Open AccessHB x protein‐mediated ATOH 1 downregulation suppresses ARID 2 expression and promotes hepatocellular carcinoma
Author(s) -
Gao Qingzhu,
Wang Kai,
Chen Ke,
Liang Li,
Zheng Yaqiu,
Zhang Yunzhi,
Xiang Jin,
Tang Ni
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13277
Subject(s) - hepatocellular carcinoma , hepatitis b virus , ectopic expression , downregulation and upregulation , cancer research , arid , biology , virology , pathogenesis , microbiology and biotechnology , virus , cell culture , gene , immunology , genetics , paleontology
Hepatitis B virus X protein plays a crucial role in the pathogenesis of hepatocellular carcinoma. We previously showed that the tumor suppressor ARID 2 inhibits hepatoma cell cycle progression and tumor growth. Here, we evaluated whether hepatitis B virus X protein was involved in the modulation of ARID 2 expression and hepatocarcinogenesis associated with hepatitis B virus infection. ARID 2 expression was downregulated in HBV ‐replicative hepatoma cells, HBV transgenic mice, and HBV ‐related clinical HCC tissues. The expression levels of HB x were negatively associated with those of ARID 2 in hepatocellular carcinoma tissues. Furthermore, HB x suppressed ARID 2 at transcriptional level. Mechanistically, the promoter region of ARID 2 gene inhibited by HB x was located at nt‐1040/nt‐601 and contained potential ATOH 1 binding elements. In addition, ectopic expression of ATOH 1 or mutation of ATOH 1 binding sites within ARID 2 promoter partially abolished HB x‐triggered ARID 2 transcriptional repression. Functionally, ARID 2 abrogated HB x‐enhanced migration and proliferation of hepatoma cells, whereas depletion of ATOH 1 enhanced tumorigenecity of HCC cells. Therefore, our findings suggested that deregulation of ARID 2 by HB x through ATOH 1 may be involved in HBV ‐related hepatocellular carcinoma development.