Rab1A通过活化IL-4Rα/JAK1/STAT6信号通路促进肺腺癌转移的实验研究

Rab1A is the founding member of the Rab family of small GTPases, which mediate dynamic membrane trafficking between the endoplasmic reticulum, Golgi and endosomes. Growing evidence indicates that Rab1A has important functions beyond its classical function of vesicular transport, and deregulation of Rab1A expression has been increasingly linked to a myriad of human diseases, including cancer. We previously reported that Rab1A is significantly overexpressed in the different histological types of lung cancer, with the level associated with clinicopathological parameters. However, the function of Rab1A and the underlying mechanisms in human lung cancer remain largely unexplored. We recently discovered that high Rab1A expression in lung adenocarcinoma is associated with metastasis and poor prognosis. Forced overexpression of Rab1A promotes cancer cell invasion and metastasis by activating JAK1/STAT6 signaling, through stabilization of the cytoplasmic IL-4Rα protein. Rab1A expression level is correlated with sensitivity to JAK1 inhibitors. Here we proposed that Rab1A promotes lung adenocarcinoma metastasis by activating IL-4Rα/JAK1/STAT6 signaling, and Rab1A is a determinant of JAK1 kinase inhibitor sensitivity. This study aimed at investigating the specific mechanism of how Rab1A regulates IL-4Rα/JAK1/STAT6 signaling pathway, and the correlation between Rab1A protein level and JAK1 kinase inhibitor efficacy in human lung adenocarcinoma. This project may provide fundamental evidence to clarify the mechanism for Rab1A pro-metastasis function. The results of this study will contribute to translate laboratory discoveries into important new clinical tools and applications that will improve the target therapy of lung adenocarcinoma.

Rab1A是负责膜运输的经典分子，其在肿瘤发生发展中的作用日益受到关注，但远未明确。我们曾经在国际上首次报道Rab1A在肺癌高表达，随后发现肺腺癌Rab1A高表达与肿瘤转移及预后不良相关；Rab1A通过活化JAK1/STAT6信号通路促进肺腺癌细胞迁移侵袭，该通路上游的IL-4Rα是Rab1A的调控位点；肺腺癌细胞的Rab1A表达水平与其对JAK1激酶抑制剂的敏感性相关。由此，我们假设：Rab1A通过调节IL-4Rα/JAK1/STAT6信号通路促进肺腺癌转移，肺腺癌Rab1A表达水平决定JAK1激酶抑制剂的敏感性。本项目将在以往的工作基础上进一步探讨Rab1A调节IL-4Rα/JAK1/STAT6信号通路的确切机制，明确Rab1A表达水平对JAK1激酶抑制剂敏感性的影响。其实施将有助于阐释Rab1A促进肿瘤恶性进展的分子机制，对于肺腺癌转移的分子机理探讨、以及靶向治疗等均具重要意义。

Rab1A是调节细胞内囊泡转运的经典分子，在营养素感知、细胞信号传递方面发挥重要作用。近年来，Rab1A在肿瘤发生发展中所扮演的角色初露端倪。我们曾经首次报道Rab1A在肺癌中高表达，其表达水平与临床病理参数密切相关，但尚不明确其确切功能和作用机制。本项目以肿瘤细胞系、人肺癌组织芯片、人原代肿瘤裸鼠移植瘤模型等为研究载体，应用磷酸化蛋白质组芯片、免疫沉淀、免疫荧光、18F-FDG micro-PET/CT等检测手段，开展了一系列体外及体内研究，发现：在肺腺癌患者，Rab1A高表达与肿瘤转移相关，且提示预后不良；Rab1A通过活化JAK1/STAT6信号通路促进肺腺癌细胞迁移侵袭，抑制IL-4Rα/JAK1/STAT6信号通路，可阻断Rab1A过表达所导致的促癌表型；Rab1A直接结合IL-4Rα蛋白，延长IL-4Rα蛋白半衰期，抑制IL-4Rα降解，进而活化JAK1/STAT6信号通路；肺腺癌细胞的Rab1A表达水平与其对JAK激酶抑制剂的敏感性相关；Rab1A高表达肺癌对JAK1抑制剂敏感。本项目的实施阐释了Rab1A促进肿瘤恶性生物学行为的分子机制，对于肺腺癌转移的分子机理探讨、以及分子靶向治疗等均具重要意义。