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

TFEB 自噬 癌症研究 胰腺癌 细胞生物学 生物 袋3 化学 细胞凋亡 癌症 生物化学 遗传学
作者
Ruizhi He,Min Wang,Chunle Zhao,Ming Shen,Yahong Yu,Li He,Yan Zhao,Hua Chen,Xiuhui Shi,Min Zhou,Shutao Pan,Yuhui Liu,Xiaomao Guo,Li Xu,Renyi Qin
出处
期刊:Journal of Experimental & Clinical Cancer Research [Springer Nature]
卷期号:38 (1) 被引量:55
标识
DOI:10.1186/s13046-019-1343-4
摘要

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. 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. 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. 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.
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