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Alpha fetoprotein mediates HB x induced carcinogenesis in the hepatocyte cytoplasm
Author(s) -
Zhang Chao,
Chen Xiangmei,
Liu Hui,
Li Hui,
Jiang Wei,
Hou Wenting,
McNutt Michael A.,
Lu Fengmin,
Li Gang
Publication year - 2015
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.29548
Subject(s) - hbx , carcinogenesis , transfection , gene knockdown , downregulation and upregulation , cytoplasm , biology , cancer research , alpha fetoprotein , microbiology and biotechnology , cell culture , gene , hepatocellular carcinoma , genetics
Although tumor‐associated fetal protein AFP has demonstrated utility as a clinical tumor marker, the significance of intracellular AFP is still unclear. The aim of this study was to explore the role of cytoplasmic AFP during HBx induced carcinogenesis, which had not previously been recognized; 614 HCC patients were analyzed for correlation of HBV infection with AFP level, and much higher AFP levels were found in HBsAg positive patients. Tumor tissue specimens from 20 HCC patients were used for analysis of AFP and GADD45α. Analysis of HCC specimens showed that upregulation of cytoplasmic AFP is associated with down‐regulation of GADD45α in neoplastic tissue. Transfected HBx promotes transcription of AFP by acting on the elements in the AFP gene regulatory region. HBx itself did not directly impact transcription of GADD45α . However, the obstruction of RAR signaling by HBx induced elevation of AFP, which led to down‐regulation of GADD45α . Cytoplasmic AFP was able to interact with RAR, disrupting its entrance into the nucleus and binding to the elements in the regulatory region of the GADD45α gene. Knockdown of AFP in siRNA‐transfected AFP positive cell lines was synchronously associated with an incremental increase of RAR binding to DNA, as well as upregulation of GADD45α and it was contrary in AFP gene‐transfected AFP negative cell lines. These results indicate cytoplasmic AFP is not only a histochemical tumor biomarker for human hepatoma but is also an intracellular signal molecule and potential participant in HBx induced hepatocarcinogenesis.