HIF-2α通过GRP78介导的内质网应激调控乳腺癌干细胞药物敏感性的机制研究

生长在低氧龛环境中的BCSCs是乳腺癌耐药的根源。低氧可激活GRP78介导的ERS，但是否与BCSCs耐药相关？未见报道。针对低氧龛发现参与GRP78介导的ERS的调控因素是研究BCSCs耐药的切入点。课题组发现BCSCs药物敏感性与GRP78表达相关；HIF-2α在BCSCs中特异高表达；HIF-2α阻断剂增加BCSCs药物敏感性、并与GRP78表达变化相关；但HIF-2α对GRP78介导的BCSCs耐药调控机制尚不明确。本课题拟通过检测BCSCs-MCF7/S细胞及荷瘤组织中干预GRP78表达对BCSCs药物敏感性及IREl-XBPl／PERK-eIF2-ATF4／ATF6等ERS-UPR通路功能变化，比较HIF-2α抑制剂作用前后异同，明确HIF-2α通过GRP78介导的ERS调控BCSCs药物敏感性作用与机制。本课题将为深入探讨BCSCs介导的乳腺癌耐药性研究提供新思路和新靶点。

Breast cancer stem cells (BCSCs) which survive in hypoxia niche may be the root of drug resistance. It has been reported that hypoxia microenvironment can activate glucose-regulated protein 78 (GRP78)-mediated endoplasmic reticulum stress (ERS), but it is unknown whether this is related to drug resistance in BCSCs. So, perhaps it will be a worth exploring issue that hypoxia niche may be involved in GRP78-mediated ERS to regulate drug resistance of BCSCs. In our study, we have found that the expression of GRP78 was related to BCSCs drug sensitivity and HIF-2α was high expressed in BCSCs. We also found when BCSCs were treated with HIF-2α inhibitor, the drug sensitivity increased and GRP78 expression changed. However, how HIF-2α regulates GRP78-mediated BCSCs drug resistance is still unclear. Hence, to elucidate the potential mechanism, we plan to interfere the expression of GRP78 in BCSCs-MCF7/S cells and xdenograft, detect its impact on BCSCs drug sensitivity and the changed functions of IREl-XBPl/PERK-eIF2-ATF4/ATF6 ERS signal pathways, then compare the different effects with or without HIF-2α inhibitor treatment. Our study will propose a new target or a new method for deep researching the mechanism of BCSCs drug resistance.