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The lncRNA-GAS5/miR-221-3p/DKK2 Axis Modulates ABCB1-Mediated Adriamycin Resistance of Breast Cancer via the Wnt/β-Catenin Signaling Pathway
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2020-02-01 , DOI: 10.1016/j.omtn.2020.01.030 Zhaolin Chen 1 , Tingting Pan 2 , Duochen Jiang 3 , Le Jin 3 , Yadi Geng 1 , Xiaojun Feng 1 , Aizong Shen 1 , Lei Zhang 1
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2020-02-01 , DOI: 10.1016/j.omtn.2020.01.030 Zhaolin Chen 1 , Tingting Pan 2 , Duochen Jiang 3 , Le Jin 3 , Yadi Geng 1 , Xiaojun Feng 1 , Aizong Shen 1 , Lei Zhang 1
Affiliation
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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 , 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 . 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.
中文翻译：
lncRNA-GAS5/miR-221-3p/DKK2 轴通过 Wnt/β-Catenin 信号通路调节 ABCB1 介导的乳腺癌阿霉素耐药性
耐药性，包括基于阿霉素（ADR）的治疗耐药性，是乳腺癌治疗化疗失败的一个重要原因。已发现获得性化疗耐药与 P-糖蛋白 (P-gp/ABCB1) 的过度表达密切相关。长链非编码RNA（lncRNA）生长停滞特异性5（GAS5）可能参与癌变；然而，其在 ABCB1 介导的 ADR 耐药性中的作用尚不清楚。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 lncRNA、mRNA 和 microRNA (miRNA)。在耐药乳腺癌组织和细胞中，GAS5水平下调，而ABCB1水平上调。 GAS5的过表达显着增强了ADR敏感性和细胞凋亡，并抑制了ABCB1的外排功能和表达，而GAS5的敲低则具有相反的效果。进一步的机制相关研究表明，GAS5作为内源性“海绵”，通过竞争miR-221-3p结合来调节其靶标dickkopf 2（DKK2），进而抑制Wnt/β-catenin通路的激活。从功能上来说，GAS5增强了ADR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 耐药中发挥调节功能，为开发克服乳腺癌患者化疗耐药性的有前景的治疗策略提供了一种新方法。
更新日期：2020-02-01
中文翻译：
lncRNA-GAS5/miR-221-3p/DKK2 轴通过 Wnt/β-Catenin 信号通路调节 ABCB1 介导的乳腺癌阿霉素耐药性
耐药性，包括基于阿霉素（ADR）的治疗耐药性，是乳腺癌治疗化疗失败的一个重要原因。已发现获得性化疗耐药与 P-糖蛋白 (P-gp/ABCB1) 的过度表达密切相关。长链非编码RNA（lncRNA）生长停滞特异性5（GAS5）可能参与癌变；然而，其在 ABCB1 介导的 ADR 耐药性中的作用尚不清楚。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 lncRNA、mRNA 和 microRNA (miRNA)。在耐药乳腺癌组织和细胞中，GAS5水平下调，而ABCB1水平上调。 GAS5的过表达显着增强了ADR敏感性和细胞凋亡，并抑制了ABCB1的外排功能和表达，而GAS5的敲低则具有相反的效果。进一步的机制相关研究表明，GAS5作为内源性“海绵”，通过竞争miR-221-3p结合来调节其靶标dickkopf 2（DKK2），进而抑制Wnt/β-catenin通路的激活。从功能上来说，GAS5增强了ADR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 耐药中发挥调节功能，为开发克服乳腺癌患者化疗耐药性的有前景的治疗策略提供了一种新方法。
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