Open AccessNFAT c1 is a tumor suppressor in hepatocellular carcinoma and induces tumor cell apoptosis by activating the FasL‐mediated extrinsic signaling pathway
Author(s) -
Xu Sanrong,
Shu Penghao,
Zou Song,
Shen Xiaofeng,
Qu Yuanqian,
Zhang Yong,
Sun Kang,
Zhang Jin
Publication year - 2018
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.1716
Subject(s) - nfat , cancer research , fas ligand , ectopic expression , apoptosis , hepatocellular carcinoma , cell growth , signal transduction , carcinogenesis , transcription factor , biology , cell culture , medicine , microbiology and biotechnology , programmed cell death , cancer , gene , biochemistry , genetics
Nuclear factor of activated T cells ( NFAT ) is a family of transcription factors that have important functions in many tumors. However, the expression level and functional role of NFAT in hepatocellular carcinoma ( HCC ) remain unclear. In this study, we showed that NFAT c1 expression was decreased in both HCC tissues and cell lines. Low expression of NFAT c1 was correlated with larger tumor size, advanced tumor‐node‐metastasis ( TNM ) stage, high serum AFP level, and liver cirrhosis. Furthermore, patients with low NFAT c1 expression exhibited poor prognosis. Ectopic expression of NFAT c1 in HCC cells inhibited proliferation and colony formation, leading to G1 arrest and induction of apoptosis. In addition, we demonstrated that NFAT c1 increased Fas ligand (FasL) expression by directly binding to its promoter and activated the extrinsic apoptotic pathway. NFAT c1 and FasL expression patterns and their prognostic value for patients with HCC were also evaluated in TCGA Liver Hepatocellular Carcinoma database. Knock‐down of FasL expression by si RNA in HCC cell lines abolished NFAT c1's antiproliferative and pro‐apoptotic effects. In conclusion, NFAT c1 is frequently inactivated in HCC and functions as a tumor suppressor in liver carcinogenesis. Ectopic expression of NFAT c1 in HCC cells induces apoptosis by activating the FasL‐mediated extrinsic signaling pathway.