Wnt/beta-catenin signaling pathway in hepatocellular carcinomas cases from Colombia.

BACKGROUND AND AIM Hepatocellular carcinoma (HCC) is the most common primary liver cancer diagnosed worldwide. Deregulation of Wnt/beta-catenin pathway has been associated with the development of HCC in a substantial number of cases in Europe and far less in Asia. Nothing is known about this pathway in HCC cases from South America. This study aimed to investigate the frequency of mutations in beta-catenin gene (CTNNB1) and the subcellular localization of beta-catenin in HCC cases from Colombia. MATERIAL AND METHODS We determine by direct sequencing the frequency of mutations in exon 3 of CTNNB1 gene and by immunohistochemistry the subcellular localization of beta-catenin in 54 samples of HCC obtained from three pathology units in Bogota and Medellin cities. RESULTS Only three HCC cases (5.6%) were found mutated at residues (G34E, S45P, P44S, T41I) important for phosphorylation and ubiquitination of beta-catenin protein. Strikingly, nuclear or cytoplasmic accumulation of beta-catenin, hallmark of Wnt pathway activation, was found in 42.6% HCC cases (23/54). Interestingly, beta-catenin accumulation was significantly more frequent in young patients and hepatitis B virus-related HCC. CONCLUSIONS Although, CTNNB1 exon 3 mutations are not frequent in HCC from Colombian patients, our findings indicate that Wnt/beta-catenin signaling is activated in 42.6% of HCC samples. Furthermore, Wnt signaling was demonstrated in HCC cases associated of HBV infection, one of the most important HCC risk factors in Colombia.

[1]  Fan Zhou,et al.  Epigenetic silencing of SFRP1 and SFRP5 by hepatitis B virus X protein enhances hepatoma cell tumorigenicity through Wnt signaling pathway , 2014, International journal of cancer.

[2]  S. Friedman,et al.  β-Catenin signaling in hepatocellular cancer: Implications in inflammation, fibrosis, and proliferation. , 2014, Cancer letters.

[3]  P. Pineau,et al.  Somatic changes in primary liver cancer in Russia: a pilot study. , 2013, Mutation research.

[4]  F. Izzo,et al.  Mutations in TP53, CTNNB1 and PIK3CA genes in hepatocellular carcinoma associated with hepatitis B and hepatitis C virus infections. , 2013, Genomics.

[5]  Yiliang Zhang,et al.  Hepatitis C virus‐induced up‐regulation of microRNA‐155 promotes hepatocarcinogenesis by activating Wnt signaling , 2012, Hepatology.

[6]  M. Ozturk,et al.  Genetics and epigenetics of liver cancer. , 2012, New biotechnology.

[7]  S. Imbeaud,et al.  Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma , 2012, Nature Genetics.

[8]  T. He,et al.  Enhancement of Canonical Wnt/β-Catenin Signaling Activity by HCV Core Protein Promotes Cell Growth of Hepatocellular Carcinoma Cells , 2011, PloS one.

[9]  P. Hainaut,et al.  Hepatitis B and Hepatitis C Infection Biomarkers and TP53 Mutations in Hepatocellular Carcinomas from Colombia , 2011, Hepatitis Research and Treatment.

[10]  M. Navas,et al.  Etiology and Viral Genotype in Patients with End-Stage Liver Diseases admitted to a Hepatology Unit in Colombia , 2011, Hepatitis research and treatment.

[11]  S. Monga,et al.  Role of Wnt/β-catenin signaling in liver metabolism and cancer. , 2011, The international journal of biochemistry & cell biology.

[12]  K. McGlynn,et al.  The global epidemiology of hepatocellular carcinoma: present and future. , 2011, Clinics in liver disease.

[13]  N. Nishida,et al.  Genetic and Epigenetic Signatures in Human Hepatocellular Carcinoma: A Systematic Review , 2011, Current genomics.

[14]  Seung-Oe Lim,et al.  Hepatitis B viral X protein interacts with tumor suppressor adenomatous polyposis coli to activate Wnt/β-catenin signaling. , 2011, Cancer letters.

[15]  J. Plouhinec,et al.  Wnt Signaling Requires Sequestration of Glycogen Synthase Kinase 3 inside Multivesicular Endosomes , 2010, Cell.

[16]  W. Blonski,et al.  Non-viral causes of hepatocellular carcinoma. , 2010, World journal of gastroenterology.

[17]  Seung-Oe Lim,et al.  Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: methylation of the E-cadherin promoter. , 2008, Gastroenterology.

[18]  M. Toyota,et al.  Frequent epigenetic inactivation of SFRP genes in hepatocellular carcinoma , 2008, Journal of Gastroenterology.

[19]  P. Hainaut,et al.  Ser-249 TP53 and CTNNB1 mutations in circulating free DNA of Egyptian patients with hepatocellular carcinoma versus chronic liver diseases. , 2008, Cancer letters.

[20]  Jing Zhao,et al.  Large-scale analysis of the genetic and epigenetic alterations in hepatocellular carcinoma from Southeast China. , 2008, Mutation research.

[21]  Xi He,et al.  Wnt/beta-catenin signaling: new (and old) players and new insights. , 2008, Current opinion in cell biology.

[22]  Ji-yong Wang,et al.  Nuclear Dvl, c-Jun, β-catenin, and TCF form a complex leading to stabiLization of β-catenin–TCF interaction , 2008, The Journal of cell biology.

[23]  Rolf Gebhardt,et al.  Correlation between β-catenin mutations and expression of Wnt-signaling target genes in hepatocellular carcinoma , 2008, Molecular Cancer.

[24]  Ji-Shin Lee,et al.  Genetic alterations of Wnt signaling pathway–associated genes in hepatocellular carcinoma , 2007, Journal of gastroenterology and hepatology.

[25]  Xin Wei Wang,et al.  Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma. , 2007, Cancer research.

[26]  S. Boyault,et al.  Differential effects of inactivated Axin1 and activated β-catenin mutations in human hepatocellular carcinomas , 2007, Oncogene.

[27]  S. Hirohashi,et al.  Genetic inactivation of the APC gene contributes to the malignant progression of sporadic hepatocellular carcinoma: A case report , 2006, Genes, chromosomes & cancer.

[28]  B. Gumbiner,et al.  Regulation of cadherin-mediated adhesion in morphogenesis , 2005, Nature Reviews Molecular Cell Biology.

[29]  W. Park,et al.  Mutations of β‐catenin and AXIN I genes are a late event in human hepatocellular carcinogenesis , 2005, Liver international : official journal of the International Association for the Study of the Liver.

[30]  Miran Kim,et al.  Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma. , 2004, Gastroenterology.

[31]  T. Kurihara,et al.  Immunohistochemical analysis and mutational analyses of beta-catenin, Axin family and APC genes in hepatocellular carcinomas. , 2004, International journal of oncology.

[32]  M. Matsuda,et al.  Alterations of RB1, p53 and Wnt pathways in hepatocellular carcinomas associated with hepatitis C, hepatitis B and alcoholic liver cirrhosis , 2003, International journal of cancer.

[33]  David I. Smith,et al.  Mutational spectrum of β-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas , 2002, Oncogene.

[34]  G. Thomas,et al.  Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. , 2001, Gastroenterology.

[35]  C. Li,et al.  Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Y. Jeng,et al.  Beta-catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. , 2000, The American journal of pathology.

[37]  Y. L. Le Treut,et al.  Immunoexpression of E-cadherin and beta-catenin correlates to survival of patients with hepatocellular carcinomas. , 1998, International journal of oncology.

[38]  S. Monga,et al.  WNT/beta-catenin signaling in liver health and disease. , 2007, Hepatology.

[39]  H. Clevers.  Wnt/beta-catenin signaling in development and disease. , 2006, Cell.

[40]  Masahiro Ito,et al.  Expression of beta-catenin in hepatocellular carcinoma. , 2005, World journal of gastroenterology.

[41]  R. Gaynor,et al.  Functional correlates of mutations in beta-catenin exon 3 phosphorylation sites. , 2003, The Journal of biological chemistry.

[42]  H. Seow,et al.  GSK-3beta phosphorylation and alteration of beta-catenin in hepatocellular carcinoma. , 2003, Cancer letters.

[43]  M. Romeih,et al.  Alterations of beta-catenin and Tcf-4 instead of GSK-3beta contribute to activation of Wnt pathway in hepatocellular carcinoma. , 2003, Chinese medical journal.

[44]  S. Fan,et al.  beta-Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance. , 2001, Cancer.

[45]  A. G. de Herreros,et al.  Regulation of beta-catenin structure and activity by tyrosine phosphorylation. , 2001, The Journal of biological chemistry.

[46]  Jack A. Taylor,et al.  CTNNB1 mutations and β‐catenin protein accumulation in human hepatocellular carcinomas associated with high exposure to aflatoxin B1 † , 2001, Molecular carcinogenesis.

[47]  M. Matsuda,et al.  Beta-catenin mutations are frequent in human hepatocellular carcinomas associated with hepatitis C virus infection. , 1999, The American journal of pathology.