circEIF3a对肺癌铂类药物化疗反应的影响及机制研究

Chemotherapy resistance is still the main cause of lung cancer treatment failure. Our preliminary studies showed EIF3a can affect platinum response by regulating DNA repair activity. Recently, our preexperimental results showed that CircEIF3a transcripts from eIF3a gene is overexpressed in cisplatin resistance lung cancer cell line (A549-DDP). Knockdown of CircEIF3a would increase cisplatin sensitivity of A549-DDP cells. By bioinformatics prediction, we found that miR197 can combine with CircEIF3a and the DNA repair pathway protein Rad 51 is a target of miR197. In this study, we will elucidate the role of CircEIF3a in platinum resistance and its mechanism by using RNA interference, MTT, miRNA pull down, luciferase reporter assay and so on. We will also analyze associations of CircEIF3a expression with platinum-based chemotherapy response and survival in lung cancer patients by detecting the CircEIF3a expression level in plasma. Our study aimed to elucidate the mechanism of CircEIF3a regulates platinum response by CeRNA, and provide some scientific evidences for eIF3a as a new biomarkers for platinum chemotherapy response prediction and personalized therapy of lung cancer.

化疗耐药仍然是肺癌治疗失败的主要原因。我们前期研究表明真核生物翻译起始因子3a (eIF3a)通过调控DNA修复通路影响铂类药物化疗反应。CircEIF3a转录自eIF3a基因，预实验结果发现CircEIF3a在肺癌顺铂耐药细胞株呈高表达，下调CircEIF3a表达可降低细胞的耐药性；miR197与CircEIF3a结合程度非常高；DNA修复通路蛋白Rad51是miR197靶蛋白。本项目将率先明确CircEIF3a对铂类药物敏感性及相关通路活性的影响；然后采用miRNA pull down和单细胞凝胶电泳技术明确CircEIF3a与mi197的结合情况及对下游通路及靶蛋白的作用；同时阐明肺癌患者血浆CircEIF3a水平与铂类化疗反应及预后的关系。本课题旨在从表观遗传学角度阐明CircEIF3a调控肺癌铂类化疗反应的机制，为进一步阐明eIF3a作为肺癌个体化治疗新的分子靶标提供科学依据。

化疗耐药仍然是肺癌治疗失败的主要原因。我们前期研究表明真核生物翻译起始因子3A (EIF3A)通过调控DNA修复通路影响铂类药物化疗反应。CircEIF3A转录自EIF3A基因。我们的研究表明，CircEIF3A与非小细胞肺癌进展、顺铂化疗敏感性及翻译调控相关。同时，我们也以此为基础，围绕肺癌铂类化疗反应、CircRNA和EIF3A对课题进行了延申。我们发现环状RNA分子hsa_ circ_ 0001946, CircKIAA0182对非小细胞肺癌进展及顺铂化疗敏感性具有一定的调控作用；我们还发现体细胞突变EIF3A R803K与肺癌的化疗耐受相关，并基于EIF3A R803K突变细胞模型验证了EIF3A R803K促进化疗耐受的表型。本课题研究了CircEIF3A， hsa_ circ_ 0001946，CircKIAA0182和EIF3A R803K在调控肺癌铂类化疗反应中的作用与机制，并为进一步寻找肺癌个体化治疗新的分子靶标提供科学依据。