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Chen H, Li YY, Nio K, Tang H. Unveiling the Impact of BMP9 in Liver Diseases: Insights into Pathogenesis and Therapeutic Potential. Biomolecules 2024; 14:1013. [PMID: 39199400 PMCID: PMC11353080 DOI: 10.3390/biom14081013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 08/08/2024] [Accepted: 08/13/2024] [Indexed: 09/01/2024] Open
Abstract
Bone morphogenetic proteins (BMPs) are a group of growth factors belonging to the transforming growth factor β(TGF-β) family. While initially recognized for their role in bone formation, BMPs have emerged as significant players in liver diseases. Among BMPs with various physiological activities, this comprehensive review aims to delve into the involvement of BMP9 specifically in liver diseases and provide insights into the complex BMP signaling pathway. Through an enhanced understanding of BMP9, we anticipate the discovery of new therapeutic options and potential strategies for managing liver diseases.
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Affiliation(s)
- Han Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China;
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Ying-Yi Li
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa 9208641, Japan;
| | - Kouki Nio
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa 9208641, Japan;
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China;
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
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Zhang F, Hu K, Liu W, Quan B, Li M, Lu S, Chen R, Ren Z, Yin X. Oxaliplatin-Resistant Hepatocellular Carcinoma Drives Immune Evasion Through PD-L1 Up-Regulation and PMN-Singular Recruitment. Cell Mol Gastroenterol Hepatol 2023; 15:573-591. [PMID: 36513250 PMCID: PMC9868681 DOI: 10.1016/j.jcmgh.2022.12.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 12/06/2022] [Accepted: 12/06/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Previously, we showed the inhibitor of differentiation or DNA binding 1 (ID1)/Myc signaling is highly expressed in oxaliplatin-resistant hepatocellular carcinoma (HCC). This study sought to investigate the role of ID1/Myc signaling on immune evasion in oxaliplatin-resistant HCC. METHODS The oxaliplatin (OXA)-resistant HCC cell lines (Hepa 1-6-OXA, 97H-OXA, and 3B-OXA) were established and their oxaliplatin tolerance was confirmed in vitro and in vivo. The relationship between ID1/Myc and programmed death-ligand 1 (PD-L1) up-regulation and polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) accumulation was explored. The underlying mechanism in which ID1/Myc signaling regulated PD-L1 expression and PMN-MDSC accumulation was investigated in vitro and vivo. RESULTS Increased ID1/Myc expression was identified in oxaliplatin-resistant HCC and correlated with PD-L1 up-regulation and PMN-MDSC accumulation. The knockdown of Myc sensitized oxaliplatin-resistant HCC cells to oxaliplatin and resulted in a decrease of PMN-MDSCs and an increase of interferon-γ+ CD8+ T cells in a tumor microenvironment. Polymerase chain reaction array, enzyme-linked immunosorbent assay, and MDSC Transwell migration assay indicated that oxaliplatin-resistant HCC cells recruited PMN-MDSCs through chemokine (C-C motif) ligand 5 (CCL5). The dual luciferase reporter assay and chromatin immunoprecipitation assay indicated that Myc could directly increase the transcriptions of PD-L1 and CCL5. Furthermore, anti-PD-L1 antibody combined with CCL5 blockade showed significant antitumor effects in oxaliplatin-resistant HCC. CONCLUSIONS ID1/Myc signaling drives immune evasion in oxaliplatin-resistant HCC via PD-L1 up-regulation and PMN-MDSC recruitment. Blocking the ID1/Myc-induced immune tolerance represents a promising treatment target to conquer chemoresistance in HCC.
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Affiliation(s)
- Feng Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Keshu Hu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wenfeng Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bing Quan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Miao Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shenxin Lu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Rongxin Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhenggang Ren
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xin Yin
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
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Huang YJ, Cao J, Lee CY, Wu YM. Umbilical cord blood plasma-derived exosomes as a novel therapy to reverse liver fibrosis. Stem Cell Res Ther 2021; 12:568. [PMID: 34772443 PMCID: PMC8588641 DOI: 10.1186/s13287-021-02641-x] [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: 07/11/2021] [Accepted: 10/28/2021] [Indexed: 02/08/2023] Open
Abstract
Background Cirrhosis is a chronic liver disease whereby scar tissue replaces healthy liver parenchyma, leading to disruption of the liver architecture and hepatic dysfunction. Currently, there is no effective disease-modifying therapy for liver fibrosis. Recently, our group demonstrated that human umbilical cord blood (UCB) plasma possesses therapeutic effects in a rat model of acute liver failure. Methods In the current study, we tested whether exosomes (Exo) existed in UCB plasma and if they produced any antifibrotic benefits in a liver fibrosis model. Results Our results showed that UCB-Exo improved liver function and increased matrix metalloproteinase/tissue inhibitor of metalloproteinase degradation to reduce the degree of fibrosis. Moreover, UCB-Exo were found to suppress hepatic stellate cell (HSC) activity in vitro. These effects were associated with suppression of transforming growth factor-β/inhibitor of DNA binding 1 signaling. Conclusions These results further support that UCB-Exo have antifibrotic effects in mice with liver fibrosis and activated HSCs and may herald a new cell-free antifibrotic therapy.
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Affiliation(s)
- Yu-Jen Huang
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Jerry Cao
- Department of Surgery, Wollongong Hospital, Loftus Street, Wollongong, NSW, 2500, Australia
| | - Chih-Yuan Lee
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Yao-Ming Wu
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan. .,Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Chung-Shan South Road, Taipei, Taiwan.
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Wojnarowicz PM, Escolano MG, Huang YH, Desai B, Chin Y, Shah R, Xu S, Yadav S, Yaklichkin S, Ouerfelli O, Soni RK, Philip J, Montrose DC, Healey JH, Rajasekhar VK, Garland WA, Ratiu J, Zhuang Y, Norton L, Rosen N, Hendrickson RC, Zhou XK, Iavarone A, Massague J, Dannenberg AJ, Lasorella A, Benezra R. Anti-tumor effects of an ID antagonist with no observed acquired resistance. NPJ Breast Cancer 2021; 7:58. [PMID: 34031428 PMCID: PMC8144414 DOI: 10.1038/s41523-021-00266-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 04/15/2021] [Indexed: 12/19/2022] Open
Abstract
ID proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. ID proteins inhibit basic-HLH transcription factors often blocking differentiation and sustaining proliferation. A small-molecule, AGX51, targets ID proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impairs cell growth and viability that results from an increase in reactive oxygen species (ROS) production upon ID degradation. In mouse models, AGX51 treatment suppresses breast cancer colonization in the lung, regresses the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduces tumor burden in sporadic colorectal neoplasia. Furthermore, in cells and mice, we fail to observe acquired resistance to AGX51 likely the result of the inability to mutate the binding pocket without loss of ID function and efficient degradation of the ID proteins. Thus, AGX51 is a first-in-class compound that antagonizes ID proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.
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Affiliation(s)
- Paulina M Wojnarowicz
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Marta Garcia Escolano
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yun-Han Huang
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell/Sloan Kettering/Rockefeller Tri-Institutional MD-PhD Program, New York, NY, 10065, USA
- Gerstner Sloan Kettering Graduate School of Biomedical Sciences, New York, NY, 10065, USA
| | - Bina Desai
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yvette Chin
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Riddhi Shah
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sijia Xu
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Saurabh Yadav
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sergey Yaklichkin
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ouathek Ouerfelli
- Organic Synthesis Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rajesh Kumar Soni
- Proteomics & Microchemistry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - John Philip
- Proteomics & Microchemistry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - David C Montrose
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - John H Healey
- Orthopedics Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | | | - Jeremy Ratiu
- Department of Immunology, Duke University, Durham, NC, USA
| | - Yuan Zhuang
- Department of Immunology, Duke University, Durham, NC, USA
| | - Larry Norton
- Evelyn H. Lauder Breast Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Neal Rosen
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ronald C Hendrickson
- Proteomics & Microchemistry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Xi Kathy Zhou
- Department of Healthcare Policy and Research Weill Cornell Medical College, New York, NY, USA
| | - Antonio Iavarone
- Department of Neurology, Department of Pathology, Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA
| | - Joan Massague
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Anna Lasorella
- Department of Pediatrics, Department of Pathology, Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA
| | - Robert Benezra
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Zhao Z, Bo Z, Gong W, Guo Y. Inhibitor of Differentiation 1 (Id1) in Cancer and Cancer Therapy. Int J Med Sci 2020; 17:995-1005. [PMID: 32410828 PMCID: PMC7211148 DOI: 10.7150/ijms.42805] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 03/20/2020] [Indexed: 02/07/2023] Open
Abstract
The inhibitor of DNA binding (Id) proteins are regulators of cell cycle and cell differentiation. Of all Id family proteins, Id1 is mostly linked to tumorigenesis, cellular senescence as well as cell proliferation and survival. Id1 is a stem cell-like gene more than a classical oncogene. Id1 is overexpressed in numerous types of cancers and exerts its promotion effect to these tumors through different pathways. Briefly, Id1 was found significantly correlated with EMT-related proteins, K-Ras signaling, EGFR signaling, BMP signaling, PI3K/Akt signaling, WNT and SHH signaling, c-Myc signaling, STAT3 signaling, RK1/2 MAPK/Egr1 pathway and TGF-β pathway, etc. Id1 has potent effect on facilitating tumorous angiogenesis and metastasis. Moreover, high expression of Id1 plays a facilitating role in the development of drug resistance, including chemoresistance, radiation resistance and resistance to drugs targeting angiogenesis. However, controversial results were also obtained. Overall, Id1 represent a promising target of anti-tumor therapeutics based on its potent promotion effect to cancer. Numerous drugs were found exerting their anti-tumor function through Id1-related signaling pathways, such as fucoidan, berberine, tetramethylpyrazine, crizotinib, cannabidiol and vinblastine.
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Affiliation(s)
- Zhengxiao Zhao
- Department of Oncology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, China
| | - Zhiyuan Bo
- The Second Department of Biliary Tract Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China
| | - Weiyi Gong
- The Department of Integrative Medicine, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 200040, PR China
| | - Yong Guo
- Department of Oncology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, China
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CCN2-MAPK-Id-1 loop feedback amplification is involved in maintaining stemness in oxaliplatin-resistant hepatocellular carcinoma. Hepatol Int 2019; 13:440-453. [PMID: 31250351 PMCID: PMC6661033 DOI: 10.1007/s12072-019-09960-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 06/11/2019] [Indexed: 12/24/2022]
Abstract
Background Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Chemotherapy is an alternative treatment for advanced HCCs, but chemo-resistance prevents cancer therapies from achieving stable and complete responses. Understanding the underlying mechanisms in chemo-resistance is critical to improve the efficacy of HCC. Methods The expression levels of Id-1 and CCN2 were detected in large cohorts of HCCs, and functional analyses of Id-1 and CCN2 were performed both in vitro and in vivo. cDNA microarrays were performed to evaluate the alterations of expression profiling of HCC cells with overexpression of CCN2. Finally, the role of downstream signaling of MAPK/Id-1 signaling pathway in oxaliplatin resistance were also explored. Results The increased expression of Id-1 and CCN2 were closely related to oxaliplatin resistance in HCC. Upregulation of CCN2 and Id-1 was independently associated with shorter survival and increased recurrence in HCC patients, and significantly enhanced oxaliplatin resistance and promoted lung metastasis in vivo, whereas knock-down of their expression significantly reversed the chemo-resistance and inhibited HCC cell stemness. cDNA microarrays and PCR revealed that Id-1 and MAPK pathway were the downstream signaling of CCN2. CCN2 significantly enhanced oxaliplatin resistance by activating the MAPK/Id-1 signaling pathway, and Id-1 could upregulate CCN2 in a positive feedback manner. Conclusions CCN2/MAPK/Id-1 loop feedback amplification is involved in oxaliplatin resistance, and the combination of oxaliplatin with inhibitor of CCN2 or MAPK signaling could provide a promising approach to ameliorating oxaliplatin resistance in HCC. Electronic supplementary material The online version of this article (10.1007/s12072-019-09960-5) contains supplementary material, which is available to authorized users.
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Polyamine flux suppresses histone lysine demethylases and enhances ID1 expression in cancer stem cells. Cell Death Discov 2018; 4:104. [PMID: 30455990 PMCID: PMC6234213 DOI: 10.1038/s41420-018-0117-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/09/2018] [Accepted: 10/16/2018] [Indexed: 01/08/2023] Open
Abstract
Cancer stem cells (CSCs) exhibit tumorigenic potential and can generate resistance to chemotherapy and radiotherapy. A labeled ornithine decarboxylase (ODC, a rate-limiting enzyme involved in polyamine [PA] biosynthesis) degradation motif (degron) system allows visualization of a fraction of CSC-like cells in heterogeneous tumor populations. A labeled ODC degradation motif system allowed visualization of a fraction of CSC-like cells in heterogeneous tumor populations. Using this system, analysis of polyamine flux indicated that polyamine metabolism is active in CSCs. The results showed that intracellular polyamines inhibited the activity of histone lysine 4 demethylase enzymes, including lysine-specific demethylase-1 (LSD1). Chromatin immunoprecipitation with Pol II antibody followed by massively parallel DNA sequencing, revealed the global enrichment of Pol II in transcription start sites in CSCs. Increase of polyamines within cells resulted in an enhancement of ID1 gene expression. The results of this study reveal details of metabolic pathways that drive epigenetic control of cancer cell stemness and determine effective therapeutic targets in CSCs.
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Jiang K, Centeno BA. Primary Liver Cancers, Part 2: Progression Pathways and Carcinogenesis. Cancer Control 2018; 25:1073274817744658. [PMID: 29353494 PMCID: PMC5933573 DOI: 10.1177/1073274817744658] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) and primary intrahepatic cholangiocarcinoma (ICC) have been increasing in incidence worldwide and are leading causes of cancer death. Studies of the molecular alterations leading to these carcinomas provide insights into the key mechanisms involved. A literature review was conducted to identify articles with information relevant to current understanding of the etiologies and molecular pathogenesis of HCC and ICC. Chronic inflammatory diseases are the key etiological risk factors for both HCC and ICC, although other diseases play a role, and for many ICCs, an underlying risk factor is not identified. Mutations in catenin beta 1 ( CTNBB1) and tumor protein 53 (P53) are the main genetic alterations in HCC. Isocitrate dehydrogenases 1 and 2 (IDH1/2), KRAS protooncogene GTPase (KRAS), a RAS Viral Oncogene Homolog in neoroblastoma (NRAS) and P53 are primary genetic alterations in ICC. In both diseases, the mutational landscape is dependent on the underlying etiology. The most significant etiologies and genetic processes involved in the carcinogenesis of HCC and ICC are reviewed.
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Affiliation(s)
- Kun Jiang
- 1 Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL, USA.,2 Department of Oncologic Sciences, Morsani College of Medicine at University of South Florida, Tampa, FL, USA
| | - Barbara A Centeno
- 1 Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL, USA.,2 Department of Oncologic Sciences, Morsani College of Medicine at University of South Florida, Tampa, FL, USA
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Role of Glypican-3 in the growth, migration and invasion of primary hepatocytes isolated from patients with hepatocellular carcinoma. Cell Oncol (Dordr) 2017; 41:169-184. [PMID: 29204978 DOI: 10.1007/s13402-017-0364-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2017] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Recently, Glypican-3 (GPC3) has been identified as a potential hepatocellular carcinoma (HCC) diagnostic and/or therapeutic target. GPC3 has been found to be up-regulated in HCC and to be absent in normal and cirrhotic liver. As yet, however, the molecular characteristics of GPC3 and its role in HCC cell physiology and development are still undefined. METHODS Human hepatocyte cultures were established from 10 HCC patients. Additional liver samples were obtained from 5 patients without cirrhosis and/or HCC. Soft agar colony formation, (co-)immunofluorescence and Western blot assays were used to characterize the hapatocyte cultures. The expression of GPC3 in the hepatocytes was silenced using siRNA, after which, apoptosis, scratch wound migration and transwell invasion assays were performed. RESULTS We found that in HCC precursor hepatocytes GPC3 is increasingly expressed in different forms and at different locations, i.e., a non-cleaved form (70 kDa) was found to be localized in the cytoplasm while a N-terminal cleaved form (N-GPC3: 40 kDa) was fond to be localized in the cytoplasm and at the extracellular side of hepatocyte membranes. In addition, we found that the non-cleaved form of GPC3 co-localizes with Furin-Convertase in the Golgi apparatus. We also found that, similar to GPC3, Furin-Convertase is expressed in HCC precursor cells, suggesting a role in GPC3 processing. Subsequent siRNA-mediated GPC3 silencing resulted in a temporary inhibition of cell proliferation, migration and ivasion, while inducing apoptosis in transformed hepatocytes. CONCLUSION Our data reveal new aspects of the role of GPC3 in early hepatocyte transformation. In addition we conclude that GPC3 may serve as a new HCC immune-therapeutic target.
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Abstract
Inhibitors of DNA binding and cell differentiation (Id) proteins are members of the large family of the helix-loop-helix (HLH) transcription factors, but they lack any DNA-binding motif. During development, the Id proteins play a key role in the regulation of cell-cycle progression and cell differentiation by modulating different cell-cycle regulators both by direct and indirect mechanisms. Several Id-protein interacting partners have been identified thus far, which belong to structurally and functionally unrelated families, including, among others, the class I and II bHLH transcription factors, the retinoblastoma protein and related pocket proteins, the paired-box transcription factors, and the S5a subunit of the 26 S proteasome. Although the HLH domain of the Id proteins is involved in most of their protein-protein interaction events, additional motifs located in their N-terminal and C-terminal regions are required for the recognition of diverse protein partners. The ability of the Id proteins to interact with structurally different proteins is likely to arise from their conformational flexibility: indeed, these proteins contain intrinsically disordered regions that, in the case of the HLH region, undergo folding upon self- or heteroassociation. Besides their crucial role for cell-fate determination and cell-cycle progression during development, other important cellular events have been related to the Id-protein expression in a number of pathologies. Dysregulated Id-protein expression has been associated with tumor growth, vascularization, invasiveness, metastasis, chemoresistance and stemness, as well as with various developmental defects and diseases. Herein we provide an overview on the structural properties, mode of action, biological function and therapeutic potential of these regulatory proteins.
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Affiliation(s)
- Cornelia Roschger
- Department of Molecular Biology, University of Salzburg, Billrothstrasse 11, Salzburg, 5020, Austria
| | - Chiara Cabrele
- Department of Molecular Biology, University of Salzburg, Billrothstrasse 11, Salzburg, 5020, Austria.
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Roschger C, Cabrele C. The Id-protein family in developmental and cancer-associated pathways. Cell Commun Signal 2017; 15:7. [PMID: 28122577 PMCID: PMC5267474 DOI: 10.1186/s12964-016-0161-y] [Citation(s) in RCA: 135] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 12/29/2016] [Indexed: 01/15/2023] Open
Abstract
Inhibitors of DNA binding and cell differentiation (Id) proteins are members of the large family of the helix-loop-helix (HLH) transcription factors, but they lack any DNA-binding motif. During development, the Id proteins play a key role in the regulation of cell-cycle progression and cell differentiation by modulating different cell-cycle regulators both by direct and indirect mechanisms. Several Id-protein interacting partners have been identified thus far, which belong to structurally and functionally unrelated families, including, among others, the class I and II bHLH transcription factors, the retinoblastoma protein and related pocket proteins, the paired-box transcription factors, and the S5a subunit of the 26 S proteasome. Although the HLH domain of the Id proteins is involved in most of their protein-protein interaction events, additional motifs located in their N-terminal and C-terminal regions are required for the recognition of diverse protein partners. The ability of the Id proteins to interact with structurally different proteins is likely to arise from their conformational flexibility: indeed, these proteins contain intrinsically disordered regions that, in the case of the HLH region, undergo folding upon self- or heteroassociation. Besides their crucial role for cell-fate determination and cell-cycle progression during development, other important cellular events have been related to the Id-protein expression in a number of pathologies. Dysregulated Id-protein expression has been associated with tumor growth, vascularization, invasiveness, metastasis, chemoresistance and stemness, as well as with various developmental defects and diseases. Herein we provide an overview on the structural properties, mode of action, biological function and therapeutic potential of these regulatory proteins.
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Affiliation(s)
- Cornelia Roschger
- Department of Molecular Biology, University of Salzburg, Billrothstrasse 11, Salzburg, 5020, Austria
| | - Chiara Cabrele
- Department of Molecular Biology, University of Salzburg, Billrothstrasse 11, Salzburg, 5020, Austria.
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BMP4 promotes metastasis of hepatocellular carcinoma by an induction of epithelial-mesenchymal transition via upregulating ID2. Cancer Lett 2017; 390:67-76. [PMID: 28093286 DOI: 10.1016/j.canlet.2016.12.042] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Revised: 12/23/2016] [Accepted: 12/24/2016] [Indexed: 12/12/2022]
Abstract
The role of bone morphogenetic protein 4 (BMP4), a crucial epithelial-mesenchymal transition (EMT) mediator, in the progression of hepatocellular carcinoma (HCC) patients heretofore has not been elucidated. The present study analyzed BMP4 expression in tumors and paired non-tumorous liver tissue and its correlation with clinicopathological characteristics from two independent cohorts consisting of 420 HCC patients. Functional analysis of BMP4 was performed in Bel-7402 and HCCLM3 HCC cells, and in a murine HCC model. The downstream targets of BMP4 in HCC were screened and confirmed. The results indicated that BMP4 expression was significantly increased in HCC tissue and highly metastatic HCC cells. BMP4 expression was correlated with vein invasion, overall survival and recurrence-free survival of HCC. BMP4 promoted HCC EMT and metastasis in vitro, and consistently in vivo. BMP4 knockdown blocked EMT and tumor metastasis in nude mice. ID2 was up-regulated by recombinant human BMP4, resulting in HCC EMT. Knockdown of ID2 blocked BMP4-induced EMT. In conclusion, BMP4 promotes invasion and metastasis of HCC by an induction of EMT via up-regulating ID2. BMP4 may be a valuable prognostic factor and potential therapeutic target for HCC therapy.
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Bi J, Ge S. Potential roles of BMP9 in liver fibrosis. Int J Mol Sci 2014; 15:20656-67. [PMID: 25393508 PMCID: PMC4264188 DOI: 10.3390/ijms151120656] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 10/13/2014] [Accepted: 11/04/2014] [Indexed: 02/07/2023] Open
Abstract
Liver fibrosis is a common phenomenon that is associated with several pathologies and is characterized by excessive extracellular matrix deposition that leads to progressive liver dysfunction. Bone morphogenetic protein 9 (BMP9) is the most recently discovered member of the BMP family. BMP9 bound with high affinity to activin receptor-like kinase 1 (ALK1) and endoglin in non-parenchymal liver cells. In addition, BMP9 activated Smad1/Smad5/Smad8 and induced the expression of the target genes inhibitor of differentiation 1 (Id1), hepcidin, Snail and the co-receptor endoglin in liver cells. Although the role of BMP9 in liver fibrosis is currently poorly understood, the presence of BMP9-activated proteins and its target genes have been reported to be associated with liver fibrosis development. This review summarizes the indirect connection between BMP9 and liver fibrosis, with a focus on the BMP9 signaling pathway members ALK1, endoglin, Id1, hepcidin and Snail. The observations on the role of BMP9 in regulating liver fibrosis may help in understanding the pathology mechanisms of liver disease. Furthermore, BMP9 could be served as a potent biomarker and the target of potential therapeutic drugs to treat hepatocytes fibrosis.
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Affiliation(s)
- Jianjun Bi
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
| | - Shengfang Ge
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
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14
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ID proteins regulate diverse aspects of cancer progression and provide novel therapeutic opportunities. Mol Ther 2014; 22:1407-1415. [PMID: 24827908 DOI: 10.1038/mt.2014.83] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Accepted: 04/28/2014] [Indexed: 12/12/2022] Open
Abstract
The inhibitor of differentiation (ID) proteins are helix-loop-helix transcriptional repressors with established roles in stem cell self-renewal, lineage commitment, and niche interactions. While deregulated expression of ID proteins in cancer was identified more than a decade ago, emerging evidence has revealed a central role for ID proteins in neoplastic progression of multiple tumor types that often mirrors their function in physiological stem and progenitor cells. ID proteins are required for the maintenance of cancer stem cells, self-renewal, and proliferation in a range of malignancies. Furthermore, ID proteins promote metastatic dissemination through their role in remodeling the tumor microenvironment and by promoting tumor-associated endothelial progenitor cell proliferation and mobilization. Here, we discuss the latest findings in this area and the clinical opportunities that they provide.
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15
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Lasorella A, Benezra R, Iavarone A. The ID proteins: master regulators of cancer stem cells and tumour aggressiveness. Nat Rev Cancer 2014; 14:77-91. [PMID: 24442143 DOI: 10.1038/nrc3638] [Citation(s) in RCA: 281] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Inhibitor of DNA binding (ID) proteins are transcriptional regulators that control the timing of cell fate determination and differentiation in stem and progenitor cells during normal development and adult life. ID genes are frequently deregulated in many types of human neoplasms, and they endow cancer cells with biological features that are hijacked from normal stem cells. The ability of ID proteins to function as central 'hubs' for the coordination of multiple cancer hallmarks has established these transcriptional regulators as therapeutic targets and biomarkers in specific types of human tumours.
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Affiliation(s)
- Anna Lasorella
- Institute for Cancer Genetics, Department of Pathology and Pediatrics, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, 10032 New York, USA
| | - Robert Benezra
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 241, New York, 10065 New York, USA
| | - Antonio Iavarone
- Institute for Cancer Genetics, Department of Pathology and Neurology, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, 10032 New York, USA
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16
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Harder J, Müller MJ, Fuchs M, Gumpp V, Schmitt-Graeff A, Fischer R, Frank M, Opitz O, Hasskarl J. Inhibitor of differentiation proteins do not influence prognosis of biliary tract cancer. World J Gastroenterol 2013; 19:9334-9342. [PMID: 24409060 PMCID: PMC3882406 DOI: 10.3748/wjg.v19.i48.9334] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Revised: 08/15/2013] [Accepted: 09/29/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression and clinical relevance of inhibitor of differentiation (ID) proteins in biliary tract cancer.
METHODS: ID protein expression was analyzed in 129 samples from patients with advanced biliary tract cancer (BTC) (45 extrahepatic, 50 intrahepatic, and 34 gallbladder cancers), compared to normal controls and correlated with clinical an pathological parameters.
RESULTS: ID1-3 proteins are frequently overexpressed in all BTC subtypes analyzed. No correlation between increased ID protein expression and tumor grading, tumor subtype or treatment response was detected. Survival was influenced primary tumor localization (extrahepatic vs intrahepatic and gall bladder cancer, OS 1.5 years vs 0.9 years vs 0.7 years, P = 0.002), by stage at diagnosis (OS 2.7 years in stage I vs 0.6 years in stage IV, P < 0.001), resection status and response to systemic chemotherapy. In a multivariate model, ID protein expression did not correlate with clinical prognosis. Nevertheless, there was a trend of shorter OS in patients with loss of cytoplasmic ID4 protein expression (P = 0.076).
CONCLUSION: ID protein expression is frequently deregulated in BTC but does not influence clinical prognosis. Their usefulness as prognostic biomarkers in BTC is very limited.
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17
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Matsuda Y, Wakai T, Kubota M, Takamura M, Yamagiwa S, Aoyagi Y, Osawa M, Fujimaki S, Sanpei A, Genda T, Ichida T. Clinical significance of cell cycle inhibitors in hepatocellular carcinoma. Med Mol Morphol 2013; 46:185-92. [PMID: 23640750 DOI: 10.1007/s00795-013-0047-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Accepted: 04/03/2013] [Indexed: 01/11/2023]
Abstract
It is well accepted that cell cycle regulators are strongly implicated in the progression of cancer development. p16 and p27 are potent cyclin-dependent kinase (CDK) inhibitors involved in G1 phase progression, and are regarded as adverse prognostic biomarkers for various types of cancers. It has been reported that the main mechanism for p16 inactivation is aberrant DNA methylation, while p27 is exclusively inactivated by proteasome-mediated protein degradation. We have found that p27 is decreased in around half of hepatocellular carcinomas (HCCs), and in some cases p27 is inactivated by inappropriate interaction with cyclin D1/CDK4 complexes. In such cases, p16 is concomitantly inactivated through DNA methylation. Taking into consideration the complex interaction between p16 and p27, a comprehensive analysis including p16 and p27 would be useful for predicting the prognosis of HCC patients.
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Affiliation(s)
- Yasunobu Matsuda
- Department of Medical Technology, Niigata University Graduate School of Health Sciences, 2-746 Asahimachi-dori, Niigata, 951-8518, Japan,
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18
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Tsunedomi R, Iizuka N, Harada S, Oka M. Susceptibility of hepatoma-derived cells to histone deacetylase inhibitors is associated with ID2 expression. Int J Oncol 2013; 42:1159-66. [PMID: 23403953 PMCID: PMC3622658 DOI: 10.3892/ijo.2013.1811] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Accepted: 12/05/2012] [Indexed: 12/28/2022] Open
Abstract
Downregulation of inhibitor of DNA binding 2 (ID2) is associated with poor prognosis in cases of hepatocellular carcinoma (HCC). Therefore, to search for effective antitumor drugs for the treatment of HCC exhibiting poor prognostic indicators, we used two HCC-derived cell lines (HuH-7 and HLE) to alter ID2 levels. Specifically, ID2 expression was knocked down in HuH-7 cells via transfection with ID2-specific small interfering RNAs and separately ID2 was overexpressed in HLE cells via an ID2 expression plasmid vector. To assess the effect of antitumor drugs, MTS assay was performed. Annexin V staining was used to evaluate apoptosis and real-time RT-PCR was used to measure mRNA levels. ID2 knockdown cells were more susceptible to histone deacethylase (HDAC) inhibitors including sodium butyrate (NaB), sodium 4-phenyl-butyrate, tricostatin A, suberoylanilide hydroxamic acid, MS-275, apicidin and HC-toxin. Conversely, cells that overexpressed ID2 were less susceptible than control cells to HDAC inhibitors. NaB-induced apoptosis was inversely correlated with ID2 expression. Expression of the anti-apoptotic mRNA BCL2 was induced by NaB in control cells, but this induction of BCL2 was inhibited by ID2 knockdown and strengthened by ID2 overexpression. Expression of another anti-apoptotic mRNA, BCL2L1, was decreased by NaB administration and then partially recovered. However, in ID2 knockdown cells, BCL2L1 levels did not recover from NaB-induced suppression. ID2 affected the susceptibility of two HCC-derived cell lines to an HDAC inhibitor by regulating the expression of anti-apoptotic genes. Therefore, HDAC inhibitors may be effective for the treatment of HCC for which the prognosis is poor based on ID2 downregulation and ID2 could serve as a marker that is predictive of the clinical response to HDAC inhibitors.
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Affiliation(s)
- Ryouichi Tsunedomi
- Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
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19
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El-Serag HB, Lechel A, Rudolph KL. Epidemiology and Molecular Mechanisms of Hepatocarcinogenesis. ZAKIM AND BOYER'S HEPATOLOGY 2012:142-156. [DOI: 10.1016/b978-1-4377-0881-3.00010-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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20
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Maegdefrau U, Bosserhoff AK. BMP activated Smad signaling strongly promotes migration and invasion of hepatocellular carcinoma cells. Exp Mol Pathol 2011; 92:74-81. [PMID: 22024355 DOI: 10.1016/j.yexmp.2011.10.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2011] [Accepted: 10/08/2011] [Indexed: 02/07/2023]
Abstract
Several of the different bone morphogenetic proteins (BMPs) are involved in development and progression of specific tumors. For hepatocellular carcinoma (HCC) only BMP4 and BMP6 are described to be important for carcinogenesis. However, up to now neither the influence of other BMPs on tumor progression, nor the responsible signaling pathways to mediate target gene expression in HCC are known. In order to characterize BMP expression pattern in HCC cell lines, we performed RT-PCR analysis and revealed enhanced expression levels of several BMPs (BMP4, 6, 7, 8, 9, 10, 11, 13 and 15) in HCC. Thus, we treated HCC cells with the general BMP inhibitors chordin and noggin to determine the functional relevance of BMP overexpression and observed decreased migration and invasion of HCC cells. A cDNA microarray of noggin treated HCC cells was performed to analyze downstream targets of BMPs mediating these oncogenic functions. Subsequent analysis identified collagen XVI as 'Smad signaling specific' and nidogen-2 as 'MAPK/ERK signaling specific' BMP-target genes. To examine which signaling pathway is mainly responsible for the oncogenic role of BMPs in HCC, we treated HCC cells with dorsomorphin to determine the influence of BMP activated Smad signaling. Interestingly, also migratory and invasive behavior of dorsomorphin treated HCC cells was diminished. In summary, our findings demonstrate enhanced expression levels of several BMPs in HCC supporting enhanced migratory and invasive phenotype of HCC cells mainly via activation of Smad signaling.
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21
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Matsuda Y, Ichida T, Fukumoto M. Hepatocellular carcinoma and liver transplantation: clinical perspective on molecular targeted strategies. Med Mol Morphol 2011; 44:117-24. [PMID: 21922382 DOI: 10.1007/s00795-011-0547-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2011] [Accepted: 04/20/2011] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) has an aggressive clinical course with frequent recurrence and metastasis. Orthotopic liver transplantation has been the only curative tool for unresectable HCC; therefore, recent advances in molecular targeted therapy may improve the prognosis of HCC. The multiple kinase inhibitor sorafenib and the macrolide antibiotic rapamycin are currently the most promising agents for treating unresectable HCC. A large population-based clinical trial revealed that sorafenib significantly prolonged the overall survival of HCC patients. However, subsequent clinical studies showed that sorafenib rarely reduced tumor volume and inadequately prolonged survival of patients with severe liver damage. To improve its therapeutic effect, the development of a predictive biomarker and a sorafenib-based combination is awaited. Another molecular targeting agent, rapamycin, has now been considered as a putative agent for preventing tumor recurrence in post-liver transplantation HCC patients, because it not only has immunosuppressive activity but also exerts an anti-tumor effect. In the near future, a combination of molecular targeting agents, such as sorafenib and rapamycin, may become a standard protocol for treating unresectable HCC. For specifying cases with more effective and less harmful modalities, further investigation in clinical and basic research to identify unexpected effects are needed.
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Affiliation(s)
- Yasunobu Matsuda
- Department of Medical Technology, Niigata University Graduate School of Health Sciences, 2-746 Asahimachi-dori, Niigata 951-8518, Japan.
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22
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Shin DH, Jang SH, Kang BC, Kim HJ, Oh SH, Kong G. Constitutive overexpression of Id-1 in mammary glands of transgenic mice results in precocious and increased formation of terminal end buds, enhanced alveologenesis, delayed involution. J Cell Physiol 2011; 226:1340-52. [DOI: 10.1002/jcp.22462] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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23
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Perugorria MJ, Castillo J, Latasa MU, Goñi S, Segura V, Sangro B, Prieto J, Avila MA, Berasain C. Wilms' tumor 1 gene expression in hepatocellular carcinoma promotes cell dedifferentiation and resistance to chemotherapy. Cancer Res 2009; 69:1358-67. [PMID: 19190340 DOI: 10.1158/0008-5472.can-08-2545] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The Wilms' tumor 1 gene (WT1) encodes a transcription factor involved in cell growth and development. As we previously reported, WT1 expression is hardly detectable in normal hepatic tissue but is induced in liver cirrhosis. Although WT1 has been found to be overexpressed in a number of malignancies, the role of WT1 in hepatocarcinogenesis has not been clarified. We found that WT1 is expressed in several human hepatocellular carcinoma (HCC) cell lines, including PLC/PRF/5 and HepG2, and in HCC tumor tissue in 42% of patients. WT1 small interfering RNAs did not affect proliferation rate of HCC cells but abrogated their resistance to anoikis. Transcriptome analysis of PLC/PRF/5 cells after WT1 knockdown showed up-regulation of 251 genes and down-regulation of 321. Ninety percent of the former corresponded to metabolic genes, mostly those characterizing the mature hepatocyte phenotype. On the contrary, genes that decreased upon WT1 inhibition were mainly related to defense against apoptosis, cell cycle, and tumor progression. In agreement with these findings, WT1 expression increased the resistance of liver tumor cells to doxorubicin, a compound used to treat HCC. Interestingly, doxorubicin strongly enhanced WT1 expression in both HCC cells and normal human hepatocytes. Among different chemotherapeutics, induction of WT1 transcription was restricted to topoisomerase 2 inhibitors. When WT1 expression was prohibited, doxorubicin caused a marked increase in caspase-3 activation. In conclusion, WT1 is expressed in a substantial proportion of HCC contributing to tumor progression and resistance to chemotherapy, suggesting that WT1 may be an important target for HCC treatment.
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Affiliation(s)
- Maria J Perugorria
- Division of Hepatology and Gene Therapy,CIMA and CIBERehd, University Clinic, University of Navarra, Pamplona, Spain
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24
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Meteoglu I, Meydan N, Erkus M. Id-1: regulator of EGFR and VEGF and potential target for colorectal cancer therapy. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2008; 27:69. [PMID: 19014499 PMCID: PMC2588562 DOI: 10.1186/1756-9966-27-69] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2008] [Accepted: 11/12/2008] [Indexed: 05/03/2023]
Abstract
Background The helix-loop-helix transcription factor Id-1 (an inhibitor of differentiation and DNA binding) plays a role in development and progression of many tumours. Id-1 is known to exert its effects on the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF). The aim of this study was to reveal whether there was a relationship between Id-1 and EGFR and VEGF in colorectal carcinoma. Methods Tumour and non-tumour tissue specimens from 46 cases of colorectal carcinoma were exposed to immunohistochemical staining for Id-1, EGFR and VEGF. The relationship between the degree of staining and tumour grade, tumour stage and all tumour markers was investigated. Results Tumour cells showed positive staining for Id-1 in 43 cases (93.5%), for EGFR in 41 cases (89%) and for VEGF in 42 cases (91%). There was a significant relation between the tumour grade and the degree of staining for Id-1, EGFR and VEGF. The relation between the tumour stage and the degree of staining for Id-1, EGFR and VEGF was also significant. There was a significant relation between Id-1 expression and EGFR and VEGF expressions. Non-tumoural tissue specimens were not stained with Id-1 and EGFR antibodies in any of the cases, but stained with VEGF antibody in 3 cases. Conclusion This study revealed that Id-1, EGFR and VEGF took part in development and progression of colorectal carcinomas and that Id-1 was associated with regulations of EGFR and VEGF. The results of this study support the idea that not only EGFR and VEGF but also Id-1 could be new targets in cancer treatment.
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Affiliation(s)
- Ibrahim Meteoglu
- Adnan Menderes University, Medical Faculty, Department of Pathology, 09100-Aydin/Turkey.
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25
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Gho JWM, Ip WK, Chan KYY, Law PTY, Lai PBS, Wong N. Re-expression of transcription factor ATF5 in hepatocellular carcinoma induces G2-M arrest. Cancer Res 2008; 68:6743-51. [PMID: 18701499 DOI: 10.1158/0008-5472.can-07-6469] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Transcription factors represent an important class of genes that play key roles in controlling cellular proliferation, cell cycle modulation, and attractive targets for cancer therapy. Here, we report on the novel finding of common ATF5 down-regulations in hepatocellular carcinoma (HCC), a highly malignant tumor with a dismal clinical course. Array-based mapping in HCC highlighted a high and consistent incidence of transcription factor ATF5 repressions on regional chr.19q13. By quantitative reverse transcription-PCR, profound down-regulations of ATF5 were further suggested in 78% of HCC tumors (60 of 77 cases) compared to their adjacent nontumoral liver (P = 0.0004). Restoration of ATF5 expression in 3 nonexpressing HCC cell lines demonstrated a consistent growth inhibitory effect (P < 0.029) but minimal induction on cellular apoptosis. Subsequent flow cytometric investigations revealed a G(2)-M cell cycle arrest in HCC cells that were ectopically transfected with ATF5 (P < 0.002). The differential expressed genes from the functional effects of ATF5 were examined by array profiling. Over a hundred genes were identified, among which ID1 contains the ATF/CREB target binding sequences within its promoter region. An inverse relationship between ATF5 expressions with ID1 transcriptions was verified in HCC (P = 0.019), and a direct interaction of ATF5 on the promoter of ID1 was further demonstrated from electromobility shift assay. Examination of causal events underlying the silencing of ATF5 in HCC suggested copy number losses, promoter hypermethylation, histone deacetylation, and DNA mutations to be the likely inactivating mechanisms. In conclusion, our finding supports a tumor suppressive role for ATF5 in HCC, and highlighted ID1 as a potential downstream target.
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Affiliation(s)
- Jennifer W-M Gho
- Li Ka-Shing Institute of Health Sciences, Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong, China
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26
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Inhibitor of DNA binding-1 overexpression in prostate cancer: relevance to tumor differentiation. Pathol Oncol Res 2008; 15:91-6. [PMID: 18752043 DOI: 10.1007/s12253-008-9096-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2008] [Accepted: 08/01/2008] [Indexed: 12/25/2022]
Abstract
Inhibitor of DNA binding-1 (Id1) is a dominant-negative regulator of basic helix-loop-helix transcription factor, which control malignant cell behaviors in several types of carcinomas. This study aimed to find the relationship between Id1 expression and some clinical parameters. Paraffin-embedded tissue specimens from two normal human prostates, 12 benign prostatic hyperplasia (BPH), 43 prostate cancers(PCa) were detected by immunofluorescence assay. Prostatectomy samples from 11 BPH and 28 PCa were used for real time RT-PCR. The relationship between Id1 staining and several patient's clinical parameters, including Gleason grade, PSA, clinical stage, and size of tumor, was further analyzed. Significant up-regulated Id1 protein was shown in prostate cancer specimens, while only weak expression in some BPH samples (5/12). Analyzed by image software, the mean proportion of Id1 positive staining remarkably increased with the increasing of Gleason grade in prostate cancer specimens (r = 0.9967, P < 0.01). Id1 expression was not significantly associated with PSA, TNM stage or tumor size. Furthermore, the average mRNA of prostate cancer was 3.09 times of BPH. This study confirms that Id1 protein and mRNA are over expressed in prostate cancer tissues. Overexpression of Id1 protein correlates with tumor tissue differentiation. We propose that Id1 over expression can be used in the analysis of the progression of prostate cancer.
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Tsunedomi R, Iizuka N, Tamesa T, Sakamoto K, Hamaguchi T, Somura H, Yamada M, Oka M. Decreased ID2 promotes metastatic potentials of hepatocellular carcinoma by altering secretion of vascular endothelial growth factor. Clin Cancer Res 2008; 14:1025-31. [PMID: 18281534 DOI: 10.1158/1078-0432.ccr-07-1116] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE We aimed to explore the molecular and biological functions of Inhibitor of DNA binding/differentiation 2 (ID2), which was found to be responsible for portal vein invasion of hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN We measured ID2 mRNA levels in 92 HCC patients by real-time reverse transcription-PCR and examined the relation to clinicopathologic features. To clarify the precise roles of ID2, we did in vitro analysis with expression vectors and small interfering RNAs. Effects of ID2 on cell invasive potential and expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1alpha were analyzed by Matrigel-coated invasion chamber, ELISA, and Western blot analysis, respectively. RESULTS ID2 mRNA level correlated inversely with portal vein invasion (P < 0.001), tumor-node-metastasis stage (P < 0.001), tumor size (P < 0.001), and early intrahepatic recurrence (P < 0.05). When limited to a cohort of hepatitis C virus-related HCCs, patients with low levels of ID2 had significantly shorter disease-free survival time than those with high levels of ID2. Invasive potential of cells transfected with ID2 expression vector was lower than that of empty vector-transfected cells. Cells overexpressing ID2 also showed decreased VEGF secretion and hypoxia-inducible factor-1alpha protein levels. The results of ID2-knockdown experiments were opposite to those of ID2 overexpression experiments. CONCLUSIONS On the basis of our clinical and in vitro data, we suggest that ID2 plays a significant role in the metastatic process during progression of HCC. This action might be explained, at least in part, by altered cell mobility due to decreased secretion of VEGF.
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Affiliation(s)
- Ryouichi Tsunedomi
- Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
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Matsuda Y. Molecular mechanism underlying the functional loss of cyclindependent kinase inhibitors p16 and p27 in hepatocellular carcinoma. World J Gastroenterol 2008; 14:1734-40. [PMID: 18350604 PMCID: PMC2695913 DOI: 10.3748/wjg.14.1734] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common human cancers, and its incidence is still increasing in many countries. The prognosis of HCC patients remains poor, and identification of useful molecular prognostic markers is required. Many recent studies have shown that functional alterations of cell-cycle regulators can be observed in HCC. Among the various types of cell-cycle regulators, p16 and p27 are frequently inactivated in HCC and are considered to be potent tumor suppressors. p16, a G1-specific cell-cycle inhibitor that prevents the association of cyclindependent kinase (CDK) 4 and CDK6 with cyclin D1, is frequently inactivated in HCC via CpG methylation of its promoter region. p16 may be involved in the early steps of hepatocarcinogenesis, since p16 gene methylation has been detected in subsets of pre-neoplastic liver cirrhosis patients. p27, a negative regulator of the G1-S phase transition through inhibition of the kinase activities of Cdk2/cyclin A and Cdk2/cyclin E complexes, is now considered to be an adverse prognostic factor in HCC. In some cases of HCC with increased cell proliferation, p27 is overexpressed but inactivated by sequestration into cyclin D1-CDK4-containing complexes. Since loss of p16 is closely related to functional inactivation of p27 in HCC, investigating both p16 and p27 may be useful for precise prognostic predictions in individuals with HCC.
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29
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Lee TK, Poon RTP, Yuen AP, Ling MT, Wang XH, Wong YC, Guan XY, Man K, Tang ZY, Fan ST. Regulation of angiogenesis by Id-1 through hypoxia-inducible factor-1alpha-mediated vascular endothelial growth factor up-regulation in hepatocellular carcinoma. Clin Cancer Res 2007; 12:6910-9. [PMID: 17145808 DOI: 10.1158/1078-0432.ccr-06-0489] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE Metastasis is commonly associated with poor prognosis of hepatocellular carcinoma (HCC). Being an important angiogenic factor, vascular endothelial growth factor (VEGF) plays a central role in HCC growth and metastasis. Recently, Id-1 (inhibitor of differentiation/DNA synthesis) has been suggested to be a key factor in cancer progression but the molecular mechanism remains unknown. EXPERIMENTAL DESIGN We first showed that overexpression of Id-1 was correlated with HCC metastasis (P < 0.001) and its expression was significantly correlated with VEGF expression by tissue microarray. By ectopic transfection of Id-1 into HCC cells, Id-1 was able to induce VEGF secretion through activation of VEGF transcription. RESULTS Increased VEGF secretion in Id-1 transfectants induced morphologic change and proliferation of human umbilical vascular endothelial cell resulting in promotion of angiogenesis. Id-1 induced transcriptional activation of VEGF by stabilizing hypoxia-inducible factor-1alpha protein. Down-regulation of Id-1 by antisense approach led to suppression of hypoxia-inducible factor-1alpha-mediated VEGF production. In addition, Id-1 suppression resulted in retardation of cell invasion through down-regulation of VEGF. CONCLUSIONS Id-1 is a novel angiogenic factor for HCC metastasis and down-regulation of Id-1 may be a novel target to inhibit HCC metastasis through suppression of angiogenesis.
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MESH Headings
- Animals
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/physiopathology
- Carcinoma, Hepatocellular/secondary
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Down-Regulation/drug effects
- Endothelial Cells/drug effects
- Gene Expression Profiling
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Inhibitor of Differentiation Protein 1/antagonists & inhibitors
- Inhibitor of Differentiation Protein 1/genetics
- Inhibitor of Differentiation Protein 1/metabolism
- Liver Neoplasms/drug therapy
- Liver Neoplasms/physiopathology
- Liver Neoplasms/secondary
- Mice
- Mice, Nude
- Neovascularization, Pathologic/metabolism
- Oligodeoxyribonucleotides, Antisense/pharmacology
- Oligodeoxyribonucleotides, Antisense/therapeutic use
- Reverse Transcriptase Polymerase Chain Reaction
- Structure-Activity Relationship
- Tissue Array Analysis
- Transplantation, Heterologous
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Terence K Lee
- Department of Surgery, The University of Hong Kong, Hong Kong, China
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Tajima K, Terai S, Takami T, Kawaguchi K, Okita K, Sakaida I. Importance of inhibitor of DNA binding/differentiation 2 in hepatic stellate cell differentiation and proliferation. Hepatol Res 2007; 37:647-55. [PMID: 17559421 DOI: 10.1111/j.1872-034x.2007.00089.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIM In liver fibrosis, activated hepatic stellate cells (HSC) are transformed into myofibroblasts. Helix-loop-helix (HLH) transcriptional factors such as MyoD regulate the differentiation of myocytes, and the inhibitor of DNA binding/differentiation (Id) family comprises dominant negative HLH transcriptional regulators that inhibit differentiation and promote cell proliferation. In the present study, we investigated how the Id family proteins regulate HSC. METHODS In primary rat HSC, inhibitor of DNA binding/differentiation (Id)2 and alpha-smooth muscle actin (alpha-SMA) mRNA expression increased 4 days after isolation. Next we established Id2 expressing HSC (HSC-T6-Id2-green fluorescent protein (GFP)) using HSC-T6 cells with retrovirus that expressed GFP-tagged Id2. RESULTS HSC-T6-Id2-GFP increased cell proliferation with cyclin D1 expression. In contrast, alpha-SMA expression wassuppressed. Real-time reverse transcription-polymerase chain reaction analysis showed Id2 induction significantly suppressed alpha-SMA, collagen-1, matrix metalloproteinase (MMP)-2, and MMP-9 mRNA (P < 0.05) but had no effect on tissue inhibitor of metalloproteinase or transforming growth factor-beta1 levels. CONCLUSION These findings suggest Id2, an HLH transcriptional regulator, plays an important regulatory role in the proliferation and differentiation of HSC.
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Affiliation(s)
- Kunihiko Tajima
- Department of Molecular Science and Applied Medicine (Gastroenterology and Hepatology), Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
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Forootan SS, Wong YC, Dodson A, Wang X, Lin K, Smith PH, Foster CS, Ke Y. Increased Id-1 expression is significantly associated with poor survival of patients with prostate cancer. Hum Pathol 2007; 38:1321-9. [PMID: 17599389 DOI: 10.1016/j.humpath.2007.02.011] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2006] [Revised: 01/15/2007] [Indexed: 01/14/2023]
Abstract
The levels of Id-1 (inhibitor of DNA binding or inhibitor of cell differentiation) expression in a series of prostate cell lines and in an archival set of prostate tissues were examined. Western blot analysis showed that the level of Id-1 expressed in the androgen sensitive cell line LNCaP was 1.2 +/- 0.2 times that detected in the benign cell line PNT-2. The level of Id-1 increased further to 1.8 +/- 0.2 and 2.9 +/- 0.3 in the androgen-insensitive cell lines Du-145 and PC-3, respectively. Immunohistochemical staining with Id-1 antibody performed on 113 cases of prostate tissues showed that among the 7 normal cases, 6 (86%) stained either negative or weakly positive whereas only 1 (14%) stained moderately positive. Among the 36 benign prostatic hyperplasia (BPH) samples, 34 (94%) stained either negative or weakly positive; only 1 (3%) stained moderately and 1 (3%) stained strongly. Of the 70 carcinomas, 8 (11.5%) stained weakly, 34 (48.5%) stained moderately, and 28 (40%) stained strongly positive. The intensity of Id-1 staining in carcinomas was significantly stronger than that detected in the normal prostate and BPH (chi(2) test, P < .001) and it was significantly increased as the increasing malignancy of carcinomas measured by Gleason score (chi(2) test, P < .001). The intensity of Id-1 staining was partially associated with the levels of prostate-specific antigen, but not related to the level of androgen receptor. Kaplan-Meier survival curve analysis showed that, similar to Gleason scores, overexpression of Id-1 was significantly associated with the reduced length of patient survival (log-rank test, P = .01). These results suggest that Id-1 is a useful prognostic marker to predict the outcomes of patients with prostate cancer.
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Affiliation(s)
- Shiva S Forootan
- Molecular Pathology Laboratory, School of Cancer Studies, Faculty of Medicine, University of Liverpool, L69 3GA Liverpool, United Kingdom.
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El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132:2557-76. [PMID: 17570226 DOI: 10.1053/j.gastro.2007.04.061] [Citation(s) in RCA: 4239] [Impact Index Per Article: 235.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2007] [Accepted: 04/18/2007] [Indexed: 02/06/2023]
Abstract
Primary liver cancer, which consists predominantly of hepatocellular carcinoma (HCC), is the fifth most common cancer worldwide and the third most common cause of cancer mortality. HCC has several interesting epidemiologic features including dynamic temporal trends; marked variations among geographic regions, racial and ethnic groups, and between men and women; and the presence of several well-documented environmental potentially preventable risk factors. Moreover, there is a growing understanding on the molecular mechanisms inducing hepatocarcinogenesis, which almost never occurs in healthy liver, but the cancer risk increases sharply in response to chronic liver injury at the cirrhosis stage. A detailed understanding of epidemiologic factors and molecular mechanisms associated with HCC ultimately could improve our current concepts for screening and treatment of this disease.
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Affiliation(s)
- Hashem B El-Serag
- Michael E. DeBakey Veterans Administration Medical Center and Baylor College of Medicine, Houston Center for Quality of Care and Utilization Studies, Houston, Texas, USA.
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Zhang X, Ling MT, Wong YC, Wang X. Evidence of a novel antiapoptotic factor: role of inhibitor of differentiation or DNA binding (Id-1) in anticancer drug-induced apoptosis. Cancer Sci 2007; 98:308-14. [PMID: 17214747 PMCID: PMC11159113 DOI: 10.1111/j.1349-7006.2007.00400.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Id-1 (inhibitor of differentiation or DNA binding), a member of the basic helix-loop-helix transcription factor family, is up-regulated in many types of human cancer and its expression levels are correlated with poor treatment outcome and shorter survival. In this study, we provided evidence to suggest that Id-1 is a universal survival factor that plays a key role in protection against anticancer drug-induced apoptosis. Using nine anticancer drugs and five cancer cell lines derived from nasopharyngeal carcinoma (CNE1), cervical carcinoma (HeLa), breast cancer (MCF7), hepatocarcinoma (Huh7) and prostate cancer (PC3), we found that down-regulation of Id-1 expression at both transcriptional and protein levels was associated with increased apoptosis rates and increased cleaved PARP after exposure to all anticancer agents. Treatment with a caspase 9 inhibitor, Z-LEHD-FMK, protected cancer cells from drug-induced PARP cleavage. However, overexpression of Id-1 in a p53 mutated cell line, CNE1, was able to suppress PARP cleavage in response to all anticancer drugs examined. In contrast, down-regulation of Id-1 through small RNA technology in CNE1 cells led to increased sensitivity to all six types of chemotherapeutic drugs. Our results demonstrate that Id-1 may be a general negative regulator of anticancer drug-induced apoptosis and suggest a novel therapeutic target in inducing chemosensitization in cancer cells. Our evidence also provides a possible underlying mechanism responsible for the positive role of Id-1 in the progression of human cancer.
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Affiliation(s)
- Xiaomeng Zhang
- Cancer Biology Group, Department of Anatomy, Faculty of Medicine, The University of Hong Kong, Hong Kong
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Matsuda Y, Ichida T. p16 and p27 are functionally correlated during the progress of hepatocarcinogenesis. Med Mol Morphol 2006; 39:169-75. [PMID: 17187177 DOI: 10.1007/s00795-006-0339-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2006] [Accepted: 08/30/2006] [Indexed: 10/23/2022]
Abstract
The molecular mechanism of the cell-cycle machinery in hepatocellular carcinoma (HCC) has not yet been fully elucidated. Among the various types of cell-cycle regulators, p16 and p27 are now considered to be potent tumor suppressors. p16 is a G1-specific cell-cycle inhibitor that prevents the association of cyclin-dependent kinase (CDK) 4 and CDK6 with cyclin D(1). Many studies have reported that p16 is inactivated not only in aggressive types of HCC but also in preneoplastic liver cirrhosis. In many cases of HCC, p16 is mainly inactivated by extensive CpG methylation, suggesting that epigenetic changes in the p16 gene may be important events during hepatocarcinogenesis. p27, an inhibitor of CDK2, is presently regarded as a potent adverse prognostic factor in many aggressive cancers. It should be noted that some cases of HCC show increased cell proliferation despite the expression of considerable amounts of p27. In these cases, p27 is inactivated by sequestration into cyclin D(1)-CDK4-containing complexes. Although the reason for the compositional changes in the p27-containing complexes is unclear, our experimental results indicate that loss of p16 following DNA methylation is closely related to the functional inactivation of p27 in HCC. We suggest that assessment of the p16 status may be useful for a precise prognostic prediction for individuals with HCCs expressing high levels of p27.
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Affiliation(s)
- Yasunobu Matsuda
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi-dori 1-757, Niigata, 951-8510, Japan.
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Jang KS, Han HX, Paik SS, Brown PH, Kong G. Id-1 overexpression in invasive ductal carcinoma cells is significantly associated with intratumoral microvessel density in ER-negative/node-positive breast cancer. Cancer Lett 2006; 244:203-10. [PMID: 16469432 DOI: 10.1016/j.canlet.2005.12.016] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2005] [Revised: 12/08/2005] [Accepted: 12/09/2005] [Indexed: 10/25/2022]
Abstract
The aim of this study is to investigate the possible role of inhibitor of DNA binding (Id-1) overexpression in human breast cancer. We examined Id-1 expression by immunohistochemistry in 263 human breast cancers, 15 in situ lesions and 248 invasive cancers to investigate the relationship between its expression and various clinicopathological factors. Id-1 expression was significantly higher in invasive ductal carcinoma than in in situ ductal carcinoma or other invasive cancer subtypes (P=0.029 and 0.006, respectively). We also examined the association between Id-1 expression and tumor angiogenesis by measuring microvessel densities (MVD). Regarding the endothelial cells of microvessels showed negative or very weak Id-1 expression, Id-1 overexpression was found to be significantly related to MVD (P=0.014). Furthermore, Id-1 overexpression was found to be significantly associated with higher MVD in the ER-negative and node-involved subgroups of breast cancer (P=0.040 and 0.046, respectively). These data indicate that Id-1 overexpression is significantly associated with tumor angiogenesis, especially in the ER-negative and node-positive subtypes of invasive breast cancer. Thus, Id-1 presents a possible therapeutic antitumor target molecule in ER-negative and node-positive breast cancer.
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MESH Headings
- Adenocarcinoma/blood supply
- Adenocarcinoma/metabolism
- Adenocarcinoma/pathology
- Breast Neoplasms/blood supply
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Carcinoma, Ductal, Breast/blood supply
- Carcinoma, Ductal, Breast/metabolism
- Carcinoma, Ductal, Breast/pathology
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Immunoenzyme Techniques
- Inhibitor of Differentiation Protein 1/metabolism
- Lymph Nodes/pathology
- Microcirculation
- Middle Aged
- Neoplasm Invasiveness/pathology
- Neoplasm Staging
- Neoplasms, Ductal, Lobular, and Medullary/blood supply
- Neoplasms, Ductal, Lobular, and Medullary/metabolism
- Neoplasms, Ductal, Lobular, and Medullary/pathology
- Neovascularization, Pathologic/metabolism
- Prognosis
- Receptors, Estrogen/metabolism
- Receptors, Progesterone/metabolism
- Retrospective Studies
- Survival Rate
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Affiliation(s)
- Ki-Seok Jang
- Department of Pathology, College of Medicine, Hanyang University, 17 Haengdang-dang, Seongdong-Gu, Seoul 133-791, South Korea
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N/A, 刘 连, 曲 志, 刘 改, 陈 炜, 郭 化, 陈 曦. N/A. Shijie Huaren Xiaohua Zazhi 2005; 13:2238-2242. [DOI: 10.11569/wcjd.v13.i18.2238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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