including some related to growth factor signaling (e.g., IGF, EGF, PDGF, FGF, HGF), cell differentiation (WNT, Hedgehog, Notch), and angiogenesis (VEGF). Intracellular mediators such as RAS and AKT/MTOR may also play a role in HCC development and progression. Different molecular mechanisms have been shown to induce aberrant pathway activation. These include point mutations, chromosomal aberrations, and epigenetically driven down-regulation. The use of novel molecular technologies such as next-generation sequencing in HCC research has enabled the identification of novel pathways previously underexplored in the HCC field, such as chromatin remodeling and autophagy. Considering recent failures of molecular therapies in advanced clinical trials (e.g., sunitinib, brivanib), survey of these and other new pathways may provide alternative therapeutic targets.
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Affiliation(s)
- Agrin Moeini
- HCC Translational Research Laboratory, Barcelona-Clinic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Liver Unit, Hospital Clínic, Catalonia, Madrid, Spain ; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto Carlos III, Madrid, Spain
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28
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Xu C, Zhou W, Wang Y, Qiao L. Hepatitis B virus-induced hepatocellular carcinoma. Cancer Lett 2014; 345:216-222. [PMID: 23981576 DOI: 10.1016/j.canlet.2013.08.035] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Revised: 08/10/2013] [Accepted: 08/18/2013] [Indexed: 12/12/2022]
Abstract
Many factors are considered to contribute to hepatitis B virus (HBV) associated hepatocellular carcinoma (HCC), including products of HBV, HBV integration and mutation, and host susceptibility. HBV X protein (HBx) can interfere with several signal pathways that associated with cell proliferation and apoptosis, and the impact of HBx C-terminal truncation in the development of HCC has been implicated. Recent studies by advanced sequencing technologies have revealed recurrent HBV DNA integration sites in hepatoma cells and susceptible genes/SNPs play an important role in the pathogenesis of liver cancer. Epigenetic changes, immune and inflammatory factors are also important contributing factors for liver cancer. This mini-review provides an overview on the recent development of HBV induced HCC.
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Affiliation(s)
- Cheng Xu
- Institute for Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Wence Zhou
- The Department of General Surgery II, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yuming Wang
- Institute for Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
| | - Liang Qiao
- Storr Liver Unit, University of Sydney, Westmead Millennium Institute, Westmead Hospital, Westmead, NSW 2145, Australia.
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29
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Shi J, Keller JM, Zhang J, Keller ET. A review on the diagnosis and treatment of hepatocellular carcinoma with a focus on the role of Wnts and the dickkopf family of Wnt inhibitors. J Hepatocell Carcinoma 2014; 1:1-7. [PMID: 27508171 PMCID: PMC4918262 DOI: 10.2147/jhc.s44537] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide. There are multiple etiologic factors including viral and environmental influences that can lead to HCC. Successful screening for early HCC is challenging due to the lack of well characterized and specific biomarkers. However, achieving successful screening is critically important as early diagnosis can potentially provide curative opportunities. Once HCC is advanced, there are multiple therapeutic venues, but most eventually fail, therefore developing new targeted therapies may provide greater chance for effective therapies. Along these lines, the Wnt pathway has been identified as contributing to the development and progression of HCC. Wnts can modify HCC growth and invasive ability. A key factor in the Wnt pathway is the dickkopf (DKK) family of Wnt inhibitors. DKKs have also been shown to modulate HCC progression. Additionally, several studies have suggested that DKK expression in tissue and serum has diagnostic and prognostic value.
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Affiliation(s)
- Junlin Shi
- Key Laboratory of Longevity and Ageing-Related Diseases, Ministry of Education, Nanning, Guangxi, People's Republic of China; Center for Translational Medicine, Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Jill M Keller
- Department of Urology, School of Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Jian Zhang
- Key Laboratory of Longevity and Ageing-Related Diseases, Ministry of Education, Nanning, Guangxi, People's Republic of China; Center for Translational Medicine, Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Evan T Keller
- Key Laboratory of Longevity and Ageing-Related Diseases, Ministry of Education, Nanning, Guangxi, People's Republic of China; Center for Translational Medicine, Guangxi Medical University, Nanning, Guangxi, People's Republic of China; Department of Urology, School of Medicine, University of Michigan, Ann Arbor, MI, USA
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30
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Megger DA, Naboulsi W, Meyer HE, Sitek B. Proteome Analyses of Hepatocellular Carcinoma. J Clin Transl Hepatol 2014; 2:23-30. [PMID: 26357614 PMCID: PMC4521250 DOI: 10.14218/jcth.2013.00022] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 12/06/2013] [Accepted: 12/07/2013] [Indexed: 12/16/2022] Open
Abstract
Proteomics has evolved into a powerful and widely used bioanalytical technique in the study of cancer, especially hepatocellular carcinoma (HCC). In this review, we provide an up to date overview of feasible proteome-analytical techniques for clinical questions. In addition, we present a broad summary of proteomic studies of HCC utilizing various technical approaches for the analysis of samples derived from diverse sources like HCC cell lines, animal models, human tissue and body fluids.
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Affiliation(s)
- Dominik A. Megger
- Medizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum, Germany
- Contributed equally
- Correspondence to: Dominik A. Megger, Medizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum 44801, Germany. Tel: +49-234/32-26119. E-mail: ; Barbara Sitek, Medizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum 44801, Germany. Tel: +49-234/32-24362. E-mail:
| | - Wael Naboulsi
- Medizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum, Germany
- Contributed equally
| | - Helmut E. Meyer
- Medizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum, Germany
- Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany
| | - Barbara Sitek
- Medizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum, Germany
- Correspondence to: Dominik A. Megger, Medizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum 44801, Germany. Tel: +49-234/32-26119. E-mail: ; Barbara Sitek, Medizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum 44801, Germany. Tel: +49-234/32-24362. E-mail:
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31
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Bharadwaj M, Roy G, Dutta K, Misbah M, Husain M, Hussain S. Tackling hepatitis B virus-associated hepatocellular carcinoma--the future is now. Cancer Metastasis Rev 2013; 32:229-68. [PMID: 23114844 DOI: 10.1007/s10555-012-9412-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent cancers in many developing countries including India. Among the various etiological factors being implicated in the cause of HCC, the most important cause, however, is hepatitis B virus (HBV) infection. Among all HBV genes, HBx is the most critical carcinogenic component, the molecular mechanisms of which have not been completely elucidated. Despite its clinical significance, there exists a very elemental understanding of the molecular, cellular, and environmental mechanisms that drive disease pathogenesis in HCC infected with HBV. Furthermore, there are only limited therapeutic options, the clinical benefits of which are insignificant. Therefore, the quest for novel and effective therapeutic regimen against HBV-related HCC is of paramount importance. This review attempts to epitomize the current state of knowledge of this most common and dreaded liver neoplasm, highlighting the putative treatment avenues and therapeutic research strategies that need to be implemented with immediate effect for tackling HBV-related HCC that has plagued the medical and scientific fraternity for decades. Additionally, this review proposes a novel "five-point" management algorithm for HBV-related HCC apart from portraying the unmet needs, principal challenges, and scientific perspectives that are relevant to controlling this accelerating global health crisis.
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Affiliation(s)
- Mausumi Bharadwaj
- Division of Molecular Genetics & Biochemistry, Institute of Cytology & Preventive Oncology (ICMR), Noida, India.
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32
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Notch1 is a potential therapeutic target for the treatment of human hepatitis B virus X protein-associated hepatocellular carcinoma. Oncol Rep 2013; 31:933-9. [PMID: 24336972 DOI: 10.3892/or.2013.2917] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Accepted: 11/27/2013] [Indexed: 11/05/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly lethal cancer with increasing worldwide incidence, and there are few therapeutics options available for patients with HCC. Thus, novel therapeutic targets for this disease are desperately needed. Chronic infection with hepatitis B virus (HBV) is the major risk factor for the development of HCC, while hepatitis B virus X protein (HBx) is essential for HBV-associated HCC. Based on our previous studies showing that HBx promoted hepatocarcinogenesis of the human non-tumor hepatic cell line L02 and activated Notch1 signaling, Notch1 short hairpin RNA (shRNA) was utilized to inhibit Notch1 mRNA in the present study. We observed that Notch1 shRNA inhibited cell proliferation together with decreased activity of the Notch1 pathway in vitro, and also markedly suppressed tumor formation of L02/HBx cells in a BALB/c nude mouse model in vivo. Furthermore, the blockade of Notch1 was capable of arresting the cell cycle in the G0/G1 phase through the downregulation of CyclinD1, CDK4, E2F1 and the upregulation of p21 and Rb, while all of these factors were involved in the CyclinD1/CDK4 pathway. Inhibition of Notch1 by shRNA markedly promoted the apoptosis of L02/HBx cells via the caspase-9-caspase-3 pathway. These data suggest that inhibition of Notch1 impairs the growth of human HBx-transformed L02 cells, and Notch1 may be a putative therapeutic target for human HBx-associated HCC.
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33
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Liu B, Wen X, Huang C, Wei Y. Unraveling the complexity of hepatitis B virus: from molecular understanding to therapeutic strategy in 50 years. Int J Biochem Cell Biol 2013; 45:1987-96. [PMID: 23819994 DOI: 10.1016/j.biocel.2013.06.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2013] [Revised: 06/18/2013] [Accepted: 06/21/2013] [Indexed: 02/05/2023]
Abstract
Hepatitis B virus (HBV) is a well-known hepadnavirus with a double-stranded circular DNA genome. Although HBV was first described approximately 50 years ago, the precise mechanisms of HBV infection and effective therapeutic strategies remain unclear. Here, we focus on summarizing the complicated mechanisms of HBV replication and infection, as well as genomic factors and epigenetic regulation. Additionally, we discuss in vivo models of HBV, as well as diagnosis, prevention and therapeutic drugs for HBV. Together, the data in this 50-year review may provide new clues to elucidate molecular mechanisms of HBV pathogenesis and shed new light on the future HBV therapies.
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Affiliation(s)
- Bo Liu
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
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34
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Lim L, Tran BM, Vincan E, Locarnini S, Warner N. HBV-related hepatocellular carcinoma: the role of integration, viral proteins and miRNA. Future Virol 2012. [DOI: 10.2217/fvl.12.113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The development of hepatocellular carcinoma during chronic hepatitis B infection is a multifactorial process thought to be a consequence of several direct and indirect mechanisms. In this review we discuss how viral proteins and cycles of ongoing liver damage and regeneration, coupled with HBV DNA integration and aberrant miRNA expression may enhance the risk for the development of hepatocellular carcinoma.
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Affiliation(s)
- Lucy Lim
- Victorian Infectious Diseases Reference Laboratories, North Melbourne, Victoria, Australia
- Austin Liver Transplant Unit, Heidelberg, Victoria, Australia
| | - Bang Manh Tran
- Victorian Infectious Diseases Reference Laboratories, North Melbourne, Victoria, Australia
- Cancer Biology Laboratory, Department of Anatomy & Neuroscience, The University of Melbourne, Parkville, Victoria, Australia
| | - Elizabeth Vincan
- Victorian Infectious Diseases Reference Laboratories, North Melbourne, Victoria, Australia
- Cancer Biology Laboratory, Department of Anatomy & Neuroscience, The University of Melbourne, Parkville, Victoria, Australia
| | - Stephen Locarnini
- Victorian Infectious Diseases Reference Laboratories, North Melbourne, Victoria, Australia
| | - Nadia Warner
- Victorian Infectious Diseases Reference Laboratories, North Melbourne, Victoria, Australia
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35
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Abstract
Signaling pathways have become a major source of targets for novel therapies in hepatocellular carcinoma (HCC). Survival benefits achieved with sorafenib, a multikinase inhibitor, are unprecedented and underscore the importance of improving our understanding of how signaling networks interact in transformed cells. Numerous signaling modules are de-regulated in HCC, including some related to growth factor signaling (e.g., IGF, EGF, PDGF, FGF, HGF), cell differentiation (WNT, Hedgehog, Notch), and angiogenesis (VEGF). Intracellular mediators such as RAS and AKT/MTOR may also play a role in HCC development and progression. Different molecular mechanisms have been shown to induce aberrant pathway activation. These include point mutations, chromosomal aberrations, and epigenetically driven down-regulation. The use of novel molecular technologies such as next-generation sequencing in HCC research has enabled the identification of novel pathways previously underexplored in the HCC field, such as chromatin remodeling and autophagy. Considering recent failures of molecular therapies in advanced clinical trials (e.g., sunitinib, brivanib), survey of these and other new pathways may provide alternative therapeutic targets.
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Affiliation(s)
- Agrin Moeini
- HCC Translational Research Laboratory, Barcelona-Clinic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Liver Unit, Hospital Clínic, Catalonia, Madrid, Spain,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto Carlos III, Madrid, Spain
| | - Helena Cornellà
- HCC Translational Research Laboratory, Barcelona-Clinic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Liver Unit, Hospital Clínic, Catalonia, Madrid, Spain,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto Carlos III, Madrid, Spain
| | - Augusto Villanueva
- HCC Translational Research Laboratory, Barcelona-Clinic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Liver Unit, Hospital Clínic, Catalonia, Madrid, Spain,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto Carlos III, Madrid, Spain,*Augusto Villanueva, MD, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y, Digestivas, Esther Koplowitz Planta 3 Rosselló, 153. 08036 Barcelona (Spain), Tel. +34 93 2279155, E-Mail
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