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Yu X, Wu H, Wu Z, Lan Y, Chen W, Wu B, Deng Y, Liu J. Nuclear pore complex protein RANBP2 and related SUMOylation in solid malignancies. Genes Dis 2025; 12:101407. [PMID: 40271196 PMCID: PMC12017851 DOI: 10.1016/j.gendis.2024.101407] [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: 02/09/2024] [Revised: 04/28/2024] [Accepted: 06/21/2024] [Indexed: 04/25/2025] Open
Abstract
The growing interest in post-translational protein modification, particularly in SUMOylation, is driven by its crucial role in cell cycle regulation. SUMOylation affects various cell cycle regulators, including oncogenes, suggesting its relevance in cancer. SUMO E3 ligases are pivotal in this process, exhibiting diverse functionalities through structural domains and subcellular localizations. A less-explored SUMO E3 ligase, RANBP2, a component of the vertebrate nuclear pore complex, emerges as a central player in cellular cycle processes, as well as in tumorigenesis. The current studies illuminate the importance of RANBP2 and underscore the need for more extensive studies to validate its clinical applicability in neoplastic interventions. Our review elucidates the significance of RANBP2 across various types of malignancies. Additionally, it delves into exploring RANBP2 as a prospective therapeutic target for cancer treatment, offering insights into the avenues that scholars should pursue in their subsequent research endeavors. Thus, further investigation into RANBP2's role in solid tumorigenesis is eagerly awaited.
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Affiliation(s)
- Xinning Yu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Huatao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Zheng Wu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
- Department of Physiology, Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Yangzheng Lan
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
- Department of Physiology, Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Wenjia Chen
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
- Department of Physiology, Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Bingxuan Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Yu Deng
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Jing Liu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
- Department of Physiology, Shantou University Medical College, Shantou, Guangdong 515041, China
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2
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Younis MA, Harashima H. Understanding Gene Involvement in Hepatocellular Carcinoma: Implications for Gene Therapy and Personalized Medicine. Pharmgenomics Pers Med 2024; 17:193-213. [PMID: 38737776 PMCID: PMC11088404 DOI: 10.2147/pgpm.s431346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 04/09/2024] [Indexed: 05/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the dominant type of liver cancers and is one of the deadliest health threats globally. The conventional therapeutic options for HCC are hampered by low efficiency and intolerable side effects. Gene therapy, however, now offers hope for the treatment of many disorders previously considered incurable, and gene therapy is beginning to address many of the shortcomings of conventional therapies. Herein, we summarize the involvement of genes in the pathogenesis and prognosis of HCC, with a special focus on dysregulated signaling pathways, genes involved in immune evasion, and non-coding RNAs as novel two-edged players, which collectively offer potential targets for the gene therapy of HCC. Herein, the opportunities and challenges of HCC gene therapy are discussed. These include innovative therapies such as genome editing and cell therapies. Moreover, advanced gene delivery technologies that recruit nanomedicines for use in gene therapy for HCC are highlighted. Finally, suggestions are offered for improved clinical translation and future directions in this area of endeavor.
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Affiliation(s)
- Mahmoud A Younis
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan
- Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt
| | - Hideyoshi Harashima
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan
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3
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Feitelson MA, Arzumanyan A, Medhat A, Spector I. Short-chain fatty acids in cancer pathogenesis. Cancer Metastasis Rev 2023; 42:677-698. [PMID: 37432606 PMCID: PMC10584782 DOI: 10.1007/s10555-023-10117-y] [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: 01/11/2023] [Accepted: 06/05/2023] [Indexed: 07/12/2023]
Abstract
Cancer is a multi-step process that can be viewed as a cellular and immunological shift away from homeostasis in response to selected infectious agents, mutations, diet, and environmental carcinogens. Homeostasis, which contributes importantly to the definition of "health," is maintained, in part by the production of short-chain fatty acids (SCFAs), which are metabolites of specific gut bacteria. Alteration in the composition of gut bacteria, or dysbiosis, is often a major risk factor for some two dozen tumor types. Dysbiosis is often characterized by diminished levels of SCFAs in the stool, and the presence of a "leaky gut," permitting the penetration of microbes and microbial derived molecules (e.g., lipopolysaccharides) through the gut wall, thereby triggering chronic inflammation. SCFAs attenuate inflammation by inhibiting the activation of nuclear factor kappa B, by decreasing the expression of pro-inflammatory cytokines such as tumor necrosis factor alpha, by stimulating the expression of anti-inflammatory cytokines such as interleukin-10 and transforming growth factor beta, and by promoting the differentiation of naïve T cells into T regulatory cells, which down-regulate immune responses by immunomodulation. SCFA function epigenetically by inhibiting selected histone acetyltransferases that alter the expression of multiple genes and the activity of many signaling pathways (e.g., Wnt, Hedgehog, Hippo, and Notch) that contribute to the pathogenesis of cancer. SCFAs block cancer stem cell proliferation, thereby potentially delaying or inhibiting cancer development or relapse by targeting genes and pathways that are mutated in tumors (e.g., epidermal growth factor receptor, hepatocyte growth factor, and MET) and by promoting the expression of tumor suppressors (e.g., by up-regulating PTEN and p53). When administered properly, SCFAs have many advantages compared to probiotic bacteria and fecal transplants. In carcinogenesis, SCFAs are toxic against tumor cells but not to surrounding tissue due to differences in their metabolic fate. Multiple hallmarks of cancer are also targets of SCFAs. These data suggest that SCFAs may re-establish homeostasis without overt toxicity and either delay or prevent the development of various tumor types.
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Affiliation(s)
- Mark A Feitelson
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, 19122, USA.
| | - Alla Arzumanyan
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, 19122, USA
| | - Arvin Medhat
- Department of Molecular Cell Biology, Islamic Azad University Tehran North Branch, Tehran, 1975933411, Iran
| | - Ira Spector
- SFA Therapeutics, Jenkintown, PA, 19046, USA
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Rou WS, Eun HS, Choung S, Jeon HJ, Joo JS, Kang SH, Lee ES, Kim SH, Kwon IS, Ku BJ, Lee BS. Prognostic Value of Erythroblastic Leukemia Viral Oncogene Homolog 2 and Neuregulin 4 in Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:cancers15092634. [PMID: 37174100 PMCID: PMC10177431 DOI: 10.3390/cancers15092634] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/03/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023] Open
Abstract
Although the roles of erythroblastic leukemia viral oncogene homolog 2 (ERBB2), neuregulin 4 (NRG4), and mitogen-inducible gene 6 (MIG6) in epidermal growth factor receptor signaling in hepatocellular carcinoma (HCC) and other malignancies have been previously investigated, the prognostic value of their serum levels in HCC remains undetermined. In the present study, correlations between serum levels and tumor characteristics, overall survival, and tumor recurrence were analyzed. Furthermore, the prognostic potential of the serum levels of these biomarkers was evaluated relative to that of alpha-fetoprotein. Both ERBB2 and NRG4 correlated with the Barcelona Clinic Liver Cancer stage, ERBB2 correlated with the tumor-maximal diameter, and NRG4 correlated with a tumor number. Cox proportional hazards regression analysis revealed that ERBB2 (hazard ratio [HR], 2.719; p = 0.007) was an independent prognostic factor for overall survival. Furthermore, ERBB2 (HR, 2.338; p = 0.002) and NRG4 (HR, 431.763; p = 0.001) were independent prognostic factors for tumor recurrence. The products of ERBB2 and NRG4 had a better area under the curve than alpha-fetoprotein for predicting 6-month, 1-year, 3-year, and 5-year mortality. Therefore, these factors could be used to evaluate prognosis and monitor treatment response in patients with HCC.
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Affiliation(s)
- Woo Sun Rou
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chungnam National University Sejong Hospital, Sejong 30099, Republic of Korea
| | - Hyuk Soo Eun
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Sorim Choung
- Department of Medical Science, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea
| | - Hong Jae Jeon
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chungnam National University Sejong Hospital, Sejong 30099, Republic of Korea
| | - Jong Seok Joo
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chungnam National University Sejong Hospital, Sejong 30099, Republic of Korea
| | - Sun Hyung Kang
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Eaum Seok Lee
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Seok Hyun Kim
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - In Sun Kwon
- Clinical Trial Center, Statistics Office, Biomedical Research Institute, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Bon Jeong Ku
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea
- Division of Endocrinology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Byung Seok Lee
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
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You H, Yuan D, Li Q, Zhang N, Kong D, Yu T, Liu X, Liu X, Zhou R, Kong F, Zheng K, Tang R. Hepatitis B virus X protein increases LASP1 SUMOylation to stabilize HER2 and facilitate hepatocarcinogenesis. Int J Biol Macromol 2023; 226:996-1009. [PMID: 36473530 DOI: 10.1016/j.ijbiomac.2022.11.312] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 07/05/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
The hepatitis B virus (HBV) X protein (HBX), a viral macromolecule, plays a vital role in the development of HBV-related hepatocellular carcinoma (HCC). Increased expression of HER2 is linked to HBV infection, and HBX is responsible for HER2 upregulation in HCC. Nevertheless, the underlying molecular mechanisms are not yet fully understood. In the study, we discovered that HBX promoted HER2 expression to facilitate the sensitization of the insulin signaling pathway and enhance the growth and migration of HCC cells. Mechanistically, the viral protein enhanced the stability of HER2 by preventing its ubiquitination-mediated proteasomal degradation through LASP1, which could bind to HER2. Furthermore, increased SUMOylation of LASP1 contributed to the upregulation of HER2 and the interaction of LASP1 with HER2. In addition, RANBP2 and RANGAP1 were found to interact with LASP1 and promote SUMOylation of LASP1 to upregulate HER2 expression in HBX-associated hepatoma cells. In summary, our work provides a novel insight into hepatocarcinogenesis mediated by HBX and estimates the detailed mechanisms related to the increase in HER2 regulated by the viral protein, which might help provide a theoretical basis for identifying novel targets for HBV-positive HCC treatment.
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Affiliation(s)
- Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Dongchen Yuan
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Qi Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Ning Zhang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Delong Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Tong Yu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiangye Liu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiaomei Liu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Rui Zhou
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China; National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China; National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China.
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6
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Goya T, Horisawa K, Udono M, Ohkawa Y, Ogawa Y, Sekiya S, Suzuki A. Direct Conversion of Human Endothelial Cells Into Liver Cancer-Forming Cells Using Nonintegrative Episomal Vectors. Hepatol Commun 2022; 6:1725-1740. [PMID: 35220676 PMCID: PMC9234650 DOI: 10.1002/hep4.1911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Liver cancer is an aggressive cancer associated with a poor prognosis. Development of therapeutic strategies for liver cancer requires fundamental research using suitable experimental models. Recent progress in direct reprogramming technology has enabled the generation of many types of cells that are difficult to obtain and provide a cellular resource in experimental models of human diseases. In this study, we aimed to establish a simple one-step method for inducing cells that can form malignant human liver tumors directly from healthy endothelial cells using nonintegrating episomal vectors. To screen for factors capable of inducing liver cancer-forming cells (LCCs), we selected nine genes and one short hairpin RNA that suppresses tumor protein p53 (TP53) expression and introduced them into human umbilical vein endothelial cells (HUVECs), using episomal vectors. To identify the essential factors, we examined the effect of changing the amounts and withdrawing individual factors. We then analyzed the proliferation, gene and protein expression, morphologic and chromosomal abnormality, transcriptome, and tumor formation ability of the induced cells. We found that a set of six factors, forkhead box A3 (FOXA3), hepatocyte nuclear factor homeobox 1A (HNF1A), HNF1B, lin-28 homolog B (LIN28B), MYCL proto-oncogene, bHLH transcription factor (L-MYC), and Kruppel-like factor 5 (KLF5), induced direct conversion of HUVECs into LCCs. The gene expression profile of these induced LCCs (iLCCs) was similar to that of human liver cancer cells, and these cells effectively formed tumors that resembled human combined hepatocellular-cholangiocarcinoma following transplantation into immunodeficient mice. Conclusion: We succeeded in the direct induction of iLCCs from HUVECs by using nonintegrating episomal vectors. iLCCs generated from patients with cancer and healthy volunteers will be useful for further advancements in cancer research and for developing methods for the diagnosis, treatment, and prognosis of liver cancer.
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Affiliation(s)
- Takeshi Goya
- Division of Organogenesis and RegenerationMedical Institute of BioregulationKyushu UniversityFukuokaJapan.,Department of Medicine and Bioregulatory ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Kenichi Horisawa
- Division of Organogenesis and RegenerationMedical Institute of BioregulationKyushu UniversityFukuokaJapan
| | - Miyako Udono
- Division of Organogenesis and RegenerationMedical Institute of BioregulationKyushu UniversityFukuokaJapan
| | - Yasuyuki Ohkawa
- Division of TranscriptomicsMedical Institute of BioregulationKyushu UniversityFukuokaJapan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Sayaka Sekiya
- Division of Organogenesis and RegenerationMedical Institute of BioregulationKyushu UniversityFukuokaJapan
| | - Atsushi Suzuki
- Division of Organogenesis and RegenerationMedical Institute of BioregulationKyushu UniversityFukuokaJapan
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Chen Y, Yang W, Chen Q, Liu Q, Liu J, Zhang Y, Li B, Li D, Nan J, Li X, Wu H, Xiang X, Peng Y, Wang J, Su S, Wang Z. Prediction of hepatocellular carcinoma risk in patients with chronic liver disease from dynamic modular networks. J Transl Med 2021; 19:122. [PMID: 33757544 PMCID: PMC7989040 DOI: 10.1186/s12967-021-02791-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 03/16/2021] [Indexed: 12/17/2022] Open
Abstract
Background Discovering potential predictive risks in the super precarcinomatous phase of hepatocellular carcinoma (HCC) without any clinical manifestations is impossible under normal paradigm but critical to control this complex disease. Methods In this study, we utilized a proposed sequential allosteric modules (AMs)-based approach and quantitatively calculated the topological structural variations of these AMs. Results We found the total of 13 oncogenic allosteric modules (OAMs) among chronic hepatitis B (CHB), cirrhosis and HCC network used SimiNEF. We obtained the 11 highly correlated gene pairs involving 15 genes (r > 0.8, P < 0.001) from the 12 OAMs (the out-of-bag (OOB) classification error rate < 0.5) partial consistent with those in independent clinical microarray data, then a three-gene set (cyp1a2-cyp2c19-il6) was optimized to distinguish HCC from non-tumor liver tissues using random forests with an average area under the curve (AUC) of 0.973. Furthermore, we found significant inhibitory effect on the tumor growth of Bel-7402, Hep 3B and Huh7 cell lines in zebrafish treated with the compounds affected those three genes. Conclusions These findings indicated that the sequential AMs-based approach could detect HCC risk in the patients with chronic liver disease and might be applied to any time-dependent risk of cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-02791-9.
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Affiliation(s)
- Yinying Chen
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixian Ge, Xicheng District, Beijing, 100053, China.,Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimen, Beijing, 100700, China.,Postdoctoral Research Station, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wei Yang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimen, Beijing, 100700, China
| | - Qilong Chen
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong, Shanghai, 201203, China
| | - Qiong Liu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimen, Beijing, 100700, China
| | - Jun Liu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimen, Beijing, 100700, China
| | - Yingying Zhang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimen, Beijing, 100700, China
| | - Bing Li
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimen, Beijing, 100700, China
| | - Dongfeng Li
- School of Mathematical Sciences, Peking University, Beijing, China
| | - Jingyi Nan
- Shandong Danhong Pharmaceutical Co. Ltd., Heze, China
| | - Xiaodong Li
- Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Huikun Wu
- Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Xinghua Xiang
- School of Mathematics and Computational Science, Hunan University of Science and Technology, Xiangtan, China
| | - Yehui Peng
- School of Mathematics and Computational Science, Hunan University of Science and Technology, Xiangtan, China
| | - Jie Wang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixian Ge, Xicheng District, Beijing, 100053, China.
| | - Shibing Su
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong, Shanghai, 201203, China.
| | - Zhong Wang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimen, Beijing, 100700, China.
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Saki K, Mansouri V, Asri N, Fathi M, Razzaghi Z. Common and differential features of liver and pancreatic cancers: molecular mechanism approach. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2021; 14:S87-S93. [PMID: 35154607 PMCID: PMC8817745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 08/21/2021] [Indexed: 11/13/2022]
Abstract
AIM The aim of this study was to introduce biomarkers commonly involved in pancreatic cancer metastasis to the liver. BACKGROUND The liver is affected by metastatic disease in pancreatic cancer. METHODS Two cancer biomarkers were distinguished through a STRING database protein query. The dysregulated proteins of the two cancers were included in 2 networks drawn by Cytoscape software v 3.2.7. 20 top nodes and achieved by the Network analyzer application of Cytoscape based on degree value. The common hub nodes were determined, and action maps were analyzed. RESULTS Among 20 hubs of each studied cancer, 18 common hub nodes (90% of hubs) were identified and screened by action maps. Four proteins, AKT1, CDKN2A, ERBB2, and IL6, were identified as common central proteins related to the two studied diseases. CONCLUSION AKT1, CDKN2A, ERBB2, and IL6 are common protein core of liver and pancreatic cancers, while STAT3, CASP3, NOTCH1, and CTNNB1 are possible differential proteins to discriminate these cancers.
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Affiliation(s)
- Kourosh Saki
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Mansouri
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nastaran Asri
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Fathi
- Critical Care Quality Improvement Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Razzaghi
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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9
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Human antigen R: A potential therapeutic target for liver diseases. Pharmacol Res 2020; 155:104684. [PMID: 32045667 DOI: 10.1016/j.phrs.2020.104684] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 02/07/2020] [Accepted: 02/07/2020] [Indexed: 02/08/2023]
Abstract
Human antigen R (HuR), also known as HuA and embryonic lethal abnormal vision-like 1 (ELAVL1), is a ubiquitously expressed RNA binding protein and functions as an RNA regulator and mediates the expression of various proteins by diverse post-transcriptional mechanisms. HuR has been well characterized in the inflammatory responses and in the development of various cancers. The importance of HuR-mediated roles in cell signaling, inflammation, fibrogenesis and cancer development in the liver has attracted a great deal of attention. However, there is still a substantial gap between the current understanding of the potential roles of HuR in the progression of liver disease and whether HuR can be targeted for the treatment of liver diseases. In this review, we introduce the function and mechanistic characterization of HuR, and then focus on the physiopathological roles of HuR in the development of different liver diseases, including hepatic inflammation, alcoholic liver diseases, non-alcoholic fatty liver diseases, viral hepatitis, liver fibrosis and liver cancers. We also summarize existing approaches targeting HuR function. In conclusion, although characterizing the liver-specific HuR function and demonstrating the multi-level regulative networks of HuR in the liver are still required, emerging evidence supports the notion that HuR represents a potential therapeutic target for the treatment of chronic liver diseases.
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10
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Jiang LH, Hao YL, Zhu JW. Expression and prognostic value of HER-2/neu, STAT3 and SOCS3 in hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2019; 43:282-291. [PMID: 30385249 DOI: 10.1016/j.clinre.2018.09.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/18/2018] [Accepted: 09/28/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several genomic alterations, while the viral-chemical etiology along with molecular mechanisms of HCC pathogenesis remains largely unknown. This study aimed to determine expression profile and prognostic value of HER-2/neu, STAT3 and SOCS3 in HCC. METHODS Immunohistochemistry and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were performed to evaluate the expression of HER-2/neu, STAT3 and SOCS3 in HCC tissues and adjacent normal tissues collected from 176 HCC patients. RESULTS HER-2/neu and STAT3 levels were higher and SOCS3 expression was lower in HCC tissues than in adjacent normal tissues. HER-2/neu, STAT3 and SOCS3 levels were associated with histological grade, tumor diameter, TNM stage, vascular invasion, lymph node metastasis and distant metastasis in HCC. SOCS3 expression was negatively associated with HER-2/neu and STAT3 expression. HCC patients with higher HER-2/neu and STAT3 levels had shorter overall, disease-free and disease-specific survival, whereas the opposite was found in patients with higher SOCS3 expression. In Cox regression analysis, tumor size, TNM stage, and STAT3 expression were identified as independent prognostic factors of HCC. CONCLUSION Taken together, these observations suggest that HER-2/neu, STAT3 and, SOCS3 are related to the aggressive tumor behavior and STAT3 has potential value as a prognostic factor for HCC.
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Affiliation(s)
- Li-Hua Jiang
- Department of Clinical Laboratory, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20, Yuhuangding East Road, Yantai 264000, Shandong Province, PR China
| | - Ying-Li Hao
- Department of Clinical Laboratory, Yantaishan Hospital, Yantai 264001, Shandong Province, PR China
| | - Jing-Wei Zhu
- Department of Clinical Laboratory, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20, Yuhuangding East Road, Yantai 264000, Shandong Province, PR China.
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11
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Role of Epidermal Growth Factor Receptor (EGFR) and Its Ligands in Kidney Inflammation and Damage. Mediators Inflamm 2018; 2018:8739473. [PMID: 30670929 PMCID: PMC6323488 DOI: 10.1155/2018/8739473] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 10/29/2018] [Accepted: 11/07/2018] [Indexed: 12/29/2022] Open
Abstract
Chronic kidney disease (CKD) is characterized by persistent inflammation and progressive fibrosis, ultimately leading to end-stage renal disease. Although many studies have investigated the factors involved in the progressive deterioration of renal function, current therapeutic strategies only delay disease progression, leaving an unmet need for effective therapeutic interventions that target the cause behind the inflammatory process and could slow down or reverse the development and progression of CKD. Epidermal growth factor receptor (EGFR) (ERBB1), a membrane tyrosine kinase receptor expressed in the kidney, is activated after renal damage, and preclinical studies have evidenced its potential as a therapeutic target in CKD therapy. To date, seven official EGFR ligands have been described, including epidermal growth factor (EGF) (canonical ligand), transforming growth factor-α, heparin-binding epidermal growth factor, amphiregulin, betacellulin, epiregulin, and epigen. Recently, the connective tissue growth factor (CTGF/CCN2) has been described as a novel EGFR ligand. The direct activation of EGFR by its ligands can exert different cellular responses, depending on the specific ligand, tissue, and pathological condition. Among all EGFR ligands, CTGF/CCN2 is of special relevance in CKD. This growth factor, by binding to EGFR and downstream signaling pathway activation, regulates renal inflammation, cell growth, and fibrosis. EGFR can also be “transactivated” by extracellular stimuli, including several key factors involved in renal disease, such as angiotensin II, transforming growth factor beta (TGFB), and other cytokines, including members of the tumor necrosis factor superfamily, showing another important mechanism involved in renal pathology. The aim of this review is to summarize the contribution of EGFR pathway activation in experimental kidney damage, with special attention to the regulation of the inflammatory response and the role of some EGFR ligands in this process. Better insights in EGFR signaling in renal disease could improve our current knowledge of renal pathology contributing to therapeutic strategies for CKD development and progression.
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12
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Shao X, Lu Q, Wang G, Huang W, Yang L, Chen Z. Reduced expression of Nrdp1 predicts a poor prognosis in human hepatocellular carcinoma. Onco Targets Ther 2018; 11:4955-4963. [PMID: 30154664 PMCID: PMC6103654 DOI: 10.2147/ott.s160638] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is an aggressive form of liver cancer with particularly poor survival rates for patients. Targeted molecular therapies are lacking, and current treatment is generally limited to surgical resection or liver transplantation. Overexpression and aberrant signaling of the ErbB family of receptors has been implicated in HCC, but the mechanisms underlying ErbB overexpression are unclear. In this study, we investigated the potential role of neuregulin receptor degradation protein-1 (Nrdp1), a regulator of ErbB3 protein stability, in HCC progression. Methods We compared the expression of Nrdp1 in various HCC cell lines and in 8 pairs of tumor and peritumor tissue samples using Western blot analysis. Changes in the degree of proliferation were determined before and after small interfering RNA (siRNA)-induced knockdown of Nrdp1 using a cell counting Kit-8 (ccK-8) assay and cell-cycle analysis. The correlation between Nrdp1 expression and prognosis was determined in specimens of 89 HCC patients. Results Nrdp1 expression is significantly reduced in HCC tissues compared with adjacent healthy tissues. Higher Nrdp1 expression corresponds to lower maximal tumor size (χ2, P<0.05), lower histological grade (χ2, P<0.05), and higher survival rates by Kaplan–Meier estimate (P<0.05). Higher Nrdp1 expression also corresponds to reduced expression of Ki-67, a marker of cell proliferation (Spearman, r2=0.734; P<0.05). Nrdp1 accumulates in serum-starved HepG2 cancer cells and progressively decreases in expression after re-feeding. Furthermore, depletion of Nrdp1 in healthy L02 cells by siRNA results in enhanced cell proliferation and a greater proportion of cells in S phase. Conclusions Our findings suggest an inhibitory role for Nrdp1 in HCC tumorigenesis, and we propose that Nrdp1 may serve as a prognostic biomarker for HCC and as a potential therapeutic target for the treatment of HCC.
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Affiliation(s)
- Xian Shao
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong 226001, People's Republic of China, .,Department of Hepatobiliary Surgery, Affiliated Hospital of Jiangsu University, The First People's Hospital of KunShan, KunShan 215300, People's Republic of China
| | - Qian Lu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong 226001, People's Republic of China,
| | - Gang Wang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong 226001, People's Republic of China,
| | - Wei Huang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong 226001, People's Republic of China,
| | - Linlin Yang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong 226001, People's Republic of China,
| | - Zhong Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong 226001, People's Republic of China,
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13
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Wang EY, Cheng JC, Thakur A, Yi Y, Tsai SH, Hoodless PA. YAP transcriptionally regulates ErbB2 to promote liver cell proliferation. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2018; 1861:S1874-9399(18)30039-7. [PMID: 30025876 DOI: 10.1016/j.bbagrm.2018.07.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 07/04/2018] [Accepted: 07/09/2018] [Indexed: 01/20/2023]
Abstract
The Hippo signaling pathway is implicated in regulation of liver size and dysregulation of this pathway contributes to tumorigenesis. The transcriptional targets and downstream pathways of the Hippo pathway effector YAP that contribute to liver growth have yet to be well-characterized. We examined the liver transcriptome in response to YAP overexpression and identify the ErbB signaling pathway as a mediator of cell growth downstream of YAP. ErbB2 is transcriptionally regulated by YAP in both the mouse liver and in HepG2 human hepatoma cells. Knockdown of YAP or pharmacological inhibition with verteporfin reduced ERBB2 levels in HepG2 cells. Analysis of ChIP-seq data revealed enrichment of the transcription factor TEAD4 at the ERBB2 promoter. Using luciferase reporter and chromatin immunoprecipitation assays, we show that YAP and TEAD4 directly bind to and activate a regulatory element in the ErbB2 promoter in both the mouse liver and HepG2 cells. Functionally, knockdown of YAP reduced EGF-induced ERBB2-mediated HepG2 cell proliferation and PI3K/AKT activation. Our findings highlight a mechanism by which YAP exerts its effects on liver cell proliferation through the ErbB signaling pathway by directly regulating the transcription of ErbB2.
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Affiliation(s)
- Evan Y Wang
- Terry Fox Laboratory, BC Cancer, Vancouver, British Columbia V5Z 1L3, Canada; Cell and Developmental Biology Program, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
| | - Jung-Chien Cheng
- Terry Fox Laboratory, BC Cancer, Vancouver, British Columbia V5Z 1L3, Canada; Department of Medical Genetics, University of British Columbia, Vancouver V6T 1Z4, Canada
| | - Avinash Thakur
- Terry Fox Laboratory, BC Cancer, Vancouver, British Columbia V5Z 1L3, Canada; Department of Medical Genetics, University of British Columbia, Vancouver V6T 1Z4, Canada
| | - Yuyin Yi
- Terry Fox Laboratory, BC Cancer, Vancouver, British Columbia V5Z 1L3, Canada; Cell and Developmental Biology Program, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
| | - Shu-Huei Tsai
- Terry Fox Laboratory, BC Cancer, Vancouver, British Columbia V5Z 1L3, Canada
| | - Pamela A Hoodless
- Terry Fox Laboratory, BC Cancer, Vancouver, British Columbia V5Z 1L3, Canada; Cell and Developmental Biology Program, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver V6T 1Z4, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver V6T 1Z4, Canada.
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14
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Li L, Jia L, Ding Y. Upregulation of miR-375 inhibits human liver cancer cell growth by modulating cell proliferation and apoptosis via targeting ErbB2. Oncol Lett 2018; 16:3319-3326. [PMID: 30127930 DOI: 10.3892/ol.2018.9011] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 12/06/2017] [Indexed: 12/18/2022] Open
Abstract
microRNAs (miRNA/miRs) are a class of small non-coding RNAs; they serve important biological roles in tumorigenesis through the regulation of oncogene expression, and they may be used for the diagnosis and treatment of human cancer. miR-375 was identified to exhibit abnormal expression levels in a number of types of tumor; however, the biological role of miR-375 in human hepatocellular carcinoma (HCC) remains incompletely characterized. The present study investigated the expression of miR-375 in human HCC tissues and human liver cancer cell lines; results from a reverse transcription quantitative polymerase chain reaction analysis indicated that the expression of miR-375 was significantly decreased in tissues and live cancer cell lines, compared with normal tissues and PHH cells. Additional studies demonstrated that the upregulation of miR-375 inhibited human liver cancer cell growth via regulation of cell apoptosis. It was also revealed that the receptor tyrosine-protein kinase erbB-2 (ErbB2) gene was a direct target gene of miR-375, and that the regulation of ErbB2 was associated with the human liver cancer growth. Therefore, the present study demonstrated that miR-375 was expressed at low levels both in human HCC tissues and cell line, compared with normal tissues and PHH cells, and that the induction of miR-375 expression may regulate human liver cancer cell function through targeting the ErbB2 gene, which may potentially improve the diagnosis and treatment of patients with HCC in the future.
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Affiliation(s)
- Lina Li
- Department of Digestive Diseases, Daqing Longnan Hospital, Daqing, Heilongjiang 163453, P.R. China
| | - Liping Jia
- Department of Digestive Diseases, Daqing Longnan Hospital, Daqing, Heilongjiang 163453, P.R. China
| | - Yan Ding
- The First Department of General Surgery, Daqing Oilfield General Hospital, Daqing, Heilongjiang 163000, P.R. China
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15
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Huang N, Ji F, Zhang S, Pu Y, Jiang A, Zhou R, Ji Y, Wei W, Yang J, Li Z. Effect of Splenectomy on Serum Cytokine Profiles in Hepatitis B Virus-Related Cirrhosis Patients with Portal Hypertension. Viral Immunol 2018; 31:371-378. [PMID: 29565232 DOI: 10.1089/vim.2017.0176] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Emerging evidences showed the promoting role of spleen in the development of cirrhosis and hepatocellular carcinoma, in the context of portal hypertension and hypersplenism due to hepatitis B virus-related cirrhosis. In this study, we tried to explore the precise mechanism of how spleen regulates this process from the serum cytokines profile level. Compared with the 16 healthy subjects, the RayBio Human Cytokine Antibody Array identified 136 cytokines differentially expressed in 36 cirrhotic patients. Splenectomy resulted in significant changes in 28 cytokines. Differentially expressed cytokines were mainly involved in cellular processes, responses to stimuli, immune processes, binding, extracellular regions, and extracellular matrix. These cytokines were mainly enriched in cytokine-cytokine receptor interactions, Jak-STAT and MAPK signaling pathways, and pathways in cancer. These results may provide new clues to the function of the spleen, and modulation of cytokine expression maybe a potential alternative therapeutic strategy for these patients.
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Affiliation(s)
- Na Huang
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 2 Shaanxi Provincial Engineering Research Center of Biotherapy & Translational Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - Fanpu Ji
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 3 Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - Shu Zhang
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 3 Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - Yansong Pu
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 3 Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - An Jiang
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 3 Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - Rui Zhou
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 3 Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - Yuanyuan Ji
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - Wei Wei
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - Jun Yang
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 2 Shaanxi Provincial Engineering Research Center of Biotherapy & Translational Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - Zongfang Li
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 2 Shaanxi Provincial Engineering Research Center of Biotherapy & Translational Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 3 Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 4 Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University , Xi'an, People's Republic of China
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16
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Lin Z, Lu Y, Meng Q, Wang C, Li X, Yang Y, Xin X, Zheng Q, Xu J, Gui X, Li T, Pu H, Xiong W, Li J, Jia S, Lu D. miR372 Promotes Progression of Liver Cancer Cells by Upregulating erbB-2 through Enhancement of YB-1. MOLECULAR THERAPY. NUCLEIC ACIDS 2018; 11:494-507. [PMID: 29858084 PMCID: PMC5992473 DOI: 10.1016/j.omtn.2018.04.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Revised: 03/30/2018] [Accepted: 04/04/2018] [Indexed: 12/16/2022]
Abstract
MicroRNAs are known to be involved in carcinogenesis. Recently, microRNA-372 (miR372) has been proven to play a substantial role in several human cancers, but its functions in liver cancer remain unclear. Herein, our results demonstrate that miR372 accelerates growth of liver cancer cells in vitro and in vivo. Mechanistically, miR372 enhances expression of Y-box-binding protein 1 (YB-1) by targeting for phosphatase and tensin homolog (PTEN) directly and consequently promotes phosphorylation of YB-1 via HULC looping dependent on ERK1/2 and PTEN. In particular, HULC knockdown or PTEN overexpression abrogated this miR372 action. Moreover, miR372 inhibits the degradation of β-catenin dependent on phosphorylation of YB-1 and then enhances the expression and activity of pyruvate kinase M2 isoform (PKM2) by β-catenin-LEF/TCF4 pathway. Furthermore, the loading of LEF/TCF4 on PKM2 promoter region was significantly increased in miR372 overexpressing Hep3B, and thus, glycolytic proton efflux rate (glycoPER) was significantly increased in rLV-miR372 group compared to the rLV group. Moreover, β-catenin knockdown abrogates this function of miR372. Ultimately, miR372 promotes the expression of erbB-2 through PKM2-pH3T11-acetylation on histone H3 lysine 9 (H3K9Ac) pathway. Of significance, both YB-1 knockdown and erbB-2 knockdown abrogate oncogenic action of miR372. Our observations suggest that miR372 promotes liver cancer cell cycle progress by activating cyclin-dependent kinase 2 (CDK2)-cyclin E-P21/Cip1 complex through miR372-YB-1-β-catenin-LEF/TCF4-PKM2-erbB-2 axis. This study elucidates a novel mechanism for miR372 in liver cancer cells and suggests that miR372 can be used as a novel therapeutic target of liver cancer.
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Affiliation(s)
- Zhuojia Lin
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Yanan Lu
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Qiuyu Meng
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Chen Wang
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Xiaonan Li
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Yuxin Yang
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Xiaoru Xin
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Qidi Zheng
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Jie Xu
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Xin Gui
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Tianming Li
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Hu Pu
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Wujun Xiong
- Department of Hepatology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Jiao Li
- School of Medicine, Tongji University, Shanghai 200092, China
| | - Song Jia
- School of Medicine, Tongji University, Shanghai 200092, China
| | - Dongdong Lu
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
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17
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Yung MK, Lo KW, Yip CW, Chung GTY, Tong CYK, Cheung PFY, Cheung TT, Poon RTP, So S, Fan ST, Cheung ST. Copy number gain of granulin-epithelin precursor (GEP) at chromosome 17q21 associates with overexpression in human liver cancer. BMC Cancer 2015; 15:264. [PMID: 25885205 PMCID: PMC4403714 DOI: 10.1186/s12885-015-1294-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 03/31/2015] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Granulin-epithelin precursor (GEP), a secretory growth factor, demonstrated overexpression in various human cancers, however, mechanism remain elusive. Primary liver cancer, hepatocellular carcinoma (HCC), ranks the second in cancer-related death globally. GEP controlled growth, invasion, metastasis and chemo-resistance in liver cancer. Noted that GEP gene locates at 17q21 and the region has been frequently reported to be amplified in subset of HCC. The study aims to investigate if copy number gain would associate with GEP overexpression. METHODS Quantitative Microsatellite Analysis (QuMA) was used to quantify the GEP DNA copy number, and fluorescent in situ hybridization (FISH) was performed to consolidate the amplification status. GEP gene copy number, mRNA expression level and clinico-pathological features were analyzed. RESULTS GEP DNA copy number determined by QuMA corroborated well with the FISH data, and the gene copy number correlated with the expression levels (n = 60, r = 0.331, P = 0.010). Gain of GEP copy number was observed in 20% (12/60) HCC and associated with hepatitis B virus infection status (P = 0.015). In HCC with increased GEP copy number, tight association between GEP DNA and mRNA levels were observed (n = 12, r = 0.664, P = 0.019). CONCLUSIONS Gain of the GEP gene copy number was observed in 20% HCC and the frequency comparable to literatures reported on the chromosome region 17q. Increased gene copy number contributed to GEP overexpression in subset of HCC.
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Affiliation(s)
- Man Kuen Yung
- Department of Surgery, The University of Hong Kong, Hong Kong, China.
| | - Kwok Wai Lo
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China.
| | - Chi Wai Yip
- Department of Surgery, The University of Hong Kong, Hong Kong, China. .,Centre for Cancer Research, The University of Hong Kong, Hong Kong, China.
| | - Grace T Y Chung
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China.
| | - Carol Y K Tong
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China.
| | - Phyllis F Y Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong, China. .,Centre for Cancer Research, The University of Hong Kong, Hong Kong, China.
| | - Tan To Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong, China. .,Department of Surgery, Queen Mary Hospital, Hong Kong, China.
| | - Ronnie T P Poon
- Department of Surgery, The University of Hong Kong, Hong Kong, China. .,Centre for Cancer Research, The University of Hong Kong, Hong Kong, China. .,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
| | - Samuel So
- Department of Surgery, Stanford University, Stanford, USA.
| | - Sheung Tat Fan
- Department of Surgery, The University of Hong Kong, Hong Kong, China. .,Centre for Cancer Research, The University of Hong Kong, Hong Kong, China. .,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
| | - Siu Tim Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong, China. .,Centre for Cancer Research, The University of Hong Kong, Hong Kong, China. .,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China. .,Department of Surgery, The University of Hong Kong, L9-55, Laboratory Block, Faculty of Medicine Building, 21 Sassoon Road, Hong Kong, China.
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18
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Kim BY, Choi DW, Woo SR, Park ER, Lee JG, Kim SH, Koo I, Park SH, Han CJ, Kim SB, Yeom YI, Yang SJ, Yu A, Lee JW, Jang JJ, Cho MH, Jeon WK, Park YN, Suh KS, Lee KH. Recurrence-associated pathways in hepatitis B virus-positive hepatocellular carcinoma. BMC Genomics 2015; 16:279. [PMID: 25888140 PMCID: PMC4448317 DOI: 10.1186/s12864-015-1472-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Accepted: 03/20/2015] [Indexed: 02/01/2023] Open
Abstract
Background Despite the recent identification of several prognostic gene signatures, the lack of common genes among experimental cohorts has posed a considerable challenge in uncovering the molecular basis underlying hepatocellular carcinoma (HCC) recurrence for application in clinical purposes. To overcome the limitations of individual gene-based analysis, we applied a pathway-based approach for analysis of HCC recurrence. Results By implementing a permutation-based semi-supervised principal component analysis algorithm using the optimal principal component, we selected sixty-four pathways associated with hepatitis B virus (HBV)-positive HCC recurrence (p < 0.01), from our microarray dataset composed of 142 HBV-positive HCCs. In relation to the public HBV- and public hepatitis C virus (HCV)-positive HCC datasets, we detected 46 (71.9%) and 18 (28.1%) common recurrence-associated pathways, respectively. However, overlap of recurrence-associated genes between datasets was rare, further supporting the utility of the pathway-based approach for recurrence analysis between different HCC datasets. Non-supervised clustering of the 64 recurrence-associated pathways facilitated the classification of HCC patients into high- and low-risk subgroups, based on risk of recurrence (p < 0.0001). The pathways identified were additionally successfully applied to discriminate subgroups depending on recurrence risk within the public HCC datasets. Through multivariate analysis, these recurrence-associated pathways were identified as an independent prognostic factor (p < 0.0001) along with tumor number, tumor size and Edmondson’s grade. Moreover, the pathway-based approach had a clinical advantage in terms of discriminating the high-risk subgroup (N = 12) among patients (N = 26) with small HCC (<3 cm). Conclusions Using pathway-based analysis, we successfully identified the pathways involved in recurrence of HBV-positive HCC that may be effectively used as prognostic markers. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-1472-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Bu-Yeo Kim
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, Korea.
| | - Dong Wook Choi
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-ku, Seoul, 139-706, Korea. .,Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
| | - Seon Rang Woo
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-ku, Seoul, 139-706, Korea.
| | - Eun-Ran Park
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-ku, Seoul, 139-706, Korea. .,Department of Pathology and BK 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
| | - Je-Geun Lee
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-ku, Seoul, 139-706, Korea.
| | - Su-Hyeon Kim
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-ku, Seoul, 139-706, Korea.
| | - Imhoi Koo
- Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, USA.
| | - Sun-Hoo Park
- Department of Pathology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
| | - Chul Ju Han
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-ku, Seoul, 139-706, Korea. .,Department of Internal Medicine, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
| | - Sang Bum Kim
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-ku, Seoul, 139-706, Korea. .,Department of Surgery, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
| | - Young Il Yeom
- Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
| | - Suk-Jin Yang
- Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
| | - Ami Yu
- Department of Statistics, Korea University, Seoul, Korea. .,Korean Medicine Clinical Trial Center, Kyung Hee University Oriental Medicine Hospital, Seoul, Korea.
| | - Jae Won Lee
- Department of Statistics, Korea University, Seoul, Korea.
| | - Ja June Jang
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
| | - Myung-Haing Cho
- Laboratory of Toxicology and Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, Korea.
| | - Won Kyung Jeon
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, Korea.
| | - Young Nyun Park
- Department of Pathology and BK 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.
| | - Kee-Ho Lee
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-ku, Seoul, 139-706, Korea. .,Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, Korea.
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Ringelhan M, O'Connor T, Protzer U, Heikenwalder M. The direct and indirect roles of HBV in liver cancer: prospective markers for HCC screening and potential therapeutic targets. J Pathol 2015; 235:355-67. [PMID: 25196558 DOI: 10.1002/path.4434] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 09/01/2014] [Accepted: 09/02/2014] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis B virus (HBV) infection remains the number one risk factor for hepatocellular carcinoma (HCC), accounting for more than 600 000 deaths/year. Despite highly effective antiviral treatment options, chronic hepatitis B (CHB), subsequent end-stage liver disease and HCC development remain a major challenge worldwide. In CHB, liver damage is mainly caused by the influx of immune cells and destruction of infected hepatocytes, causing necro-inflammation. Treatment with nucleoside/nucleotide analogues can effectively suppress HBV replication in patients with CHB and thus decrease the risk for HCC development. Nevertheless, the risk of HCC in treated patients showing sufficient suppression of HBV DNA replication is significantly higher than in patients with inactive CHB, regardless of the presence of baseline liver cirrhosis, suggesting direct, long-lasting, predisposing effects of HBV. Direct oncogenic effects of HBV include integration in the host genome, leading to deletions, cis/trans-activation, translocations, the production of fusion transcripts and generalized genomic instability, as well as pleiotropic effects of viral transcripts (HBsAg and HBx). Analysis of these viral factors in active surveillance may allow early identification of high-risk patients, and their integration into a molecular classification of HCC subtypes might help in the development of novel therapeutic approaches.
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Affiliation(s)
- Marc Ringelhan
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany; Second Medical Department, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany; German Centre for Infection research (DZIF), Munich Partner Site, Germany
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Jiang R, Chen D, Hou J, Tan Z, Wang Y, Huang X, Wang X, Sun B. Survival and inflammation promotion effect of PTPRO in fulminant hepatitis is associated with NF-κB activation. THE JOURNAL OF IMMUNOLOGY 2014; 193:5161-70. [PMID: 25339662 DOI: 10.4049/jimmunol.1303354] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Previous investigations demonstrated that protein tyrosine phosphatase, receptor type, O (PTPRO) acts as a tumor suppressor in liver cancer; however, little is known about its role in liver inflammation. Thus, we investigated the role of PTPRO in fulminant hepatitis (FH) using a Con A-induced mouse model. Significantly more severe liver damage, but attenuated inflammation, was detected in PTPRO-knockout (KO) mice, and PTPRO deficiency could confer this phenotype to wild-type mice in bone marrow transplantation. Moreover, hepatocytes with PTPRO depletion were more sensitive to TNF-α-induced apoptosis, and secretion of cytokines was significantly decreased in both T and NK/NKT cells and led to marked impairment of NF-κB activation. Intriguingly, wild-type and PTPRO-KO cells responded equally to TNF-α in activation of IKK, but NF-κB activation was clearly decreased in PTPRO-KO cells. PTPRO associated with ErbB2, and loss of PTPRO potentiated activation of the ErbB2/Akt/GSK-3β/β-catenin cascade. Increased β-catenin formed a complex with NF-κB and attenuated its nuclear translocation and activation. Importantly, in humans, PTPRO was much decreased in FH, and this was associated with enhanced β-catenin accumulation but reduced IFN-γ secretion. Taken together, our study identified a novel PTPRO/ErbB2/Akt/GSK-3β/β-catenin/NF-κB axis in FH, which suggests that PTPRO may have therapeutic potential in this liver disease.
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Affiliation(s)
- Runqiu Jiang
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and
| | - Dianyu Chen
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and
| | - Jiajie Hou
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and
| | - Zhongming Tan
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and
| | - Youjing Wang
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and
| | - Xingxu Huang
- Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, People's Republic of China
| | - Xuehao Wang
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and
| | - Beicheng Sun
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and
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Tong GD, Zhang X, Zhou DQ, Wei CS, He JS, Xiao CL, Liu XL, Zheng YJ, Chen SN, Tang HH. Efficacy of early treatment on 52 patients with preneoplastic hepatitis B virus-associated hepatocellular carcinoma by compound Phyllanthus Urinaria L. Chin J Integr Med 2014; 20:263-271. [PMID: 23529834 DOI: 10.1007/s11655-013-1320-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2011] [Indexed: 12/26/2022]
Abstract
OBJECTIVE To observe the change in the number of antibodies of preneoplastic hepatocellular carcinoma (HCC) using early treatment by Compound Phyllanthus Urinaria L. (CPUL) on patients with preneoplastic hepatitis B virus (HBV)-associated HCC. METHODS A total of 102 cirrhosis patients with regenerative or dysplastic nodules whose sera were tested positive for at least one of these six proteins (five up-regulated genes URG4, URG7, URG11, URG12 and URG19, and one down-regulated gene DRG2) were assigned randomly to two groups using continual random codes by SPSS software. Fifty-two patients were in the treatment group and 50 patients were in the control group. CPUL was used in the treatment group for 3 years, while the control group did not receive any treatment. The changes in HBV-DNA level, number of antibodies, and hepatocarcinogenesis occurred were observed. Patients who did not develop HCC were followed up for another 2 years. RESULTS HBV-DNA levels decreased ⩾2log in 22.2% (10/45) of patients in the treatment group in contrast to only 5.0% (2/40) of patients in the control group (P=0.0228). The number of antibodies that were tested positive in the treatment group (1.08±1.01) was significantly lower compared with the control group (2.11±1.12) after 24 months of drug treatment (P<0.01). Both the positive rates of anti-URG11 (33/52) and anti-URG19 (31/52) were over 60% at baseline in the two groups, and were decreased to 48.1% (25/52) and 46.2% (24/52) respectively at 36 months of drug treatment, while the rates increased to 68.0% (34/50) and 66.0% (33/50) respectively (P=0.0417, P=0.0436) in the control group. The positive rate of anti-DRG2 was increased to 55.8% (29/52) at 36 months of drug treatment, while in the control group was decreased to 36.0% (18/50, P=0.0452). Among the 102 patients who developed HCC, 2 were in the treatment group and 9 were in the control group, meaning that a significant difference between the two groups (P=0.0212). In 11 patients who developed HCC, anti-URG11 and anti-URG19 were always positive, while anti-DRG2 was negative. Patients newly developing HCC were 6 (20.0%) in the control group, and only one (2.5%) in the treatment group (P=0.0441) during 2-year follow-up after the end of the treatment. CONCLUSIONS Anti-URG11, anti-URG19 and anti-DRG2 could be used as early markers in the prediction of the therapeutic efficacy of CPUL in treating preneoplastic HCC. CPUL is useful in preventing or delaying the development of HBV-associated cirrhosis to HCC.
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Affiliation(s)
- Guang-dong Tong
- Department of Liver Disease, Shenzhen Hospital Affiliated to Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, 518033, China.
| | - Xi Zhang
- Department of Liver Disease, Shenzhen Hospital Affiliated to Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, 518033, China
| | - Da-qiao Zhou
- Department of Liver Disease, Shenzhen Hospital Affiliated to Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, 518033, China
| | - Chun-shan Wei
- Department of Liver Disease, Shenzhen Hospital Affiliated to Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, 518033, China
| | - Jin-song He
- Department of Liver Disease, Shenzhen Hospital Affiliated to Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, 518033, China
| | - Chun-ling Xiao
- Department of Liver Disease, Shenzhen Hospital Affiliated to Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, 518033, China
| | - Xin-liang Liu
- Department of Liver Disease, Shenzhen Hospital Affiliated to Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, 518033, China
| | - Ying-jun Zheng
- Department of Liver Disease, Shenzhen Hospital Affiliated to Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, 518033, China
| | - Si-nuan Chen
- Department of Liver Disease, Shenzhen Hospital Affiliated to Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, 518033, China
| | - Hai-hong Tang
- Department of Liver Disease, Shenzhen Hospital Affiliated to Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, 518033, China
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Cuninghame S, Jackson R, Zehbe I. Hypoxia-inducible factor 1 and its role in viral carcinogenesis. Virology 2014; 456-457:370-83. [PMID: 24698149 DOI: 10.1016/j.virol.2014.02.027] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 01/17/2014] [Accepted: 02/26/2014] [Indexed: 01/05/2023]
Abstract
The advent of modern molecular biology has allowed for the discovery of several mechanisms by which oncoviruses promote carcinogenesis. Remarkably, nearly all human oncogenic viruses increase levels of the transcription factor hypoxia-inducible factor 1 (HIF-1). In this review, we highlight HIF-1׳s significance in viral oncogenesis, while providing an in-depth analysis of its activation mechanisms by the following oncoviruses: human papillomaviruses (HPVs), hepatitis B/C viruses (HBV/HCVs), Epstein-Barr virus (EBV), Kaposi׳s sarcoma-associated herpes virus (KSHV), and human T-cell lymphotropic virus (HTLV-1). We discuss virus-induced HIF-1׳s role in transcriptional upregulation of metabolic, angiogenic, and microenvironmental factors that are integral for oncogenesis. Admittedly, conclusive evidence is lacking as to whether activation of HIF-1 target genes is necessary for malignant transformation or merely a result thereof. In addition, a complete understanding of host-virus interactions, the effect of viral genomic variation, and the clinical (and potential therapeutic) relevance of HIF-1 in viral oncogenesis warrant further investigation.
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Affiliation(s)
- Sean Cuninghame
- Probe Development & Biomarker Exploration, Thunder Bay Regional Research Institute, 980 Oliver Rd, Thunder Bay, Ont., Canada P7B 6V4; Department of Biology, Lakehead University, Thunder Bay, Ont., Canada
| | - Robert Jackson
- Probe Development & Biomarker Exploration, Thunder Bay Regional Research Institute, 980 Oliver Rd, Thunder Bay, Ont., Canada P7B 6V4; Department of Biology, Lakehead University, Thunder Bay, Ont., Canada
| | - Ingeborg Zehbe
- Probe Development & Biomarker Exploration, Thunder Bay Regional Research Institute, 980 Oliver Rd, Thunder Bay, Ont., Canada P7B 6V4; Department of Biology, Lakehead University, Thunder Bay, Ont., Canada.
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Hepatitis B virus X upregulates HuR protein level to stabilize HER2 expression in hepatocellular carcinoma cells. BIOMED RESEARCH INTERNATIONAL 2014; 2014:827415. [PMID: 24719890 PMCID: PMC3955687 DOI: 10.1155/2014/827415] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Revised: 12/23/2013] [Accepted: 01/13/2014] [Indexed: 01/14/2023]
Abstract
Hepatitis B virus- (HBV-) associated hepatocellular carcinoma (HCC) is the most common type of liver cancer. However, the underlying mechanism of HCC tumorigenesis is very complicated and HBV-encoded X protein (HBx) has been reported to play the most important role in this process. Activation of downstream signal pathways of epidermal growth factor receptor (EGFR) family is known to mediate HBx-dependent HCC tumor progression. Interestingly, HER2 (also known as ErbB2/Neu/EGFR2) is frequently overexpressed in HBx-expressing HCC patients and is associated with their poor prognosis. However, it remains unclear whether and how HBx regulates HER2 expression. In this study, our data showed that HBx expression increased HER2 protein level via enhancing its mRNA stability. The induction of RNA-binding protein HuR expression by HBx mediated the HER2 mRNA stabilization. Finally, the upregulated HER2 expression promoted the migration ability of HBx-expressing HCC cells. These findings deciphered the molecular mechanism of HBx-mediated HER2 upregulation in HBV-associated HCC.
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Arzumanyan A, Reis HMGPV, Feitelson MA. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer 2013; 13:123-35. [PMID: 23344543 DOI: 10.1038/nrc3449] [Citation(s) in RCA: 626] [Impact Index Per Article: 52.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a highly lethal cancer, with increasing worldwide incidence, that is mainly associated with chronic hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections. There are few effective treatments partly because the cell- and molecular-based mechanisms that contribute to the pathogenesis of this tumour type are poorly understood. This Review outlines pathogenic mechanisms that seem to be common to both viruses and which suggest innovative approaches to the prevention and treatment of HCC.
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Affiliation(s)
- Alla Arzumanyan
- Department of Biology and Sbarro Health Research Organization, College of Science and Technology, Temple University, 1900 N. 12th Street, Philadelphia, Pennsylvania 19122, USA
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25
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Bassullu N, Turkmen I, Dayangac M, Yagiz Korkmaz P, Yasar R, Akyildiz M, Yaprak O, Tokat Y, Yuzer Y, Bulbul Dogusoy G. The Predictive and Prognostic Significance of c-erb-B2, EGFR, PTEN, mTOR, PI3K, p27, and ERCC1 Expression in Hepatocellular Carcinoma. HEPATITIS MONTHLY 2012; 12:e7492. [PMID: 23162604 PMCID: PMC3496900 DOI: 10.5812/hepatmon.7492] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2012] [Revised: 07/04/2012] [Accepted: 07/17/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the fifth most common fatal cancer and an important healthcare problem worldwide. There are many studies describing the prognostic and predictive effects of epidermal growth factor receptor 2 (c-erb-B2) and epidermal growth factor receptor 1 (EGFR), transmembrane tyrosine kinases that influence cell growth and proliferation in many tumors. OBJECTIVES The current study aimed to investigate the expression levels of c-erb-B2, EGFR, PTEN, mTOR, PI3K, p27, and ERCC1 in hepatocellular carcinoma (HCC) and their correlation with other clinicopathologic features. PATIENTS AND METHODS Fifty HCC cases were stained immunohistochemically with these markers. Correlations between the markers and clinicopathologic characteristics and survival rates were analyzed. RESULTS No membranous c-erb-B2 staining was seen, whereas cytoplasmic positivity was present in 92% of HCC samples, membranous EGFR was observed in 40%, PI3K was found in all samples, and mTOR was seen in 30%, whereas reduced or absent PTEN expression was observed in 56% of samples and loss of p27 was seen in 92% of the cases. c-erb-B2 and mTOR overexpression, as well as reduced expression of p27, all correlated with multiple tumors (P = 0.041, P < 0.001, and P < 0.001, respectively). P27 loss, and mTOR and EGFR positivity were significantly correlated with AFP (P = 0.047, P = 0.004, and P = 0.008, respectively). Angiolymphatic invasion was more commonly seen in EGFR- and ERCC1-positive cases (P = 0.003 and P = 0.005). EGFR was also correlated with histological grade (P = 0.039). No significant correlations were found among PTEN , PI3K, and the clinicopathological parameters. Disease-free or overall survival rates showed significant differences among therapy modalities, AFP levels, angiolymphatic or lymph node invasions, and ERCC1 and p27 expression levels (P < 0.05). CONCLUSIONS c-erb-B2, EGFR, mTOR, ERCC1 overexpression levels, and loss of p27 may play roles in hepatocarcinogenesis and may be significant predictors of aggressive tumor behavior. These markers were found to be correlated with certain clinicopathologic features, therapy modalities, and survival rates in the current study. These findings may help in planning new, targeted treatment strategies .
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Affiliation(s)
- Nuray Bassullu
- Department of Pathology, Istanbul Bilim University Medical Faculty, Istanbul, Turkey
- Corresponding author: Nuray Bassullu, Department of Pathology, Istanbul Bilim University Medical Faculty, Mehmetcik Street, Cahit Yalcın Sokak No: 1 Mecidiyeköy, Sisli, Istanbul, Turkey. Tel.: +90-2122883400/4819, Fax: +90-2122883456, E-mail:
| | - Ilknur Turkmen
- Department of Pathology, Istanbul Bilim University Medical Faculty, Istanbul, Turkey
| | - Murat Dayangac
- Department of General Surgery, Florence Nigthingale Hospital, Istanbul, Turkey
| | | | - Reyhan Yasar
- Department of Pathology, Florence Nigthingale Hospital, Istanbul, Turkey
| | - Murat Akyildiz
- Department of Gastroenterology, Istanbul Bilim University Medical Faculty, Istanbul, Turkey
| | - Onur Yaprak
- Department of General Surgery, Florence Nigthingale Hospital, Istanbul, Turkey
| | - Yaman Tokat
- Department of General Surgery, Florence Nigthingale Hospital, Istanbul, Turkey
| | - Yildiray Yuzer
- Department of General Surgery, Florence Nigthingale Hospital, Istanbul, Turkey
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Zhang Y, Li J, Cao L, Xu W, Yin Z. Circulating tumor cells in hepatocellular carcinoma: detection techniques, clinical implications, and future perspectives. Semin Oncol 2012; 39:449-60. [PMID: 22846862 DOI: 10.1053/j.seminoncol.2012.05.012] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer with a huge challenge in terms of its complex etiology and its management. The fact that the most common site of early tumor recurrence in liver transplantation for HCC is the transplanted allograft strongly suggests that circulating tumor cells (CTCs) are really an active source of HCC metastasis or recurrence. In the past decade, with the tremendous progress in the technology of CTC detection, there is convincing evidence that CTCs have great potential as a marker for metastatic disease and poor prognosis in patients with a malignancy. Currently some interesting and encouraging results have been achieved in HCC CTC detection, although the knowledge about its clinical relevance in HCC is lagging behind other major tumor types. Here we will review existing and developing methodologies for CTC detection, discuss future perspectives, and describe the potential clinical impact of the identification and molecular characterization of CTC subset or circulating cancer stem cells in HCC patients. Particular attention is given to the results based on the HCC CTC study.
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Affiliation(s)
- Yu Zhang
- Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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27
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Zha TZ, Hu BS, Yu HF, Tan YF, Zhang Y, Zhang K. Overexpression of HOXA1 correlates with poor prognosis in patients with hepatocellular carcinoma. Tumour Biol 2012; 33:2125-34. [PMID: 22864671 DOI: 10.1007/s13277-012-0472-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2012] [Accepted: 07/23/2012] [Indexed: 01/06/2023] Open
Abstract
HOXA1 overexpression is sufficient for malignant transformation of nontumorigenic epithelial cells. It is known that HOXA1, which was upregulated in squamous cell carcinomas, affects both cell growth and death. The forced expression of HOXA1 in human breast cancer cells results in increased cell growth activity. However, it has not been reported in hepatocellular carcinoma (HCC). In this study, we used immunohistochemistry to compare HOXA1 protein expression in HCC and normal liver tissues and further analyzed HOXA1 protein expression in 156 clinicopathologically characterized HCC cases. We stably knocked down the endogenous expression level of HOXA1 in HepG2 cells with specific shRNA-expressing lentiviral vector. Following the successful establishment of stable cells, we examined in vitro cell growth by the MTT assay, anchorage-independent growth through a soft agar colony formation assay and cell migration/invasion by transwell and Boyden chamber assay. In addition, we also investigated in vivo tumor growth by xenograft transplantation of HepG2 cells into nude mice. Our results showed that the protein expression level of HOXA1 was markedly higher in HCC tissues than that in normal liver tissue (P = 0.019). In addition, a high expression level of HOXA1 protein was positively correlated with the T classification (P < 0.001), the N classification (P < 0.001), distant metastasis (P = 0.004), and the clinical stage (P < 0.001) of HCC patients. Patients with higher HOXA1 expression showed a significantly shorter overall survival time compared with patients with low HOXA1 expression. Multivariate analysis suggested that HOXA1 expression might be an independent prognostic indicator (P < 0.001) for the survival of patients with HCC. HOXA1-specific shRNA (shHOXA1) successfully knocked down HOXA1 endogenous expression in HepG2 cells. Compared to the parental and control shRNA-transfected (shCtrl) HepG2 cells, the shHOXA1 cells exhibited significantly reduced in vitro cell growth, anchorage-independent growth, and cell migration and invasion (P < 0.05). In vivo, the xenograft transplants from shHOXA1 cells gave rise to much smaller tumors compared with those from shCtrl cells. Collectively, high HOXA1 expression is associated with poor overall survival in patients with HCC. The downregulation of HOXA1 inhibits growth, anchorage-independent growth, and migration and invasion of HepG2 cells.
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Affiliation(s)
- Tian-Zhou Zha
- Department of General Surgery, Yixing People's Hospital, No 75, Tongzhen Guan Rd, Yixing 214200, China
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Han YF, Zhao J, Ma LY, Yin JH, Chang WJ, Zhang HW, Cao GW. Factors predicting occurrence and prognosis of hepatitis-B-virus-related hepatocellular carcinoma. World J Gastroenterol 2011; 17:4258-70. [PMID: 22090781 PMCID: PMC3214700 DOI: 10.3748/wjg.v17.i38.4258] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2011] [Revised: 07/12/2011] [Accepted: 07/19/2011] [Indexed: 02/06/2023] Open
Abstract
Primary liver cancer is an important cause of cancer death, and hepatocellular carcinoma (HCC) accounts for 70%-85% of total liver cancer worldwide. Chronic hepatitis B virus (HBV) infection contributes to > 75% of HCC cases. High serum viral load is the most reliable indicator of viral replication in predicting development of HCC. HBV genotype C is closely associated with HCC in cirrhotic patients aged > 50 years, whereas genotype B is associated with development of HCC in non-cirrhotic young patients and postoperative relapse of HCC. Different HBV subgenotypes have distinct patterns of mutations, which are clearly associated with increased risk of HCC. Mutations accumulate during chronic HBV infection and predict occurrence of HCC. Chronic inflammation leads to increased frequency of viral mutation via cellular cytidine deaminase induction. Mutations are negatively selected by host immunity, whereas some immuno-escaped HBV mutants are active in hepatocarcinogenesis. Inflammatory pathways contribute to the inflammation-necrosis-regeneration process, ultimately HCC. Their hallmark molecules can predict malignancy in HBV-infected subjects. Continuing inflammation is involved in hepatocarcinogenesis and closely related to recurrence and metastasis. HBV load, genotype C, viral mutations and expression of inflammatory molecules in HBV-related HCC tissues are significantly associated with poor prognosis. Imbalance between intratumoral CD8+ T cells and regulatory T cells or Th1 and Th2 cytokines in peritumoral tissues can predict prognosis of HBV-related HCC. These factors are important for developing active prevention and surveillance of HBV-infected subjects who are more likely to develop HCC, or for tailoring suitable treatment to improve survival or postpone postoperative recurrence of HCC.
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Orbán E, Manea M, Marquadt A, Bánóczi Z, Csík G, Fellinger E, Bosze S, Hudecz F. A new daunomycin-peptide conjugate: synthesis, characterization and the effect on the protein expression profile of HL-60 cells in vitro. Bioconjug Chem 2011; 22:2154-65. [PMID: 21950465 DOI: 10.1021/bc2004236] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Daunomycin (Dau) is a DNA-binding antineoplastic agent in the treatment of various types of cancer, such as osteosarcomas and acute myeloid leukemia. One approach to improve its selectivity and to decrease the side effects is the conjugation of Dau with oligopeptide carriers, which might alter the drug uptake and intracellular fate. Here, we report on the synthesis, characterization, and in vitro biological properties of a novel conjugate in which Dau is attached, via an oxime bond, to one of the cancer specific small peptides (LTVSPWY) selected from a random phage peptide library. The in vitro cytostatic effect and cellular uptake of Dau═Aoa-LTVSPWY-NH(2) conjugate were studied on various human cancer cell lines expressing different levels of ErbB2 receptor which could be targeted by the peptide. We found that the new daunomycin-peptide conjugate is highly cytostatic and could be taken up efficiently by the human cancer cells studied. However, the conjugate was less effective than the free drug itself. RP-HPLC data indicate that the conjugate is stable at least for 24 h in the pH 2.5-7.0 range of buffers, as well as in cell culture medium. The conjugate in the presence of rat liver lysosomal homogenate, as indicated by LC-MS analysis, could be degraded. The smallest, Dau-containing metabolite (Dau═Aoa-Leu-OH) identified and prepared expresses DNA-binding ability. In order to get insight on the potential mechanism of action, we compared the protein expression profile of HL-60 human leukemia cells after treatment with the free and peptide conjugated daunomycin. Proteomic analysis suggests that the expression of several proteins has been altered. This includes three proteins, whose expression was lower (tubulin β chain) or markedly higher (proliferating cell nuclear antigen and protein kinase C inhibitor protein 1) after administration of cells with Dau-conjugate vs free drug.
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Affiliation(s)
- Erika Orbán
- Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös Loránd University, Budapest, Hungary
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Epidermal Growth Factor Receptor (EGFR) Crosstalks in Liver Cancer. Cancers (Basel) 2011; 3:2444-61. [PMID: 24212818 PMCID: PMC3757426 DOI: 10.3390/cancers3022444] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2011] [Revised: 05/06/2011] [Accepted: 05/12/2011] [Indexed: 01/11/2023] Open
Abstract
Hepatocarcinogenesis is a complex multistep process in which many different molecular pathways have been implicated. Hepatocellular carcinoma (HCC) is refractory to conventional chemotherapeutic agents, and the new targeted therapies are meeting with limited success. Interreceptor crosstalk and the positive feedback between different signaling systems are emerging as mechanisms of targeted therapy resistance. The identification of such interactions is therefore of particular relevance to improve therapeutic efficacy. Among the different signaling pathways activated in hepatocarcinogenesis the epidermal growth factor receptor (EGFR) system plays a prominent role, being recognized as a “signaling hub” where different extracellular growth and survival signals converge. EGFR can be transactivated in response to multiple heterologous ligands through the physical interaction with multiple receptors, the activity of intracellular kinases or the shedding of EGFR-ligands. In this article we review the crosstalk between the EGFR and other signaling pathways that could be relevant to liver cancer development and treatment.
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Xu W, Cao L, Chen L, Li J, Zhang XF, Qian HH, Kang XY, Zhang Y, Liao J, Shi LH, Yang YF, Wu MC, Yin ZF. Isolation of circulating tumor cells in patients with hepatocellular carcinoma using a novel cell separation strategy. Clin Cancer Res 2011; 17:3783-93. [PMID: 21527564 DOI: 10.1158/1078-0432.ccr-10-0498] [Citation(s) in RCA: 119] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE To establish a sensitive and specific isolation and enumeration system for circulating tumor cells (CTC) in patients with hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN HCC cells were bound by biotinylated asialofetuin, a ligand of asialoglycoprotein receptor, and subsequently magnetically labeled by antibiotin antibody-coated magnetic beads, followed by magnetic separation. Isolated HCC cells were identified by immunofluorescence staining using Hep Par 1 antibody. The system was used to detect CTCs in 5 mL blood. Blood samples spiked with Hep3B cells (ranging from 10 to 810 cells) were used to determine recovery and sensitivity. Prevalence of CTCs was examined in samples from HCC patients, healthy volunteers, and patients with benign liver diseases or non-HCC cancers. CTC samples were also analyzed by FISH. RESULTS The average recovery was 61% or more at each spiking level. No healthy, benign liver disease or non-HCC cancer subjects had CTCs detected. CTCs were identified in 69 of 85 (81%) HCC patients, with an average of 19 ± 24 CTCs per 5 mL. Both the positivity rate and the number of CTCs were significantly correlated with tumor size, portal vein tumor thrombus, differentiation status, and the disease extent as classified by the TNM (tumor-node-metastasis) classification and the Milan criteria. HER-2 gene amplification and TP53 gene deletion were detected in CTCs. CONCLUSION Our system provides a new tool allowing for highly sensitive and specific detection and genetic analysis of CTCs in HCC patients. It is likely clinically useful in diagnosis and monitoring of HCC and may have a role in clinical decision making.
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Affiliation(s)
- Wen Xu
- Molecular Oncology Laboratory, and Departments of Comprehensive Treatment and Radio-intervention Therapy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, PR China
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Zhou Y, Zhou N, Fang W, Huo J. Overexpressed HDGF as an independent prognostic factor is involved in poor prognosis in Chinese patients with liver cancer. Diagn Pathol 2010; 5:58. [PMID: 20846397 PMCID: PMC2949719 DOI: 10.1186/1746-1596-5-58] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2010] [Accepted: 09/16/2010] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Hepatoma-derived growth factor (HDGF) is involved in the hepatocarcinogenesis. In this study, we investigated the HDGF expression in hepatocellular carcinoma (HCC) and its correlation with clinicopathologic features, including the survival of patients with HCC. Furthermore, we examined the biological processes regulated by HDGF during the development of using HepG2 cell line as a model system. METHODS We used immunohistochemistry to compare HDGF protein expression in HCC and normal liver tissues and further analyze the HDGF protein expression in clinicopathologically characterized 137 HCC cases. We stably knocked down the endogenous expression level of HDGF in HepG2 cells with specific shRNA-expressing lentiviral vector. Following the successful establishment of stable cells, we examined in vitro cell growth by MTT assay, anchorage-independent growth by soft-agar colony formation assay and cell migration/invasion by transwell and boyden chamber assay. And in addition, we also investigated the in vivo tumor growth by xenograft transplantation of HepG2 cells into nude mice. RESULTS Protein expression level of HDGF was markedly higher in HCC tissues than that in the normal liver tissues(P = 0.011). In addition, high expression of HDGF protein was positively correlated with T classification(p < 0.001), N classification (p < 0.001), and clinical stage (p < 0.001) of HCC patients. Patients with higher HDGF expression showed a significantly shorter overall survival time than did patients with low HDGF expression. Multivariate analysis suggested that HDGF expression might be an independent prognostic indicator(p < 0.001) for the survival of patients with HCC. HDGF-specific shRNA (shHDGF) successfully knocked down its endogenous expression in HepG2 cells. Compared to the parental and control shRNA-transfected (shCtrl) HepG2 cells, the shHDGF cells exhibited significantly reduced in vitro cell growth, anchorage-independent growth, cell migration and invasion (p < 0.05). In vivo, the xenograft transplants from shHDGF cells gave rise to much smaller tumors as compared to those from shCtrl cells. CONCLUSION High HDGF expression is associated with poor overall survival in patients with HCC. Down-regulation of HDGF inhibits the growth, anchorage-independent growth, migration and invasion of HepG2 cells.
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Affiliation(s)
- Yanyan Zhou
- Department of Gastroenterology, Second Xiangya Hospital of Central South University, People's Road 139, Changsha, 410011, China
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Colak D, Chishti MA, Al-Bakheet AB, Al-Qahtani A, Shoukri MM, Goyns MH, Ozand PT, Quackenbush J, Park BH, Kaya N. Integrative and comparative genomics analysis of early hepatocellular carcinoma differentiated from liver regeneration in young and old. Mol Cancer 2010; 9:146. [PMID: 20540791 PMCID: PMC2898705 DOI: 10.1186/1476-4598-9-146] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2009] [Accepted: 06/12/2010] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related deaths worldwide. It is often diagnosed at an advanced stage, and hence typically has a poor prognosis. To identify distinct molecular mechanisms for early HCC we developed a rat model of liver regeneration post-hepatectomy, as well as liver cells undergoing malignant transformation and compared them to normal liver using a microarray approach. Subsequently, we performed cross-species comparative analysis coupled with copy number alterations (CNA) of independent early human HCC microarray studies to facilitate the identification of critical regulatory modules conserved across species. RESULTS We identified 35 signature genes conserved across species, and shared among different types of early human HCCs. Over 70% of signature genes were cancer-related, and more than 50% of the conserved genes were mapped to human genomic CNA regions. Functional annotation revealed genes already implicated in HCC, as well as novel genes which were not previously reported in liver tumors. A subset of differentially expressed genes was validated using quantitative RT-PCR. Concordance was also confirmed for a significant number of genes and pathways in five independent validation microarray datasets. Our results indicated alterations in a number of cancer related pathways, including p53, p38 MAPK, ERK/MAPK, PI3K/AKT, and TGF-beta signaling pathways, and potential critical regulatory role of MYC, ERBB2, HNF4A, and SMAD3 for early HCC transformation. CONCLUSIONS The integrative analysis of transcriptional deregulation, genomic CNA and comparative cross species analysis brings new insights into the molecular profile of early hepatoma formation. This approach may lead to robust biomarkers for the detection of early human HCC.
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Affiliation(s)
- Dilek Colak
- Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
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