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Epigenetic silencing of SFRP1 and SFRP5 by hepatitis B virus X protein enhances hepatoma cell tumorigenicity through Wnt signaling pathway
Author(s) -
Xie Qing,
Chen Linlin,
Shan Xuefeng,
Shan Xiaoliang,
Tang Jia,
Zhou Fan,
Chen Qingmei,
Quan Huiqin,
Nie Dan,
Zhang Wenlu,
Huang AiLong,
Tang Ni
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28697
Subject(s) - wnt signaling pathway , epigenetics , gene silencing , virology , biology , signal transduction , virus , cancer research , microbiology and biotechnology , genetics , gene
Secreted frizzled‐related proteins (SFRPs) are antagonists of the Wnt signaling pathway whose epigenetic downregulation have been shown to be involved in hepatocarcinogenesis. However, dysregulation of SFRPs induced by hepatitis B virus (HBV) X protein (HBx) has never been studied in HBV‐related hepatocellular carcinoma (HBV‐HCC). In this study, we sought to determine the clinical significance and underlying mechanism of HBx‐induced SFRPs dysregulation in hepatoma cells and HBV‐HCC patients. Our results showed that SFRP1 and SFRP5 expression were dramatically decreased by HBx in hepatoma cells. The repressed expression in hepatoma cells was partially rescued by a DNA methylation inhibitor and synergistically increased by a combination treatment with a histone deacetyltransferases inhibitor. In addition, we identified that SFRP1 and SFRP5 promoters were hypermethylated in both HBx‐expressing hepatoma cells and HBV‐HCC tissues. Downregulation of SFRP1 and SFRP5 in HBV‐HCC tissues was significantly correlated with overexpression of DNA methyltransferase 1 (DNMT1) and poor tumor differentiation. HBx facilitated the binding of DNMT1 and DNMT3A to SFRP1 and SFRP5 promoters, and resulted in epigenetic silencing of SFRP1 and SFRP5. Moreover, overexpression of SFRP1, SFRP5 or RNA interference mediated silencing of DNMT1 inactivated the Wnt signaling pathway and decreased the expression levels of Wnt target genes c‐Myc and CyclinD1 , thus impeding HCC growth in vitro and in vivo , and regressing HBx‐induced epithelial–mesenchymal transition (EMT). Our findings strongly suggest that epigenetic silencing of SFRP1 and SFRP5 by HBx allows constitutive activation of Wnt signaling pathway and hence contributes to hepatocarcinogenesis.