TFEB-driven autophagy potentiates TGF-β induced migration in pancreatic cancer cells

Journal of Experimental & Clinical Cancer Research

Li He¹  Renyi Qin¹  Ming Shen¹  Chunle Zhao¹  Min Zhou¹  Xiuhui Shi¹  Yuhui Liu¹  Hua Chen¹  Xingjun Guo¹  Xu Li¹  Shutao Pan¹  Min Wang¹  Ruizhi He¹  Yahong Yu¹  Yan Zhao² 

[1] Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology;Department of Trauma Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology;

关键词: Autophagy;    TFEB;    Endocytosis;    Focal adhesion;    Pancreatic cancer;   

DOI  :  10.1186/s13046-019-1343-4

来源: DOAJ

【 摘 要 】

Abstract Background Pancreatic ductal adenocarcinoma is one of the most aggressive cancers, with a 5-year survival rate of less than 8%. The complicated tumor microenvironment, particularly TGF-β, provides possible convenience for the progression of PC cells. TGF-β regulates critical cellular processes, including autophagy. However, the mechanism and effects of TGF-β-mediated autophagy are still poorly understood. Methods Bioinformatics analysis, western blot, transmission electron microscopy and confocal microscopy were used to identify that TFEB is the key factors in TGF-β-induced autophagy. The biological effects of TFEB-driven autophagy were investigated in vitro using transwell and wound healing assays and in vivo using liver metastasis and LSL-KrasG12D/Pdx1-Cre mice models. Luciferase assays and motif analysis were used to assess regulation of RAB5A gene promoter activity by TGF-β-induced TFEB. TFEB levels were measured by real-time PCR, western blot and immunohistochemical staining in clinical pancreatic ductal adenocarcinoma tissues. Results We demonstrated that TGF-β induces TFEB expression via the canonical smad pathway in Smad4-positive PC cells and facilitates TFEB-mediated autophagic activation. TFEB-driven autophagy caused by TGF-β regulates RAB5A-dependent endocytosis of Itgα5 and promotes progression of PC cells. We further showed that enhanced TFEB expression and its direct target RAB5A both predict poor prognosis in PC patients. Conclusions Our findings reveal TFEB-driven autophagy is required for TGF-β induced migration and metastasis of PC cells by promoting endocytosis of Itgα5β1 and focal adhesion disassembly through the TGF-β-TFEB-RAB5A axis. Our results highlight the potential utility of suppressing TFEB-driven autophagy to block PC metastasis.

【 授权许可】

Unknown