miR-4496多靶向调控乳腺癌细胞BCRP表达逆转乳腺癌耐药性的机制

Inhibiting the expression of BCRP can effectively reverse the chemotherapeutic drug-resistance of breast cancer. Also the BCRP expression is limited by Wnt pathway. We detect the microRNA expression profile in breast cancer cell lines that over express BCRP by miRNA array and find the expression of miR-4496 declined significantly, and the result has been validated in breast cancer tissue. Theoretical prediction showed that there are binding sites in BCRP mRNA-3'UTR for miR-4496, meanwhile, in Wnt pathway, Frizzled 4/5 and β-catenin are also miR-4496's target genes. Presumably, miR-4496 regulate BCRP expression by Wnt/β-catenin signaling pathway and directed targeting effects. The present study is proposed: ①study the interaction between miR-4496 and BCRP, Frizzled 4/5 and β-catenin by Luc reporter gene technique; ② Detect the inhibition of BCRP expression via miR4496 in breast cancer cell lines;③study the relationship between Wnt pathway and miR4496 regulating BCRP expression by targeting Frizzled 4/5 and β-catenin;find the reversal mechanism of miR-4496 on BCRP mediate drug resistance of breast cancer cells in vitro and in vivo. Our study are intend to providing theoretical and experimental foundation for reversing drug resistance.

靶向抑制BCRP表达可有效逆转乳腺癌耐药。Wnt通路参与BCRP表达调控。申请者分析miRNA芯片发现 miR4496与BCRP表达负相关，且在乳腺癌组织得到验证，理论预测BCRP3'UTR与miR4496存在结合位点，表明miR4496可靶向调控BCRP；还发现Wnt通路的Frizzled 4/5与β-catenin 3'UTR亦存在miR4496结合位点，提示miR4496可通过Wnt通路抑制BCRP表达。本项目拟①研究miR4496与BCRP、Frizzled 4/5和β-catenin 3'UTR的靶向结合；②检测miR4496对乳腺癌细胞BCRP表达的靶向抑制作用；③分析miR4496靶向作用Frizzled 4/5和β-catenin影响Wnt通路与BCRP表达的相关性；探讨miR4496多靶向调控BCRP介导的乳腺癌耐药作用与机制。本研究结果有望发现逆转乳腺癌耐药作用新靶点。