Linc00312通过SRSF1调节S6K1可变剪切影响鼻咽癌化疗敏感性研究

鼻咽癌在我国发病率极高，放化疗抵抗是导致鼻咽癌患者死亡的主要原因，但其分子机制尚未完全阐明。我们发现linc00312高表达的鼻咽癌患者治疗效果较好，过表达linc00312可增加鼻咽癌细胞对放射线和顺铂的敏感性。通过RNA pull down-MS和RNA芯片，我们发现剪切因子SRSF1是linc00312新的结合蛋白，且linc00312调控基因富集在mTOR通路。S6K1是mTOR的底物并受SRSF1的可变剪切调控。因此，我们推测linc00312通过SRSF1调节S6K1的可变剪切影响mTOR通路的激活，从而影响鼻咽癌对顺铂的敏感性。本项目将通过linc00312功能增强/缺失实验明确linc00312在顺铂治疗鼻咽癌中的作用，查明linc00312与SRSF1的结合作用，阐明linc00312-SRSF1-S6K1-mTOR的调控机制，为探索克服鼻咽癌治疗抵抗提供科学依据。

The incidence rate of nasopharyngeal carcinoma (NPC) is extremely high in China. Chemoradiotherapy resistance is the main cause of death of NPC patients. However, the molecular mechanism of treatment resistance of NPC has not been fully elucidated. Our previous study found that NPC patients with high expression of linc00312 have better therapeutic effect. Overexpression of linc00312 can increase the sensitivity of NPC cells to radiation and cisplatin. Using RNA pull down-MS and RNA microarray, we found that splicing factor SRSF1 is a new binding protein of linc00312, and linc00312 regulatory genes are mainly enriched in mTOR pathway. S6K1 is the substrate of mTOR and could be spliced by SRSF1. We speculate that linc00312 may affect the sensitivity of NPC cells to cisplatin treatment by regulating SRSF1 mediated alternative splicing of S6K1 and activation of mTOR pathway. Therefore, we intend to clarify the role of linc00312 in cisplatin resistance of NPC through linc00312 function gain/loss experiment, determine the effect of linc00312 on the function of SRSF1, and elucidate the regulatory mechanism of linc00312-SRSF1-S6K1-mTOR pathway. This project would provide scientific evidence for overcoming the treatment resistance of NPC.