Knockdown of IRE1α inhibits colonic tumorigenesis through decreasing β-catenin and IRE1α targeting suppresses colon cancer cells
Knockdown of IRE1α inhibits colonic tumorigenesis through decreasing β-catenin and IRE1α targeting suppresses colon cancer cells
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敲低 IRE1 α 通过减少 β-连环蛋白抑制结肠肿瘤发生，并且 IRE1 α 靶向抑制结肠癌细胞
DOI：
10.1038/onc.2017.284
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发表时间：
2017-11-30
期刊：
影响因子：
8
通讯作者：
Fang, J.
中科院分区：
文献类型：
--
作者：
Li, X-X;Zhang, H-S;Fang, J.
内质网（ER）应激在癌症中经常发生。未折叠蛋白反应（UPR）被激活以应对内质网应激。这引起了人们对以 UPR 作为治疗策略的广泛兴趣。需要肌醇的跨膜激酶/核酸内切酶 1 α (IRE1 α) 是一种 ER 应激传感器，是 UPR 的关键组成部分。然而，IRE1α在肿瘤发生中的作用仍不清楚。这项工作的目的是研究 IRE1 α 在结肠癌中的作用，并确定 IRE1 α 是否可以作为治疗靶点。我们发现 IRE1 α 的敲低抑制了体外结肠癌细胞的增殖和体内异种移植物的生长。抑制 IRE1 α 的表达会降低结肠癌干细胞 (CSC) 的干细胞性并减弱肠道类器官的生长。 IRE1 α 的基因消除可防止小鼠结肠炎相关的结肠肿瘤发生。机制研究表明，IRE1 α 的敲低通过激活胰腺 ER 激酶/真核翻译起始因子 2 α 信号传导来抑制β-连环蛋白的表达，β-连环蛋白是驱动结肠肿瘤发生的关键因素。我们发现IRE1a特异性抑制剂4 mu 8C可以抑制β-catenin的产生，抑制结肠癌细胞的增殖，抑制结肠CSC并阻止异种移植物的生长。结果表明，IRE1a 在结肠肿瘤发生中起着关键作用，IRE1 α 靶向可能是治疗结肠癌的一种策略。
The endoplasmic reticulum (ER) stress occurs frequently in cancers. The unfolded protein response (UPR) is activated to cope with ER stress. This has generated widespread interest in targeting UPR as therapeutic strategies. Inositol-requiring transmembrane kinase/endonuclease 1 alpha (IRE1 alpha), an ER stress sensor, is a key component of UPR. However, the role of IRE1 alpha in tumorigenesis remains unclear. The purpose of this work is to investigate the role of IRE1 alpha in colon cancer and to determine whether IRE1 alpha could serve as a target for therapy. We found that knockdown of IRE1 alpha suppressed the proliferation of colon cancer cells in vitro and xenograft growth in vivo. Inhibition of expression of IRE1 alpha decreased stemness of colon cancer stem cells (CSCs) and attenuated growth of intestinal organoids. Genetic ablation of IRE1 alpha prevented the colitis-associated colonic tumorigenesis in mice. The mechanistic study indicates that knockdown of IRE1 alpha repressed the expression of beta-catenin, a key factor that drives colonic tumorigenesis, through activating pancreatic ER kinase/eukaryotic translation initiation factor 2 alpha signaling. We found that the IRE1a-specific inhibitor 4 mu 8C could suppress the production of beta-catenin, inhibited the proliferation of colon cancer cells, repressed colon CSCs and prevented xenograft growth. The results suggest that IRE1a has a critical role in colonic tumorigenesis and IRE1 alpha targeting might be a strategy for treatment of colon cancers.