IRS4 promotes the progression of non-small cell lung cancer and confers resistance to EGFR-TKI through the activation of PI3K/Akt and Ras-MAPK pathways
IRS4 promotes the progression of non-small cell lung cancer and confers resistance to EGFR-TKI through the activation of PI3K/Akt and Ras-MAPK pathways
复制标题
IRS4 通过激活 PI3K/Akt 和 Ras-MAPK 通路促进非小细胞肺癌的进展并赋予 EGFR-TKI 耐药性
DOI：
10.1016/j.yexcr.2021.112615
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发表时间：
2021-04-27
影响因子：
3.7
通讯作者：
Xu, Tian-Rui
中科院分区：
文献类型：
--
作者：
Hao, Peiqi;Huang, Ying;Xu, Tian-Rui
IRS 4是胰岛素受体底物（IRS）蛋白家族的成员。它作为一种细胞质衔接蛋白，整合并传递信号从受体蛋白酪氨酸激酶到细胞内环境。IRS 4可诱导乳腺肿瘤发生，并且通常在非小细胞肺癌（NSCLC）中过表达。然而，关于IRS 4在肺癌的发展和进展中的作用知之甚少。在这项研究中，我们表明，IRS 4基因敲除抑制A549肺癌细胞的增殖，集落形成，迁移和侵袭，以及裸鼠异种移植模型中的肿瘤生长。相反，IRS 4的稳定表达表现出相反的效果。正如预期的那样，IRS 4被发现激活PI 3 K/Akt和Ras-MAPK通路，我们还发现IRS 4缺失显著增强了EGFR酪氨酸激酶抑制剂（EGFR-TKI）耐药细胞对吉非替尼的敏感性。综上所述，这些结果表明IRS 4促进NSCLC进展，并可能代表EGFR-TKI耐药NSCLC的潜在治疗靶点。
IRS4 is a member of the insulin receptor substrate (IRS) protein family. It acts as a cytoplasmic adaptor protein, integrating and transmitting signals from receptor protein tyrosine kinases to the intracellular environment. IRS4 can induce mammary tumorigenesis and is usually overexpressed in non-small cell lung cancer (NSCLC). However, little is known about the role of IRS4 in the development and progression of lung cancer. In this study, we show that IRS4 knockout suppresses the proliferation, colony formation, migration, and invasion of A549 lung cancer cells, as well as tumor growth in a nude mouse xenograft model. In contrast, stable expression of IRS4 showed the opposite effects. As expected, IRS4 was found to activate the PI3K/Akt and Ras-MAPK pathways, and we also showed that IRS4 depletion significantly enhanced the sensitivity of EGFR tyrosine kinase inhibitor (EGFR-TKI)-resistant cells to gefitinib. Taken together, these results show that IRS4 promotes NSCLC progression and may represent a potential therapeutic target for EGFR-TKI-resistant NSCLC.