Open AccessAutophagy induces transforming growth factor‐β‐dependent epithelial‐mesenchymal transition in hepatocarcinoma cells through cAMP response element binding signalling
Author(s) -
Hu Shaobo,
Wang Liyu,
Zhang Xi,
Wu Yongzhong,
Yang Jing,
Li Jun
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13825
Subject(s) - creb , autophagy , epithelial–mesenchymal transition , microbiology and biotechnology , gene knockdown , signal transduction , transforming growth factor , downregulation and upregulation , chemistry , biology , cancer research , cell culture , transcription factor , biochemistry , apoptosis , genetics , gene
Autophagy promotes invasion of hepatocarcinoma cells through transforming growth factor (TGF)‐β‐dependent epithelial‐mesenchymal transition (EMT). This study investigated the mechanism by which autophagy induces TGF ‐β‐triggered EMT and invasion of hepatocarcinoma cells. Autophagy was induced in HepG2 and BEL 7402 cells by starvation in Hank's balanced salt solution. Induction of autophagy degraded phosphodiesterase ( PDE ) 4A and increased intracellular cAMP , PKA activity and PKA phosphorylation, resulting in increased cAMP response element binding ( CREB ) phosphorylation in hepatocarcinoma cells. Autophagy‐induced activation of cAMP / PKA / CREB signalling further enhanced TGF ‐β1 expression, downregulated the expression of epithelial markers and upregulated the expression of mesenchymal markers, accelerating invasion of hepatocarcinoma cells. Inhibition of autophagy by Atg3 and Atg7 knockdown or by chloroquine treatment prevented degradation of PDE 4A and activation of cAMP / PKA / CREB signalling, suppressing TGF ‐β1 expression, EMT and invasion in hepatocarcinoma cells. In addition, inhibition of cAMP / PKA / CREB signalling also blocked autophagy‐induced TGF ‐β1 expression and prevented EMT and invasion of hepatocarcinoma cells under starvation. Furthermore, exogenous inhibition of PDE 4A or activation of cAMP / PKA / CREB signalling rescued TGF ‐β1 expression, EMT and invasion in autophagy‐deficient hepatocarcinoma cells. These findings suggest that autophagy induces TGF ‐β1 expression and EMT in hepatocarcinoma cells via cAMP / PKA / CREB signalling, which is activated by autophagy‐dependent PDE 4A degradation.