血清和糖皮质激素调节蛋白激酶1（SGK1）在RON介导的肺腺癌细胞侵袭性生长中的作用

Studies showed that RON proto-oncogene is a tyrosine kinase receptor, the ligand for macrophage stimulating protein, which is closely related to the pathogensis and the development of lung cancer. It promotes metastasis and invasion of adenocarcinoma by activating Erk1/2 andβ-catenin mediate epithelial-mesenchymal transition(EMT). But key proteins associated with signaling of RON, Erk1/2, β-catenin and EMT effect are not known yet. Serum and glucocorticoid inducible protein kinase(SGK1) is a kinase subfamily that is currently known as AGC-kinase, and it isthe upstream signal molecule of mitogen-activated protein kinase (MAPK) signaling pathway, involved in life activities, such as cellular survival, proliferation and movement. Our study revealed that inhibition of SGK1 gene expression or activation may reverse invasive growth of RON mediated lung adenocarcinoma cell, and we assumed that SGK1 is a key factor in regulation of RON mediated cell phenotypic change and invasive growth. This study is tend to systematically analyze the relationship between abnormal expression of RON and SGK1 expression based on our previous work, observe whether SGK1 is involved in the formation of RON mediated intracellular signal transduction chain, and SGK1`is an essential molecule in RON activation pathway of cancer information. We also assume that SKG1 expression has an important role in RON induced invasive growth through our animal models. Finally, we aim to find out the effects of SGK1 on RON induced invasive growth and metastasis of adenocarcinoma and its molecular mechanism.

原癌基因RON是具有独特生物学功能的受体型酪氨酸激酶，与肺腺癌的恶性发展密切相关。RON通过激活Erk1/2和β-catenin诱导上皮间质转化（EMT）促进肺腺癌的侵袭转移。但是传递RON与Erk1/2、β-catenin以及EMT效应间的关键蛋白尚未明确。血清和糖皮质激素调节蛋白激酶1（SGK1）属于AGC激酶家族，是MAPK途径的上游分子，与细胞的生存、增殖和运动有关。我们发现，抑制SGK1的表达或激活能够逆转RON介导的肺腺癌细胞侵袭性生长，推测SGK1是调节RON介导的侵袭性生长的关键因子。本课题将在前期基础上，系统的研究RON异常表达与SGK1表达的相关性，SGK1是否参与形成RON介导的信息传导链，明确SGK1是RON介导EMT效应的必要分子，并通过动物模型验证SGK1在RON介导的肺腺癌侵袭性生长中的重要作用，最终阐明SGK1参与RON介导的肺腺癌细胞侵袭性生长的分子机制。

RON 是具有独特生物学功能的受体型酪氨酸激酶，其异常激活在肺泡上皮细胞恶性化转变过程中起着关键性作用。SGK1 属于AGC 激酶家族，是MAPK 途径的上游分子，与细胞的生存、增殖和运动有关。前期工作发现肺腺癌细胞表面的受体RON与MSP结合被激活后，Erk1/2 的磷酸化水平增高和β-catenin 的细胞核转位增加，并伴随细胞表型由上皮向间质转化，癌细胞侵袭性增强；抑制SGK1 的表达或激活能够逆转RON介导的肺腺癌细胞侵袭性改变。本项目在前期研究基础上，通过免疫共沉淀、共聚焦免疫荧光检测等技术，发现SGK1是传递RON 与Erk1/2、β-catenin 以及EMT 效应之间的一个关键性蛋白。进一步阐明SGK1 在RON 介导肺腺癌侵袭性生长和转移过程中的关键作用及其分子机制。本研究结果对阐明肺癌恶性化发展的病理机制，设计和研发特异性靶向抗肿瘤的生物药物等，具有重要的科学和临床意义。