Knockdown of IRE1 alpha suppresses metastatic potential of colon cancer cells through inhibiting FN1-Src/FAK-GTPases signaling
Knockdown of IRE1 alpha suppresses metastatic potential of colon cancer cells through inhibiting FN1-Src/FAK-GTPases signaling
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IRE1 α 的敲低通过抑制 FN1-Src/FAK-GTPase 信号传导抑制结肠癌细胞的转移潜力
DOI：
10.1016/j.biocel.2019.105572
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发表时间：
2019
影响因子：
4
通讯作者：
Fang Jing
中科院分区：
文献类型：
--
作者：
Xie Yinghui;Liu Cui;Qin Yanqing;Chen Jianfeng;Fang Jing
肌醇需求酶 1α (IRE1α) 是一种内质网 (ER) 驻留跨膜蛋白，可感知细胞未折叠/错误折叠蛋白。激活后，IRE1α 从编码 X-box 结合蛋白 (XBP) 1 的 mRNA 中去除 26 bp 核苷酸，以生成该转录因子 (XBP1s) 的剪接活性形式。尽管 IRE1α 与癌症的发展有关，但其作用和潜在机制仍不清楚。在这里，我们证明IRE1α通过调节纤连蛋白-1（FN1）的表达来调节结肠癌细胞转移。我们发现IRE1α的敲低可抑制结肠癌细胞的体外迁移和侵袭以及体内转移。 IRE1α 的敲除减少了 XBP1 的形成并减弱了 FN1 的表达，导致 Src 和 FAK 的磷酸化受到抑制，并使下游效应 GTP 酶（包括 RhoA、Rac1 和 CDC42）失活。添加外源 FN1 可逆转 IRE1α 敲低所抑制的 Src/FAK 磷酸化和细胞迁移。我们发现XBP1结合FN1启动子并作为转录因子启动FN1表达。我们的结果表明IRE1α通过调节FN1的表达来调节结肠癌细胞的转移潜力。
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 invasionin vitroand metastasisin 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 boundFN1promoter and acted as a transcription factor to initiateFN1expression. Our results suggest that IRE1α modulates metastatic potential of colon cancer cells through regulating the expression of FN1.