title: Activation of IRE1α-XBP1 pathway induces cell proliferation and invasion in colorectal carcinoma.
abstract: Cell proliferation and tumor metastasis are considered as the main reasons for death in colorectal carcinoma (CRC). IRE1α-XBP1 pathway is the most conserved UPR pathways, which are activated during ER stress caused by the accumulation of unfolded or misfolded protein in the lumen of ER. Here, we demonstrated the critical role of IRE1α-XBP1 pathway and underlying molecular mechanism in cell proliferation and tumor metastasis in CRC. By the use of tissue microarray analysis of samples from 119 patients with CRC, IRE1α was determined to be an independent predictor of overall survival as higher expression of IRE1α in CRC patients showed lower survival rates (p = 0.0041). RNA interference and ectopic expression of IRE1α were applied to determine the molecular effects of IRE1α in CRC cells. The silencing of IRE1α inhibited the proliferation and blocked the invasion of CRC cells in vitro, while ectopic expression of IRE1α in turn promoted cell proliferation and invasion. IRE1α-XBP1 pathway regulated the mitosis of CRC cells through the directly binding of XBP1s to Cyclin D1 promoter to activate Cyclin D1 expression. Our results reveal that IRE1α-XBP1 pathway plays an important role in tumor progression and epithelial-to-mesenchymal transition (EMT), and IRE1α could be employed as a novel prognostic marker and a promising therapeutic target for CRC.
authors.affiliation: Department of Coloproctology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, PR China.
authors.forename: Chun
authors.initials: C
authors.lastname: Jin
authors.affiliation: Department of Coloproctology, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Wenzhou 325000, PR China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Department of Medicine, The Chinese Medicine Hospital of Wenzhou, Wenzhou 325000, PR China.
authors.forename: Nian-Zhao
authors.initials: NZ
authors.lastname: Chen
authors.affiliation: Department of Coloproctology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Coloproctology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, PR China.
authors.forename: Chang-Bao
authors.initials: CB
authors.lastname: Liu
authors.affiliation: Department of Coloproctology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, PR China.
authors.forename: Wan-Le
authors.initials: WL
authors.lastname: Hu
authors.affiliation: Department of Coloproctology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, PR China. Electronic address: zhengchenguo80@163.com.
authors.forename: Chen-Guo
authors.initials: CG
authors.lastname: Zheng
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation; D002681:China / Q000453:epidemiology; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004722:Endoribonucleases / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D015995:Prevalence; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism*; D000071717:X-Box Binding Protein 1
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases
keywords: Cell proliferation; Colorectal carcinoma; ER stress; Epithelial-to-mesenchymal transition; IRE1α