调控Rictor基因表达及其介导的肺癌细胞可逆性EMT和转移的分子机制

上皮肿瘤中EMT的发生是引起侵袭和转移的重要途径。mTORC2特有组分Rictor可独立于mTORC2存在，参与多种肿瘤的发生、侵袭和转移，但其表达调控机制及上游调节子与EMT之间的联系尚未见报道。课题组基于Rictor在肺癌细胞和组织内高表达并受转录水平调控，沉默Rictor改变肺癌细胞的上皮和间质表型并抑制其体外迁移及侵袭能力的前期发现，首次克隆及确定了调控rictor转录的核心启动子。在此基础上，本项目将首先明确调控Rictor表达的转录因子，进一步推测该转录因子有可能通过调控Rictor表达及EMT相关的Rictor复合体形成而调节Rictor介导的肺癌细胞可逆性EMT及转移。通过本项目的研究，将首次阐明调控Rictor表达的转录因子及其与EMT、肿瘤转移之间的新联系，为开发针对肿瘤侵袭与转移新靶点的小分子抑制剂以及不同靶向的抑制剂联用治疗肿瘤转移提供重要的理论依据。

Metastasis is considered as one of the main causes of treatment failure and death in cancer patients. Epithelial-Mesenchymal Transition (EMT) has been shown to play a critical role in promoting metastasis in epithelium-derived carcinoma. Rictor, the unique component of mTORC2, has been reportedly involved in tumorgenesis, invasion and metastasis of many cancers. However, the regulatory mechanisms of Rictor expression and by which regulates Rictor-mediated EMT and metastasis in cancer cells remain unknown. Our previous results indicated that Rictor is overexpression in both human lung cancer tissues and cell lines tested and is regulated, at least in part, at transcriptional level. Additionally, knockdown of Rictor expression caused phenotype alterations through EMT, which is accompany with the impairment of migration and invasion ability in lung cancer cells. Moreover, we have cloned and identified, for the first time, the rictor core promoter and have been screening for the transcription factor(s) that regulates rictor gene transcription and expression. Thus, we hypothesize that the Rictor-regulating transcription factor(s) may involve in the reversible EMT procession and metastasis through regulating the formation of EMT-related Rictor complexes in lung cancer cells. This project would establish new relationships among the Rictor-regulating transcription factor(s), EMT and metastasis. The understanding of the regulator upstream of Rictor may afford an opportunity for the development of new inhibitors and the rational design of combination regimens based on different metastasis-related molecular targets, and finally prevents cancer metastasis.