2. Academic Validation
  3. Knockdown of IRE1ɑ suppresses metastatic potential of colon cancer cells through inhibiting FN1-Src/FAK-GTPases signaling

Knockdown of IRE1ɑ suppresses metastatic potential of colon cancer cells through inhibiting FN1-Src/FAK-GTPases signaling

  • Int J Biochem Cell Biol. 2019 Sep;114:105572. doi: 10.1016/j.biocel.2019.105572.
Yinghui Xie 1,  Cui Liu 2,  Yanqing Qin 1,  Jianfeng Chen 3,  Jing Fang 4
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 2 State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 20031, China.
  • 3 State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 20031, China. Electronic address: jfchen@sibcb.ac.cn.
  • 4 Cancer Institute, the Affiliated Hospital of Qingdao University, Qingdao, 266061, China; Qingdao Cancer Institute, Qingdao, 266061, China. Electronic address: jfang2018@163.com.
PMID: 31326465 DOI: 10.1016/j.biocel.2019.105572
Abstract

The inositol-requiring Enzyme 1α (IRE1α) is an endoplasmic reticulum (ER)-resident transmembrane protein and senses cellular unfolded/misfolded proteins. Upon activation, IRE1α removes a 26-bp nucleotide from the mRNA encoding X-box binding protein (XBP) 1 to generate a spliced active form of this transcription factor (XBP1s). Though IRE1α is implicated in development of Cancer, the role and underlying mechanism remain unclear. Here, we demonstrate that IRE1α regulates colon Cancer cell metastasis through regulating the expression of fibronectin-1 (FN1). We found that knockdown of IRE1α inhibited colon Cancer cell migration and invasion in vitro and metastasis in vivo. Knockdown of IRE1α decreased the formation of XBP1s and attenuated the expression of FN1, leading to inhibition of phosphorylation of Src and FAK and inactivation the downstream effector GTPases including RhoA, Rac1 and CDC42. Addition of exogenous FN1 reversed Src/FAK phosphorylation and cell migration inhibited by IRE1α knockdown. We found that XBP1s bound FN1 promoter and acted as a transcription factor to initiate FN1 expression. Our results suggest that IRE1α modulates metastatic potential of colon Cancer cells through regulating the expression of FN1.

Keywords

Colon cancer; Fibronectin; IRE1α; Invasion; Migration.

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