N6-methyladenosine-mediated upregulation of LINC00520 accelerates breast cancer progression via regulating miR-577/POSTN axis and downstream ILK/AKT/mTOR signaling pathway

• Published in: Archives of biochemistry and biophysics Vol. 729; p. 109381
• Main Authors: Guo, Yang, Feng, Liang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.10.2022
• Subjects: Adenosine - analogs & derivatives; biomarkers; biophysics; Breast cancer; breast neoplasms; carcinogenesis; Cell Line, Tumor; Cell Movement - genetics; cell proliferation; Cell Proliferation - genetics; ILK/Akt/mTOR pathway; LINC00520; loss-of-function mutation; MicroRNAs - genetics; N6-methyladenosine modification; neoplasm progression; Neoplasms; POSTN; Proto-Oncogene Proteins c-akt - metabolism; RNA, Long Noncoding - genetics; Signal Transduction - physiology; therapeutics; TOR Serine-Threonine Kinases - metabolism; Up-Regulation; ILK/Akt/mTOR pathway; POSTN; Breast cancer; N6-methyladenosine modification; LINC00520
• ISSN: 0003-9861; 1096-0384; 1096-0384
• DOI: 10.1016/j.abb.2022.109381

Various lncRNAs have been reported to be closely associated with cancer initiation and progression in breast cancer (BC), including LINC00520. However, the role and underlying mechanisms by which LINC00520 affects BC aggressiveness have not been fully delineated, and this study aimed to explore this issue. Through performing qRT-PCR analysis, we proved that LINC00520 was significantly upregulated in BC tissues and cells, compared with normal tissues and cells. Higher expression of LINC00520 was closely related to higher tumor grade, poor differentiation and shorter survival in BC patients. Next, the loss-of-function experiments evidenced that silencing LINC00520 suppressed BC cell proliferation, migration and epithelial-mesenchymal transition (EMT) in vitro, and inhibited tumorigenesis in vivo. Interestingly, we found that LINC00520 expression was positively regulated by METTL3-mediated N6-methyladenosine(m6A) modification in BC. Furthermore, we identified the tumor-suppressor miR-577 as the binding target of LINC00520 in BC. Mechanistically, LINC00520 elevated POSTN level via sponging miR-577, resulting in the activation of the downstream tumor-promoting ILK/Akt/mTOR pathway. Finally, the rescuing experiments evidenced that both POSTN knockdown and ILK/Akt/mTOR pathway inhibitor OSU-T315 abrogated the promoting effects of miR-577 ablation on the malignant phenotypes in BC. Collectively, this study firstly verified that LINC00520 acted as a ceRNA of miR-577 to advance BC aggressiveness in a m6A-dependent manner, providing novel biomarkers for BC diagnosis and therapy. [Display omitted]