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Bayat M, Golestani S, Motlaghzadeh S, Bannazadeh Baghi H, Lalehzadeh A, Sadri Nahand J. War or peace: Viruses and metastasis. Biochim Biophys Acta Rev Cancer 2024; 1879:189179. [PMID: 39299491 DOI: 10.1016/j.bbcan.2024.189179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 09/04/2024] [Accepted: 09/07/2024] [Indexed: 09/22/2024]
Abstract
Metastasis, the dissemination of malignant cells from a primary tumor to secondary sites, poses a catastrophic burden to cancer treatment and is the predominant cause of mortality in cancer patients. Metastasis as one of the main aspects of cancer progression could be strongly under the influence of viral infections. In fact, viruses have been central to modern cancer research and are associated with a great number of cancer cases. Viral-encoded elements are involved in modulating essential pathways or specific targets that are implicated in different stages of metastasis. Considering the continuous emergence of new viruses and the establishment of their contribution to cancer progression, the warfare between viruses and cancer appears to be endless. Here we aimed to review the critical mechanism and pathways involved in cancer metastasis and the influence of viral machinery and various routes that viruses adopt to manipulate those pathways for their benefit.
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Affiliation(s)
- Mobina Bayat
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahin Golestani
- Department of ophthalmology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Motlaghzadeh
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Bannazadeh Baghi
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aidin Lalehzadeh
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Hepatitis B Viral Protein HBx and the Molecular Mechanisms Modulating the Hallmarks of Hepatocellular Carcinoma: A Comprehensive Review. Cells 2022; 11:cells11040741. [PMID: 35203390 PMCID: PMC8870387 DOI: 10.3390/cells11040741] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/10/2022] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
With 296 million cases estimated worldwide, chronic hepatitis B virus (HBV) infection is the most common risk factor for hepatocellular carcinoma (HCC). HBV-encoded oncogene X protein (HBx), a key multifunctional regulatory protein, drives viral replication and interferes with several cellular signalling pathways that drive virus-associated hepatocarcinogenesis. This review article provides a comprehensive overview of the role of HBx in modulating the various hallmarks of HCC by supporting tumour initiation, progression, invasion and metastasis. Understanding HBx-mediated dimensions of complexity in driving liver malignancies could provide the key to unlocking novel and repurposed combinatorial therapies to combat HCC.
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Nong W, Ma L, Lan B, Liu N, Yang H, Lao X, Deng Q, Huang Z. Comprehensive Identification of Bridge Genes to Explain the Progression from Chronic Hepatitis B Virus Infection to Hepatocellular Carcinoma. J Inflamm Res 2021; 14:1613-1624. [PMID: 33907440 PMCID: PMC8071210 DOI: 10.2147/jir.s298977] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 03/16/2021] [Indexed: 12/16/2022] Open
Abstract
Background Hepatitis B virus infection co-occurs in 33% of individuals with hepatocellular carcinoma worldwide. However, the molecular link between hepatitis B virus and hepatocellular carcinoma is unknown. Thus, we aimed to elucidate molecular linkages underlying pathogenesis through in-depth data mining analysis. Materials and Methods Differentially expressed genes were identified from patients with chronic hepatitis B virus infection, hepatocellular carcinoma, or both. Gene set enrichment analysis revealed signaling pathways involving differentially expressed genes. Protein-protein interaction networks, protein crosstalk, and enrichment were analyzed to determine whether differentially expressed gene products might serve as a bridge from hepatitis B virus infection to hepatocellular carcinoma pathogenesis. Prognostic potential and transcriptional and post-transcriptional regulators of bridge genes were also examined. Results We identified vital bridge factors in hepatitis B virus infection-associated hepatocellular carcinoma. Differentially expressed genes were clustered into modules based on relative protein function. Signaling pathways associated with cancer, inflammation, immune system, and microenvironment showed significant crosstalk between modules. Thirty-two genes were dysregulated in hepatitis B virus infection-mediated hepatocellular carcinoma. CPEB3, RAB26, SLCO1B1, ST3GAL6 and XK had higher connectivity in the modular network, suggesting significant associations with survival. CDC20 and NUP107 were identified as driver genes as well as markers of poor prognosis. Conclusion Our results suggest that the sustained inflammatory environment created by hepatitis B virus infection is a risk factor for hepatocellular carcinoma. The identification of hepatitis B virus infection-related hepatocellular carcinoma bridge genes provides testable hypotheses about the pathogenesis of hepatocellular carcinoma.
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Affiliation(s)
- Wenwei Nong
- Department of General Surgery, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Liping Ma
- Department of Clinical Laboratory, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Biyang Lan
- Department of General Surgery, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Ning Liu
- Department of General Surgery, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Hongzhi Yang
- Department of General Surgery, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Xiaoxia Lao
- Department of Clinical Laboratory, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Qiaomei Deng
- Department of Clinical Laboratory, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Zhihu Huang
- Department of Clinical Laboratory, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, People's Republic of China
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Wang YS, Zhu H, Li H, Li Y, Zhao B, Jin YH. Ginsenoside compound K inhibits nuclear factor-kappa B by targeting Annexin A2. J Ginseng Res 2019; 43:452-459. [PMID: 31308817 PMCID: PMC6606818 DOI: 10.1016/j.jgr.2018.04.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 04/04/2018] [Accepted: 04/16/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Ginsenoside compound K(C-K), a major metabolite of ginsenoside, exhibits anticancer activity in various cancer cells and animal models. A cell signaling study has shown that C-K inhibited nuclear factor-kappa B (NF-κB) pathway in human astroglial cells and liver cancer cells. However, the molecular targets of C-K and the initiating events were not elucidated. METHODS Interaction between C-K and Annexin A2 was determined by molecular docking and thermal shift assay. HepG2 cells were treated with C-K, followed by a luciferase reporter assay for NF-кB, immunofluorescence imaging for the subcellular localization of Annexin A2 and NF-кB p50 subunit, coimmunoprecipitation of Annexin A2 and NF-кB p50 subunit, and both cell viability assay and plate clone formation assay to determine the cell viability. RESULTS Both molecular docking and thermal shift assay positively confirmed the interaction between Annexin A2 and C-K. This interaction prevented the interaction between Annexin A2 and NF-кB p50 subunit and their nuclear colocalization, which attenuated the activation of NF-кB and the expression of its downstream genes, followed by the activation of caspase 9 and 3. In addition, the overexpression of Annexin A2-K320A, a C-K binding-deficient mutant of Annexin A2, rendered cells to resist C-K treatment, indicating that C-K exerts its cytotoxic activity mainly by targeting Annexin A2. CONCLUSION This study for the first time revealed a cellular target of C-K and the molecular mechanism for its anticancer activity.
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Affiliation(s)
- Yu-Shi Wang
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University, Changchun, China
| | - Hongyan Zhu
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University, Changchun, China
| | - He Li
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University, Changchun, China
| | - Yang Li
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University, Changchun, China
| | - Bing Zhao
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, China
| | - Ying-Hua Jin
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University, Changchun, China
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Kou Y, Yan X, Liu Q, Wei X, Zhang B, Li X, Pan W, Kong F, Wang Y, Zheng K, Tang R. HBV upregulates AP-1 complex subunit mu-1 expression via the JNK pathway to promote proliferation of liver cancer cells. Oncol Lett 2019; 18:456-464. [PMID: 31289517 PMCID: PMC6540315 DOI: 10.3892/ol.2019.10291] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 04/05/2019] [Indexed: 02/07/2023] Open
Abstract
Although hepatitis B virus (HBV) infection is responsible for liver cancer, the exact mechanism of its action remains unclear. μ1 adaptin is an intrinsic part of the clathrin adaptor AP-1 complex. In addition to its canonical biological function that involves cargo sorting and vesicular transport, recent studies have demonstrated that μ1 adaptin participates in cell growth and proliferation. The aim of the present study was to investigate the effects of the clathrin adaptor AP-1 complex subunit mu-1 (AP1M1) on liver cancer cell proliferation. The present study reports for the first time that AP1M1 is upregulated in the HBV-transfected HepG2.215 liver cancer cells. Silencing of AP1M1 in HepG2.215 cells suppressed their proliferation, while the overexpression of AP1M1 in HepG2 cells promoted cell proliferation. The data suggested that AP1M1 is one of the crucial factors involved in the progression of liver cancer caused by HBV infection. In addition, it was demonstrated that HBV facilitated AP1M1 expression in a JNK-dependent manner. The increased expression levels of AP1M1 enhanced phosphorylation of protein kinase B and accelerated cell proliferation. Unraveling the effects of AP1M1 on liver cancer cell proliferation and the mechanism of AP1M1 transcriptional regulation may provide new therapeutic targets for HBV-positive liver cancer.
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Affiliation(s)
- Yanbo Kou
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Xiaoqing Yan
- Institute of Emergency and Rescue Medicine, Laboratory of Emergency Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Qingya Liu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Xiao Wei
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Bo Zhang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Xiangyang Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Wei Pan
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Yugang Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
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Xu Q, Gu S, Liang J, Lin Z, Zheng S, Yan J. The Biological Function of Hepatitis B Virus X Protein in Hepatocellular Carcinoma. Oncol Res 2019; 27:509-514. [PMID: 29891022 PMCID: PMC7848407 DOI: 10.3727/096504018x15278771272963] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the major malignant tumors that lead to death. Chronic hepatitis B virus infection is an important risk factor for HCC initiation. HBx protein, encoded by the HBV X gene, is a significant factor that promotes HBV-related HCC, although the exact molecular mechanism remains unclear. This article summarizes the pathological roles and related mechanisms of HBx in HCC. HBx plays a carcinogenic role by promoting cell proliferation, metastasis, and angiogenesis and inhibiting apoptosis in HCC. A detailed study of the biological functions of HBx will help to elucidate the mechanism of hepatocarcinogenesis and lead to the development of novel therapeutic targets for the treatment of HBV-related HCC.
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Affiliation(s)
- Qiaodong Xu
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
| | - Songgang Gu
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
| | - Jiahong Liang
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
| | - Zhihua Lin
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
| | - Shaodong Zheng
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
| | - Jiang Yan
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
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Kim YR, Byun MR, Choi JW. Integrin α6 as an invasiveness marker for hepatitis B viral X-driven hepatocellular carcinoma. Cancer Biomark 2018; 23:135-144. [PMID: 30010110 DOI: 10.3233/cbm-181498] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) accounts for more than 60% of hepatocellular carcinoma (HCC) cases. However, there is limited information about the features of HBV-driven HCC that differentiate it from other types of HCC. OBJECTIVE The aim of this study is to find a gene specific to HBV-driven HCC and understand its role during tumorigenesis. METHODS The differences in gene expression patterns were analyzed among patients with hepatitis virus-unrelated liver cirrhosis, and hepatitis C virus- and HBV-driven HCC. Genes expressed only in HBV patients were compared to genes of transgenic mice expressing hepatitis B viral X gene. RESULTS Integrin α6 was commonly overexpressed in both HBV-driven HCC patients and transgenic mice expressing viral X. This gene's activation induced overexpression of integrin α6, as well as formation of integrins α6β1 and α6β4, without changing the expression of non-integrin laminin receptors. Suppression of integrin α6 caused significant inhibition of tumor migration in vitro. CONCLUSIONS This study found a significant association between HBV and integrin α6, which may be responsible for early migration and invasion of HCC. Thus, integrin α6 is a predictive marker for tumor recurrence and invasiveness of HBV-driven HCC.
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Affiliation(s)
- Yi Rang Kim
- Department of Hemato-Oncology, Yuseong Sun Hospital, Daejeon, Korea
| | - Mi Ran Byun
- Department of Pharmacology, College of Pharmacy, Kyung Hee University, Seoul, Korea.,Department of Life and Nanopharmaceutical Science, Graduate School, Kyung Hee University, Seoul, Korea
| | - Jin Woo Choi
- Department of Pharmacology, College of Pharmacy, Kyung Hee University, Seoul, Korea.,Department of Life and Nanopharmaceutical Science, Graduate School, Kyung Hee University, Seoul, Korea
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Zhou XL, Guo X, Song YP, Zhu CY, Zou W. The LPI/GPR55 axis enhances human breast cancer cell migration via HBXIP and p-MLC signaling. Acta Pharmacol Sin 2018; 39:459-471. [PMID: 29188802 PMCID: PMC5843836 DOI: 10.1038/aps.2017.157] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 07/09/2017] [Indexed: 01/06/2023]
Abstract
The G protein-coupled receptor 55 (GPR55) is expressed in multiple tissues, and has been implicated in cancer pathogenesis, but little is known about its role in the migratory behavior of cancer cells, particularly breast cancer cells. In this study we first showed that GPR55 expression levels in 38 metastatic lymph nodes of breast cancer patients were profoundly elevated, and were positively associated in human breast cancer cells with their migratory ability. Moreover, the plasma levels of GPR55 endogenous agonist L-a-lysophosphatidylinositol (LPI) were significantly increased in breast cancer patients compared with healthy individuals. In human breast cancer LM-MCF-7 and MDA-MB-231 cells, treatment with LPI (2.5 μmol/L) significantly increased filopodia formation and resulted in cell migration, which could be blocked either by the GPR55 antagonist CID16020046 or by siRNA-mediated GPR55 knockdown. Furthermore, dual-luciferase report gene assays showed that GPR55 upregulated HBXIP at the promoter; GPR55 expression levels were positively correlated with HBXIP expression levels in breast cancer tissues and 8 breast cancer cell lines. We also showed that the LPI/GPR55 axis promoted the migration of breast cancer cells via two mutually exclusive pathways - the HBXIP/p-ERK1/2/Capn4 and MLCK/MLC signaling pathways. In xenograft nude mouse model, loss of GPR55 mainly affected breast cancer cell metastasis and the formation of metastatic foci. Thus, GPR55 is involved in the migratory behavior of human breast cancer cells and could serve as a pharmacological target for preventing metastasis.
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Affiliation(s)
- Xiao-lei Zhou
- Public R&D Center of Bio-Manufacture, Hebei University of Science and Technology, Shijiazhuang 050018, China
| | - Xin Guo
- Department of Molecular and Cellular Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Yu-pin Song
- College of Chemical Engineering, Shijiazhuang University, Shijiazhuang 050035, China
| | - Chong-yue Zhu
- Public R&D Center of Bio-Manufacture, Hebei University of Science and Technology, Shijiazhuang 050018, China
| | - Wei Zou
- Public R&D Center of Bio-Manufacture, Hebei University of Science and Technology, Shijiazhuang 050018, China
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Li J, Xu J, Yan X, Jin K, Li W, Zhang R. Suppression of Capn4 by microRNA-1271 impedes the proliferation and invasion of colorectal cancer cells. Biomed Pharmacother 2018; 99:162-168. [PMID: 29331762 DOI: 10.1016/j.biopha.2017.12.107] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 12/14/2017] [Accepted: 12/28/2017] [Indexed: 12/21/2022] Open
Abstract
Accumulating evidence has suggested that calpain small subunit 1 (Capn4) plays an important role in the development and progression of malignant tumors. However, little is known about the role of Capn4 in colorectal cancer (CRC). In this study, we aimed to investigate the potential role of Capn4 in CRC and the regulation of Capn4 by microRNAs (miRNAs). Here, we found that Capn4 expression was highly up-regulated in CRC cell lines. Knockdown of Capn4 by siRNA significantly inhibited the proliferation and invasion of CRC cell lines. Furthermore, knockdown of Capn4 suppressed Wnt signaling in CRC cells. Interestingly, Capn4 was found to be a target gene of miR-1271, a tumor suppressive miRNA. The results showed that miR-1271 negatively regulated Capn4 expression in CRC cells. An inverse correlation between miR-1271 and Capn4 was also shown in CRC clinical tissues. Moreover, the overexpression of miR-1271 suppressed the proliferation, invasion and Wnt signaling of CRC cells. Importantly, we found that the restoration of Capn4 expression significantly reversed the antitumor effects of miR-1271 in CRC cells. Overall, these results suggest that miR-1271 inhibits the proliferation and invasion of CRC cells by down-regulating Capn4. Our study suggests that Capn4 and miR-1271 may serve as potential therapeutic targets for the treatment of CRC.
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Affiliation(s)
- Jibin Li
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province 110042, China
| | - Jian Xu
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province 110042, China
| | - Xiaofei Yan
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province 110042, China
| | - Keer Jin
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province 110042, China
| | - Wenya Li
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province 110042, China
| | - Rui Zhang
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province 110042, China.
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Yang MF, Lou YL, Liu SS, Wang SS, Yin CH, Cheng XH, Huang OP. Capn4 overexpression indicates poor prognosis of ovarian cancer patients. J Cancer 2018; 9:304-309. [PMID: 29344277 PMCID: PMC5771338 DOI: 10.7150/jca.22004] [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] [Received: 07/19/2017] [Accepted: 10/24/2017] [Indexed: 12/19/2022] Open
Abstract
Recent studies have shown a close correlation between Capn4 expression and the prognosis of patients with solid tumors. This study aimed to investigate clinical role of Capn4 in ovarian cancer. The expression of Capn4 in 113 ovarian cancer and 35 non-tumor tissue samples were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Capn4 expression was significantly upregulated in ovarian cancer tissues compared with non-tumor tissues (p < 0.01), and was positively correlated to FIGO stage, tumor grade and distant metastasis of ovarian cancer. Kaplan-Meier analysis indicated that patients with high Capn4 expression had shorter overall survival (HR = 1.929, 95%CI: 1.210-3.077, P= 0.006) and progress-free survival (PFS) (HR = 2.043, 95%CI: 1.276-3.271, P= 0.003). Moreover, univariate Cox regression analysis demonstrated that Capn4 overexpression was an unfavorable prognostic factor for ovarian cancer (HR = 2.819, 95%CI: 1.365-3.645, P = 0.003). After the adjustment with age, histological type and tumor size, multivariate Cox regression analysis showed that Capn4 expression level (HR = 2.157,95%CI: 1.091-3.138, P = 0.014), distant metastasis (HR = 1.576, 95%CI: 1.025-3.012, P = 0.028), tumor grade (HR = 1.408, 95%CI: 0.687-2.884, P = 0.037), and FIGO stage (HR = 1.791, 95%CI: 1.016-3.158, P=0.036) were independent poor prognostic indicators for ovarian cancer. In conclusion, Capn4 has the potential as a new prognostic marker for patients with ovarian cancer.
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Affiliation(s)
- Ming-Fang Yang
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Yuan-Lei Lou
- Institute of Urology, Nanchang University, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Si-Sun Liu
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Shan-Shan Wang
- Department of Pathology, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Chun-Hua Yin
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Xiao-Hua Cheng
- Department of Pharmacy, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Ou-Ping Huang
- Department of Obstetrics and Gynecology, Jiangxi Maternal and Child Health Hospital, Nanchang 330006, China
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11
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Liu C, Liu L, Wang X, Liu Y, Wang M, Zhu F. HBV X Protein induces overexpression of HERV-W env through NF-κB in HepG2 cells. Virus Genes 2017; 53:797-806. [PMID: 28639221 DOI: 10.1007/s11262-017-1479-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 06/13/2017] [Indexed: 10/19/2022]
Abstract
Human endogenous retrovirus W family (HERV-W) envelope (env) at chromosome 7 is highly expressed in the placenta and possesses fusogenic activity in trophoblast development. HERV-W env has been found to be overexpressed in some cancers and immune diseases. Viral transactivators can induce the overexpression of HERV-W env in human cell lines. Hepatitis B virus X protein (HBx) is believed to be a multifunctional oncogenic protein. Here, we reported that HBx could increase the promoter activity of HERV-W env and upregulate the mRNA levels of non-spliced and spliced HERV-W env and also its protein in human hepatoma HepG2 cells. Interestingly, we found that the inhibition of nuclear factor κB (NF-κB) using shRNA targeting NF-κB/p65 or PDTC (an inhibitor of NF-κB) could attenuate the upregulation of HERV-W env induced by HBx. These suggested that HBx might upregulate the expression of HERV-W env through NF-κB in HepG2 cells. This study might provide a new insight in HBV-associated liver diseases including HCC.
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Affiliation(s)
- Cong Liu
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, People's Republic of China
| | - Lijuan Liu
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, People's Republic of China
| | - Xiuling Wang
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, People's Republic of China
| | - Youyi Liu
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, People's Republic of China
| | - Miao Wang
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, People's Republic of China
| | - Fan Zhu
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, People's Republic of China.
- Hubei Province Key Laboratory of Allergy and Immunology, Wuhan, 430071, Hubei Province, People's Republic of China.
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12
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Kong F, You H, Tang R, Zheng K. The regulation of proteins associated with the cytoskeleton by hepatitis B virus X protein during hepatocarcinogenesis. Oncol Lett 2017; 13:2514-2520. [PMID: 28454428 DOI: 10.3892/ol.2017.5757] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 12/06/2016] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a major malignant disease worldwide, and chronic hepatitis B virus (HBV) infection is one of the primary causes for this type of cancer. Hepatitis B virus X protein (HBx) is a non-structural protein encoded by the viral genome that has significant effects on the pathogenesis of HCC. With the development of high-throughput assays and technologies, the abnormal HBx-induced expression of certain cellular proteins with assorted biological functions has been investigated. These target proteins identified by various methods include specific proteins associated with the cellular cytoskeleton, which contribute to HBx-induced hepatocarcinogenesis. In addition, the cytoskeletal proteins deregulated by HBx are involved in cell morphogenesis, adhesion, migration and proliferation. This review aims to summarize the current understanding of the expression profiles of HBx-associated cytoskeletal proteins, as well as their complex functions and underlying mechanisms in hepatocarcinogenesis. Considering that the potential therapeutics for various types of tumors may function through the stabilization of cytoskeletal proteins in order to restrict cellular movement and limit intracellular processes, clarifying the mechanisms underlying protein-associated cytoskeleton dysregulation by HBx may provide novel possibilities and potent therapeutic targets for HBV-associated HCC.
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Affiliation(s)
- Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
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Wang E, Wang D, Li B, Ma H, Wang C, Guan L, Zhang H, Yi L, Li S. Capn4 promotes epithelial-mesenchymal transition in human melanoma cells through activation of the Wnt/β-catenin pathway. Oncol Rep 2016; 37:379-387. [PMID: 27878263 DOI: 10.3892/or.2016.5247] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 07/01/2016] [Indexed: 11/06/2022] Open
Abstract
Melanoma, as one of the most highly metastatic types of cancer, is resistant to current treatment methods, including popular targeted molecular therapy. Consequently, it is essential to develop a deeper understanding of the mechanisms involved in melanoma progression so that alternative treatments may be identified. To date, accumulating evidence supports the use of calpains, including calpain small subunit 1 (also known as Capn4 or CAPNS1), which affect cancer progression through many pathways, such as epithelial‑mesenchymal transition (EMT), the Wnt/β-catenin (β-catenin) and the nuclear factor κB (NF-κB) signaling pathways. The EMT pathway is well known as one of the most important events in tumor metastasis. The present study observed cross-talk among the EMT, β-catenin and NF-κB pathways. To identify the underlying mechanisms of Capn4 activity in melanoma cells, we determined Capn4 expression by gene chip and immunohistochemistral analyses in melanoma tissues and cells in vitro. The extent of apoptosis as determined by TUNEL assay, DAPI staining, and cleaved-caspase-3 assay was increased in human melanoma cells in which Capn4 expression had been knocked down when compared with untreated cells. Transwell assays and xenograft tumorigenicity studies were also performed to assess the effects of Capn4 on migration and invasion in vitro and tumor growth in vivo, respectively. The levels of β-catenin, vimentin, E-cadherin and N-cadherin were altered in human melanoma cells as determined by western blot analysis assay. Our study demonstrated that Capn4 is an underlying target for melanoma treatment.
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Affiliation(s)
- Enwen Wang
- Department of Radiology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Donglin Wang
- Department of Medical Oncology, Chongqing Cancer Hospital and Institute and Cancer Center, Chongqing 400030, P.R. China
| | - Bing Li
- Department of Ear-Nose-Throat, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Huiwen Ma
- Department of Medical Oncology, Chongqing Cancer Hospital and Institute and Cancer Center, Chongqing 400030, P.R. China
| | - Chunmei Wang
- Department of Medical Oncology, Chongqing Cancer Hospital and Institute and Cancer Center, Chongqing 400030, P.R. China
| | - Lili Guan
- Department of Nuclear Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Haiwei Zhang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing Cancer Hospital and Institute and Cancer Center, Chongqing 400030, P.R. China
| | - Lin Yi
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing Cancer Hospital and Institute and Cancer Center, Chongqing 400030, P.R. China
| | - Shaolin Li
- Department of Radiology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
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Ismail S, Mayah W, Battia HE, Gaballah H, Jiman-Fatani A, Hamouda H, Afifi MA, Elmashad N, Saadany SE. Plasma nuclear factor kappa B and serum peroxiredoxin 3 in early diagnosis of hepatocellular carcinoma. Asian Pac J Cancer Prev 2015; 16:1657-63. [PMID: 25743848 DOI: 10.7314/apjcp.2015.16.4.1657] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Early diagnosis of hepatocellular carcinoma (HCC) is the most important step in successful treatment. However, it is usually rare due to the lack of a highly sensitive specific biomarker so that the HCC is usually fatal within few months after diagnosis. The aim of this work was to study the role of plasma nuclear factor kappa B (NF-?B) and serum peroxiredoxin 3 (PRDX3) as diagnostic biomarkers for early detection of HCC in a high-risk population. MATERIALS AND METHODS Plasma nuclear factor kappa B level (NF-?B) and serum peroxiredoxin 3 (PRDX3) levels were measured using enzyme linked immunosorbent assay (ELISA), in addition to alpha-fetoprotein (AFP) in 72 cirrhotic patients, 64 patients with HCC and 29 healthy controls. RESULTS NF-?B and PRDX3 were significantly elevated in the HCC group in relation to the others. Higher area under curve (AUC) of 0.854 (for PRDX3) and 0.825 (for NF-?B) with sensitivity of 86.3% and 84.4% and specificity of 75.8% and 75.4% respectively, were found compared to AUC of alpha-fetoprotein (AFP) (0.65) with sensitivity of 72.4% and specificity of 64.3%. CONCLUSIONS NF-?B and PRDX3 may serve as early and sensitive biomarkers for early detection of HCC facilitating improved management. The role of nuclear factor kappa B (NF-?B) as a target for treatment of liver fibrosis and HCC must be widely evaluated.
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Affiliation(s)
- Saber Ismail
- Departments of Tropical Medicine and Infectious Diseases, Faculty of Medicine Tanta University, Tanta, Egypt E-mail :
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Kong F, You H, Zhao J, Liu W, Hu L, Luo W, Hu W, Tang R, Zheng K. The enhanced expression of death receptor 5 (DR5) mediated by HBV X protein through NF-kappaB pathway is associated with cell apoptosis induced by (TNF-α related apoptosis inducing ligand) TRAIL in hepatoma cells. Virol J 2015; 12:192. [PMID: 26577955 PMCID: PMC4650207 DOI: 10.1186/s12985-015-0416-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2015] [Accepted: 11/03/2015] [Indexed: 01/28/2023] Open
Abstract
Background HBV X protein (HBX) is associated with cell apoptosis mediated by TNF-α related apoptosis inducing ligand (TRAIL), while the role of HBX on the expressions of TRAIL receptors death receptor 4 (DR4) and DR5 are unclear. In this study, we detected the cell apoptosis induced by TRAIL as well as gene and protein expressions of DR4 and DR5 in Huh-7 cells steadily transfected with HBX (Huh-7-HBX cells). In addition, we investigated the activation of different pathways associated with the expressions of TRAIL receptors in Huh-7-HBX cells. Methods The apoptosis of Huh-7-HBX cells induced by TRAIL was evaluated by flow cytometry analysis. The levels of DR4 and DR5 expression in cells were determined by real-time PCR and western blotting analysis. The activities of JNK pathway and NF-kappaB (NF-κB) pathway were demonstrated by western blotting assay. Results Compared to control cells, the percentage of cell apoptosis was increased in Huh-7-HBX cells. The increased expressions of DR4 and DR5 on gene and protein levels were observed in Huh-7-HBX cells. Further researches suggested that activation of JNK pathway was increased but not involved in the expression of TRAIL receptors in HBX positive cells. The activation of NF-κB pathway increased and was responsible for DR5 expression and cell apoptosis in HBX positive cells. Conclusions These results demonstrate that increased apoptosis induced by TRAIL is associated with increased expression of DR5 that mediated by HBX through NF-κB pathway. This finding provides a critical insight into the mechanism of hepatocyte apoptosis mediated by HBX in HBV infection.
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Affiliation(s)
- Fanyun Kong
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
| | - Hongjuan You
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
| | - Jinjin Zhao
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
| | - Wen Liu
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
| | - Lei Hu
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
| | - Wenya Luo
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
| | - Wei Hu
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
| | - Renxian Tang
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
| | - Kuiyang Zheng
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
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16
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Geng M, Xin X, Bi LQ, Zhou LT, Liu XH. Molecular mechanism of hepatitis B virus X protein function in hepatocarcinogenesis. World J Gastroenterol 2015; 21:10732-10738. [PMID: 26478665 PMCID: PMC4600575 DOI: 10.3748/wjg.v21.i38.10732] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 06/24/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
Many factors are considered to contribute to hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC), including products of HBV, HBV integration and mutation, and host susceptibility. HBV X protein (HBx) can interfere with several signaling pathways associated with cell proliferation and invasion, and HBx C-terminal truncation has been suggested to impact the development of HCC. This review focuses on the pathological functions of HBx in HBV-induced hepatocarcinogenesis. As a transactivator, HBx can affect regulatory non-coding RNAs (ncRNAs), including microRNAs and long ncRNAs. HBx is also involved in epigenetic modification and DNA repair. HBx interacts with various signal-transduction pathways, such as the p53, Wnt, and nuclear factor-κB pathways. We conclude that HBx hastens the development of hepatoma.
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17
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Peters-Hall JR, Brown KJ, Pillai DK, Tomney A, Garvin LM, Wu X, Rose MC. Quantitative proteomics reveals an altered cystic fibrosis in vitro bronchial epithelial secretome. Am J Respir Cell Mol Biol 2015; 53:22-32. [PMID: 25692303 PMCID: PMC4566109 DOI: 10.1165/rcmb.2014-0256rc] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Accepted: 02/05/2015] [Indexed: 12/25/2022] Open
Abstract
Alterations in epithelial secretions and mucociliary clearance contribute to chronic bacterial infection in cystic fibrosis (CF) lung disease, but whether CF lungs are unchanged in the absence of infection remains controversial. A proteomic comparison of airway secretions from subjects with CF and control subjects shows alterations in key biological processes, including immune response and proteolytic activity, but it is unclear if these are due to mutant CF transmembrane conductance regulator (CFTR) and/or chronic infection. We hypothesized that the CF lung apical secretome is altered under constitutive conditions in the absence of inflammatory cells and pathogens. To test this, we performed quantitative proteomics of in vitro apical secretions from air-liquid interface cultures of three life-extended CF (ΔF508/ΔF508) and three non-CF human bronchial epithelial cells after labeling of CF cells by stable isotope labeling with amino acids in cell culture. Mass spectrometry analysis identified and quantitated 666 proteins across samples, of which 70 exhibited differential enrichment or depletion in CF secretions (±1.5-fold change; P < 0.05). The key molecular functions were innate immunity (24%), cytoskeleton/extracellular matrix organization (24%), and protease/antiprotease activity (17%). Oxidative proteins and classical complement pathway proteins that are altered in CF secretions in vivo were not altered in vitro. Specific differentially increased proteins-MUC5AC and MUC5B mucins, fibronectin, and matrix metalloproteinase-9-were validated by antibody-based assays. Overall, the in vitro CF secretome data are indicative of a constitutive airway epithelium with altered innate immunity, suggesting that downstream consequences of mutant CFTR set the stage for chronic inflammation and infection in CF airways.
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Affiliation(s)
| | - Kristy J. Brown
- Departments of Integrative Systems Biology and
- Pediatrics, George Washington University School of Medicine, Washington, DC; and
- Research Center for Genetic Medicine and
| | - Dinesh K. Pillai
- Departments of Integrative Systems Biology and
- Pediatrics, George Washington University School of Medicine, Washington, DC; and
- Research Center for Genetic Medicine and
- Division of Pulmonary and Sleep Medicine, Children's National, Washington, DC
| | | | - Lindsay M. Garvin
- Departments of Integrative Systems Biology and
- Research Center for Genetic Medicine and
| | - Xiaofang Wu
- Departments of Integrative Systems Biology and
- Pediatrics, George Washington University School of Medicine, Washington, DC; and
- Research Center for Genetic Medicine and
| | - Mary C. Rose
- Departments of Integrative Systems Biology and
- Pediatrics, George Washington University School of Medicine, Washington, DC; and
- Research Center for Genetic Medicine and
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18
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Lu X, Ma P, Shi Y, Yao M, Hou L, Zhang P, Jiang L. NF-κB increased expression of 17β-hydroxysteroid dehydrogenase 4 promotes HepG2 proliferation via inactivating estradiol. Mol Cell Endocrinol 2015; 401:1-11. [PMID: 25448063 DOI: 10.1016/j.mce.2014.11.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 11/15/2014] [Accepted: 11/20/2014] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) arises in a setting of chronic inflammation induced by inflammatory cytokines, such as nuclear factor-kappaB (NF-κB). HCC is a male-predominant cancer that can be attenuated by estradiol (E2) in vitro and in vivo. Although 17β-hydroxysteroid dehydrogenase 4 (HSD17B4) has been implicated as an estradiol-inactivating enzyme, and its promoter sequence contains two putative NF-κB elements: it is currently unknown whether HSD17B4 is the link between inflammation, estradiol and proliferation in hepatoma cells. In this study, HepG2 cells were used to investigate the role of HSD17B4 in the proliferation of liver cancer cells treated with the NF-κB activator, tumor necrosis factor-alpha (TNF-α), with the inhibitor of NF-κB activation, pyrrolidinedithiocarbamate (PDTC), or with a related specific siRNA. We demonstrated that the human HSD17B4 gene is a target for NF-κB activation in inflammation-stimulated HepG2 cells. HSD17B4 is up-regulated via the binding of activated NF-κB to the distal NF-κB-responsive element via TNF-α stimulation, which then promotes cell proliferation by decreasing the levels of E2 and enhancing the expression of interleukin 6 (IL-6), cyclin D1 and proliferating cell nuclear antigen (PCAN). These results from HepG2 cells are consistent with the observation that HSD17B4 is highly expressed and activated NF-κB is highly co-localized with the NF-κB-responsive element of HSD17B4 in liver tumor tissues from HCC patients. Our findings indicate for the first time that HSD17B4 plays an important role in aggravated HCC progression and provides a novel therapeutic target for HCC.
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Affiliation(s)
- Xin Lu
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China
| | - Panpan Ma
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China
| | - Yun Shi
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China
| | - Min Yao
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China
| | - Lianguo Hou
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China
| | - Pingping Zhang
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China
| | - Lingling Jiang
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China.
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Ozkal-Baydin P. How did hepatitis B virus effect the host genome in the last decade? World J Hepatol 2014; 6:851-859. [PMID: 25544872 PMCID: PMC4269904 DOI: 10.4254/wjh.v6.i12.851] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Revised: 06/06/2014] [Accepted: 10/16/2014] [Indexed: 02/06/2023] Open
Abstract
The principal reason of chronic liver disease, cirrhosis and hepatocellular carcinoma is chronic viral hepatitis all over the world. Hepatitis B virus (HBV) has some mutagenic effects on the host genome. HBV may be exhibiting these mutagenic effects through integrating into the host genome, through its viral proteins or through some epigenetic mechanisms related with HBV proteins. This review aims to summarize the molecular mechanisms used by HBV for effecting host genome determined in the last decade. The focus will be on the effects of integration, HBV proteins, especially HBV X protein and epigenetic mechanisms on the host genome. These interactions between HBV and the host genome also forms the underlying mechanisms of the evolution of hepatocellular carcinoma.
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20
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Li Y, Zhang Z, Zhou X, Li L, Liu Q, Wang Z, Bai X, Zhao Y, Shi H, Zhang X, Ye L. The oncoprotein HBXIP enhances migration of breast cancer cells through increasing filopodia formation involving MEKK2/ERK1/2/Capn4 signaling. Cancer Lett 2014; 355:288-96. [DOI: 10.1016/j.canlet.2014.09.047] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 09/03/2014] [Accepted: 09/28/2014] [Indexed: 12/01/2022]
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Gaballah HH, Zakaria SS, Ismail SA. Activity and Expression Pattern of NF-κB/P65 in Peripheral Blood from Hepatocellular Carcinoma Patients - Link to Hypoxia Inducible Factor -1α. Asian Pac J Cancer Prev 2014; 15:6911-7. [DOI: 10.7314/apjcp.2014.15.16.6911] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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22
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Dai Z, Zhou SL, Zhou ZJ, Bai DS, Xu XY, Fu XT, Chen Q, Zhao YM, Zhu K, Yu L, Yang GH, Wang Z, Wu WZ, Zhou J, Fan J. Capn4 contributes to tumour growth and metastasis of hepatocellular carcinoma by activation of the FAK-Src signalling pathways. J Pathol 2014; 234:316-28. [PMID: 24962955 DOI: 10.1002/path.4395] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Revised: 06/10/2014] [Accepted: 06/17/2014] [Indexed: 01/04/2023]
Abstract
Calpain small subunit 1 (Capn4) has been identified as a major gene that promotes metastasis of hepatocellular carcinoma (HCC). However, the mechanism by which Capn4 promotes progression of HCC is not understood. In this study, we found that Capn4 expression was increased in highly metastatic HCC cell lines and in tumour tissue from HCC patients compared to healthy patient tissue. Over-expression of Capn4 in HCC cells enhanced tumour cell growth in vitro and increased invasiveness, tumourigenicity and lung metastasis in vivo. Protein microarray analyses showed that expression of multiple proteins was regulated by Capn4. Interestingly, Capn4 was found to physically associate with FAK and promoted hyperactivity of the FAK-Src signalling pathway via increased phosphorylation of specific tyrosine residues of FAK, Src and p130Cas. Knock-down of Capn4 expression suppressed the malignant behaviour of HCC cells and inhibited the FAK-Src signalling pathway. Furthermore, Capn4-mediated invasion and metastasis of HCC cells required up-regulation of matrix metalloproteinase-2 (MMP2) through activation of this signalling pathway. Our clinical data revealed that Capn4 expression correlated well with the levels of phospho-FAK, and over-expression of both Capn4 and phospho-FAK correlates with the poorest survival outcomes in HCC. In conclusion, our data showed that Capn4 can contribute to HCC growth and metastasis via activation of the FAK-Src signalling pathway and MMP2.
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Affiliation(s)
- Zhi Dai
- Liver Cancer Institute and Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, People's Republic of China
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Zheng PC, Chen X, Zhu HW, Zheng W, Mao LH, Lin C, Liu JN, Zheng M. Capn4 is a marker of poor clinical outcomes and promotes nasopharyngeal carcinoma metastasis via nuclear factor-κB-induced matrix metalloproteinase 2 expression. Cancer Sci 2014; 105:630-8. [PMID: 24703594 PMCID: PMC4317905 DOI: 10.1111/cas.12416] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 03/10/2014] [Accepted: 04/03/2014] [Indexed: 12/15/2022] Open
Abstract
Calpain small subunit 1 (Capn4) plays a key role in tumor migration or invasion. In this study, expression and function of Capn4 was investigated in human nasopharyngeal carcinoma (NPC). Here we report that both mRNA and protein levels of Capn4 were elevated in NPC tissues when compared to normal NP tissues. Similarly, Capn4 was also highly expressed in multiple NPC cell lines, compared to immortalized human nasopharyngeal epithelial cell line NP69. Moreover, expression of Capn4 was significantly correlated with Epstein-Barr virus infection, advanced stages, and lymph node or distant metastasis (P < 0.001). The patients with NPC displaying higher Capn4 had a significantly shorter overall survival (P = 0.002) and progression-free survival (P = 0.003). Furthermore, siRNA knockdown of Capn4 suppressed cell migration and invasion in vitro and in vivo. These events resulted from Capn4 downregulation were associated with reduced expression of matrix metalloproteinase 2 (MMP2), Snail, and Vimentin. Finally, we demonstrated that Capn4 upregulated MMP2 via nuclear factor-κB (NF-κB) activation, manifested by increased phosphorylation of p65, a subunit of NF-κB. Together, these findings argue a novel function of Capn4 in invasion and metastasis of NPC, and thereby suggest that Capn4 may represent an independent prognostic factor and a potential therapeutic target in NPC.
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Affiliation(s)
- Pei-Chan Zheng
- Department of Anatomy, School of Basic Medical Sciences, Fujian Medical UniversityFuzhou, China
| | - Xiong Chen
- Department of Oncology, Fuzhou General Hospital of Nanjing Military CommandFuzhou, China
| | - Hong-Wu Zhu
- Department of Gastroenterology, Guangzhou General Hospital of Guangzhou Military CommandGuangzhou, China
| | - Wei Zheng
- Department of Pharmacy, Fujian Provincial Cancer HospitalFuzhou, China
| | - Li-Hua Mao
- Department of Obstetrics and Gynecology, Fuzhou General Hospital of Nanjing Military CommandFuzhou, China
| | - Cheng Lin
- Department of Oncology, Fuzong Clinical College, Fujian Medical UniversityFuzhou, China
| | - Jing-Nan Liu
- Department of Oncology, Fuzong Clinical College, Fujian Medical UniversityFuzhou, China
| | - Ming Zheng
- Department of Anatomy, School of Basic Medical Sciences, Fujian Medical UniversityFuzhou, China
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Hepatitis B virus induces cell proliferation via HBx-induced microRNA-21 in hepatocellular carcinoma by targeting programmed cell death protein4 (PDCD4) and phosphatase and tensin homologue (PTEN). PLoS One 2014; 9:e91745. [PMID: 24633222 PMCID: PMC3954734 DOI: 10.1371/journal.pone.0091745] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Accepted: 02/15/2014] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B viral infection-induced hepatocellular carcinoma is one of the major problems in the developing countries. One of the HBV proteins, HBx, modulates the host cell machinery via several mechanisms. In this study we hypothesized that HBV enhances cell proliferation via HBx-induced microRNA-21 in hepatocellular carcinoma. HBx gene was over-expressed, and miRNA-21 expression and cell proliferation were measured in Huh 7 and Hep G2 cells. miRNA-21 was over-expressed in these cells, cell proliferation and the target proteins were analyzed. To confirm the role of miRNA-21 in HBx-induced proliferation, Hep G 2.2.1.5 cells (a cell line that expresses HBV stably) were used for miRNA-21 inhibition studies. HBx over-expression enhanced proliferation (3.7- and 4.5-fold increase; n = 3; p<0.01) and miRNA-21 expression (24- and 36-fold increase, normalized with 5S rRNA; p<0.001) in Huh 7 and Hep G2 cells respectively. HBx also resulted in the inhibition of miRNA-21 target proteins, PDCD4 and PTEN. miRNA-21 resulted in a significant increase in proliferation (2- and 2.3-fold increase over control cells; p<0.05 in Huh 7 and Hep G2 cells respectively) and decreased target proteins, PDCD4 and PTEN expression. Anti-miR-21 resulted in a significant decrease in proliferation (p<0.05) and increased miRNA-21 target protein expression. We conclude that HBV infection enhances cell proliferation, at least in part, via HBx-induced miRNA-21 expression during hepatocellular carcinoma progression.
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Duan CH, Tai S. Role of hepatitis B virus X protein in hepatocarcinogenesis. Shijie Huaren Xiaohua Zazhi 2013; 21:2397-2402. [DOI: 10.11569/wcjd.v21.i24.2397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer-related death. Chronic hepatitis B virus (HBV) infection has been identified as a major risk factor for HCC. Evidence suggests that the HBV X protein (HBx) plays a crucial role in the carcinogenesis of HCC. HBx is a multifunctional regulator that plays a key role in the occurrence, development, invasion and metastasis of cancers. Due to its important roles in the development of HCC, the research on the HBx protein has become a hot topic in recent years. This review describes the latest advances in understanding the role of the HBx protein in hepatocarcinogenesis.
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Wang H, Chen L. Tumor microenviroment and hepatocellular carcinoma metastasis. J Gastroenterol Hepatol 2013; 28 Suppl 1:43-8. [PMID: 23855295 DOI: 10.1111/jgh.12091] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/06/2013] [Indexed: 12/16/2022]
Abstract
The cross talk between tumor cells and the surrounding peritumoral stroma has been extensively studied as a dynamic system involving the processes of hepatocarcinogenesis, tumor invasion, and metastasis in recent few decades. Besides hepatocytes, liver tumor microenvironments are generally classified into cellular and noncellular components, including hepatic stellate cells, fibroblasts, immune, endothelial, mesenchymal stem cells, together with growth factors, cytokines, extracellular matrix, hormone as well as viruses et al. The noncellular components manipulate hepatocellular carcinoma invasion and metastasis by facilitating epithelial-mesenchymal transition, increasing proteolytic activity of matrix metalloproteinases, and regulating antitumor immunity, etc. Because the main cause of death in hepatocellular carcinoma patients is tumor progression with metastasis, a better understanding of the interplay between hepatocytes and their environment during tumor metastasis may be helpful for the discovery of novel molecular targets.
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Affiliation(s)
- Hongyang Wang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
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Liu Y, Lou G, Wu W, Shi Y, Zheng M, Chen Z. Interferon-α sensitizes HBx-expressing hepatocarcinoma cells to chemotherapeutic drugs through inhibition of HBx-mediated NF-κB activation. Virol J 2013; 10:168. [PMID: 23718853 PMCID: PMC3680016 DOI: 10.1186/1743-422x-10-168] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2012] [Accepted: 04/11/2013] [Indexed: 01/15/2023] Open
Abstract
Background Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) is characterized by high chemotherapy resistance; however, the underlying mechanism has not been fully clarified. In addition, HBx protein has been reported to play a key role in virus-mediated hepatocarcinogenesis. Therefore, the present study aims to investigate the role of HBx in the drug-resistance of HBV-related HCC and examine whether such drug-resistance can be reversed by IFN-α treatment. Methods We established HBx-expressing cells by liposome-mediated transfection of HBx into the Huh7 cell line. MTT, Annexin V/PI, and cell cycle assay were used for determining the cellular growth inhibition, apoptosis, and growth arrest, respectively, after treatment with chemical drug. We further used tumor-bearing mice model to compare the tumor growth inhibition efficacy of ADM and 5-FU between the Huh7-HBx group and the control group, as well as the ADM + IFN-α or ADM + IMD treated group and the ADM treated group. SQ-Real time-PCR was performed to analyze the expression of MDR-associated genes and anti-apoptotic genes. Moreover, immunofluorescence and Western blotting were used to determine the subcellular localization of p65 and the phosphorylation of IκBα. Results The IC50 values of Huh7-HBx cells against ADM and Amn were 2.317 and 1.828-folds higher than those of Huh7-3.1 cells, respectively. The apoptosis ratio and growth arrest was significantly lower in Huh7-HBx cells after treatment with ADM. The in vivo experiment also confirmed that the Huh7-HBx group was much more resistant to ADM or 5-FU than the control. Furthermore, the expression of MDR-associated genes, such as MDR1, MRP1, LRP1, and ABCG2, were significantly up-regulated in Huh7-HBx cells, and the NF-κB pathway was activated after HBx gene transfection in Huh7 cells. However, combined with IFN-α in ADM treatment, the HBx induced drug-resistance in Huh7-HBx cells can be partly abolished in in vitro and in vivo models. Moreover, we found that the NF-κB canonical pathway was affected by IFN-α treatment, and the expression of anti-apoptotic genes, such as Gadd45β, Survivin, and c-IAP-1 was down-regulated by IFN-α treatment in a dose-dependent manner. Conclusions HBx protein can induce MDR of HBV-related HCC by activating the NF-κB pathway, which can be partly abolished by IFN-α treatment.
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Affiliation(s)
- Yanning Liu
- State Key Laboratory of Infectious Disease Diagnosis and Treatment, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
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Liu Y, Lou G, Wu W, Shi Y, Zheng M, Chen Z. Interferon-α sensitizes HBx-expressing hepatocarcinoma cells to chemotherapeutic drugs through inhibition of HBx-mediated NF-κB activation. Virol J 2013. [PMID: 23718853 DOI: 10.1186/1743] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) is characterized by high chemotherapy resistance; however, the underlying mechanism has not been fully clarified. In addition, HBx protein has been reported to play a key role in virus-mediated hepatocarcinogenesis. Therefore, the present study aims to investigate the role of HBx in the drug-resistance of HBV-related HCC and examine whether such drug-resistance can be reversed by IFN-α treatment. METHODS We established HBx-expressing cells by liposome-mediated transfection of HBx into the Huh7 cell line. MTT, Annexin V/PI, and cell cycle assay were used for determining the cellular growth inhibition, apoptosis, and growth arrest, respectively, after treatment with chemical drug. We further used tumor-bearing mice model to compare the tumor growth inhibition efficacy of ADM and 5-FU between the Huh7-HBx group and the control group, as well as the ADM + IFN-α or ADM + IMD treated group and the ADM treated group. SQ-Real time-PCR was performed to analyze the expression of MDR-associated genes and anti-apoptotic genes. Moreover, immunofluorescence and Western blotting were used to determine the subcellular localization of p65 and the phosphorylation of IκBα. RESULTS The IC₅₀ values of Huh7-HBx cells against ADM and Amn were 2.317 and 1.828-folds higher than those of Huh7-3.1 cells, respectively. The apoptosis ratio and growth arrest was significantly lower in Huh7-HBx cells after treatment with ADM. The in vivo experiment also confirmed that the Huh7-HBx group was much more resistant to ADM or 5-FU than the control. Furthermore, the expression of MDR-associated genes, such as MDR1, MRP1, LRP1, and ABCG2, were significantly up-regulated in Huh7-HBx cells, and the NF-κB pathway was activated after HBx gene transfection in Huh7 cells. However, combined with IFN-α in ADM treatment, the HBx induced drug-resistance in Huh7-HBx cells can be partly abolished in in vitro and in vivo models. Moreover, we found that the NF-κB canonical pathway was affected by IFN-α treatment, and the expression of anti-apoptotic genes, such as Gadd45β, Survivin, and c-IAP-1 was down-regulated by IFN-α treatment in a dose-dependent manner. CONCLUSIONS HBx protein can induce MDR of HBV-related HCC by activating the NF-κB pathway, which can be partly abolished by IFN-α treatment.
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Affiliation(s)
- Yanning Liu
- State Key Laboratory of Infectious Disease Diagnosis and Treatment, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
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Zhang F, Wang Y, Xu M, Dong H, Liu N, Zhou J, Pang H, Ma N, Zhang N, Pei Y, Zhang H, Liu L. MGr1-Ag promotes invasion and bone metastasis of small-cell lung cancer in vitro and in vivo. Oncol Rep 2013; 29:2283-90. [PMID: 23588894 DOI: 10.3892/or.2013.2396] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Accepted: 03/14/2013] [Indexed: 11/06/2022] Open
Abstract
Bone metastasis of small-cell lung cancer (SCLC) usually occurs early in the progression of the disease. However, the molecular mechanism underlying bone metastasis is largely unknown. MGr1-Ag, a multifunction protein, has been suggested to play important roles in cell growth, differentiation and migration. In our present study, MGr1-Ag was found to be highly expressed in bone-metastatic SCLC cells (SBC-5 cell line) as compared with the expression in cells without bone-metastatic ability (SBC-3 cell line). Therefore, we hypothesized that MGr1-Ag is involved in bone metastasis of SCLC. Using a sense vector to upregulate MGr1-Ag expression in SBC-3 cells, we found that forced overexpression of MGr1-Ag enhanced cell invasion and migration in vitro and promoted bone metastases in vivo. Furthermore, specific siRNA-induced knockdown of MGr1-Ag expression in SBC-5 cells suppressed the potential of cell invasion and migration in vitro and dramatically decreased the number and sites of bone metastasis in vivo. We also found that MGr1-Ag induced SCLC cells to undergo epithelial-mesenchymal transition (EMT), as demonstrated by cell morphological changes, decreased expression of epithelial markers and increased expression of mesenchymal markers. Taken together, we conclude that MGr1-Ag promotes SCLC cell invasion and bone metastasis in vitro and in vivo, and that this is partially mediated via the EMT pathway.
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Affiliation(s)
- Feng Zhang
- Department of Oncology, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, PR China
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The role and clinical implications of microRNAs in hepatocellular carcinoma. SCIENCE CHINA-LIFE SCIENCES 2012; 55:906-19. [PMID: 23108868 DOI: 10.1007/s11427-012-4384-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Accepted: 09/11/2012] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is common and one of the most aggressive of all human cancers. Recent studies have indicated that miRNAs, a class of small noncoding RNAs that regulate gene expression post-transcriptionally, directly contribute to HCC by targeting many critical regulatory genes. Several miRNAs are involved in hepatitis B or hepatitis C virus replication and virus-induced changes, whereas others participate in multiple intracellular signaling pathways that modulate apoptosis, cell cycle checkpoints, and growth-factor-stimulated responses. When disturbed, these pathways appear to result in malignant transformation and ultimately HCC development. Recently, miRNAs circulating in the blood have acted as possible early diagnostic markers for HCC. These miRNA also could serve as indicators with respect to drug efficacy and be prognostic in HCC patients. Such biomarkers would assist stratification of HCC patients and help direct personalized therapy. Here, we summarize recent advances regarding the role of miRNAs in HCC development and progression. Our expectation is that these and ongoing studies will contribute to the understanding of the multiple roles of these small noncoding RNAs in liver tumorigenesis.
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Tang R, Kong F, Hu L, You H, Zhang P, Du W, Zheng K. Role of hepatitis B virus X protein in regulating LIM and SH3 protein 1 (LASP-1) expression to mediate proliferation and migration of hepatoma cells. Virol J 2012; 9:163. [PMID: 22897902 PMCID: PMC3459728 DOI: 10.1186/1743-422x-9-163] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2011] [Accepted: 07/10/2012] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Hepatitis B virus X protein (HBx) has been shown to be responsible for the development of hepatocellular carcinoma (HCC) caused by Hepatitis B virus infection. However, its potential effect on the progression of hepatocellular carcinoma remains yet unclear. LIM and SH3 protein 1 (LASP-1), a focal adhesion protein, is expressed in an up-regulation manner in the HCC tissues. LASP-1 plays an important role in the regulation of proliferation and migration of HCC. In this study, we investigated the effect of LASP-1 involved in HBx-related tumor progression. METHODS LASP-1 levels in the HBx stable transfected HepG2 and Huh-7 cells were detected by RT-PCR and western blot analysis. The cellular localization of LASP-1 was assessed by immunofluorescence analysis. The activity of phosphatidylinositol 3-kinase (PI3-K) pathway was demonstrated by western blot assay. The HBx-expressing cells were transfected with specific small interference RNA (siRNA) against LASP-1. The proliferation and migration ability of cells were evaluated by cell viability assay and plate clone formation assay. The migration ability of cells was detected by transwell assay and wound healing assay. RESULTS RT-PCR and western blot analysis indicated the expression of LASP-1 was increased in the stable HBx-expressing cells compared with the control cells. Immunofluorescence study revealed that the distributions of LASP-1 in HepG2-HBX cells were mainly in pseudopods and the cytoplasm while they were mainly localized in the cytoplasm of HepG2-Mock cells. The cellular localizations of LASP-1 in Huh-7-HBX cells were in the perinuclear fractions while they were mainly localized in the cytoplasm of Huh-7-Mock cells. The upregulation of LASP-1 was inhibited after treatment with LY294002, PI3-K pathway inhibitor. Overexpression of LASP-1 in the stable HBx-expressing cells enhanced the proliferation and migration ability of hepatocellular cells. siRNA-mediated LASP-1 knowdown in the stable HBx-expressing cells significantly suppressed hepatocellular cells proliferation and migration. CONCLUSIONS These results demonstrated that HBx could upregulate LASP-1 through PI3-K pathway to promote the proliferation and migration of hepatoma cells.
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Affiliation(s)
- Renxian Tang
- Department of Pathogenic biology and Laboratory of Infection and Immunology, Xuzhou Medical College, 84 West Huaihai Road, Xuzhou 221002, Jiangsu Province, China
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Arnandis T, Ferrer-Vicens I, García-Trevijano ER, Miralles VJ, García C, Torres L, Viña JR, Zaragozá R. Calpains mediate epithelial-cell death during mammary gland involution: mitochondria and lysosomal destabilization. Cell Death Differ 2012; 19:1536-48. [PMID: 22555453 DOI: 10.1038/cdd.2012.46] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Our aim was to elucidate the physiological role of calpains (CAPN) in mammary gland involution. Both CAPN-1 and -2 were induced after weaning and its activity increased in isolated mitochondria and lysosomes. CAPN activation within the mitochondria could trigger the release of cytochrome c and other pro-apoptotic factors, whereas in lysosomes it might be essential for tissue remodeling by releasing cathepsins into the cytosol. Immunohistochemical analysis localized CAPNs mainly at the luminal side of alveoli. During weaning, CAPNs translocate to the lysosomes processing membrane proteins. To identify these substrates, lysosomal fractions were treated with recombinant CAPN and cleaved products were identified by 2D-DIGE. The subunit b(2) of the v-type H(+) ATPase is proteolyzed and so is the lysosomal-associated membrane protein 2a (LAMP2a). Both proteins are also cleaved in vivo. Furthermore, LAMP2a cleavage was confirmed in vitro by addition of CAPNs to isolated lysosomes and several CAPN inhibitors prevented it. Finally, in vivo inhibition of CAPN1 in 72-h-weaned mice decreased LAMP2a cleavage. Indeed, calpeptin-treated mice showed a substantial delay in tissue remodeling and involution of the mammary gland. These results suggest that CAPNs are responsible for mitochondrial and lysosomal membrane permeabilization, supporting the idea that lysosomal-mediated cell death is a new hallmark of mammary gland involution.
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Affiliation(s)
- T Arnandis
- Departamento de Bioquímica y Biología Molecular, Fundación Investigación Hospital Clínico-INCLIVA, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
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Zhang X, You X, Wang Q, Zhang T, Du Y, Lv N, Zhang Z, Zhang S, Shan C, Ye L, Zhang X. Hepatitis B virus X protein drives multiple cross-talk cascade loops involving NF-κB, 5-LOX, OPN and Capn4 to promote cell migration. PLoS One 2012; 7:e31458. [PMID: 22355367 PMCID: PMC3280298 DOI: 10.1371/journal.pone.0031458] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2011] [Accepted: 01/08/2012] [Indexed: 01/14/2023] Open
Abstract
Hepatitis B virus X protein (HBx) plays an important role in the development of hepatocellular carcinoma (HCC). However, the mechanism remains unclear. Recently, we have reported that HBx promotes hepatoma cell migration through the upregulation of calpain small subunit 1 (Capn4). In addition, several reports have revealed that osteopontin (OPN) plays important roles in tumor cell migration. In this study, we investigated the signaling pathways involving the promotion of cell migration mediated by HBx. We report that HBx stimulates several factors in a network manner to promote hepatoma cell migration. We showed that HBx was able to upregulate the expression of osteopontin (OPN) through 5-lipoxygenase (5-LOX) in HepG2-X/H7402-X (stable HBx-transfected cells) cells. Furthermore, we identified that HBx could increase the expression of 5-LOX through nuclear factor-κB (NF-κB). We also found that OPN could upregulate Capn4 through NF-κB. Interestingly, we showed that Capn4 was able to upregulate OPN through NF-κB in a positive feedback manner, suggesting that the OPN and Capn4 proteins involving cell migration affect each other in a network through NF-κB. Importantly, NF-κB plays a crucial role in the regulation of 5-LOX, OPN and Capn4. Thus, we conclude that HBx drives multiple cross-talk cascade loops involving NF-κB, 5-LOX, OPN and Capn4 to promote cell migration. This finding provides new insight into the mechanism involving the promotion of cell migration by HBx.
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Affiliation(s)
- Xuan Zhang
- Department of Cancer Research, Key Laboratory of Molecular Microbiology and Technology of Ministry of Education, Institute for Molecular Biology, College of Life Sciences, Nankai University, Tianjin, People's Republic of China
| | - Xiaona You
- Department of Cancer Research, Key Laboratory of Molecular Microbiology and Technology of Ministry of Education, Institute for Molecular Biology, College of Life Sciences, Nankai University, Tianjin, People's Republic of China
| | - Qi Wang
- Department of Cancer Research, Key Laboratory of Molecular Microbiology and Technology of Ministry of Education, Institute for Molecular Biology, College of Life Sciences, Nankai University, Tianjin, People's Republic of China
| | - Tao Zhang
- Department of Cancer Research, Key Laboratory of Molecular Microbiology and Technology of Ministry of Education, Institute for Molecular Biology, College of Life Sciences, Nankai University, Tianjin, People's Republic of China
| | - Yumei Du
- Department of Cancer Research, Key Laboratory of Molecular Microbiology and Technology of Ministry of Education, Institute for Molecular Biology, College of Life Sciences, Nankai University, Tianjin, People's Republic of China
| | - Na Lv
- Department of Cancer Research, Key Laboratory of Molecular Microbiology and Technology of Ministry of Education, Institute for Molecular Biology, College of Life Sciences, Nankai University, Tianjin, People's Republic of China
| | - Zhao Zhang
- Department of Biochemistry, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, People's Republic of China
| | - Shuai Zhang
- Department of Cancer Research, Key Laboratory of Molecular Microbiology and Technology of Ministry of Education, Institute for Molecular Biology, College of Life Sciences, Nankai University, Tianjin, People's Republic of China
| | - Changliang Shan
- Department of Cancer Research, Key Laboratory of Molecular Microbiology and Technology of Ministry of Education, Institute for Molecular Biology, College of Life Sciences, Nankai University, Tianjin, People's Republic of China
| | - Lihong Ye
- Department of Biochemistry, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, People's Republic of China
- * E-mail: (XZ); (LY)
| | - Xiaodong Zhang
- Department of Cancer Research, Key Laboratory of Molecular Microbiology and Technology of Ministry of Education, Institute for Molecular Biology, College of Life Sciences, Nankai University, Tianjin, People's Republic of China
- * E-mail: (XZ); (LY)
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Zhao Y, Wang W, Wang Q, Zhang X, Ye L. Lipid metabolism enzyme 5-LOX and its metabolite LTB4 are capable of activating transcription factor NF-κB in hepatoma cells. Biochem Biophys Res Commun 2012; 418:647-51. [PMID: 22293202 DOI: 10.1016/j.bbrc.2012.01.068] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Accepted: 01/14/2012] [Indexed: 01/22/2023]
Abstract
The issue that lipid metabolism enzyme and its metabolites regulate transcription factors in cancer cell is not fully understood. In this study, we first report that the lipid metabolism enzyme 5-Lipoxygenase (5-LOX) and its metabolite leukotriene B4 (LTB4) are capable of activating nuclear factor-κB (NF-κB) in hepatoma cells. We found that the treatment of MK886 (an inhibitor of 5-LOX) or knockdown of 5-LOX was able to downregulate the expression of NF-κB p65 at the mRNA level and decreased the phosphorylation level of inhibitor κBα (IκBα) in the cytoplasm of hepatoma HepG2 or H7402 cells, which resulted in the decrease of the level of nuclear NF-κB p65. These were confirmed by immunofluorescence staining in HepG2 cell. Moreover, the above treatments were able to decrease the transcriptional activity of NF-κB in the cells. The LTB4, one of metabolites of 5-LOX, is responsible for 5-LOX-activated NF-κB in a dose-dependent manner. Thus, we conclude that the lipid metabolism enzyme 5-LOX and its metabolite LTB4 are capable of activating transcription factor NF-κB in hepatoma cells. Our finding provides new insight into the significance of lipid metabolism in activation of transcription factors in cancer.
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Affiliation(s)
- Yu Zhao
- Department of Biochemistry, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
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Fan H, Ye Y, Luo Y, Tong T, Yan G, Liao M. Quantitative Proteomics Using Stable Isotope Labeling with Amino Acids in Cell Culture Reveals Protein and Pathway Regulation in Porcine Circovirus Type 2 Infected PK-15 Cells. J Proteome Res 2011; 11:995-1008. [DOI: 10.1021/pr200755d] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Huiying Fan
- MOA Key Laboratory for Animal Vaccine Development, Guangzhou 510642, China
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642,
China
| | - Yu Ye
- MOA Key Laboratory for Animal Vaccine Development, Guangzhou 510642, China
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642,
China
| | - Yongwen Luo
- MOA Key Laboratory for Animal Vaccine Development, Guangzhou 510642, China
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642,
China
| | - Tiezhu Tong
- Huizhou Entry-Exit Inspection and Quarantine Bureau, Huizhou 516001, China
| | - Guangrong Yan
- Institute of Life and Health
Engineering and National Engineering and Research Center for Genetic
Medicine, Jinan University, Guangzhou 510632,
China
| | - Ming Liao
- MOA Key Laboratory for Animal Vaccine Development, Guangzhou 510642, China
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642,
China
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Lai Y, Riley K, Cai A, Leong JM, Herman IM. Calpain mediates epithelial cell microvillar effacement by enterohemorrhagic Escherichia coli. Front Microbiol 2011; 2:222. [PMID: 22073041 PMCID: PMC3210503 DOI: 10.3389/fmicb.2011.00222] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Accepted: 10/20/2011] [Indexed: 11/13/2022] Open
Abstract
A member of the attaching and effacing (AE) family of pathogens, enterohemorrhagic Escherichia coli (EHEC) induces dramatic changes to the intestinal cell cytoskeleton, including effacement of microvilli. Effacement by the related pathogen enteropathogenic E. coli (EPEC) requires the activity of the Ca+2-dependent host protease, calpain, which participates in a variety of cellular processes, including cell adhesion and motility. We found that EHEC infection results in an increase in epithelial (CaCo-2a) cell calpain activity and that EHEC-induced microvillar effacement was blocked by ectopic expression of calpastatin, an endogenous calpain inhibitor, or by pretreatment of intestinal cells with a cell-penetrating version of calpastatin. In addition, ezrin, a known calpain substrate that links the plasma membrane to axial actin filaments in microvilli, was cleaved in a calpain-dependent manner during EHEC infection and lost from its normal locale within microvilli. Calpain may be a central conduit through which EHEC and other AE pathogens induce enterocyte cytoskeletal remodeling and exert their pathogenic effects.
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Affiliation(s)
- Yushuan Lai
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School Worcester, MA, USA
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Upregulated microRNA-29a by hepatitis B virus X protein enhances hepatoma cell migration by targeting PTEN in cell culture model. PLoS One 2011; 6:e19518. [PMID: 21573166 PMCID: PMC3088678 DOI: 10.1371/journal.pone.0019518] [Citation(s) in RCA: 146] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Accepted: 04/06/2011] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B virus X protein (HBx) plays important roles in the development of hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) contribute to cancer development by acting as oncogenes or tumor suppressors. Previously, we reported that HBx was able to promote the migration of hepatoma HepG2 cells. However, the regulation of miRNAs in the development of HBV-related HCC is poorly understood. In the present study, we reported that miR-29a was a novel regulator of migration of hepatoma cells mediated by HBx. Our data showed that the expression of miR-29a was dramatically increased in p21-HBx transgenic mice, HBx-transfected hepatoma HepG2-X (or H7402-X) cells and HepG2.2.15 cells that constitutively replicate HBV. However, our data showed that miR-29a was upregulated in 4 of the 11 clinical HCC samples. We found that the overexpression of miR-29a promoted the migration of HepG2 cells, while a specific miR-29a inhibitor could partially abolish the enhanced migration of HepG2-X cells. Moreover, we identified PTEN was one of the target genes of miR-29a in HepG2 cells. The deletion of the miR-29a-binding site was able to abolish the role of miR-29a in suppression of luciferase activity of the PTEN 3'UTR reporter. Meanwhile, the overexpression of PTEN was able to reverse the promoted migration of HepG2 cells mediated by miR-29a. Moreover, our data showed that the modulation of Akt phosphorylation, a downstream factor of PTEN, was involved in the cell migration enhanced by miR-29a, suggesting that miR-29a is responsible for the cell migration through its target gene PTEN. Thus, we conclude that miR-29a is involved in the regulation of migration of hepatoma cells mediated by HBx through PTEN in cell culture model.
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Luedde T, Schwabe RF. NF-κB in the liver--linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2011; 8:108-18. [PMID: 21293511 PMCID: PMC3295539 DOI: 10.1038/nrgastro.2010.213] [Citation(s) in RCA: 1064] [Impact Index Per Article: 76.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatic cirrhosis and hepatocellular carcinoma (HCC) are the most common causes of death in patients with chronic liver disease. Chronic liver injury of virtually any etiology triggers inflammatory and wound-healing responses that in the long run promote the development of hepatic fibrosis and HCC. Here, we review the role of the transcription factor nuclear factor-κB (NF-κB), a master regulator of inflammation and cell death, in the development of hepatocellular injury, liver fibrosis and HCC, with a particular focus on the role of NF-κB in different cellular compartments of the liver. We propose that NF-κB acts as a central link between hepatic injury, fibrosis and HCC, and that it may represent a target for the prevention or treatment of liver fibrosis and HCC. However, NF-κB acts as a two-edged sword and inhibition of NF-κB may not only exert beneficial effects but also negatively impact hepatocyte viability, especially when NF-κB inhibition is pronounced. Finding appropriate targets or identifying drugs that either exert only a moderate effect on NF-κB activity or that can be specifically delivered to nonparenchymal cells will be essential to avoid the increase in liver injury associated with complete NF-κB blockade in hepatocytes.
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