结肠癌是常见恶性肿瘤，其发病机制不清且缺乏有效治疗手段。细胞处于内质网应激(ER stress)时激活未折叠蛋白反应(UPR)，ER stress和UPR普遍存在于肿瘤细胞中并在肿瘤生长过程中发挥重要作用。靶向UPR通路已成为肿瘤治疗的一个策略，但UPR在肿瘤中的具体作用和机制尚不十分清楚。我们发现：UPR中的一个关键调控蛋白IRE1α在结肠癌中高表达；抑制IRE1α表达导致β-catenin及其调控的下游基因如c-Myc和CCND1的水平下降，引起结肠癌细胞周期进程受阻。作为原癌基因，β-catenin可调控细胞生长，是结肠癌发展过程中的一个关键基因。基于此，我们推测：IRE1α通过β-catenin调控结肠癌细胞生长，在结肠癌的生长过程中起重要作用。本项目中，我们将利用细胞和肠上皮IRE1α敲除小鼠模型，重点研究IRE1α通过β-catenin调控结肠癌细胞生长的作用和分子机制。

Colon cancer is a common malignancy. The underlying mechanisms remain unclear and there are less effective therapeutic methods. When cells are in endoplasmic reticulum stress (ER stress), the unfolded protein response (UPR) is activated. ER stress and UPR are popular in tumor cells and they play an important role in development of cancers. Targeting UPR is already a strategy for cancer therapy, however, the exact role and molecular mechanism of UPR in cancers are not unclear. We find that expression of IRE1α, a key player in UPR, is upregulated in human colon cancers. Knockdown of IRE1α decreased the expression of β-catenin and its downstream genes c-Myc and CCND1, leading to inhibition of cell cycle progression of colon cancer cells. As a pro-oncogene, β-catenin regulates cell proliferation and plays a critical in development of colon cancer. We propose that IRE1α regulates proliferation of colon cancer cells via β-catenin and plays an important role in development of colon cancer. By using cell and IRE1α-knockout mouse models, we will study the role and mechanism of IRE1α in regulating proliferation of colon cancer cells through β-catenin.