Open AccessHB x mutations promote hepatoma cell migration through the Wnt/β‐catenin signaling pathway
Author(s) -
Chen Zhen,
Tang Jia,
Cai Xuefei,
Huang Yao,
Gao Qingzhu,
Liang Li,
Tian Ling,
Yang Yi,
Zheng Yaqiu,
Hu Yuan,
Tang Ni
Publication year - 2016
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.13014
Subject(s) - wnt signaling pathway , mutant , catenin , gene knockdown , transfection , beta catenin , hepatitis b virus , cancer research , signal transduction , cell growth , microbiology and biotechnology , biology , chemistry , cell culture , gene , virology , virus , genetics
HB x mutations (T1753V, A1762T, G1764A, and T1768A) are frequently observed in hepatitis B virus ( HBV )‐related hepatocellular carcinoma ( HCC ). Aberrant activation of the Wnt/β‐catenin signaling pathway is involved in the development of HCC . However, activation of the Wnt/β‐catenin signaling pathway by HB x mutants has not been studied in hepatoma cells or HBV ‐associated HCC samples. In this study, we examined the effects of HB x mutants on the migration and proliferation of HCC cells and evaluated the activation of Wnt/β‐catenin signaling in HB x‐transfected HCC cells and HBV ‐related HCC tissues. We found that HB x mutants (T, A, TA , and Combo) promoted the migration and proliferation of hepatoma cells. The HB x Combo mutant potentiated TOP ‐luc activity and increased nuclear translocation of β‐catenin. Moreover, the HB x Combo mutant increased and stabilized β‐catenin levels through inactivation of glycogen synthase kinase‐3β, resulting in upregulation of downstream target genes such as c‐Myc , CTGF , and WISP 2 . Enhanced activation of Wnt/β‐catenin was found in HCC tissues with HB x TA and Combo mutations. Knockdown of β‐catenin effectively abrogated cell migration and proliferation stimulated by the HB x TA and Combo mutants. Our results indicate that HB x mutants, especially the Combo mutant, allow constitutive activation of the Wnt signaling pathway and may play a pivotal role in HBV ‐associated hepatocarcinogenesis.