circAXIN1靶向miR-486-3p调控BCL11A表达在三阴性乳腺癌阿霉素耐药中的作用和机制研究

解决化疗耐药是提高三阴性乳腺癌(TNBC)治疗有效性和患者生存的最大挑战。近年研究发现circRNA在乳腺癌化疗耐药中发挥重要作用，但仍缺乏深入机制研究和有效靶点。我们在前期实验中首次发现在TNBC阿霉素耐药组织和细胞中显著上调的circAXIN1，此前尚未有在乳腺癌中的报道。我们明确circRNA对miR-486-3p的海绵作用并证实BCL11A是靶基因。我们基于国内外研究和前期结果提出假说：circAXIN1海绵吸附miR-486-3p上调BCL11A表达，通过激活Wnt/β-catenin通路增加细胞干性和EMT转化而促进TNBC阿霉素耐药发生。本研究拟从组织、细胞和动物模型多角度探讨circAXIN1在TNBC阿霉素耐药中的生物学功能和分子机制，为逆转TNBC化疗耐药提供新的潜在治疗靶点，为该领域后续研究和临床治疗奠定基础，使患者生存获益。

chemotherapy resistance is the biggest challenge to improve the therapeutic effectiveness and survival of triple negative breast cancer (TNBC). Recent studies have found that circRNA plays an important role in chemotherapy resistance of breast cancer, but it still lack of further research of mechanism and find effective target. We've found circAXIN1 for the first time, which up-regulated in doxorubicin-resistant TNBC tissues and cells, and sponges miR486-3p. We also proved BCL11A is the target gene of miR-486-3p. It has been reported that high expression of BCL11A is associated with poor prognosis of TNBC, and may participate in treatment resistance by promoting EMT, but the mechanism is unknown. In this study, we propose the hypothesis that circAXIN1 sponges mir-486-3p then upregulates BCL11A expression, activates Wnt/β-catenin signaling pathway, leads to EMT and promotes doxorubicin resistance. We will focus on the role and mechanism of circAXIN1 in doxorubicin resistance of TNBC through tissues, cells and animal models. Our study aims to reveal the mechanism of chemotherapy resistance from the new perspective of circRNA, and provide new potential therapeutic targets for reversing chemotherapy resistance of TNBC, as well as to provide the solid experimental evidences for the further researches and clinical applications in this field.