乳腺癌干细胞衍生的细胞外囊泡通过依赖miR-4731-5p/AKT1轴的机制转移ARRDC1-AS1以促进乳腺癌发生。
Breast cancer stem cell-derived extracellular vesicles transfer ARRDC1-AS1 to promote breast carcinogenesis via a miR-4731-5p/AKT1 axis-dependent mechanism.
作者信息
Li Mingzhu, Lin Conglin, Cai Zhibing
机构信息
Area N4 of Surgical Oncology, Quanzhou First Hospital Affiliated to Fujian Medical University, No. 1028, Anji South Road, Fengze District, Quanzhou, Fujian 362000, China.
Area N4 of Surgical Oncology, Quanzhou First Hospital Affiliated to Fujian Medical University, No. 1028, Anji South Road, Fengze District, Quanzhou, Fujian 362000, China.
出版信息
Transl Oncol. 2023 May;31:101639. doi: 10.1016/j.tranon.2023.101639. Epub 2023 Feb 17.
OBJECTIVES
Deregulation of long non-coding RNAs (lncRNAs) has been frequently reported in breast cancer (BC). This goes to show the importance of understanding its significant contribution towards breast carcinogenesis. In the present study, we clarified a carcinogenic mechanism based on the ARRDC1-AS1 delivered by breast cancer stem cells-derived extracellular vesicles (BCSCs-EVs) in BC.
METHODS
The isolated and well characterized BCSCs-EVs were co-cultured with BC cells. The expression of ARRDC1-AS1, miR-4731-5p, and AKT1 was determined in BC cell lines. BC cells were assayed for their viability, invasion, migration and apoptosis in vitro by CCK-8, Transwell and flow cytometry, as well as tumor growth in vivo after loss- and gain-of function assays. Dual-luciferase reporter gene, RIP and RNA pull-down assays were performed to determine the interactions among ARRDC1-AS1, miR-4731-5p, and AKT1.
RESULTS
Elevation of ARRDC1-AS1 and AKT1 as well as miR-4731-5p downregulation were observed in BC cells. ARRDC1-AS1 was enriched in BCSCs-EVs. Furthermore, EVs containing ARRDC1-AS1 enhanced the BC cell viability, invasion and migration and glutamate concentration. Mechanistically, ARRDC1-AS1 elevated the expression of AKT1 by competitively binding to miR-4731-5p. ARRDC1-AS1-containing EVs were also found to enhance tumor growth in vivo.
CONCLUSION
Collectively, BCSCs-EVs-mediated delivery of ARRDC1-AS1 may promote the malignant phenotypes of BC cells via the miR-4731-5p/AKT1 axis.
目的
长链非编码RNA（lncRNAs）失调在乳腺癌（BC）中屡有报道。这表明了解其对乳腺癌发生的重要贡献具有重要意义。在本研究中，我们阐明了基于乳腺癌干细胞衍生的细胞外囊泡（BCSCs-EVs）递送的ARRDC1-AS1在乳腺癌中的致癌机制。
方法
将分离并充分表征的BCSCs-EVs与乳腺癌细胞共培养。测定乳腺癌细胞系中ARRDC1-AS1、miR-4731-5p和AKT1的表达。通过CCK-8、Transwell和流式细胞术体外检测乳腺癌细胞的活力、侵袭、迁移和凋亡，以及在功能缺失和功能获得实验后体内肿瘤生长情况。进行双荧光素酶报告基因、RIP和RNA下拉实验以确定ARRDC1-AS1、miR-4731-5p和AKT1之间的相互作用。
结果
在乳腺癌细胞中观察到ARRDC1-AS1和AKT1升高以及miR-4731-5p下调。ARRDC1-AS1在BCSCs-EVs中富集。此外，含有ARRDC1-AS1的细胞外囊泡增强了乳腺癌细胞的活力、侵袭和迁移以及谷氨酸浓度。机制上，ARRDC1-AS1通过竞争性结合miR-4731-5p提高了AKT1的表达。还发现含有ARRDC1-AS1的细胞外囊泡可增强体内肿瘤生长。
结论
总体而言，BCSCs-EVs介导的ARRDC1-AS1递送可能通过miR-4731-5p/AKT1轴促进乳腺癌细胞的恶性表型。
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