MTDH通过促进MRP8的表达增强乳腺癌细胞耐药性的分子机制研究

Breast cancer (BC) is one of the most common malignancy. Even with the remarkable achievements we have made, chemoresistance remains one of the major challenges in the treatment of BC, which may predict poor outcome for those patients. We have found that the expression of MTDH was overexpressed in BC and was an adverse prognostic factor for invasive BC in our preliminary research. We further indicated that MTDH was overexpressed in chemoresistant breast cancer cell line than its parental cell line. Moreover, breast cancer cell line overexpressing MTDH showed relatively higher proliferation rate under adriamycin and paclitaxel exposure at different time points than those control cell line. In addition, overexpression of MTDH could activate multidrug related protein 8 (MRP8) expression in the protein level without altering its mRNA expression. By literature review, MRP8 was found to be highly expressed in aggressive breast cancer subtypes, and that MRP8 overexpression was positively associated with chemoresistance, which may predict poor outcome. We hypothesized that MTDH might promote chemoresistance through activating MRP8. The aim of this study was to further explore the underlying molecular mechanism of MTDH in mediating breast cancer chemotherapy resistance, which may provide novel insights into breast cancer treatment.

课题组证实伴随乳腺癌恶性程度增高，异粘蛋白 (Metadherin, MTDH)表达水平增加，患者预后差。初步结果显示MTDH在耐药细胞较其亲代细胞高表达，在乳腺癌细胞中过表达MTDH，加入常用化疗药物阿霉素、紫杉醇后，其细胞活性高于对照组，提示MTDH可能促进乳腺癌细胞的耐药；同时过表达MTDH可以提高ATP结合盒转运蛋白超家族多药耐药相关蛋白8（Multidrug Related Protein 8, MRP8）的蛋白表达水平。多项研究显示MRP8在人乳腺癌组织中较周围正常乳腺组织高表达，可以诱导耐药。基于此提出MTDH可能通过促进MRP8的表达水平增强乳腺癌细胞的耐药性。本课题拟：阐明MTDH、MRP8在乳腺癌耐药中的作用；明确MRP8对MTDH在乳腺癌耐药作用的影响；分析MTDH促进MRP8表达水平的分子作用机制。阐述MTDH在乳腺癌化疗药物耐药中的机制，为乳腺癌治疗提供理论参考。

伴随术后化疗和新辅助化疗，乳腺癌患者的长期生存率得到显著改善，但随之产生的对化疗药物的耐药也成为肿瘤治疗的难点。前期研究结果显示MTDH表达水平增加，患者预后差。本次研究我们重点阐述MTDH在耐药乳腺癌细胞株MCF7/Adr及相应敏感株MCF7中的作用，实验结果初步显示MTDH促进耐药乳腺癌细胞的增殖及侵袭、迁移作用，可能通过上调CyclinD1、MMP2及MMP9的蛋白水平，下调p21和p27的蛋白水平发挥作用。实验结果初步阐明MRP8在浸润性乳腺癌组织中高表达，预后更差。MTDH和MRP8在浸润性乳腺癌组织中的蛋白表达水平呈正相关。初步显示MRP8促进耐药乳腺癌细胞的增殖作用，可能通过上调CyclinB、下调p27的蛋白水平发挥作用。本项目将进一步阐明MTDH和MRP8之间的相互作用，拓展对MTDH及MRP8在乳腺癌化疗药物耐药的认识，并提供理论依据。