Rab1A promotes IL-4R/JAK1/STAT6-dependent metastasis and determines JAK1 inhibitor sensitivity in non-small cell lung cancer
Rab1A promotes IL-4R/JAK1/STAT6-dependent metastasis and determines JAK1 inhibitor sensitivity in non-small cell lung cancer
复制标题
Rab1A 促进非小细胞肺癌中 IL-4R/JAK1/STAT6 依赖性转移并决定 JAK1 抑制剂敏感性
DOI：
10.1016/j.canlet.2021.10.008
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发表时间：
2021-10-13
期刊：
影响因子：
9.7
通讯作者：
Zhang, Yanjie
中科院分区：
文献类型：
--
作者：
Huang, Tinglei;Chen, Biying;Zhang, Yanjie
已经观察到Rab1a在几种癌症类型中过表达，然而，它在非小细胞肺癌(NSCLC)中的意义和潜在机制在很大程度上仍未被探索。本研究表明，Rab1a在非小细胞肺癌中的过表达与短生存期和转移密切相关。Rab1A超表达通过稳定IL-4Rα蛋白激活JAK1/STAT6信号通路，促进癌细胞在体内外的迁移、侵袭和转移。值得注意的是，高水平的Rab1a与JAK1抑制剂的敏感性有关，而Rab1a的过度表达使癌细胞对JAK1靶向药物易感。JAK1抑制剂己二酸依他西替尼在细胞系和患者来源的异种移植模型中都显著抑制了Rab1ANSCLC的高转移。综上所述，这些发现表明Rab1a在NSCLC的侵袭性特征中起着关键作用，揭示了它促进转移的独特机制。此外，我们发现Rab1a是JAK1抑制剂敏感性的决定因素，可以探索这一点来改进JAK1靶向的癌症治疗。
Rab1A overexpression has been observed in several cancer types, however, its significance and the underlying mechanisms in non-small cell lung cancer (NSCLC) remain largely unexplored. This study demonstrated that Rab1A overexpression in NSCLC was significantly correlated to short survival and metastasis. Rab1A overexpression promoted cancer cell migration, invasion, and metastasis both in vitro and in vivo, by activating JAK1/STAT6 signaling through stabilizing IL-4R alpha protein. Strikingly, high Rab1A level was associated with sensitivity to JAK1 inhibitor, and Rab1A overexpression rendered cancer cells vulnerable to JAK1-targeted agents. JAK1 inhibitor, Itacitinib adipate, dramatically inhibited high Rab1A NSCLC metastasis, in both cell line and patient derived xenograft models. Collectively, these findings demonstrated that Rab1A plays a critical role in the aggressive properties of NSCLC, revealing a unique mechanism by which it promotes metastasis. In addition, we found that Rab1A is a determinant of JAK1 inhibitor sensitivity, which could be explored for improving JAK1-targeted cancer therapy.