Department of Pathology, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi 214002, China.
Department of Breast, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi 214002, China.
Acta Biochim Biophys Sin (Shanghai). 2022 Jan 25;54(1):37-46. doi: 10.3724/abbs.2021006.
Chemoresistance is the major cause of therapeutic failure in human triple negative breast carcinoma (TNBC). Docetaxel (DOC), a first-line therapeutic drug in TNBC treatment, is limited for long-term use due to the development of chemoresistance. Thus, overcoming chemoresistance of DOC remains an important challenge to improve patient's outcome of TNBC. In this study, we aimed to investigate the molecular mechanism behind DOC chemoresistance and the possible therapeutic effects of miRNAs. Utilizing qRT-PCR analysis, we discovered that miR-1205 is gradually downregulated in human triple negative breast carcinoma MDA-MB-231 and docetaxel-resistant MDA-MB-231 (MDA-MB-231/DOC) cells compared with Hs 578Bst normal human breast fibroblasts. Cell viability, cell cycle and apoptosis assays in MDA-MB-231/DOC cells indicated that miR-1205 overexpression enhances docetaxel sensitivity by reducing cell viability as well as inducing G2/M cell cycle arrest and cell apoptosis. Western blot analysis, dual-luciferase reporter assay, co-immunoprecipitation assay and chromatin immunoprecipitation assay revealed that miR-1205 overexpression disrupts the stable complex formation of DNAJB1, mutp53 and TAp63 by directly reducing DNAJB1 expression, which abates the sequestrating effect of mutp53 on TAp63, thereby leading to the enhanced DOC sensitivity in MDA-MB-231/DOC cells. Our findings demonstrate the role of the miR-1205/DNAJB1 axis in the docetaxel resistance of TNBC, which may offer a promising therapeutic approach to resolve docetaxel resistance in TNBC.
耐药性是导致人类三阴性乳腺癌（TNBC）治疗失败的主要原因。多西紫杉醇（DOC）是 TNBC 治疗的一线治疗药物，但由于耐药性的发展，其长期使用受到限制。因此，克服 DOC 的耐药性仍然是提高 TNBC 患者疗效的重要挑战。在这项研究中，我们旨在研究 DOC 耐药性背后的分子机制以及 miRNA 的可能治疗效果。通过 qRT-PCR 分析，我们发现与正常人类乳腺成纤维细胞 Hs 578Bst 相比，miR-1205 在人三阴性乳腺癌 MDA-MB-231 和多西紫杉醇耐药 MDA-MB-231（MDA-MB-231/DOC）细胞中逐渐下调。MDA-MB-231/DOC 细胞的细胞活力、细胞周期和凋亡分析表明，miR-1205 过表达通过降低细胞活力以及诱导 G2/M 细胞周期阻滞和细胞凋亡来增强多西紫杉醇的敏感性。Western blot 分析、双荧光素酶报告基因检测、共免疫沉淀分析和染色质免疫沉淀分析表明，miR-1205 过表达通过直接降低 DNAJB1 表达破坏 DNAJB1、mutp53 和 TAp63 的稳定复合物形成，从而减弱 mutp53 对 TAp63 的隔离作用，从而导致 MDA-MB-231/DOC 细胞对多西紫杉醇的敏感性增强。我们的研究结果表明，miR-1205/DNAJB1 轴在 TNBC 的多西紫杉醇耐药性中起作用，这可能为解决 TNBC 中的多西紫杉醇耐药性提供一种有前途的治疗方法。
