CHOP依赖性内质网应激障碍介导的自噬-凋亡通路在肺癌多药耐药形成中的作用及机制

Multidrug resistance of lung cancer will be the basic defeat reason of chemotherapy，there is no better solution. Our previous study found that: the disorder of endoplasmic reticulum stress presented in lung cancer cell which inducible resistant by cisplatin，mainly manifested the CHOP expression which is marker molecular of endoplasmic reticulum stress was significantly inhibited.At the same time,LC3-II molecule which associated to autophagy activation was also significantl downregulated.However，LC3-II expression was significantly unregulated when CHOP molecule was been compulsory overexpressed,and then the resistance index of multidrug resistance lung cancer cell decreased by 47.54%.The phenomenon indicates that endoplasmic reticulum stress which induced by autophagy/apoptosis pathway play an important role in the formation of multidrug resistance of lung cancer. We will construct the CHOP gene vector of hyperexpression and interference，fluorescent quantization PCR，immunoblotting，living body image formation and other molecular biology technology will be used at clinical，cell and animal level to investigate the molecule expression and signal transduction mechanisms of autophagy/apoptosis pathway which regulated by CHOP molecule. Research will be elucidate the effect and mechanism of lung cancer multidrug resistant formation due to CHOP-dependent endoplasmic reticulum stress autophagy/apoptosis pathway, the new formation mechanism of multidrug resistance will be explore，and the findings perhaps provide original intervention target of the reversal to multidrug resistance of lung cancer.

多药耐药是肺癌化疗失败的根本原因之一。我们前期的研究发现，顺铂诱导的多药耐药肺癌细胞存在细胞内质网应激障碍，主要表现为内质网应激标志性分子CHOP表达明显受抑，同时细胞自噬激活相关分子LC3-II表达也显著下调。强制表达CHOP分子，可使LC3-II表达显著上调，耐药肺癌细胞对顺铂的耐药指数下降47.54%。上述现象说明，内质网应激性自噬/凋亡通路在肺癌细胞多药耐药形成中发挥了重要作用。本研究拟构建CHOP基因过表达及干扰载体，采用荧光定量PCR结合免疫印迹与活体成像等技术，在临床、细胞及动物水平研究CHOP及自噬-凋亡通路在肺癌细胞多药耐药形成中的作用，进而探讨CHOP分子调控自噬-凋亡通路相关分子表达及其信号转导机制。本课题研究将深入阐明CHOP依赖性内质网应激自噬/凋亡通路在肺癌多药耐药形成中的作用及其机制，从而拓宽对肺癌多药耐药性形成机制的认识，并为其逆转提供新的干预靶点。