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J Cell Mol Med. 2018 Nov;22(11):5518-5532. doi: 10.1111/jcmm.13825. Epub 2018 Aug 22.

Autophagy induces transforming growth factor-β-dependent epithelial-mesenchymal transition in hepatocarcinoma cells through cAMP response element binding signalling.

Author information

1
Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
2
Department of Hepatobiliary Oncological Surgery, Chongqing University Cancer Hospital, Chongqing Cancer Institute, Chongqing Cancer Hospital, Chongqing, China.
3
Department of Radiotherapy, Chongqing University Cancer Hospital, Chongqing Cancer Institute, Chongqing Cancer Hospital, Chongqing, China.
4
Department of the First General Surgery, Gansu Provincial Hospital, Lanzhou, China.
5
Department of Urology Oncological Surgery, Chongqing University Cancer Hospital, Chongqing Cancer Institute, Chongqing Cancer Hospital, Chongqing, China.

Abstract

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 BEL7402 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 PDE4A 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 PDE4A 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 PDE4A degradation.

KEYWORDS:

CREB signalling; autophagy; epithelial-mesenchymal transition; hepatocarcinoma cell; phosphodiesterase 4A; transforming growth factor-β1

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