STIM1通过调控内质网应激参与三阴乳腺癌紫杉醇耐药的机制研究

STIM1 is located in the endoplasmic reticulum responsible for sensing Ca2+ leval,which mainly mediates Ca2+ influx. Studies have shown that high expression of STIM1 can promote invasion and metastasis, but little research has been done on its association with chemoresistance.Triple negative breast cancer is more invasiveness, and the prognosis is poor. Our previous study found the expression of STIM1 in drug-resistant cell line was higher than that in parent cell line, and interference of STIM1 expression with siRNA technique could increase the apoptotic and proliferative effect of paclitaxel，and inhibit Ca2+ influx. Ca2+ is an important factor in inducing endoplasmic reticulum stress (ER), and ERS is one of the mechanisms that mediate the apoptosis of paclitaxel. Therefore, we speculate that STIM1 is involved in paclitaxel chemoresistance by regulating endoplasmic reticulum stress. In this study, the relationship between STIM1 and paclitaxel chemotherapeutic resistance in breast cancer was confirmed by tissue, cell and animal experiments. The effects of STIM1 on ERS and on ERS signaling pathway PERK-eIF2a, IRE1-XBP1 and ATF6 were tested to elucidate the mechanism of STIM1 involvement in chemotherapeutic resistance.

STIM1是位于内质网上的Ca2+感受蛋白，主要介导细胞Ca2+内流。研究证实STIM1高表达能够促进多种癌细胞侵袭和转移，但其与肿瘤耐药的研究甚少。前期实验发现STIM1在三阴乳腺癌耐药细胞系表达高于亲代细胞；干扰STIM1表达能抑制细胞Ca2+内流，增加紫杉醇的细胞凋亡作用。细胞内Ca2+水平是影响内质网应激（Endoplasmic reticulum stress，ERS）的重要因素，而ERS又是介导紫杉醇细胞凋亡的机制之一。因而我们推测：STIM1通过调控内质网应激参与三阴乳腺癌紫杉醇化疗耐药。本研究拟通过乳腺癌组织、细胞及动物实验证实STIM1与三阴乳腺癌紫杉醇化疗耐药的相关性；验证STIM1表达对于紫杉醇诱发ERS的抑制作用，探究STIM1对于ERS功能通路（PERK-eIF2a,IRE1-XBP1和ATF6）的影响，阐明STIM1参与化疗耐药的机制。

STIM1是位于内质网上的Ca2+感受蛋白，主要介导细胞Ca2+内流。研究证实STIM1高表达能够促进多种癌细胞侵袭和转移，但其与肿瘤耐药的研究甚少。前期实验发现STIM1在三阴乳腺癌耐药细胞系表达高于亲代细胞；干扰STIM1表达能抑制细胞Ca2+内流，增加紫杉醇的细胞凋亡作用。细胞内Ca2+水平是影响内质网应激（Endoplasmic reticulum stress，ERS）的重要因素，而ERS又是介导紫杉醇细胞凋亡的机制之一。因而我们推测：STIM1通过调控内质网应激参与三阴乳腺癌紫杉醇化疗耐药。课题组利用细胞分子生物学技术重点研究了三阴性乳腺癌细胞STIM1表达变化 对紫杉醇化疗敏感性的影响，阐明了三阴性乳腺癌细胞STIM1通过调控细胞内Ca2+水平实现对内质网应激的调控作用，通过一系列研究已证实STIM1通过增加细胞内Ca2+水平进而抑制内质网应激的机制，并阐明STIM1表达的确对紫杉醇敏感性存在负调控作用，最终在动物模型中证实阻断三阴性乳腺癌细胞STIM1表达可以显著增加紫杉醇的治疗疗效。该研究较全面揭示了三阴性乳腺癌细胞STIM1过表达通过抑制紫杉醇的内质网应激作用来发挥促进耐药的作用，阻断STIM1可能成为三阴性乳腺癌紫杉醇治疗增敏的靶点，可能成为一个较有前景的提示抗紫杉醇治疗效果的预测指标。