Overexpression of microRNA-145 enhanced docetaxel sensitivity in breast cancer cells via inactivation of protein kinase B gamma-mediated phosphoinositide 3-kinase -protein kinase B pathway

Chemoresistance is a major challenge for the treatment of breast cancer (BC). Previous studies showed that miR-145 level decreases in chemoresistant BC tissues. Nevertheless, the biological function of miR-145 on docetaxel resistance of BC cells remains unclear, which is what our research attempted to clarify. RT-qPCR analyzed miR-145 level, and cell viability and colony formation assays assessed the impact of miR-145 on docetaxel resistance. Molecular mechanisms of miR-145-mediated docetaxel sensitivity were examined by Luciferase reporter assay and Western Blot assessed the function of AKT3 and PI3K/AKT signaling. Our research found that miR-145 expression presented significant downregulation in docetaxel-resistant BC cells. Meanwhile, miR-145 overexpression facilitated the docetaxel sensitivity of BC cells <i>in vivo</i> and <i>in vitro</i>, while the miR-145 inhibitor decreased the sensitivity of BC cells to docetaxel. We also observed that miR-145 inhibited docetaxel resistance mainly via downregulation of the AKT3 expression and further inhibited PI3K/AKT pathway. To conclude, this research provides a novel strategy for improving chemosensitivity through the newly identified miR-145-AKT3/PI3K-AKT signaling pathway in BC.

化疗耐药是乳腺癌（Breast Cancer, BC）治疗面临的核心挑战。既往研究证实，化疗耐药的乳腺癌组织中，微小RNA-145（miR-145）的表达水平显著降低。然而，miR-145对乳腺癌细胞多西他赛耐药性的生物学功能尚未明确，本研究旨在阐明这一科学问题。本研究采用实时荧光定量聚合酶链反应（Reverse Transcription Quantitative Polymerase Chain Reaction, RT-qPCR）检测miR-145的表达水平，通过细胞活力实验与集落形成实验评估miR-145对多西他赛耐药性的影响；通过荧光素酶报告基因实验（Luciferase reporter assay）与蛋白质印迹实验（Western Blot）探究miR-145介导多西他赛敏感性的分子机制，并验证AKT3及PI3K/AKT信号通路的功能。研究结果显示，多西他赛耐药的乳腺癌细胞中miR-145的表达显著下调。与此同时，miR-145过表达可在体内及体外环境中增强乳腺癌细胞对多西他赛的敏感性，而miR-145抑制剂则会降低乳腺癌细胞对多西他赛的敏感性。本研究同时发现，miR-145主要通过下调AKT3的表达，进而抑制PI3K/AKT信号通路，从而逆转乳腺癌细胞对多西他赛的耐药性。综上，本研究通过新发现的miR-145-AKT3/PI3K-AKT信号通路，为提升乳腺癌化疗敏感性提供了全新的干预策略。