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Katoozian F, Abedi Kichi Z, Sharifi R, Shirvani-Farsani Z. The Expression Analysis of Long Non-coding RNAs Related to Wnt/β-Catenin Signaling in Pancreatic Cancer Patients. Biochem Genet 2025; 63:1605-1619. [PMID: 38594570 DOI: 10.1007/s10528-024-10779-5] [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: 01/22/2024] [Accepted: 03/11/2024] [Indexed: 04/11/2024]
Abstract
Background The oncogenic Wnt/β-catenin signaling plays a critical role in carcinogenesis, prognosis, and resistance to therapy. Pancreatic cancer (PC) has high mortality because of its poor prognosis. Several studies have suggested that lncRNAs are directly involved in the development and progression of PC as well as in Wnt/β-catenin signaling. In this study, we investigated and compared the expression of Wnt/β-catenin signaling-related ZFAS1 and HCG11 lncRNAs, and their targets, CTNNB1 and IGF2BP1 genes in the blood of patients with PC and healthy individuals. A total of 47 PC patients and 50 healthy individuals participated in this study. RNA was extracted from the peripheral blood samples of participants, and cDNA was synthesized. The expression level of the selected genes was quantified by real-time PCR. The expression of HCG11 lncRNA and CTNNB1 genes in patients with PC was significantly upregulated compared to healthy individuals, and the expression of the ZFAS1 lncRNA was significantly downregulated. According to the analysis of the ROC curve, the diagnostic powers of ZFAS1 and CTNNB1 in PC were 0.67 and 0.69, respectively. Altogether, the present study suggests a role for ZFAS1 and HCG11 lncRNAs and CTNNB1 and IGF2BP1 in the pathogenesis of pancreatic cancer. Moreover, the peripheral expression of these lncRNAs may be useful as potential biomarkers for PC.
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Affiliation(s)
- Fatemeh Katoozian
- Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Zahra Abedi Kichi
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians University, Munich, Germany
| | - Roya Sharifi
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran.
| | - Zeinab Shirvani-Farsani
- Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran.
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Yu D, Lu Z, Wang R, Xiang Y, Li H, Lu J, Zhang L, Chen H, Li W, Luan X, Chen L. FXR agonists for colorectal and liver cancers, as a stand-alone or in combination therapy. Biochem Pharmacol 2023; 212:115570. [PMID: 37119860 DOI: 10.1016/j.bcp.2023.115570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/01/2023]
Abstract
Farnesoid X receptor (FXR, NR1H4) is generally considered as a tumor suppressor of colorectal and liver cancers. The interaction between FXR, bile acids (BAs) and gut microbiota is closely associated with an increased risk of colorectal and liver cancers. Increasing evidence shows that FXR agonists may be potential therapeutic agents for colorectal and liver cancers. However, FXR agonists alone do not produce the desired results due to the complicated pathogenesis and single therapeutic mechanism, which suggests that effective treatments will require a multimodal approach. Based on the principle of improvingefficacy andreducingside effects, combination therapy is currently receiving considerable attention. In this review, colorectal and liver cancers are grouped together to discuss the effects of FXR agonists alone or in combination for combating the two cancers. We hope that this review will provide a theoretical basis for the clinical application of novel FXR agonists or combination with FXR agonists against colorectal and liver cancers.
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Affiliation(s)
- Danmei Yu
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zhou Lu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
| | - Ruyu Wang
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yusen Xiang
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Hongtao Li
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jiani Lu
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lijun Zhang
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Hongzhuan Chen
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Weihua Li
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
| | - Xin Luan
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Lili Chen
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Ren Y, Song Z, Rieser J, Ackermann J, Koch I, Lv X, Ji T, Cai X. USP15 Represses Hepatocellular Carcinoma Progression by Regulation of Pathways of Cell Proliferation and Cell Migration: A System Biology Analysis. Cancers (Basel) 2023; 15:cancers15051371. [PMID: 36900163 PMCID: PMC10000201 DOI: 10.3390/cancers15051371] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 02/15/2023] [Indexed: 02/24/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) leads to 600,000 people's deaths every year. The protein ubiquitin carboxyl-terminal hydrolase 15 (USP15) is a ubiquitin-specific protease. The role of USP15 in HCC is still unclear. METHOD We studied the function of USP15 in HCC from the viewpoint of systems biology and investigated possible implications using experimental methods, such as real-time polymerase chain reaction (qPCR), Western blotting, clustered regularly interspaced short palindromic repeats (CRISPR), and next-generation sequencing (NGS). We investigated tissues samples of 102 patients who underwent liver resection between January 2006 and December 2010 at the Sir Run Run Shaw Hospital (SRRSH). Tissue samples were immunochemically stained; a trained pathologist then scored the tissue by visual inspection, and we compared the survival data of two groups of patients by means of Kaplan-Meier curves. We applied assays for cell migration, cell growth, and wound healing. We studied tumor formation in a mouse model. RESULTS HCC patients (n = 26) with high expression of USP15 had a higher survival rate than patients (n = 76) with low expression. We confirmed a suppressive role of USP15 in HCC using in vitro and in vivo tests. Based on publicly available data, we constructed a PPI network in which 143 genes were related to USP15 (HCC genes). We combined the 143 HCC genes with results of an experimental investigation to identify 225 pathways that may be related simultaneously to USP15 and HCC (tumor pathways). We found the 225 pathways enriched in the functional groups of cell proliferation and cell migration. The 225 pathways determined six clusters of pathways in which terms such as signal transduction, cell cycle, gene expression, and DNA repair related the expression of USP15 to tumorigenesis. CONCLUSION USP15 may suppress tumorigenesis of HCC by regulating pathway clusters of signal transduction for gene expression, cell cycle, and DNA repair. For the first time, the tumorigenesis of HCC is studied from the viewpoint of the pathway cluster.
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Affiliation(s)
- Yiyue Ren
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine and Innovation Center for Minimally Invasive Technique and Device, Zhejiang University, Hangzhou 310016, China
| | - Zhen Song
- Molecular Bioinformatics Group, Institute of Computer Science, Faculty of Computer Science and Mathematics, Goethe University Frankfurt, 60325 Frankfurt am Main, Germany
- Correspondence: (Z.S.); (T.J.); (X.C.)
| | - Jens Rieser
- Molecular Bioinformatics Group, Institute of Computer Science, Faculty of Computer Science and Mathematics, Goethe University Frankfurt, 60325 Frankfurt am Main, Germany
| | - Jörg Ackermann
- Molecular Bioinformatics Group, Institute of Computer Science, Faculty of Computer Science and Mathematics, Goethe University Frankfurt, 60325 Frankfurt am Main, Germany
| | - Ina Koch
- Molecular Bioinformatics Group, Institute of Computer Science, Faculty of Computer Science and Mathematics, Goethe University Frankfurt, 60325 Frankfurt am Main, Germany
| | - Xingyu Lv
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine and Innovation Center for Minimally Invasive Technique and Device, Zhejiang University, Hangzhou 310016, China
| | - Tong Ji
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine and Innovation Center for Minimally Invasive Technique and Device, Zhejiang University, Hangzhou 310016, China
- Correspondence: (Z.S.); (T.J.); (X.C.)
| | - Xiujun Cai
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine and Innovation Center for Minimally Invasive Technique and Device, Zhejiang University, Hangzhou 310016, China
- Correspondence: (Z.S.); (T.J.); (X.C.)
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Rahadiani N, Andhini Retnowulan I, Stephanie M, Rini Handjari D, Krisnuhoni E. β-Catenin Expression and Its Association with Prognostic Factors in Hepatocellular Carcinoma: A Study on Alpha-fetoprotein, Histologic Grade, and Microvascular Invasion. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.6123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Background. Hepatocellular carcinoma (HCC), the most common primary liver cancer. In addition to its high incidence, the disease burden is high due to its poor prognosis and high recurrence rate. Some of the currently known clinicopathologic prognostic factors include alpha-fetoprotein (AFP) level, histologic grade, and microvascular invasion. At the molecular level, β-catenin is one of the most common driver mutation found in HCC. The Wnt/β-catenin pathway regulates cellular processes related to initiation, growth, survival, migration, differentiation, and apoptosis. Although the underlying pathogenesis of hepatocarcinogenesis is known, clinical application warrants a greater understanding of the molecular characteristics and tumor phenotype, especially for determining the prognosis. This study aims to analyze the expression of β-catenin and its association with AFP, histologic grade, and microvascular invasion. Materials and methods. Thirty-five samples of surgically resected HCCs at Cipto Mangunkusumo National Referral Hospital were examined. Diagnoses were made based on histopathological and immunohistochemical findings followed by β-catenin staining. β-catenin expression was analyzed to determine difference between variables. Results and conclusions. Here we show that β-catenin expression is significantly associated with low serum alpha-fetoprotein and well to moderate differentiation Implications. Strong nuclear β-catenin expression implies better prognosis in HCC.
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Gao J, Hou D, Hu P, Mao G. Curcumol increases the sensitivity of colon cancer to 5-FU by regulating Wnt/β-catenin signaling. Transl Cancer Res 2021; 10:2437-2450. [PMID: 35116559 PMCID: PMC8798486 DOI: 10.21037/tcr-21-689] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 05/06/2021] [Indexed: 12/16/2022]
Abstract
Background 5-fluorouracil (5-FU) resistance is the leading cause of treatment failure in colon cancer. Combination therapy is an effective strategy to inhibit cancer cells and prevent drug resistance. Therefore, we studied the antitumor effect of curcumol alone or combined with 5-FU on human colon cancer drug-resistant cells. Methods The 5-FU resistant HCT116 cell line (HCT116/5-FU) was established by repeated exposure to gradually increasing concentrations of 5-FU; Cell viability was measured by cell counting kit-8 (CCK-8); apoptosis rate of HCT116 cells was detected using Annexin V-fluorescein isothiocyanate (FITC) assay kit; cell proliferation and invasion were detected using colony formation assays, wound healing assay and transwell invasion assays; activity of transplanted tumor in vivo in specific pathogen free (SPF) BALB/c nude mice (6 weeks old, male) was monitored by bioluminescence imaging, immunohistochemistry and western blot analysis. Results Our study showed the potent antitumor effect of curcumol by induction of apoptosis, inhibition of proliferation, invasion, migration, and improvement of the therapeutic efficacy of 5-FU toward human colon cancer HCT116 cells. From our results, curcumol could chemosensitize 5-FU-resistant HCT116 cells. The combination of curcumol and 5-FU exerted a synergistic inhibitory effect on the induction of apoptosis. Also, this combination inhibited the proliferation, invasion, and migration of both chemo-resistant and sensitive cells. Curcumol treatment decreased multidrug resistance-associated protein 2 (MRP-2), P-glycoprotein (P-gp), survivin, and β-catenin expression, which correlated with multidrug resistance (MDR) and the target genes of Wnt/β-catenin. It significantly increased the p-β-catenin level and Bad/Bcl-2 ratio in HCT116/5-FU cells compared with 5-FU treatment. In vivo, curcumol significantly inhibited the growth of transplanted tumors and the expression of Ki-67, proliferating cell nuclear antigen (PCNA), and vascular endothelial growth factor (VEGF) in colon cancer cells. Conclusions Curcumol as a potential chemotherapeutic agent combined with 5-FU can overcome colon cancer resistance.
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Affiliation(s)
- Jinfeng Gao
- Department of Oncology, Affiliated Nanjing Jiangbei Hospital to Nantong University, Nanjing, China
| | - Daorong Hou
- Animal Core Facility, Nanjing Medical University, Nanjing, China
| | - Ping Hu
- Department of Oncology, Affiliated Nanjing Jiangbei Hospital to Nantong University, Nanjing, China
| | - Guoxin Mao
- Department of Chemotherapy, Affiliated Hospital of Nantong University, Nantong, China
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Evaluation of Apelin/APJ system expression in hepatocellular carcinoma as a function of clinical severity. Clin Exp Med 2020; 21:269-275. [DOI: 10.1007/s10238-020-00672-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 11/04/2020] [Indexed: 12/14/2022]
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Riou R, Ladli M, Gerbal-Chaloin S, Bossard P, Gougelet A, Godard C, Loesch R, Lagoutte I, Lager F, Calderaro J, Dos Santos A, Wang Z, Verdier F, Colnot S. ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription. eLife 2020; 9:e53550. [PMID: 33084574 PMCID: PMC7641585 DOI: 10.7554/elife.53550] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 10/20/2020] [Indexed: 12/13/2022] Open
Abstract
Erythropoietin (EPO) is a key regulator of erythropoiesis. The embryonic liver is the main site of erythropoietin synthesis, after which the kidney takes over. The adult liver retains the ability to express EPO, and we discovered here new players of this transcription, distinct from the classical hypoxia-inducible factor pathway. In mice, genetically invalidated in hepatocytes for the chromatin remodeler Arid1a, and for Apc, the major silencer of Wnt pathway, chromatin was more accessible and histone marks turned into active ones at the Epo downstream enhancer. Activating β-catenin signaling increased binding of Tcf4/β-catenin complex and upregulated its enhancer function. The loss of Arid1a together with β-catenin signaling, resulted in cell-autonomous EPO transcription in mouse and human hepatocytes. In mice with Apc-Arid1a gene invalidations in single hepatocytes, Epo de novo synthesis led to its secretion, to splenic erythropoiesis and to dramatic erythrocytosis. Thus, we identified new hepatic EPO regulation mechanism stimulating erythropoiesis.
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Affiliation(s)
- Rozenn Riou
- INSERM, Sorbonne Université, Université de Paris, Centre de Recherche des Cordeliers (CRC)ParisFrance
- Equipe labellisée Ligue Nationale Contre le CancerParisFrance
- INSERM, CNRS, Institut COCHINParisFrance
| | | | - Sabine Gerbal-Chaloin
- INSERM U1183, Université Montpellier, Institute for Regenerative Medicine & Biotherapy (IRMB)MontpellierFrance
| | - Pascale Bossard
- Equipe labellisée Ligue Nationale Contre le CancerParisFrance
- INSERM, CNRS, Institut COCHINParisFrance
| | - Angélique Gougelet
- INSERM, Sorbonne Université, Université de Paris, Centre de Recherche des Cordeliers (CRC)ParisFrance
- Equipe labellisée Ligue Nationale Contre le CancerParisFrance
- INSERM, CNRS, Institut COCHINParisFrance
| | - Cécile Godard
- INSERM, Sorbonne Université, Université de Paris, Centre de Recherche des Cordeliers (CRC)ParisFrance
- Equipe labellisée Ligue Nationale Contre le CancerParisFrance
- INSERM, CNRS, Institut COCHINParisFrance
| | - Robin Loesch
- INSERM, Sorbonne Université, Université de Paris, Centre de Recherche des Cordeliers (CRC)ParisFrance
- Equipe labellisée Ligue Nationale Contre le CancerParisFrance
- INSERM, CNRS, Institut COCHINParisFrance
| | - Isabelle Lagoutte
- INSERM, CNRS, Institut COCHINParisFrance
- Plateforme d’Imageries du Vivant de l’Université de ParisParisFrance
| | - Franck Lager
- INSERM, CNRS, Institut COCHINParisFrance
- Plateforme d’Imageries du Vivant de l’Université de ParisParisFrance
| | - Julien Calderaro
- INSERM, Université Paris-Est UPECCréteilFrance
- Department of Pathology, Henri Mondor HospitalCréteilFrance
| | | | - Zhong Wang
- Department of Cardiac Surgery Cardiovascular Research Center, University of MichiganAnn ArborUnited States
| | | | - Sabine Colnot
- INSERM, Sorbonne Université, Université de Paris, Centre de Recherche des Cordeliers (CRC)ParisFrance
- Equipe labellisée Ligue Nationale Contre le CancerParisFrance
- INSERM, CNRS, Institut COCHINParisFrance
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8
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Mao J, Chen X, Wang C, Li W, Li J. Effects and mechanism of the bile acid (farnesoid X) receptor on the Wnt/β-catenin signaling pathway in colon cancer. Oncol Lett 2020; 20:337-345. [PMID: 32565960 PMCID: PMC7285806 DOI: 10.3892/ol.2020.11545] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 02/28/2020] [Indexed: 12/12/2022] Open
Abstract
The downregulation of farnesoid X receptor (FXR; gene name, nuclear receptor subfamily 1 group h member 4), an enteric nuclear bile acid receptor, has been reported in colorectal carcinoma (CRC), and FXR expression has been inversely correlated with CRC stage and clinical outcome. FXR knockdown in chronic colitis mouse models of intestinal tumorigenesis results in early mortality and increased tumor progression via promoting Wnt signaling. The aim of the present study was to explore the effects and mechanism of FXR on the Wnt/β-catenin signal pathway in CRC. FXR and β-catenin protein expression levels were detected in an ulcerative colitis mouse model and human colon cancer cell lines (HT-29, Caco-2 and HCT-116). Gain- and loss-of-function studies were conducted by transfecting colon cancer cells with FXR siRNA and treating them with the FXR agonist GW4064. Subsequently, β-catenin transcriptional activity was measured using the dual-luciferase assay, and β-catenin/TCF4 complex levels and β-catenin protein and mRNA expression levels were determined. FXR and β-catenin expression levels were inversely associated in both the animal model and colon cancer cells. The Wnt signaling pathway was activated by increased β-catenin/TCF4 complex levels upon FXR silencing; however, mRNA and protein levels of β-catenin were not significantly affected. The FXR agonist GW4064 significantly inhibited the proliferation of cells but promoted the transcriptional activity of β-catenin. Thus, the present study demonstrated that FXR influences the Wnt/β-catenin signaling pathway. Furthermore, loss of FXR expression promotes the transcriptional activity of β-catenin, whereas FXR activation results in the opposite effect.
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Affiliation(s)
- Jiayu Mao
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, P.R. China
| | - Xueqi Chen
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, P.R. China
| | - Chunsaier Wang
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, P.R. China
| | - Wenbin Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, P.R. China
| | - Jingnan Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, P.R. China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Chinese Academy of Medical Science, Beijing 100730, P.R. China
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9
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Hu B, Yang XB, Sang XT. Development of an immune-related prognostic index associated with hepatocellular carcinoma. Aging (Albany NY) 2020; 12:5010-5030. [PMID: 32191631 PMCID: PMC7138589 DOI: 10.18632/aging.102926] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 03/02/2020] [Indexed: 12/18/2022]
Abstract
Liver hepatocellular carcinoma (LIHC), an inflammation-associated cancer induced by a variety of etiological factors, is still one of the most prevalent and lethal cancers in human population. In this study, the expression profiles of immune-related genes (IRGs) were integrated with the overall survival (OS) of 378 LIHC patients based on the Cancer Genome Atlas (TCGA) dataset. Moreover, the differentially expressed and survival related IRGs among LIHC patients were predicted through the computational difference algorithm and COX regression analysis. As a result, 7 genes, including HSPA4, S100A10, FABP6, CACYBP, HDAC1, FCGR2B and SHC1, were retrieved to construct a predictive model associated with the overall survival (OS) of LIHC patients. Typically, the as-constructed model performed moderately in predicting prognosis, which was also correlated with tumor grade. Functional enrichment analysis revealed that the genes of high-risk group were actively involved in mRNA binding and the spliceosome pathway. Intriguingly, the prognostic index established based on IRGs reflected infiltration by multiple types of immunocytes. Our findings screen several IRGs with clinical significance, reveal the drivers of immune repertoire, and illustrate the importance of a personalized, IRG-based immune signature in LIHC recognition, surveillance, and prognosis prediction.
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Affiliation(s)
- Bo Hu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100010, China
| | - Xiao-Bo Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100010, China
| | - Xin-Ting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100010, China
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10
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Fekry B, Ribas-Latre A, Baumgartner C, Mohamed AMT, Kolonin MG, Sladek FM, Younes M, Eckel-Mahan KL. HNF4α-Deficient Fatty Liver Provides a Permissive Environment for Sex-Independent Hepatocellular Carcinoma. Cancer Res 2019; 79:5860-5873. [PMID: 31575546 DOI: 10.1158/0008-5472.can-19-1277] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 08/02/2019] [Accepted: 09/23/2019] [Indexed: 02/07/2023]
Abstract
The incidence of hepatocellular carcinoma (HCC) is on the rise worldwide. Although the incidence of HCC in males is considerably higher than in females, the projected rates of HCC incidence are increasing for both sexes. A recently appreciated risk factor for HCC is the growing problem of nonalcoholic fatty liver disease, which is usually associated with obesity and the metabolic syndrome. In this study, we showed that under conditions of fatty liver, female mice were more likely to develop HCC than expected from previous models. Using an inducible knockout model of the tumor-suppressive isoform of hepatocyte nuclear factor 4 alpha ("P1-HNF4α") in the liver in combination with prolonged high fat (HF) diet, we found that HCC developed equally in male and female mice as early as 38 weeks of age. Similar sex-independent HCC occurred in the "STAM" model of mice, in which severe hyperglycemia and HF feeding results in rapid hepatic lipid deposition, fibrosis, and ultimately HCC. In both sexes, reduced P1-HNF4α activity, which also occurs under chronic HF diet feeding, increased hepatic lipid deposition and produced a greatly augmented circadian rhythm in IL6, a factor previously linked with higher HCC incidence in males. Loss of HNF4α combined with HF feeding induced epithelial-mesenchymal transition in an IL6-dependent manner. Collectively, these data provide a mechanism-based working hypothesis that could explain the rising incidence of aggressive HCC. SIGNIFICANCE: This study provides a mechanism for the growing incidence of hepatocellular carcinoma in both men and women, which is linked to nonalcoholic fatty liver disease.
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Affiliation(s)
- Baharan Fekry
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas
| | - Aleix Ribas-Latre
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas
| | - Corrine Baumgartner
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas
| | - Alaa M T Mohamed
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas
| | - Mikhail G Kolonin
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas.,Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas
| | - Frances M Sladek
- Department of Molecular, Cell and Systems Biology, University of California Riverside, Riverside, California
| | - Mamoun Younes
- Department of Pathology and Laboratory Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas
| | - Kristin L Eckel-Mahan
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas. .,Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas
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11
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Gougelet A, Sartor C, Senni N, Calderaro J, Fartoux L, Lequoy M, Wendum D, Talbot JN, Prignon A, Chalaye J, Imbeaud S, Zucman-Rossi J, Tordjmann T, Godard C, Bossard P, Rosmorduc O, Amaddeo G, Colnot S. Hepatocellular Carcinomas With Mutational Activation of Beta-Catenin Require Choline and Can Be Detected by Positron Emission Tomography. Gastroenterology 2019; 157:807-822. [PMID: 31194980 DOI: 10.1053/j.gastro.2019.05.069] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 05/18/2019] [Accepted: 05/28/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS In one-third of hepatocellular carcinomas (HCCs), cancer cells have mutations that activate β-catenin pathway. These cells have alterations in glutamine, bile, and lipid metabolism. We investigated whether positron emission tomography (PET) imaging allows identification of altered metabolic pathways that might be targeted therapeutically. METHODS We studied mice with activation of β-catenin in liver (Apcko-liv mice) and male C57Bl/6 mice given injections of diethylnitrosamine, which each develop HCCs. Mice were fed a conventional or a methionine- and choline-deficient diet or a choline-deficient (CD) diet. Choline uptake and metabolism in HCCs were analyzed by micro-PET imaging of mice; livers were collected and analyzed by histologic, metabolomic, messenger RNA quantification, and RNA-sequencing analyses. Fifty-two patients with HCC underwent PET imaging with 18F-fluorodeoxyglucose, followed by 18F-fluorocholine tracer metabolites. Human HCC specimens were analyzed by immunohistochemistry, quantitative polymerase chain reaction, and DNA sequencing. We used hepatocytes and mouse tumor explants for studies of incorporation of radiolabeled choline into phospholipids and its contribution to DNA methylation. We analyzed HCC progression in mice fed a CD diet. RESULTS Livers and tumors from Apcko-liv mice had increased uptake of dietary choline, which contributes to phospholipid formation and DNA methylation in hepatocytes. In patients and in mice, HCCs with activated β-catenin were positive in 18F-fluorocholine PET, but not 18F-fluorodeoxyglucose PET, and they overexpressed the choline transporter organic cation transporter 3. The HCC cells from Apcko-liv mice incorporated radiolabeled methyl groups of choline into phospholipids and DNA. In Apcko-liv mice, the methionine- and choline-deficient diet reduced proliferation and DNA hypermethylation of hepatocytes and HCC cells, and the CD diet reduced long-term progression of tumors. CONCLUSIONS In mice and humans, HCCs with mutations that activate β-catenin are characterized by increased uptake of a fluorocholine tracer, but not 18F-fluorodeoxyglucose, revealed by PET. The increased uptake of choline by HCCs promotes phospholipid formation, DNA hypermethylation, and hepatocyte proliferation. In mice, the CD diet reverses these effects and promotes regression of HCCs that overexpress β-catenin.
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Affiliation(s)
- Angélique Gougelet
- Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique, Unité Mixte De Recherché 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale Unité Mixte De Recherche 1138, Equipe Labellisée Ligue Contre le Cancer, Paris, France
| | - Chiara Sartor
- Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique, Unité Mixte De Recherché 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Nadia Senni
- Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique, Unité Mixte De Recherché 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Julien Calderaro
- Assistance Publique-Hôpitaux de Paris, Département de Pathologie, Hôpital Universitaire Henri Mondor, Créteil, France; Institut National de la Santé et de la Recherche Médicale U955, Team 18, Institut Mondor de Recherche Biomédicale; Université Paris Est Créteil, Créteil, France
| | - Laetitia Fartoux
- Assistance Publique-Hôpitaux de Paris, Service d'Hépatologie, Hôpital St-Antoine, Sorbonne Université, Paris, France; Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre de Recherche Saint-Antoine, Paris, France
| | - Marie Lequoy
- Assistance Publique-Hôpitaux de Paris, Service d'Hépatologie, Hôpital St-Antoine, Sorbonne Université, Paris, France; Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre de Recherche Saint-Antoine, Paris, France
| | - Dominique Wendum
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre de Recherche Saint-Antoine, Paris, France; Assistance Publique-Hôpitaux de Paris, Anatomie Pathologique, Hôpital St-Antoine, Sorbonne Université, Paris, France
| | - Jean-Noël Talbot
- Assistance Publique-Hôpitaux de Paris, Médecine Nucléaire, Hôpital Tenon, Sorbonne Université, Paris, France; Laboratoire d'Imagerie Moléculaire Photonique, UMS28, Phénotypage du Petit Animal, Sorbonne Université, Paris, France
| | - Aurélie Prignon
- Laboratoire d'Imagerie Moléculaire Photonique, UMS28, Phénotypage du Petit Animal, Sorbonne Université, Paris, France
| | - Julia Chalaye
- Assistance Publique-Hôpitaux de Paris, Médecine Nucléaire, Hôpital Universitaire Henri Mondor, Créteil, France
| | - Sandrine Imbeaud
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte De Recherché 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hematologie, Paris, France
| | - Jessica Zucman-Rossi
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte De Recherché 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hematologie, Paris, France
| | - Thierry Tordjmann
- Institut National de la Santé et de la Recherche Médicale U1174, Université Paris Sud, Orsay, France
| | - Cécile Godard
- Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique, Unité Mixte De Recherché 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale Unité Mixte De Recherche 1138, Equipe Labellisée Ligue Contre le Cancer, Paris, France
| | - Pascale Bossard
- Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique, Unité Mixte De Recherché 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale Unité Mixte De Recherche 1138, Equipe Labellisée Ligue Contre le Cancer, Paris, France
| | - Olivier Rosmorduc
- Assistance Publique-Hôpitaux de Paris, Service d'Hépatologie, Hôpital St-Antoine, Sorbonne Université, Paris, France; Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre de Recherche Saint-Antoine, Paris, France
| | - Giuliana Amaddeo
- Assistance Publique-Hôpitaux de Paris, Médecine Interne, Hôpital Universitaire Henri Mondor, Créteil, France
| | - Sabine Colnot
- Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique, Unité Mixte De Recherché 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale Unité Mixte De Recherche 1138, Equipe Labellisée Ligue Contre le Cancer, Paris, France.
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Chen H, Wong CC, Liu D, Go MY, Wu B, Peng S, Kuang M, Wong N, Yu J. APLN promotes hepatocellular carcinoma through activating PI3K/Akt pathway and is a druggable target. Am J Cancer Res 2019; 9:5246-5260. [PMID: 31410213 PMCID: PMC6691573 DOI: 10.7150/thno.34713] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 06/11/2019] [Indexed: 12/24/2022] Open
Abstract
Background: The pathogenesis of hepatocellular carcinoma (HCC) is a multistep process contributed by the accumulation of molecular alterations. We identified Apelin (APLN) as an outlier gene up-regulated in hepatocellular carcinoma (HCC) through RNA-Seq and microarray analysis. We aimed to investigate its function, mechanism of action and clinical implication in HCC. Methods: Gene expression and clinical implication of APLN were assessed in multiple human HCC cohorts. Ectopic expression and silencing of APLN were performed to determine its function. The therapeutic potential of APLN and its downstream pathway was investigated using in vitro and in vivo models. Results: APLN overexpression was commonly observed in more than 80% of HCCs and independently predicted poorer survival of patients in three independent HCC cohorts. Apelin up-regulation was mediated by active β-catenin, which binds to the APLN promoter to induce transcription. Ectopic APLN expression in HCC cells promoted cell proliferation, accelerated G1/S progression and inhibited apoptosis, whilst APLN knockdown exerted opposite effects in vitro and inhibited HCC xenograft growth in mice. Mechanistically, APLN activated phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway via APLN receptor, leading to increased expression of phospho-glycogen synthase kinase 3β (p-GSK3β) and cyclin D1. Pharmacological targeting of APLN by ML221 was safe and effective in inhibiting APLN-PI3K/Akt cascade and HCC growth in vitro and in vivo. Conclusions: Our findings unraveled an oncogenic role of APLN in HCC, and that targeting of APLN might be a promising for HCC treatment. APLN may serve as an independent prognostic factor for HCC patients.
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Arboatti AS, Lambertucci F, Sedlmeier MG, Pisani G, Monti J, Álvarez MDL, Francés DEA, Ronco MT, Carnovale CE. Diethylnitrosamine enhances hepatic tumorigenic pathways in mice fed with high fat diet (Hfd). Chem Biol Interact 2019; 303:70-78. [PMID: 30826251 DOI: 10.1016/j.cbi.2019.02.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 01/28/2019] [Accepted: 02/24/2019] [Indexed: 12/21/2022]
Abstract
Obesity has been implicated in the genesis of metabolic syndromes including insulin resistance and Type 2 Diabetes Mellitus (T2DM). Given the association between T2DM and the risk of hepatocellular carcinoma (HCC), our specific goal was to determine whether the liver of HFD-induced T2DM mice is more sensitive to the carcinogen diethylnitrosamine (DEN), due to a modification of the molecular pathways implicated in the early stages of HCC pathogenesis. C57BL/6 male mice (five-week-old) were divided into 4 groups: C, C + DEN, HFD and HFD + DEN. Mice were euthanized twenty-five weeks after DEN-injection. Livers of HDF-fed mice showed a higher proliferative index than Control groups. In line with this, HFD groups showed an increase of nuclear β-catenin, and interestingly, DEN treatment led to a slight increase in the expression of this protein in HFD group. Based on these results, and to confirm this effect, we analyzed β-catenin target genes, finding that DEN treatment in HFD group led to a significant increase of Vegf, c-myc, c-jun and cyclin D1 expression levels. According to our results, the expression of TCF4 showed to be significantly increased in HFD + DEN vs. HFD. In this regard, the β-catenin/TCF4 complex enhanced its association with pSmads 2/3, as we observed an increase of nuclear Smads expression in HFD + DEN, suggesting a possible role of TGF-β1/Smads signaling pathway in this phenomenon. Our results show that the liver of HFD fed model that resembles early T2DM pathology in mice, is more sensitive to DEN, by inducing both Wnt/β-catenin and TGF β1/Smads tumorigenic pathways.
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Affiliation(s)
- A S Arboatti
- Instituto de Fisiología Experimental (IFISE-CONICET), Cátedra de Fisiología, Facultad de Ciencias Bioquímicas y Farmacéuticas- UNR, Suipacha 570, 2000, Rosario, Argentina
| | - F Lambertucci
- Instituto de Fisiología Experimental (IFISE-CONICET), Cátedra de Fisiología, Facultad de Ciencias Bioquímicas y Farmacéuticas- UNR, Suipacha 570, 2000, Rosario, Argentina
| | - M G Sedlmeier
- Instituto de Fisiología Experimental (IFISE-CONICET), Cátedra de Fisiología, Facultad de Ciencias Bioquímicas y Farmacéuticas- UNR, Suipacha 570, 2000, Rosario, Argentina
| | - G Pisani
- Cátedra de Morfología, Facultad de Ciencias Bioquímicas y Farmacéuticas, UNR, Suipacha 570, 2000, Rosario, Argentina
| | - J Monti
- Instituto de Fisiología Experimental (IFISE-CONICET), Cátedra de Fisiología, Facultad de Ciencias Bioquímicas y Farmacéuticas- UNR, Suipacha 570, 2000, Rosario, Argentina
| | - M de L Álvarez
- Instituto de Fisiología Experimental (IFISE-CONICET), Cátedra de Fisiología, Facultad de Ciencias Bioquímicas y Farmacéuticas- UNR, Suipacha 570, 2000, Rosario, Argentina; Cátedra de Morfología, Facultad de Ciencias Bioquímicas y Farmacéuticas, UNR, Suipacha 570, 2000, Rosario, Argentina
| | - D E A Francés
- Instituto de Fisiología Experimental (IFISE-CONICET), Cátedra de Fisiología, Facultad de Ciencias Bioquímicas y Farmacéuticas- UNR, Suipacha 570, 2000, Rosario, Argentina
| | - M T Ronco
- Instituto de Fisiología Experimental (IFISE-CONICET), Cátedra de Fisiología, Facultad de Ciencias Bioquímicas y Farmacéuticas- UNR, Suipacha 570, 2000, Rosario, Argentina
| | - C E Carnovale
- Instituto de Fisiología Experimental (IFISE-CONICET), Cátedra de Fisiología, Facultad de Ciencias Bioquímicas y Farmacéuticas- UNR, Suipacha 570, 2000, Rosario, Argentina.
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Duan L, Yang Q, Yang J, Hu Q, Wang B, Li P, Chen W. Identification of serum β-catenin as a biomarker in patients with HBV-related liver diseases. J Transl Med 2018; 16:265. [PMID: 30268125 PMCID: PMC6162905 DOI: 10.1186/s12967-018-1645-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 09/25/2018] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Substantial evidence indicates that β-catenin is a pivotal regulator that contributes to the initiation and development of various types of diseases. Recently, β-catenin can be detected in human serum and also reported to be correlated with several disease progression in a little research. However, very little is known about the relationship between serum β-catenin and HBV-related liver disease. METHODS Serum levels of β-catenin, from 77 patients with chronic hepatitis B (CHB), 63 patients with hepatitis B associated liver cirrhosis (HBLC), 61 patients with hepatocellular carcinoma (HCC), 41 healthy HBV carriers (HHCs) and 78 healthy controls (HCs) were measured by ELISA. Correlations of serum β-catenin with viral replication and liver necroinflammation parameters were analyzed. The receiver operating characteristic (ROC) curve was used to assess the discriminating power of serum β-catenin to grade different stages of HBV-related disorders. Human hepatic cell line L02 was transfected with a HBV plasmid, and β-catenin levels and the underlying mechanism were analyzed. RESULTS Chronic hepatitis B and HBLC patients but not HHC or HCC showed significantly higher serum β-catenin levels than HCs. β-catenin levels were not correlated with HBV DNA levels but were correlated with necroinflammation parameters. HBV-infected cell model showed elevated levels of phosphorylation at Ser473 in Akt (p-Akt), phosphorylation at Ser9 in GSK3β (p-GSK3β) and β-catenin, all of which was blocked by treatment with Akt inhibitor LY294002. Additionally, ROC analysis of β-catenin for discriminating patients with CHB from HHCs, which yielded an AUC of 0.71 (cutoff value, 42 pg/mL; 95% CI 0.61-0.81) with 64.93% sensitivity, 73.17% specificity and 69.05% accuracy. ROC analysis of β-catenin for discriminating patients with HCC from chronic HBV infection mainly including CHB and HBLC, which yielded an AUC of 0.75 (cutoff value, 42 pg/mL; 95% CI 0.67-0.83) with 66.43% sensitivity, 75.41% specificity and 70.92% accuracy. CONCLUSIONS HBV infection enhances β-catenin expression by activating Akt/GSK3β signaling. Serum β-catenin levels are correlated with necroinflammation parameters but not with viral load. Serum β-catenin has potential to discriminate the phase of HBV-related disorders, particularly predicts the patients with CHB from HHCs and also predicting HCC form chronic HBV infection.
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Affiliation(s)
- Liang Duan
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No.74 Linjiang Road, Yu Zhong District, Chongqing, 400010, China
| | - Qianfan Yang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No.74 Linjiang Road, Yu Zhong District, Chongqing, 400010, China
| | - Jun Yang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No.74 Linjiang Road, Yu Zhong District, Chongqing, 400010, China
| | - Qin Hu
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Bo Wang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No.74 Linjiang Road, Yu Zhong District, Chongqing, 400010, China
| | - Pu Li
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No.74 Linjiang Road, Yu Zhong District, Chongqing, 400010, China
| | - Weixian Chen
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No.74 Linjiang Road, Yu Zhong District, Chongqing, 400010, China.
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15
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Emerging role and therapeutic implication of Wnt signaling pathways in liver fibrosis. Gene 2018; 674:57-69. [PMID: 29944952 DOI: 10.1016/j.gene.2018.06.053] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 06/14/2018] [Accepted: 06/16/2018] [Indexed: 02/08/2023]
Abstract
Activation of hepatic stellate cells (HSCs) is a pivotal cellular event in liver fibrosis. Therefore, improving our understanding of the molecular pathways that are involved in these processes is essential to generate new therapies for liver fibrosis. Greater knowledge of the role of the Wnt signaling pathway in liver fibrosis could improve understanding of the liver fibrosis pathogenesis. The aim of this review is to describe the present knowledge about the Wnt signaling pathway, which significantly participates in liver fibrosis and HSC activation, and look ahead on new perspectives of Wnt signaling pathway research. Moreover, we will discuss the different interactions with Wnt signaling pathway-regulated liver fibrosis. The Wnt signaling pathway modulates several important aspects of function, including cell proliferation, activation and differentiation. Targeting the Wnt signaling pathway can be a promising direction in liver fibrosis treatment. We discuss new perspectives of Wnt signaling pathway activation in liver fibrosis. For example, antagonist to Wnt and Wnt ligands could inhibit liver fibrosis by regulating Wnt/β-catenin signaling pathway. These findings identify the Wnt signaling pathway as a potentially important for therapeutic targets in liver fibrosis. Future studies are needed in order to find safer and more effective Wnt-based drugs.
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16
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Colnot S. Focusing on beta-catenin activating mutations to refine liver tumor profiling. Hepatology 2016; 64:1850-1852. [PMID: 27515244 DOI: 10.1002/hep.28761] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 08/08/2016] [Indexed: 12/15/2022]
Affiliation(s)
- Sabine Colnot
- Inserm, U1016, Cochin Institute, Paris, France.,CNRS, UMR8104, Paris, France.,Paris Descartes University, Paris, France.,Team labelized by the French National League Against Cancer, Paris, France
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Luo K, Gu X, Liu J, Zeng G, Peng L, Huang H, Jiang M, Yang P, Li M, Yang Y, Wang Y, Peng Q, Zhu L, Zhang K. Inhibition of disheveled-2 resensitizes cisplatin-resistant lung cancer cells through down-regulating Wnt/β-catenin signaling. Exp Cell Res 2016; 347:105-113. [DOI: 10.1016/j.yexcr.2016.07.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2016] [Revised: 07/11/2016] [Accepted: 07/14/2016] [Indexed: 11/16/2022]
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Selli C, Pearce DA, Sims AH, Tosun M. Differential expression of store-operated calcium- and proliferation-related genes in hepatocellular carcinoma cells following TRPC1 ion channel silencing. Mol Cell Biochem 2016; 420:129-40. [PMID: 27443843 PMCID: PMC4992024 DOI: 10.1007/s11010-016-2776-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 07/09/2016] [Indexed: 12/19/2022]
Abstract
TRPC1 and store-operated Ca2+ (SOC) entry have previously been associated with hepatocellular carcinoma cell proliferation. The aim of the study was to determine genes and processes associated with TRPC1 down-regulation and the resulting increase of SOC entry and decrease in hepatocellular carcinoma cell proliferation. For this purpose, transcriptome analysis was performed to determine differentially expressed genes in TRPC1-silenced Huh7 cells. SOC entry- and proliferation-related genes correlated with TRPC1 down-regulation were also examined. Changes in SOC entry and cell proliferation were monitored in the TRPC1-silenced and parental cells and found to be significantly increased and decreased, respectively, in TRPC1-silenced cells. A total of 71 genes were significantly differentially expressed (40 up- and 31 down-regulated), including four mitogen-activated protein kinase (MAPK) signalling-associated genes. STIM1 levels were significantly up-regulated and negatively correlated with TRPC1 levels. In addition, expression of two cell cycle regulation genes, CDK11A/11B and URGCP, was observed to decrease, whereas ERBB3 and FGFR4, pro-survival genes, increased significantly in TRPC1-silenced cells. In conclusion, these results suggest reciprocal alterations in TRPC1 and STIM1 levels and a role for STIM1 in the regulation of SOC entry in TRPC1-silenced Huh7 cells. In addition to TRPC1, STIM1 may participate in Huh7 cell proliferation by regulating SOC entry. Alterations in MAPK signalling genes may be involved in diminished cell proliferation in TRPC1-silenced Huh7 cells. Similarly, changes in cell cycle regulating genes in TRPC1-silenced cells indicate possible cell cycle arrest along with compensatory up-regulation of ERBB3 growth factor receptor—amongst others—to maintain hepatocellular carcinoma cell proliferation.
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Affiliation(s)
- Cigdem Selli
- Department of Pharmacology, Faculty of Pharmacy, Ege University, 35040, Izmir, Turkey. .,Applied Bioinformatics of Cancer, Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research Centre, Crewe Road South, Edinburgh, EH4 2XU, UK.
| | - Dominic A Pearce
- Applied Bioinformatics of Cancer, Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research Centre, Crewe Road South, Edinburgh, EH4 2XU, UK
| | - Andrew H Sims
- Applied Bioinformatics of Cancer, Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research Centre, Crewe Road South, Edinburgh, EH4 2XU, UK
| | - Metiner Tosun
- Department of Pharmacology, Faculty of Pharmacy, Ege University, 35040, Izmir, Turkey.,Faculty of Medicine, Izmir University of Economics, 35330, Izmir, Turkey
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Niclosamide blocks glucagon phosphorylation of Ser552 on β-catenin in primary rat hepatocytes via PKA signalling. Biochem J 2016; 473:1247-55. [PMID: 26964897 DOI: 10.1042/bcj20160121] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 03/10/2016] [Indexed: 12/31/2022]
Abstract
Recently, it has been found that glucagon is able to activate the β-catenin signalling pathway leading to increased cyclin D1 and c-Myc expression in liver. Therefore the main aim of the present study is to determine whether the effect of glucagon activating β-catenin signalling leading to increased target gene expression is mediated through cAMP activation of PKA (protein kinase A). Primary rat hepatocytes were incubated with insulin, glucagon or adrenaline (epinephrine) and a range of inhibitors of PI3K (phosphoinositide 3-kinase), Wnt, mitochondrial uncoupler (niclosamide) or PKA inhibitors to dissect out the pathway leading to increased Ser(552) phosphorylation on β-catenin following glucagon exposure. In primary rat hepatocytes, we found that short exposure to glucagon or adrenaline caused a rapid increase in Ser(552) phosphorylation on β-catenin that leads to increased cyclin D1 and c-Myc expression. A range of PI3K and Wnt inhibitors were unable to block the effect of glucagon phosphorylating β-catenin. Interestingly, both niclosamide and the PKA inhibitor H89 blocked the glucagon effect on β-catenin signalling, leading to a reduction in target gene expression. Likewise, niclosamide inhibited cAMP levels and the direct addition of db-cAMP (dibutyryl-cAMP sodium salt) also resulted in Ser(552) phosphorylation of β-catenin. We have identified a new pathway via glucagon signalling that leads to increased β-catenin activity that can be reversed with the antihelminthic drug niclosamide, which has recently shown promise as a potential treatment of T2D (Type 2 diabetes). This novel finding could be useful in liver cancer treatment, particularly in the context of T2D with increased β-catenin activity.
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Liu X, Zhang X, Ji L, Gu J, Zhou M, Chen S. Farnesoid X receptor associates with β-catenin and inhibits its activity in hepatocellular carcinoma. Oncotarget 2016; 6:4226-38. [PMID: 25650661 PMCID: PMC4414185 DOI: 10.18632/oncotarget.2899] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 12/15/2014] [Indexed: 01/01/2023] Open
Abstract
The association between the temporal activation of Wnt/β-catenin pathway and the spontaneous hepatocellular carcinoma (HCC) development in Farnesoid X receptor (FXR) knockout mice is not well understood. We found that Huh7 cells depleted with FXR by RNAi showed enhanced cell growth, migration and invasion in vitro and accelerated tumor xenografts formation in nude mice. And these phenotypes were attenuated by simultaneous knockdown of β-catenin with RNAi. Furthermore, we identified that FXR could bind with β-Catenin through AF1 domain, and disrupt the assembly of the core β-Catenin/TCF4 complex. Activation of FXR attenuated the DNA-binding activity of β-Catenin/TCF4, and subsequently, its targeting gene-cyclin D1 expression. Importantly, FXR expression was markedly reduced in human HCC, an event which correlated with aberrant activation of β-Catenin. These data identified FXR as a negative regulator of HCC development through direct suppression of Wnt/β-catenin pathway.
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Affiliation(s)
- Xijun Liu
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical college, Fudan University, Shanghai, China
| | - Xingwang Zhang
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical college, Fudan University, Shanghai, China
| | - Lingling Ji
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical college, Fudan University, Shanghai, China
| | - Jianxin Gu
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical college, Fudan University, Shanghai, China
| | - Meiling Zhou
- Department of Radiology, Zhongshan Hospital of Fudan University, and Shanghai Institute of Medical Imaging, Shanghai, China
| | - She Chen
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical college, Fudan University, Shanghai, China
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Vilchez V, Turcios L, Marti F, Gedaly R. Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment. World J Gastroenterol 2016; 22:823-832. [PMID: 26811628 PMCID: PMC4716080 DOI: 10.3748/wjg.v22.i2.823] [Citation(s) in RCA: 241] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 12/05/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Liver cancer is generally related to hepatitis B or C infection and cirrhosis. Usually, patients with HCC are asymptomatic and are diagnosed at late stages when surgical treatment is no longer suitable. Limited treatment options for patients with advanced HCC are a major concern. Therefore, there is an urge for finding novel therapies to treat HCC. Liver cancer is highly heterogeneous and involved deregulation of several signaling pathways. Wnt/β-catenin pathway is frequently upregulated in HCC and it is implicated in maintenance of tumor initiating cells, drug resistance, tumor progression, and metastasis. A great effort in developing selective drugs to target components of the β-catenin pathway with anticancer activity is underway but only a few of them have reached phase I clinical trials. We aim to review the role of β-catenin pathway on hepatocarcinogenesis and liver cancer stem cell maintenance. We also evaluated the use of small molecules targeting the Wnt/β-catenin pathway with potential application for treatment of HCC.
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22
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Zhou S, Parham DM, Yung E, Pattengale P, Wang L. Quantification of glypican 3, β-catenin and claudin-1 protein expression in hepatoblastoma and paediatric hepatocellular carcinoma by colour deconvolution. Histopathology 2015; 67:905-913. [PMID: 25939253 DOI: 10.1111/his.12730] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Accepted: 04/28/2015] [Indexed: 01/05/2023]
Abstract
AIMS To identify an immunohistochemical panel for paediatric malignant epithelial liver tumours. METHODS AND RESULTS Forty-five hepatoblastomas (HBs), 13 paediatric hepatocellular carcinomas (HCCs) and two hepatocellular malignant neoplasms not otherwise specified (NOS) were chosen for immunohistochemical staining of glypican 3 (GPC3), β-catenin, claudin-1, delta-like protein (DLK), and forkhead box protein G1 (FOXG1). Immunostaining was quantitatively analysed with NIH imagej software coupled with colour deconvolution. Different subtypes of HB and HCC showed distinct staining patterns of GPC3, β-catenin, and claudin-1. Moreover, GPC3, β-catenin and claudin-1 all showed higher expression in classic HCC and embryonal HB than in fetal HB; GPC3 showed complete negativity in small-cell undifferentiated (SCU) HB and fibrolamellar HCC (FLC); β-catenin showed the strongest expression in SCU HB but the weakest expression in FLC. A panel of these three immunomarkers was useful for the diagnosis of hepatocellular malignant neoplasms NOS. The expression of DLK and FOXG1 was inconstant among fetal and embryonal HB and classic HCC. CONCLUSIONS A panel of GPC3, β-catenin and claudin-1 is helpful for differentiating HB subtypes and distinguishing HB from HCC.
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Affiliation(s)
- Shengmei Zhou
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA
- Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - David M Parham
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA
- Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Evan Yung
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA
- Department of Pathology and Laboratory Medicine, LAC+USC Medical Center, Los Angeles, CA, USA
| | - Paul Pattengale
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA
- Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Larry Wang
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA
- Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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Fernandez-Sanchez ME, Brunet T, Röper JC, Farge E. Mechanotransduction's Impact on Animal Development, Evolution, and Tumorigenesis. Annu Rev Cell Dev Biol 2015; 31:373-97. [DOI: 10.1146/annurev-cellbio-102314-112441] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Maria-Elena Fernandez-Sanchez
- Mechanics and Genetics of Embryonic and Tumor Development Team, CNRS UMR 168 Physicochimie Curie, Institut Curie Centre de Recherche, PSL Research University; Fondation Pierre-Gilles de Gennes; and INSERM, F-75005 Paris, France;
| | - Thibaut Brunet
- Mechanics and Genetics of Embryonic and Tumor Development Team, CNRS UMR 168 Physicochimie Curie, Institut Curie Centre de Recherche, PSL Research University; Fondation Pierre-Gilles de Gennes; and INSERM, F-75005 Paris, France;
- Evolution of the Nervous System in Bilateria Group, European Molecular Biology Laboratory, D-69117 Heidelberg, Germany
| | - Jens-Christian Röper
- Mechanics and Genetics of Embryonic and Tumor Development Team, CNRS UMR 168 Physicochimie Curie, Institut Curie Centre de Recherche, PSL Research University; Fondation Pierre-Gilles de Gennes; and INSERM, F-75005 Paris, France;
| | - Emmanuel Farge
- Mechanics and Genetics of Embryonic and Tumor Development Team, CNRS UMR 168 Physicochimie Curie, Institut Curie Centre de Recherche, PSL Research University; Fondation Pierre-Gilles de Gennes; and INSERM, F-75005 Paris, France;
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Ji J, Zheng X, Forgues M, Yamashita T, Wauthier EL, Reid LM, Wen X, Song Y, Wei JS, Khan J, Thorgeirsson SS, Wang XW. Identification of microRNAs specific for epithelial cell adhesion molecule-positive tumor cells in hepatocellular carcinoma. Hepatology 2015; 62:829-40. [PMID: 25953724 PMCID: PMC4549211 DOI: 10.1002/hep.27886] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 05/04/2015] [Indexed: 12/13/2022]
Abstract
UNLABELLED Therapies that target cancer stem cells (CSCs) hold promise in eliminating cancer burden. However, normal stem cells are likely to be targeted owing to their similarities to CSCs. It is established that epithelial cell adhesion molecule (EpCAM) is a biomarker for normal hepatic stem cells (HpSCs), and EpCAM(+) AFP(+) hepatocellular carcinoma (HCC) cells have enriched hepatic CSCs. We sought to determine whether specific microRNAs (miRNAs) exist in hepatic CSCs that are not expressed in normal HpSCs. We performed a pair-wise comparison of the miRNA transcriptome of EpCAM(+) and corresponding EpCAM(-) cells isolated from two primary HCC specimens, as well as from two fetal livers and three healthy adult liver donors by small RNA deep sequencing. We found that miR-150, miR-155, and miR-223 were preferentially highly expressed in EpCAM(+) HCC cells, which was further validated. Their gene surrogates, identified using miRNA and messenger RNA profiling in a cohort of 292 HCC patients, were associated with patient prognosis. We further demonstrated that miR-155 was highly expressed in EpCAM(+) HCC cells, compared to corresponding EpCAM(-) HCC cells, fetal livers with enriched normal hepatic progenitors, and normal adult livers with enriched mature hepatocytes. Suppressing miR-155 resulted in a decreased EpCAM(+) fraction in HCC cells and reduced HCC cell colony formation, migration, and invasion in vitro. The reduced levels of identified miR-155 targets predicted the shortened overall survival and time to recurrence of HCC patients. CONCLUSION miR-155 is highly elevated in EpCAM(+) HCC cells and might serve as a molecular target to eradicate the EpCAM(+) CSC population in human HCCs.
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Affiliation(s)
- Junfang Ji
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China,University of Hawaii Cancer Center, Cancer Biology Program (Ji), Epidemiology Program (Zheng), Honolulu, HI, U.S.A.,Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, U.S.A.,Corresponding authors: Dr. Xin Wei Wang, National Cancer Institute, 37 Convent Drive, MSC 4258, Bethesda, MD 20892, Tel: +1 301-496-2099, Fax: +1 301-496-0497, ; Dr. Junfang Ji, University of Hawaii Cancer Center, 701 Ilalo Street, Rm 336, Honolulu, HI 96813, Tel: +1 808 441 3492, Fax: +1 808 587 0742, , or Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang Province, China 310058,
| | - Xin Zheng
- University of Hawaii Cancer Center, Cancer Biology Program (Ji), Epidemiology Program (Zheng), Honolulu, HI, U.S.A
| | - Marshonna Forgues
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, U.S.A
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Eliane L. Wauthier
- Department of Cell Biology and Physiology and Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, U.S.A
| | - Lola M. Reid
- Department of Cell Biology and Physiology and Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, U.S.A
| | - Xinyu Wen
- Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, U.S.A
| | - Young Song
- Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, U.S.A
| | - Jun S. Wei
- Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, U.S.A
| | - Javed Khan
- Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, U.S.A
| | - Snorri S. Thorgeirsson
- Laboratory of Experimental Carcinogenesis, National Cancer Institute, NIH, Bethesda, MD, U.S.A
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, U.S.A.,Corresponding authors: Dr. Xin Wei Wang, National Cancer Institute, 37 Convent Drive, MSC 4258, Bethesda, MD 20892, Tel: +1 301-496-2099, Fax: +1 301-496-0497, ; Dr. Junfang Ji, University of Hawaii Cancer Center, 701 Ilalo Street, Rm 336, Honolulu, HI 96813, Tel: +1 808 441 3492, Fax: +1 808 587 0742, , or Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang Province, China 310058,
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Abstract
Liver cancer is an extraordinarily heterogeneous malignant disease among the tumors that have so far been identified. Hepatocellular carcinoma (HCC) arises most frequently in the setting of chronic liver inflammation and fibrosis, and takes a variety of course in individual patients to process to tumor. The risk factors such as HBV and/or HCV infections, aflatoxin infection, abuse alcohol intake, metabolic syndrome, obesity and diabetes are closely related to the environmental and genetic susceptibilities to HCC. The consequent resulting genomic instability, molecular and signal transduction network disorders and microenvironmental discrepancies are characterized by the extraordinary heterogeneity of liver cancer. The histology-based definition of the morphological heterogeneity of liver cancer has been modified and refined to treat patients with targeted therapies, but this still cannot solve all the problems. Lack of consistent outcome for anticancer agents and conventional therapies in liver cancer treatment calls for assessing the benefits of new molecularly targeted drugs and combined therapy, under the heterogeneity condition of tumor. The present review article will provide the complex mechanism and phenotype of liver cancer heterogeneity, and help us to execute precision medicine in a really personalized manner.
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Affiliation(s)
- Liang Li
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer, Shanghai, China
| | - Hongyang Wang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer, Shanghai, China; National Laboratory for Oncogenes and Related Genes, Cancer Institute, RenJi Hospital, Shanghai Jiao Tong University, Shanghai 200441, China.
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26
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The emerging role of the transcriptional coregulator RIP140 in solid tumors. Biochim Biophys Acta Rev Cancer 2015; 1856:144-50. [PMID: 26116758 DOI: 10.1016/j.bbcan.2015.06.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Revised: 06/19/2015] [Accepted: 06/23/2015] [Indexed: 11/22/2022]
Abstract
RIP140 is a transcriptional coregulator (also known as NRIP1) which plays very important physiological roles by finely tuning the activity of a large number of transcription factors. Noticeably, the RIP140 gene has been shown to be involved in the regulation of energy expenditure, in mammary gland development and intestinal homeostasis as well as in behavior and cognition. RIP140 is also involved in the regulation of various oncogenic signaling pathways and participates in the development and progression of solid tumors. This short review aims to summarize the role of this transcription factor on nuclear estrogen receptors, E2F and Wnt signaling pathways based on recent observations focusing on breast, ovary, liver and colon tumors.
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Zhang D, Wang Y, Dai Y, Wang J, Suo T, Pan H, Liu H, Shen S, Liu H. Downregulation of RIP140 in hepatocellular carcinoma promoted the growth and migration of the cancer cells. Tumour Biol 2015; 36:2077-2085. [PMID: 25391428 DOI: 10.1007/s13277-014-2815-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2014] [Accepted: 11/04/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies with a poor response to chemotherapy. It is very important to identify novel diagnosis biomarkers and therapeutic targets. RIP140, a regulator of estrogen receptor, recently has been found to be involved in the tumorigenesis. However, its function in the progression of HCC remains poorly understood. Here, we found that the expression of RIP140 was downregulated in the HCC tissues. Moreover, overexpression of RIP140 in HCC cells inhibited cell proliferation and migration, while downregulation of RIP140 promoted the tumorigenicity of HCC cells in vitro and in vivo. Mechanistically, RIP140 interacted with beta-catenin and negatively regulated beta-catenin/TCF signaling. Taken together, our study suggests the suppressive roles of RIP140 in the pathogenesis of HCC.
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Affiliation(s)
- Dexiang Zhang
- General Surgery Department, Zhongshan Hospital, General Surgery Institute, Fudan University, Shanghai, 200032, China
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28
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Abstract
Solid-pseudopapillary neoplasm of the pancreas (SPN) is an uncommon low-grade malignant neoplasm occurring mostly in young women. In addition to its distinctive pathological appearance of pseudopapillae with poorly cohesive neoplastic cells, rare variants exist raising the differential diagnosis especially with neuroendocrine neoplasms. The overall prognosis for patients with SPNs is excellent after surgical resection. Nevertheless, 10% of cases may have malignant behavior characterized by tumor recurrence and/or metastasis. Despite numerous studies, the histogenesis of this neoplasm remains unclear. Distinctive molecular alterations such as the presence of CTNNB1 mutations are observed in nearly all cases, while mutations classically observed in ductal adenocarcinoma, such as KRAS, TP53, and SMAD4, are not observed in SPNs, reinforcing its distinct nature compared to all other pancreatic neoplasms. Recent transcriptional studies have shown that activation of the Wnt/beta-catenin pathway in these tumors is associated with the upregulation of genes belonging to Notch, Hedgehog, and androgen receptor signaling pathways.
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Affiliation(s)
- Benoît Terris
- Service de Pathologie, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Hôpitaux universitaires Paris-Centre, Site Cochin, Paris, France.
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29
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Daige CL, Wiggins JF, Priddy L, Nelligan-Davis T, Zhao J, Brown D. Systemic delivery of a miR34a mimic as a potential therapeutic for liver cancer. Mol Cancer Ther 2014; 13:2352-60. [PMID: 25053820 DOI: 10.1158/1535-7163.mct-14-0209] [Citation(s) in RCA: 132] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
miR34a is a tumor-suppressor miRNA that functions within the p53 pathway to regulate cell-cycle progression and apoptosis. With apparent roles in metastasis and cancer stem cell development, miR34a provides an interesting opportunity for therapeutic development. A mimic of miR34a was complexed with an amphoteric liposomal formulation and tested in two different orthotopic models of liver cancer. Systemic dosing of the formulated miR34a mimic increased the levels of miR34a in tumors by approximately 1,000-fold and caused statistically significant decreases in the mRNA levels of several miR34a targets. The administration of the formulated miR34a mimic caused significant tumor growth inhibition in both models of liver cancer, and tumor regression was observed in more than one third of the animals. The antitumor activity was observed in the absence of any immunostimulatory effects or dose-limiting toxicities. Accumulation of the formulated miR34a mimic was also noted in the spleen, lung, and kidney, suggesting the potential for therapeutic use in other cancers.
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Affiliation(s)
| | | | | | | | - Jane Zhao
- Mirna Therapeutics, Inc., Austin, Texas
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Gebhardt R, Matz-Soja M. Liver zonation: Novel aspects of its regulation and its impact on homeostasis. World J Gastroenterol 2014; 20:8491-8504. [PMID: 25024605 PMCID: PMC4093700 DOI: 10.3748/wjg.v20.i26.8491] [Citation(s) in RCA: 200] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 02/20/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
Liver zonation, the spatial separation of the immense spectrum of different metabolic pathways along the liver sinusoids, is fundamental for proper functioning of this organ. Recent progress in elucidating localization and interactions of different metabolic pathways by using “omics” techniques and novel approaches to couple them with refined spatial resolution and in characterizing novel master regulators of zonation by using transgenic mice has created the basis for a deeper understanding of core mechanisms of zonation and their impact on liver physiology, pathology and metabolic diseases. This review summarizes the fascinating technical achievements for investigating liver zonation and the elucidation of an emerging network of master regulators of zonation that keep the plethora of interrelated and sometimes opposing functions of the liver in balance with nutritional supply and specific requirements of the entire body. In addition, a brief overview is given on newly described zonated functions and novel details on how diverse the segmentation of metabolic zonation may be. From these facts and developments a few fundamental principles are inferred which seem to rule zonation of liver parenchyma. In addition, we identify important questions that still need to be answered as well as interesting fields of research such as the connection of zonation with circadian rhythm and gender dimorphism which need to be pushed further, in order to improve our understanding of metabolic zonation. Finally, an outlook is given on how disturbance of liver zonation and its regulation may impact on liver pathology and the development of metabolic diseases.
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Lu LC, Shao YY, Lee YH, Hsieh MS, Hsiao CH, Lin HH, Kao HF, Ma YY, Yen FC, Cheng AL, Hsu CH. β-catenin (CTNNB1) mutations are not associated with prognosis in advanced hepatocellular carcinoma. Oncology 2014; 87:159-66. [PMID: 25012536 DOI: 10.1159/000362821] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Accepted: 04/08/2014] [Indexed: 12/22/2022]
Abstract
OBJECTIVES Mutation of the exon 3 of CTNNB1, the coding gene of β-catenin, is a crucial molecular mechanism leading to aberrant activation of the Wnt/β-catenin pathway, which is highly associated with the carcinogenesis of hepatocellular carcinoma (HCC). The prevalence and clinical significance of CTNNB1 mutations in advanced HCC remain unclear. METHODS Patients with advanced HCC and available pathologic tissues (either obtained when diagnosed at advanced or early stages) were enrolled in this study. Direct sequencing of exon 3 of CTNNB1 was performed to detect somatic mutations. The associations between CTNNB1 mutations and clinicopathologic features were analyzed. RESULTS A total of 115 patients were enrolled, among whom 78 (67.8%) had chronic hepatitis B virus infection. Twenty-one (18.3%) patients were found to have CTNNB1 mutations, all of which were missense mutations. The CTNNB1 mutation rates were similar among pathologic tissues obtained at advanced and early stages (17.5 and 20.0%, respectively). Patients aged over 60 years were more likely to have CTNNB1 mutations than patients younger than 60 years (32.6 vs. 8.7%, p = 0.001). The mutations were not associated with survival or other clinicopathologic features. CONCLUSION In patients with advanced HCC, CTNNB1 mutations were not prognostically significant. No apparent increase of CTNNB1 mutations occurred during the progression of HCC.
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Affiliation(s)
- Li-Chun Lu
- Department of Oncology, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan, ROC
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Yang CH, Wang HL, Lin YS, Kumar KPS, Lin HC, Chang CJ, Lu CC, Huang TT, Martel J, Ojcius DM, Chang YS, Young JD, Lai HC. Identification of CD24 as a cancer stem cell marker in human nasopharyngeal carcinoma. PLoS One 2014; 9:e99412. [PMID: 24955581 PMCID: PMC4067285 DOI: 10.1371/journal.pone.0099412] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Accepted: 05/14/2014] [Indexed: 12/18/2022] Open
Abstract
Cancer stem cells (CSCs) represent a unique sub-population of tumor cells with the ability to initiate tumor growth and sustain self-renewal. Although CSC biomarkers have been described for various tumors, only a few markers have been identified for nasopharyngeal carcinoma (NPC). In this study, we show that CD24+ cells isolated from human NPC cell lines express stem cell genes (Sox2, Oct4, Nanog, Bmi-1, and Rex-1), and show activation of the Wnt/β-catenin signaling pathway. CD24+ cells possess typical CSC characteristics that include enhanced cell proliferation, increased colony and sphere formation, maintenance of cell differentiation potential in prolonged culture, and enhanced resistance to chemotherapeutic drugs. Notably, CD24+ cells produce tumors following inoculation of as few as 500 cells in immunodeficient NOD/SCID mice. CD24+ cells further show increased invasion ability in vitro, which correlates with enhanced expression of matrix metalloproteinase 2 and 9. In summary, our results suggest that CD24 represents a novel CSC biomarker in NPC.
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Affiliation(s)
- Chun-Hung Yang
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
- Division of Applied Toxicology, Taiwan Agricultural Chemicals and Toxic Substances Research Institute, Council of Agriculture, Executive Yuan, Taichung, Taiwan, Republic of China
| | - Hui-Ling Wang
- Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, Republic of China
| | - Yi-Sheng Lin
- Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, Republic of China
| | - K. P. Shravan Kumar
- Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, Republic of China
| | - Hung-Chi Lin
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
- Division of Applied Toxicology, Taiwan Agricultural Chemicals and Toxic Substances Research Institute, Council of Agriculture, Executive Yuan, Taichung, Taiwan, Republic of China
| | - Chih-Jung Chang
- Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, Republic of China
- Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
| | - Chia-Chen Lu
- Department of Respiratory Therapy, Fu Jen Catholic University, Taipei, Taiwan, Republic of China
| | - Tsung-Teng Huang
- Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, Republic of China
- Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
- Research Center of Bacterial Pathogenesis, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
| | - Jan Martel
- Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
| | - David M. Ojcius
- Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
- Department of Molecular Cell Biology and Health Sciences Research Institute, University of California Merced, Merced, California, United States of America
| | - Yu-Sun Chang
- Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
| | - John D. Young
- Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
- Laboratory of Cellular Physiology and Immunology, Rockefeller University, New York, New York, United States of America
- Biochemical Engineering Research Center, Ming Chi University of Technology, Taipei, Taiwan, Republic of China
- * E-mail: (JDY); (HCL)
| | - Hsin-Chih Lai
- Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, Republic of China
- Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
- Research Center of Bacterial Pathogenesis, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
- * E-mail: (JDY); (HCL)
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Galuppo R, Maynard E, Shah M, Daily MF, Chen C, Spear BT, Gedaly R. Synergistic inhibition of HCC and liver cancer stem cell proliferation by targeting RAS/RAF/MAPK and WNT/β-catenin pathways. Anticancer Res 2014; 34:1709-1713. [PMID: 24692700 PMCID: PMC5733784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
BACKGROUND/AIM The aim of this study is to find synergistic effect using FH535 and sorafenib by targeting the RAS/RAF/MAPK and WNT/β-catenin pathways. MATERIALS AND METHODS 3H-Thymidine incorporation assays were performed to address Huh7 and liver cancer stem cell (LCSC) inhibition using FH535 and sorafenib, alone and in combination. Calcusyn analysis was used to calculate the combination index (CI). A western blot assay was performed to check for potential targets. RESULTS FH535 and sorafenib caused inhibition of Huh7 and LCSC. Combination therapy was significantly better than monotherapy in inhibition of HuH7. Combination with sorafenib and FH535 was found to be synergistic in inhibition of LCSC with a CI of less than 1. The western blot assay demonstrated enhanced cleaved poly (ADP-ribose) polymerase (PARP) and inhibition of cyclin D1, B-cell lymphoma 2 (Bcl2), survivin and cellular myelocytomatosis oncogene (c-MYC). CONCLUSION FH535 and sorafenib combination produced synergistic effect on inhibition of HCC and LCSC. Our study demonstrated that FH535 can induce apoptosis in these two different hepatocellular carcinoma (HCC) cell lines.
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Affiliation(s)
- Roberto Galuppo
- 800 Rose Street, Room C453, Lexington, Kentucky 40536-0293, U.S.A.
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Gu X, Yao L, Ma G, Cui L, Li Y, Liang W, Zhao B, Li K. TCTP promotes glioma cell proliferation in vitro and in vivo via enhanced β-catenin/TCF-4 transcription. Neuro Oncol 2013; 16:217-27. [PMID: 24311645 DOI: 10.1093/neuonc/not194] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Background The translationally controlled tumor protein (TCTP) is a multifunctional protein that plays important roles in immune responses, cell proliferation, tumorigenicity and cell apoptosis. Here, we examined the clinical value of TCTP in glioma patient survival and investigated the functional roles and mechanism of TCTP in glioma development. Methods TCTP expression was determined through immunohistochemical staining, immunoblotting, and quantitative real-time PCR (qRT-PCR). TCTP or TCF-4 expression was silenced using short hairpin (sh) RNA. In vitro cell proliferation was detected using MTT, BrdU and colony formation assays, and in vivo tumor growth was performed using the xenograft model. TCTP/TCF-4/β-catenin association was detected using a co-immunoprecipitation (co-IP) assay. TCF-4 transcription activity was detected using a TOPflash/FOPflash report gene assay. Wnt/β-catenin-targeted gene expression was detected through Western blotting. Results TCTP protein levels were significantly elevated in high-grade gliomas compared with low-grade gliomas and normal brain tissues. Importantly, the expression of TCTP was significantly associated with poorer overall survival and disease-free survival, and TCTP also reduced the survival rate after treatment with radiotherapy and temozolomide (RT-TMZ) for glioma patients. The ectopic expression of TCTP enhanced glioma cell proliferation both in vitro and in vivo, whereas the knockdown of TCTP inhibited this effect. Similarly, the overexpression of TCTP increased β-catenin binding to TCF-4, TOPflash report gene transcription activity, and the expression of Wnt/β-catenin signaling target genes including c-Myc and cyclin D1; notably, the knockdown of TCTP reduced these effects. The knockdown of TCF-4 using shRNA rescued the enhanced cell proliferation induced by the overexpression of TCTP. Conclusion TCTP is associated with reduced survival of glioma patients and induces glioma tumor growth through enhanced Wnt/β-catenin signaling.
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Affiliation(s)
- Xuefeng Gu
- Corresponding authors: Keshen Li, MD, PhD, Institute of Neurology, Guangdong Medical College, Zhanjiang 524001, China. ); Bin Zhao, MD, PhD, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, China (
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Shen L, Zhang X, Hu D, Feng T, Li H, Lu Y, Huang J. Hepatitis B virus X (HBx) play an anti-apoptosis role in hepatic progenitor cells by activating Wnt/β-catenin pathway. Mol Cell Biochem 2013; 383:213-22. [PMID: 23934090 DOI: 10.1007/s11010-013-1769-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Accepted: 08/02/2013] [Indexed: 12/16/2022]
Abstract
Increasing evidence has shown that normal stem cells may act as cancer-initiating cells and contribute to the development and progression of cancer. HBx has a close relationship with hepatocellular carcinoma, however, the role of HBx in hepatic progenitor cells (HPCs) is poorly understood. In this study, we sought to determine the role of HBx in regulating HPCs apoptosis and the underlying molecular mechanism(s) using HPCs derived from mouse fetal liver. The apoptotic ratio of HPCs infected with adenovirus-expressing HBx (Ad-HBx) was examined using flow cytometry. Results showed that the Ad-HBx treatment led to substantially decreased apoptotic ratio of HPCs, as confirmed by the Hoechst 33342 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL). Possible alterations of relative proteins were examined using Western blot and real-time PCR assays. The HBx expression in HPCs increased the expression levels of Bcl2 and Mcl1 while decreasing the expression levels of Bax and cleaved caspase-9 and -3. In addition, the mRNA and protein expression levels of β-catenin were both increased. The β-catenin protein were mainly accumulated in cytoplasm and tended to transfer into cell nucleus after Ad-HBx treatment. The over-expression of β-catenin decreased the apoptotic ratio of HPCs and inhibited the expression of cleaved caspase-9 and -3 while blocking β-catenin expression resulted in the opposite results. Taken together, our results strongly suggested that the HBx protein may inhibits apoptosis of hepatic progenitor cells, at least in part by activating the WNT/β-catenin pathway. This provided a new insight into the molecular mechanism of HBx-mediated live carcinogenesis.
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Affiliation(s)
- Lihong Shen
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, People's Republic of China
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Radulescu S, Ridgway RA, Cordero J, Athineos D, Salgueiro P, Poulsom R, Neumann J, Jung A, Patel S, Woodgett J, Barker N, Pritchard DM, Oien K, Sansom OJ. Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation. Oncogene 2013; 32:2048-57. [PMID: 22665058 PMCID: PMC3631308 DOI: 10.1038/onc.2012.224] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Revised: 04/13/2012] [Accepted: 04/22/2012] [Indexed: 02/08/2023]
Abstract
A role for WNT signalling in gastric carcinogenesis has been suggested due to two major observations. First, patients with germline mutations in adenomatous polyposis coli (APC) are susceptible to stomach polyps and second, in gastric cancer, WNT activation confers a poor prognosis. However, the functional significance of deregulated WNT signalling in gastric homoeostasis and cancer is still unclear. In this study we have addressed this by investigating the immediate effects of WNT signalling activation within the stomach epithelium. We have specifically activated the WNT signalling pathway within the mouse adult gastric epithelium via deletion of either glycogen synthase kinase 3 (GSK3) or APC or via expression of a constitutively active β-catenin protein. WNT pathway deregulation dramatically affects stomach homoeostasis at very short latencies. In the corpus, there is rapid loss of parietal cells with fundic gland polyp (FGP) formation and adenomatous change, which are similar to those observed in familial adenomatous polyposis. In the antrum, adenomas occur from 4 days post-WNT activation. Taken together, these data show a pivotal role for WNT signalling in gastric homoeostasis, FGP formation and adenomagenesis. Loss of the parietal cell population and corresponding FGP formation, an early event in gastric carcinogenesis, as well as antral adenoma formation are immediate effects of nuclear β-catenin translocation and WNT target gene expression. Furthermore, our inducible murine model will permit a better understanding of the molecular changes required to drive tumourigenesis in the stomach.
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Affiliation(s)
- S Radulescu
- CR-UK Beatson Institute of Cancer Research, Glasgow, UK
| | - R A Ridgway
- CR-UK Beatson Institute of Cancer Research, Glasgow, UK
| | - J Cordero
- CR-UK Beatson Institute of Cancer Research, Glasgow, UK
| | - D Athineos
- CR-UK Beatson Institute of Cancer Research, Glasgow, UK
| | - P Salgueiro
- CR-UK Beatson Institute of Cancer Research, Glasgow, UK
- Institute of Medical Biology, A*STAR, 8A Biomedical Grove, Immunos, Singapore
| | - R Poulsom
- Histopathology Lab, CR-UK London Research Institute, London, UK
| | - J Neumann
- Pathologisches Institut, Ludwig-Maximilians Universität München, München, Germany
| | - A Jung
- Pathologisches Institut, Ludwig-Maximilians Universität München, München, Germany
| | - S Patel
- Samuel Lunenfeld Research Institute, Toronto, ON, Canada
| | - J Woodgett
- Samuel Lunenfeld Research Institute, Toronto, ON, Canada
| | - N Barker
- Institute of Medical Biology, A*STAR, 8A Biomedical Grove, Immunos, Singapore
| | - D M Pritchard
- Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - K Oien
- Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - O J Sansom
- CR-UK Beatson Institute of Cancer Research, Glasgow, UK
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Shen HJ, Zhu HY, Yang C, Ji F. SENP2 regulates hepatocellular carcinoma cell growth by modulating the stability of β-catenin. Asian Pac J Cancer Prev 2013; 13:3583-7. [PMID: 23098437 DOI: 10.7314/apjcp.2012.13.8.3583] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
SUMOylation has emerged as an important post-translational modification that modulates the localization, stability and activity of a broad spectrum of proteins. A dynamic process, it can be reversed by a family of SUMO- specific proteases (SENPs). However, the biological roles of SENPs in mammalian development and pathogenesis remain largely elusive. Here, we demonstrated that SENP2 plays a critical role in the control of hepatocellular carcinoma cell growth. SENP2 was found to be down-regulated in hepatocellular carcinoma (HCC) tissues and over-expression suppressed the growth and colony formation of HCC cells. In contrast, silencing of SENP2 by siRNAs promoted cancer cell growth. We further found that stability of β-catenin was markedly decreased when SENP2 was over-expressed. Interestingly, the decrease was dependent on the de-SUMOylation activity of SENP2, because over-expression of a SENP2 catalytic mutant form had no obviously effects on β-catenin. Our results suggest that SENP2 might play a role in hepatocellular carcinoma cell growth control by modulating the stability of β-catenin.
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Affiliation(s)
- Huo-Jian Shen
- Department of General Surgery, Renji hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Abstract
Solid tumors are thought to contain cancer stem cells (CSCs) as a distinct population responsible for tumor relapse and metastasis due to their abilities to self-renew, differentiate, and give rise to a new tumor in local or distant organs. CSCs have been identified in many tumor types, including hepatocellular carcinoma (HCC), the fifth most common and third most deadly malignancy with observable heterogeneity. Numerous studies have shown that hepatic CSCs could be enriched via different cell surface markers, eg, CD13, CD24, CD44, CD90, CD133, EpCAM (CD326), and OV6. They also could be identified through functional assays such as isolating the side population cells by Hoechst dye staining or screening cells with a high activity of aldehyde dehydrogenase. Functional characterization of hepatic CSCs has revealed several deregulated signaling pathways, such as Wnt/β-catenin, AKT, transforming growth factor-beta (TGF-β), interleukin (IL)-6/STAT3 pathways to be critical in inducing "stemness" of HCC and in promoting self-renewal, tumorigenicity, and chemoresistance. An increased understanding of hepatic CSC biology facilitated the development of new diagnostic, prognostic, and therapeutic strategies for improving HCC clinical management. In this review, we summarize recent evidence including the identification of the hepatic CSC and its underlying biological mechanisms, and discuss the potential clinical implications in HCC.
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Affiliation(s)
- Junfang Ji
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Yang T, Cai SY, Zhang J, Lu JH, Lin C, Zhai J, Wu MC, Shen F. Krüppel-like factor 8 is a new Wnt/beta-catenin signaling target gene and regulator in hepatocellular carcinoma. PLoS One 2012; 7:e39668. [PMID: 22761862 PMCID: PMC3384617 DOI: 10.1371/journal.pone.0039668] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Accepted: 05/24/2012] [Indexed: 12/31/2022] Open
Abstract
Krüppel-like factor 8 (KLF8) plays important role in cell cycle and oncogenic transformation. Here we report the mechanisms by which KLF8 crosstalks with Wnt/β-catenin signaling pathway and regulates hepatocellular carcinoma (HCC) cells proliferation. We show that overexpression of KLF8 and nucleus accumulation of β-catenin in the human HCC samples are positively correlated. More importantly, KLF8 protein levels plus nucleus accumulation of β-catenin levels were significantly elevated in high-grade HCC compared to low-grade HCC. Using HCC HepG2 cells we find that, on the one hand both protein and mRNA of KLF8 are up-regulated under Wnt3a stimulation, on the other hand overexpression of KLF8 increases the cytoplasm and nucleus accumulation of β-catenin, recruits p300 to β-catenin/T-cell factor 4 (TCF4) transcription complex, enhances TOP flash report gene transcription, and induces Wnt/β-catenin signaling target genes c-Myc, cyclin D1 and Axin1 expression. Knockdown of KLF8 using shRNA inhibits Wnt3a induced transcription of TOP flash report gene and expression of c-Myc, cyclin D1 and Axin1. Knockdown of β-catenin by shRNA rescues the enhanced HepG2 and Hep3B cells proliferation ability induced by overexpression of KLF8.
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Affiliation(s)
- Tian Yang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Sheng-Yun Cai
- Department of Gynaecology and Obstetrics, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Jin Zhang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jun-Hua Lu
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Chuan Lin
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jian Zhai
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Meng-Chao Wu
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Feng Shen
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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Waly Raphael S, Yangde Z, YuXiang C. Hepatocellular carcinoma: focus on different aspects of management. ISRN ONCOLOGY 2012; 2012:421673. [PMID: 22655206 PMCID: PMC3359687 DOI: 10.5402/2012/421673] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/08/2012] [Accepted: 03/04/2012] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third cause of cancer-related mortality worldwide. Its incidence is clearly arising comprised by the prevalence of major risk factors mainly hepatitis B and hepatitis C. The population at risk is composed of chronic liver patients at the stage of extensive fibrosis or cirrhosis. The monitoring programs of this population have allowed early detection of disease management to promote a radical therapy. Understanding the carcinogenic process and the mastery of the staging systems remain essential keys in diagnosis and treatment of HCC. Recent advances in diagnosis and new treatments have made important impacts on the disease by increasing survival rates and improving quality of life for HCC patients. This paper outlines the different management aspects of HCC which include epidemiology, prevention, carcinogenesis, staging systems, diagnosis, surveillance, and the treatment.
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Affiliation(s)
- Sene Waly Raphael
- National Hepatobiliary and Enteric Surgery Research Center of Ministry of Health, Central South University, Changsha, Hunan 410008, China
| | - Zhang Yangde
- National Hepatobiliary and Enteric Surgery Research Center of Ministry of Health, Central South University, Changsha, Hunan 410008, China
| | - Chen YuXiang
- National Hepatobiliary and Enteric Surgery Research Center of Ministry of Health, Central South University, Changsha, Hunan 410008, China
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A Complex Interplay between Wnt/β-Catenin Signalling and the Cell Cycle in the Adult Liver. Int J Hepatol 2012; 2012:816125. [PMID: 22973520 PMCID: PMC3438741 DOI: 10.1155/2012/816125] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Accepted: 08/02/2012] [Indexed: 12/19/2022] Open
Abstract
Canonical Wnt signalling, governed by its effector β-catenin, is known for a long time as playing an important role in development, tissue homeostasis, and cancer. In the liver, it was unravelled as both an oncogenic pathway involved in a subset of liver cancers and a physiological signalling identified as the "zonation-keeper" of the quiescent liver lobule. This duality has encouraged to explore the role of canonical Wnt in liver regeneration and liver-cell proliferation mainly using murine genetic models of β-catenin overactivation or inactivation. These studies definitely integrate Wnt signalling within the hepatic network driving regeneration and proliferation. We will review here the current knowledge concerning the mitogenic effect of Wnt, to switch on its specific role in the liver, which is quiescent but with a great capacity to regenerate. The duality of β-catenin signalling, associated both with liver quiescence and liver-cell proliferation, will be brought forward.
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Depletion of β-catenin from mature hepatocytes of mice promotes expansion of hepatic progenitor cells and tumor development. Proc Natl Acad Sci U S A 2011; 108:18384-9. [PMID: 22042854 DOI: 10.1073/pnas.1116386108] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Depletion of β-catenin impairs regeneration of the rapid turn-over gut epithelial cells, but appears dispensable for that of the slow turn-over mature hepatocytes in mice until 1 y of age. As the life span of mature murine hepatocytes is about 400 d, we studied conditional β-catenin knockout mice (Alb-Cre;Ctnnb1(flx/flx)) until 20 mo of age to determine the function of β-catenin in the postnatal liver. β-catenin was absent from the hepatocytes of β-catenin knockout mice 4 wk after delivery. From 9 mo of age, hepatocytes were gradually replaced by newly formed β-catenin-positive hepatocytes, which constituted about 90% of hepatocytes at 18-20 mo of age. This process was accompanied by active proliferation of bile duct/ductule cells. β-catenin-positive hepatocytes exhibited elevated proliferation activity and expression of progenitor cell markers, but lower albumin and Cre. This might explain their intact β-catenin protein, and suggest their origins from hepatic progenitor cells. Liver tumors arose spontaneously from β-catenin-positive cells, and tumorigenesis was accelerated by hepatitis B X protein. These results indicate β-catenin critical for the regeneration of mature hepatocytes. Failure to regenerate mature hepatocytes results in proliferation of hepatic progenitor cells that are able to maintain liver function but are predisposed to form liver tumors.
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Torre C, Perret C, Colnot S. Molecular determinants of liver zonation. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2011; 97:127-50. [PMID: 21074732 DOI: 10.1016/b978-0-12-385233-5.00005-2] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The phenomenon of "liver zonation" is a remarkable process by which the liver fulfills its metabolic functions, involving highly dynamic transcriptional mechanisms. Its understanding is therefore a challenging issue. Zonation is reflected in heterogeneity of hepatocytes along the porto-central axis of the liver: periportal hepatocytes, located in the vicinity of the afferent portal vein, do not express the same metabolic enzymes than pericentral hepatocytes located near the efferent central vein. This is mainly dictated at the transcriptional level by specific pericentral versus periportal genetic programs. The mechanisms by which zonation is established have been extensively investigated since its initial discovery 40 years ago. The discovery in 2006 that Wnt/β-catenin pericentral signaling was a master regulator of this complex liver topology has been a major breakthrough. A major current priority in the field is the integration of the β-catenin pathway with other determinants that govern zonation of the liver.
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Affiliation(s)
- Cyril Torre
- Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
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Torre C, Benhamouche S, Mitchell C, Godard C, Veber P, Letourneur F, Cagnard N, Jacques S, Finzi L, Perret C, Colnot S. The transforming growth factor-α and cyclin D1 genes are direct targets of β-catenin signaling in hepatocyte proliferation. J Hepatol 2011; 55:86-95. [PMID: 21145869 DOI: 10.1016/j.jhep.2010.10.021] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2010] [Revised: 10/11/2010] [Accepted: 10/18/2010] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS β-Catenin is an oncogene frequently mutated in hepatocellular carcinoma. In this study, we investigated target genes of β-catenin signaling in hepatocyte proliferation. METHODS We studied transgenic mice displaying either inactivation or activation of the β-catenin pathway, focusing on analysis of liver proliferation due to aberrant β-catenin activation, and on the regeneration process during which β-catenin signaling is transiently activated. We localized in situ the various partners involved in proliferation or identified as targets of β-catenin in these transgenic and regenerating livers. We also performed comparative transcriptome analyses, using microarrays. Finally, we extracted, from deep-sequencing data, both the DNA regulatory elements bound to the β-catenin/Tcf nuclear complex and the expression levels of critical targets identified in microarrays. RESULTS β-Catenin activation during liver regeneration occurred during G1/S cell cycle progression and allowed zonal extension of the normal territory of active β-catenin and panlobular proliferation. We found that β-catenin controlled both cell-autonomous and non-cell-autonomous hepatocyte proliferation, through direct transcriptional and complex control of cyclin D1 gene expression and of the expression of a new target gene, Tgfα. CONCLUSIONS We propose that β-catenin controls panlobular hepatocyte proliferation partly by controlling, together with its Tcf4 nuclear partner, expression of the pro-proliferation cyclin D1 and Tgfα genes. This study constitutes a first step toward understanding the oncogenic properties of this prominent signaling pathway in the liver.
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Affiliation(s)
- Cyril Torre
- Institut Cochin, Université Paris Descartes, CNRS UMR 8104 Paris, France
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TP63 P2 promoter functional analysis identifies β-catenin as a key regulator of ΔNp63 expression. Oncogene 2011; 30:4656-65. [PMID: 21643019 DOI: 10.1038/onc.2011.171] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The ΔNp63 protein, a product of the TP63 gene that lacks the N-terminal domain, has a critical role in the maintenance of self renewal and progenitor capacity in several types of epithelial tissues. ΔNp63 is frequently overexpressed in squamous cell carcinoma (SCC) and in some other epithelial tumours. This overexpression may contribute to tumour progression through dominant-negative effects on the transcriptionally active (TA) isoforms of the p53 family (TAp63, TAp73 and p53), as well as through independent mechanisms. However, the molecular basis of ΔNp63 overexpression is not fully understood. Here, we show that the expression of ΔNp63 is regulated by the Wnt/β-catenin pathway in human hepatocellular carcinoma (HCC) and SCC cell lines. This regulation operates in particular through TCF/LEF sites present in the P2 promoter of TP63. In addition, we show that ΔNp63 and β-catenin are frequently coexpressed and accumulated in oesophageal SCC, but not in HCC. These results suggest that activation of the β-catenin pathway may contribute to overexpression of ΔNp63 during tumour progression, in a cell type-specific manner.
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Stauffer JK, Scarzello AJ, Andersen JB, DeKluyver RL, Back TC, Weiss JM, Thorgeirsson SS, Wiltrout RH. Coactivation of AKT and β-catenin in mice rapidly induces formation of lipogenic liver tumors. Cancer Res 2011; 71:2718-27. [PMID: 21324921 PMCID: PMC3074499 DOI: 10.1158/0008-5472.can-10-2705] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Obesity is a risk factor for development of certain cancers but the basis for this risk is unclear. In this study, we developed a novel mouse model that demonstrates directly how lipogenic phenotypes commonly associated with diet-induced metabolic syndromes can influence hepatic cancer development. Activated AKT and β-catenin (AKT/CAT) genes were hydrodynamically codelivered using the Sleeping Beauty transposon to initiate liver tumorigenesis. AKT/CAT and MET/CAT combination induced microscopic tumor foci by 4 weeks, whereas no tumorigenesis resulted from delivery of AKT, MET, or CAT alone. Primary AKT/CAT tumor cells were steatotic (fatty) hepatocellular adenomas which progressed to hepatocellular carcinomas (HCC) upon in vivo passage, whereas primary MET/CAT tumors emerged directly as frank HCC. Conversion of AKT/CAT tumor cells to frank HCC during passage was associated with induction of the human HCC marker α-fetoprotein and the stem cell marker CD133. Using hierarchical clustering and gene set enrichment analysis, we compared the primary murine AKT/CAT and MET/CAT tumors to a panel of 53 human HCCs and determined that these two mouse models could be stratified as distinct subtypes associated in humans with poor clinical prognosis. The chief molecular networks identified in primary and passaged AKT/CAT tumors were steatosis and lipid metabolic pathways, respectively. Our findings show how coactivation of the AKT and CAT pathways in hepatocytes can efficiently model development of a lipogenic tumor phenotype. Furthermore, we believe that our approach could speed the dissection of microenvironmental factors responsible for driving steatotic-neoplastic transformation to frank carcinoma, through genetic modification of existing immunodefined transgenic models.
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Choi SS, Omenetti A, Syn WK, Diehl AM. The role of Hedgehog signaling in fibrogenic liver repair. Int J Biochem Cell Biol 2011; 43:238-44. [PMID: 21056686 PMCID: PMC3022074 DOI: 10.1016/j.biocel.2010.10.015] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2009] [Revised: 09/14/2010] [Accepted: 10/28/2010] [Indexed: 12/13/2022]
Abstract
Repair of adult liver, like many tissues, involves the coordinated response of a number of different cell types. In adult livers, fibroblastic cells, ductular cells, inflammatory cells, and progenitor cells contribute to this process. Our studies demonstrate that the fates of such cells are dictated, at least in part, by Hedgehog, a fetal morphogenic pathway that was once thought to be active mainly during embryogenesis. Studies of injured adult human and rodent livers demonstrate that injury-related activation of the Hedgehog pathway modulates several important aspects of repair, including the growth of hepatic progenitor populations, hepatic accumulation of myofibroblasts, repair-related inflammatory responses, vascular remodeling, liver fibrosis and hepatocarcinogenesis. These findings identify the Hedgehog pathway as a potentially important target for biomarker development and therapeutic manipulation, and emphasize the need for further research to advance knowledge about how this pathway is regulated by and interacts with other signals that regulate adult liver repair.
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Affiliation(s)
- Steve S. Choi
- Division of Gastroenterology, Duke University Medical Center, Durham, NC
- Section of Gastroenterology, Durham Veterans Affairs Medical Center, Durham, NC
| | - Alessia Omenetti
- Division of Gastroenterology, Duke University Medical Center, Durham, NC
| | - Wing-Kin Syn
- Division of Gastroenterology, Duke University Medical Center, Durham, NC
| | - Anna Mae Diehl
- Division of Gastroenterology, Duke University Medical Center, Durham, NC
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Mécanismes de carcinogenèse hépatique : quelles pistes pour la radiosensibilisation ? Cancer Radiother 2011; 15:32-8. [DOI: 10.1016/j.canrad.2010.11.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2010] [Accepted: 07/27/2010] [Indexed: 01/18/2023]
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Kumar M, Zhao X, Wang XW. Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: one step closer to personalized medicine? Cell Biosci 2011. [PMID: 21711594 DOI: 10.1186/2045-3701-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two major forms of primary liver cancers (PLC), accounting for approximately 90% and 5% respectively. The incidence of each is increasing rapidly in the western world, however our knowledge of the underlying mechanisms remains limited and the outcome, dismal. The etiologies of each vary geographically; nevertheless, chronic inflammation has been identified in more than 80% of the cases and appears to be a key mediator in altering the liver microenvironment, increasing the risk of carcinogenesis. However, since not all HCC and especially ICC cases have a recognized risk factor, there are currently two proposed models for liver carcinogenesis. The clonal evolution model demonstrates a multi-step process of tumor development from precancerous lesions to metastatic carcinoma, arising from the accumulation of genetic and epigenetic changes in a cell in the setting of chronic inflammation. While the majority of cases do occur as a consequence of chronic inflammation, most individuals with chronic infection do not develop PLC, suggesting the involvement of individual genetic and environmental factors. Further, since hepatocytes and cholangiocytes both have regenerative potential and arise from the same bi-potential progenitor cell, the more recently proposed cancer stem cell model is gaining its due attention. The integration of these models and the constant improvement in molecular profiling platforms is enabling a broader understanding of the mechanisms underlying these two devastating malignancies, perhaps moving us closer to a new world of molecularly-informed personalized medicine.
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Affiliation(s)
- Mia Kumar
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
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Kumar M, Zhao X, Wang XW. Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: one step closer to personalized medicine? Cell Biosci 2011; 1:5. [PMID: 21711594 PMCID: PMC3116244 DOI: 10.1186/2045-3701-1-5] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Accepted: 01/24/2011] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two major forms of primary liver cancers (PLC), accounting for approximately 90% and 5% respectively. The incidence of each is increasing rapidly in the western world, however our knowledge of the underlying mechanisms remains limited and the outcome, dismal. The etiologies of each vary geographically; nevertheless, chronic inflammation has been identified in more than 80% of the cases and appears to be a key mediator in altering the liver microenvironment, increasing the risk of carcinogenesis. However, since not all HCC and especially ICC cases have a recognized risk factor, there are currently two proposed models for liver carcinogenesis. The clonal evolution model demonstrates a multi-step process of tumor development from precancerous lesions to metastatic carcinoma, arising from the accumulation of genetic and epigenetic changes in a cell in the setting of chronic inflammation. While the majority of cases do occur as a consequence of chronic inflammation, most individuals with chronic infection do not develop PLC, suggesting the involvement of individual genetic and environmental factors. Further, since hepatocytes and cholangiocytes both have regenerative potential and arise from the same bi-potential progenitor cell, the more recently proposed cancer stem cell model is gaining its due attention. The integration of these models and the constant improvement in molecular profiling platforms is enabling a broader understanding of the mechanisms underlying these two devastating malignancies, perhaps moving us closer to a new world of molecularly-informed personalized medicine.
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Affiliation(s)
- Mia Kumar
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
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