[en] [en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
He, Ruizhi; Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Wuhan, 430030, China
Wang, Min; Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Wuhan, 430030, China
Zhao, Chunle; Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Wuhan, 430030, China
Shen, Ming; Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Wuhan, 430030, China
Yu, Yahong; Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Wuhan, 430030, China
He, Li; Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Wuhan, 430030, China
Zhao, Yan; Department of Trauma Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
Chen, Hua; Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Wuhan, 430030, China
Shi, Xiuhui ; Université de Liège - ULiège > Département de pharmacie ; Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Wuhan, 430030, China
Zhou, Min; Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Wuhan, 430030, China
Pan, Shutao; Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Wuhan, 430030, China
Liu, Yuhui; Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Wuhan, 430030, China
Guo, Xingjun; Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Wuhan, 430030, China
Li, Xu; Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Wuhan, 430030, China. 2013tj0574@hust.edu.cn
Qin, Renyi; Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Wuhan, 430030, China. ryqin@tjh.tjmu.edu.cn
NSCF - National Natural Science Foundation of China
Funding text :
This study was supported by grants from the National Natural Science Foundation of China (No. 81772950 to RY Q, No. 81502633 to XL, No. 81773160 to MW), HUBEI Natural Science Foundation (2017CFB467) to MW, Wuhan applied basic research project (2016060101010070) to RYQ, and Tongji Hospital Science Fund for Distinguished Young Scholars (2016YQ08) to MW.
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