Chen Zhaolin, Pan Tingting, Jiang Duochen, Jin Le, Geng Yadi, Feng Xiaojun, Shen Aizong, Zhang Lei
Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Hospital, Hefei, Anhui 230001, P.R. China.
Department of General Surgery, Diagnosis and Therapy Center of Thyroid and Breast, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Hospital, Hefei, Anhui 230001, P.R. China.
Mol Ther Nucleic Acids. 2020 Mar 6;19:1434-1448. doi: 10.1016/j.omtn.2020.01.030. Epub 2020 Feb 1.
Drug resistance, including adriamycin (ADR)-based therapeutic resistance, is a crucial cause of chemotherapy failure in breast cancer treatment. Acquired chemoresistance has been identified to be closely associated with the overexpression of P-glycoprotein (P-gp/ABCB1). Long non-coding RNA (lncRNA) growth arrest-specific 5 (GAS5) can be involved in carcinogenesis; however, its roles in ABCB1-mediated ADR resistance are poorly understood. In this study, we identified a panel of differentially expressed lncRNAs, mRNAs, and microRNAs (miRNAs) in MCF-7 and MCF-7/ADR cell lines through RNA sequencing (RNA-seq) technologies. GAS5 level was downregulated whereas ABCB1 level was upregulated in the resistant breast cancer tissues and cells. Overexpression of GAS5 significantly enhanced the ADR sensitivity and apoptosis, and it inhibited the efflux function and expression of ABCB1 in vitro, while knockdown of GAS5 had the opposite effects. Further mechanism-related investigations indicated that GAS5 acted as an endogenous "sponge" by competing for miR-221-3p binding to regulate its target dickkopf 2 (DKK2), and then it inhibited the activation of the Wnt/β-catenin pathway. Functionally, GAS5 enhanced the anti-tumor effect of ADR in vivo. Collectively, our findings reveal that GAS5 exerted regulatory function in ADR resistance possibly through the miR-221-3p/DKK2 axis, providing a novel approach to develop promising therapeutic strategy for overcoming chemoresistance in breast cancer patients.
耐药性，包括基于阿霉素（ADR）的治疗耐药性，是乳腺癌治疗中化疗失败的关键原因。已确定获得性化疗耐药与P-糖蛋白（P-gp/ABCB1）的过表达密切相关。长链非编码RNA（lncRNA）生长停滞特异性5（GAS5）可能参与致癌过程；然而，其在ABCB1介导的ADR耐药中的作用尚不清楚。在本研究中，我们通过RNA测序（RNA-seq）技术鉴定了MCF-7和MCF-7/ADR细胞系中一组差异表达的lncRNAs、mRNAs和微小RNA（miRNAs）。在耐药乳腺癌组织和细胞中，GAS5水平下调而ABCB1水平上调。GAS5的过表达显著增强了ADR敏感性和细胞凋亡，并在体外抑制了ABCB1的外排功能和表达，而敲低GAS5则产生相反的效果。进一步的机制相关研究表明，GAS5通过竞争与miR-221-3p结合来调节其靶标Dickkopf 2（DKK2），从而发挥内源性“海绵”作用，进而抑制Wnt/β-连环蛋白通路的激活。在功能上，GAS5增强了ADR在体内的抗肿瘤作用。总的来说，我们的研究结果表明，GAS5可能通过miR-221-3p/DKK2轴在ADR耐药中发挥调节作用，为开发克服乳腺癌患者化疗耐药的有前景的治疗策略提供了一种新方法。
