Caveolin-1通过活化STAT3调控肺癌细胞定向迁移的作用和机制

Epithelial-to-Mesenchymal Transition (EMT) and directional migration are key steps in cancer invasion and metastasis. Caveolin-1 was reported to promote EMT and cancer invasion, but the underlying mechanisms are not fully understood. Based on previous reports that caveolin-1 regulates lung cancer cell proliferation through activation of STAT3, we invesgated the role of caveolin-1 and STAT3 in directional migration of lung cancer cells. We found that lung cancer cells displayed increased caveolin-1 and pSTAT3 expression, increased motility and invasiveness after EMT. Moreover, caveolin-1 accumulated at the leading edge of directionally migrating cells, while pSTAT3 expression increased significantly and displayed neuclear translocation. Moreover, siRNA-knockdown of caveolin-1 decreased cellular motility, invasiveness, as well as expression of an EMT regulator, Snail. Based on these results, we hypothesized that "Caveolin-1 regulates EMT and directioanl migration of lung cancer cells through activation of STAT3". Using a directional-cell-migration model, we aim to study new mechanisms controling EMT and directioanl migration of lung cancer cells, focsing on relationship between Caveolin-1 and STAT3 activation. We will provide new insights and experimental evidence for mechanisms controling lung cancer invasion and metastasis.

肿瘤细胞发生EMT并定向迁移是肿瘤侵袭转移的重要环节。Caveolin-1（Cav1）能促使肿瘤细胞发生EMT并增强侵袭性，但具体机制仍待深入研究。既往研究表明，Cav1通过调控STAT3信号在肺癌细胞增殖中发挥作用，我们进一步研究发现发生EMT后肺癌细胞Cav1和磷酸化STAT3表达增高，迁移加快，侵袭增强。而且，定向迁移的肺癌细胞中，Cav1在前进一侧出现极化分布，STAT3则显著磷酸化并发生核转位。干扰Cav1表达后侵袭和迁移减弱，EMT关键分子Snail表达下调。由此，我们提出"Caveolin-1可能通过活化STAT3调控肺癌细胞发生EMT和定向迁移，进而促进肺癌的侵袭转移"。本研究拟在建立肺癌细胞定向迁移模型基础上，以"Caveolin-1和STAT3活化"的相互关系为切入点，探讨调控肺癌细胞EMT和定向迁移的新机制，为寻找阻断肺癌侵袭转移的关键分子靶点提供新的思路和实验依据。

肿瘤细胞发生EMT并定向迁移是肿瘤侵袭转移的重要环节。Caveolin-1（Cav1）能促使肿瘤细胞发生EMT并增强侵袭性，但具体机制仍待深入研究。既往研究表明，Cav1通过调控STAT3信号在肺癌细胞增殖中发挥作用，我们进一步研究发现发生EMT后肺癌细胞Cav1和磷酸化STAT3表达增高，迁移加快，侵袭增强。由此，我们提出"Caveolin-1可能通过活化STAT3调控肺癌细胞发生EMT和定向迁移，进而促进肺癌的侵袭转移"的假说。通过系列研究，本项目取得了以下进展：1、上皮样形态H1650细胞在定向性信号的刺激下无明显定向运动，而发生EMT后的肺癌细胞定向运动能力显著增强；2、STAT3是介导H1650-M3细胞发生EMT的关键分子，在发生EMT的H1650-M3细胞中STAT3活化明显增强；3、STAT3介导的EMT是H1650-M3细胞发生定向运动的关键机制，生物电刺激后H1650-M3细胞发生定向运动，STAT3活化增强，使用STATTIC抑制STAT3活化后，细胞对生物电的反应显著减弱；4、Cav1活化是肺癌细胞定向运动的关键机制，表现为生物电刺激后磷酸化Cav1表达显著上调，而总的Cav1表达未见明显变化，使用sh RNA技术构建Cav1-KD细胞株，发现Cav1-KD细胞株对生物电反应显著减弱，从而提示Cav1是细胞定向运动的关键机制；5、证实Cav1通过活化STAT3介导肺癌细胞定向运动，发现Cav1-KD后细胞STAT3活化显著减弱，而且在Cav1-KD细胞株中采用IL-6刺激活化STAT3后，细胞趋电性显著增强。综上所述，本研究证实了Cav1介导的STAT3活化是肺癌细胞发生定向运动的关键机制，且STAT3不仅介导了肺癌细胞侵袭，还参与介导肺癌细胞对EGFR-TKI耐药。