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TFEB-driven autophagy potentiates TGF-β induced migration in pancreatic cancer cells
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TFEB-driven autophagy potentiates TGF-β induced migration in pancreatic cancer cells
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TFEB-driven autophagy potentiates TGF-β induced migration in pancreatic cancer cells
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Journal Article
TFEB-driven autophagy potentiates TGF-β induced migration in pancreatic cancer cells
2019
Overview
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.
Publisher
BioMed Central,BioMed Central Ltd,BMC
Subject
/ Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
/ Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics
/ Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism
/ Biochemistry, biophysics & molecular biology
/ Biochimie, biophysique & biologie moléculaire
/ Biomedical and Life Sciences
/ Female
/ Humans
/ Mice
/ Oncology
/ Pancreatic Neoplasms - genetics
/ Pancreatic Neoplasms - metabolism
/ Pancreatic Neoplasms - pathology
/ TFEB
