Cell proliferation and tumor metastasis are considered as the main reasons for death in colorectal carcinoma (CRC). IRE1 alpha-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 IRE1 alpha-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, IRE1 alpha was determined to be an independent predictor of overall survival as higher expression of IRE1 alpha in CRC patients showed lower survival rates (p = 0.0041). RNA interference and ectopic expression of IRE1 alpha were applied to determine the molecular effects of IRE1 alpha in CRC cells. The silencing of IRE1 alpha inhibited the proliferation and blocked the invasion of CRC cells in vitro, while ectopic expression of IRE1 alpha in turn promoted cell proliferation and invasion. IRE1 alpha-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 IRE1 alpha-XBP1 pathway plays an important role in tumor progression and epithelial-to-mesenchymal transition (EMT), and IRE1 alpha could be employed as a novel prognostic marker and a promising therapeutic target for CRC. (C) 2016 Elsevier Inc. All rights reserved.