Hsa_circ_0000199 通过干扰 miR-206/613 介导的 PI3K/Akt/mTOR 信号通路促进三阴性乳腺癌的化疗耐受。

Hsa_circ_0000199 facilitates chemo-tolerance of triple-negative breast cancer by interfering with miR-206/613-led PI3K/Akt/mTOR signaling.

机构信息

Department of General Surgery, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201100, China.

State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.

出版信息

Aging (Albany NY). 2021 Jan 20;13(3):4522-4551. doi: 10.18632/aging.202415.

DOI:10.18632/aging.202415

PMID:33495420

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7906206/

Abstract

Increasing attentions have been paid to the role of circRNAs in the etiology of triple-negative breast cancer (TNBC), and we strived to figure out the association of circRNA AKT3/miRNA axis with TNBC chemo-resistance. Altogether 207 BC patients were divided into TNBC group (n=83) and non-TNBC group (n=124), and MCF-10A, MDA-MB-231, MDA-MB-468, SK-BR-3 and MCF-7 cell lines were prepared in advance. Expressions of AKT3-derived circRNAs and relevant miRNAs in the TNBC tissues and cell lines were determined by employing real-time polymerase chain reaction (PCR). It was indicated that hsa_circ_0000199 expression was higher in TNBC tissues than in non-TNBC tissues, and high hsa_circ_0000199 expression was predictive of large tumor size, advanced TNM grade, high Ki-67 level and poor 3-year survival of TNBC patients (all <0.05). Furthermore, miR-613 and miR-206 were sponged and negatively regulated by hsa_circ_0000199 (<0.001), and PI3K/Akt/mTOR signaling was depressed by si-hsa_circ_0000199 in TNBC cell lines (<0.01). Ultimately, miR-206/miR-613 inhibitor reversed impacts of si-hsa_circ_0000199 on PI3K/Akt/mTOR signaling, proliferation, migration, invasion, chemo-sensitivity and autophagy of TNBC cells (all <0.01). Conclusively, silencing of hsa_circ_0000199 enhanced TNBC chemo-sensitivity by promoting miR-206/miR-613 expression and deactivating PI3K/Akt/mTOR signaling, which was conducive to improving chemotherapeutic efficacy of TNBC patients.

摘要

circRNA 在三阴性乳腺癌（TNBC）发病机制中的作用受到越来越多的关注，我们努力探讨 circRNA AKT3/miRNA 轴与 TNBC 化疗耐药的关系。共纳入 207 例 BC 患者，分为 TNBC 组（n=83）和非 TNBC 组（n=124），并提前准备 MCF-10A、MDA-MB-231、MDA-MB-468、SK-BR-3 和 MCF-7 细胞系。采用实时聚合酶链反应（PCR）检测 TNBC 组织和细胞系中 AKT3 衍生 circRNAs 和相关 miRNA 的表达。结果表明，TNBC 组织中 hsa_circ_0000199 的表达高于非 TNBC 组织，且 hsa_circ_0000199 高表达与大肿瘤大小、晚期 TNM 分级、高 Ki-67 水平和 TNBC 患者 3 年生存率差相关（均<0.05）。此外，hsa_circ_0000199 可吸附 miR-613 和 miR-206，并负调控其表达（<0.001），且 si-hsa_circ_0000199 可抑制 TNBC 细胞系中 PI3K/Akt/mTOR 信号（<0.01）。最终，miR-206/miR-613 抑制剂逆转了 si-hsa_circ_0000199 对 TNBC 细胞 PI3K/Akt/mTOR 信号、增殖、迁移、侵袭、化疗敏感性和自噬的影响（均<0.01）。综上所述，沉默 hsa_circ_0000199 通过促进 miR-206/miR-613 的表达和抑制 PI3K/Akt/mTOR 信号来增强 TNBC 的化疗敏感性，有利于提高 TNBC 患者的化疗疗效。