miRNA-lncRNA网络调控eIF3a基因的表达及其在肺癌铂类化疗耐药中的作用及机制研究

Cisplatin is the basic chemotherapy in advanced lung cancer, but there are large individual differences in the chemotherapy efficacy and side -effect of platinum-based drugs. Our previous studies found that eIF3a gene and its polymorphisms could regulate sensitivity of platinum- based chemotherapy in lung cancer patients by changing the activities of DNA repair enzymes. Based on these works, we try to further identify the relationship between the miR-26a, miR-26b, miR-186 and the lncRNAs (AC058791.2，CTD-2314B22.3，AL589743.1；RP11-218M22.1，PVT1，DCP1A) with endogenous competitive and the expression of eIF3a gene. At the same time, we will further elucidate the interaction of miRNA-lncRNA how to regulate the expression of eIF3a gene and their effections and possible molecular mechanism of resistance to platinum-based chemotherapy in patients with lung cancer. The aim of this study is probably going to provides a new explanation and give a further understanding of the eIF3a action in platinum-based drugs resistance in lung cancer from the perspective of epigenetics and ceRNA hypothesis, and provide some new scientific evidences in eIF3a and miRNA or lncRNA as a molecular target for personalized pharmacotherapy of lung cancer.

进展期肺癌化疗主要以铂类药物为主，但疗效和毒副反应的个体反应差异很大。我们前期研究发现 eIF3a基因及其多态性通过调控DNA修复酶表达来调节肺癌铂类药物化疗的敏感性。在此基础上，本研究通过双荧光素酶报告基因及基因转染等技术，进一步查明miR-26a，miR-26b和miR-186以及具有内源性竞争作用的６种lncRNAs (AC058791.2，CTD-2314B22.3，AL589743.1；RP11-218M22.1，PVT1，DCP1A) 如何调控eIF3a基因的表达，同时阐明上述miRNAs-lncNAs与肺癌铂类药物化疗敏感性及预后的相关性，最后明确这些miRNA-lncRNA网络影响肺癌铂类化疗耐药及预后的分子机制。本课题旨在从表观遗传学及ceRNA假说角度为肺癌铂类药物化疗耐药的发生提供全新的解释机制，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。

进展期肺癌化疗主要以铂类药物为主，但疗效和毒副反应的个体反应差异很大。我们前期研究发现 eIF3a基因及其多态性通过调控DNA修复酶表达来调节肺癌铂类药物化疗的敏感性。在此基础上，本研究通过细胞实验，动物实验与临床实验，进一步阐明了miRNA-488, LncRNA FOXD1-AS1,miR-339/342如何调控eIF3a基因的表达。同时阐明了miRNA-488，LncRNA FOXD1 AS1, hsa_circ_0001946, circKIAA0182与肺癌铂类药物化疗敏感性及预后的相关性，最后明确这些miRNA-lncRNA-circRNA网络影响肺癌铂类化疗耐药及预后的分子机制。本课题旨在从表观遗传学角度为肺癌铂类药物化疗耐药的发生提供全新的解释机制，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。