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Autoregulatory suppression of c-Myc by miR-185-3p.

ABSTRACT: The expression of the c-myc oncogene at both protein and mRNA levels is transient and begins to be turned off 3-6 h after growth stimulation of cultured cells. The exact mechanism(s) underlying this down-regulation of c-Myc remains incompletely understood. Here we report the identification of miR-185-3p as a novel feedback regulator of c-Myc. This microRNA (miRNA) was initially identified as one of the c-Myc target miRNA transcripts through analysis of RNA samples isolated from cells prior to and after serum stimulation and further verified by real-time PCR, luciferase reporter, and ChIP assays. Interestingly, overexpression of wild type, but not mutant, miR-185-3p decreased the protein, but not mRNA, level of c-Myc in a dose-dependent fashion and also drastically abated the serum induction of c-Myc level in human cancer cells by targeting the coding sequence of c-Myc mRNA, consequently suppressing c-Myc-mediated proliferation. A miR-185-3p inhibitor rescued the inhibition of c-Myc expression by endogenous miR-185-3p. Thus, our results unveil miR-185-3p as the first miRNA that monitors c-Myc levels via an autoregulatory feedback mechanism in response to serum stimulation.

SUBMITTER: Liao JM

PROVIDER: S-EPMC3190790 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Breast cancer (BC) is the leading cause of female cancer-related mortalities. Evidence has illustrated the role of long non-coding RNAs (lncRNA) and microRNAs (miRNA) as promising pool of protein non-coding regulators, for tuning the aggressiveness of several malignancies. This research aims to unravel the expression pattern and the emphases of the diagnostic value of the long intergenic ncRNA00511 (LINC00511) and its downstream microRNA (miR-185-3p) and the pathogenic significance of the onco-miR-301a-3p in naïve BC patients. LINC00511 was chosen and validated, and its molecular binding was confirmed using bioinformatics. LINC00511 was measured in 25 controls and 70 patients using qPCR. The association between the investigated ncRNA’s expression and the BC patients’ clinicopathological features was assessed. Receiver operating characteristic (ROC) curve was blotted to weigh out their diagnostic efficacy over the classical tumor markers (TMs). Bioinformatics and Spearman correlation were used to predict the interaction between LINC00511, miR-185-3p, and miR-301a-3p altogether to patients’ features. LINC00511 and miR-301a-3p, in BC patients’ blood, were overexpressed, and their median levels increased significantly, while miR-185-3p was, in contrast, downregulated, being decreased fourfold. LINC00511 was elevated in BC early stages, when compared to late stages (p < 0.0003). LINC00511, miR-185-3p, and miR-301a-3p showed AUC superior to classical TMs, allowing us to conclude that the investigated ncRNAs, in BC patients’ liquid biopsy, are novel diagnostic molecular biomarker signatures. Lymph node metastasis (LNM) and advanced tumor grade were directly correlated with LINC00511 significantly. Additionally, both LINC00511 and miR-301a-3p were positively correlated with the aggressiveness of BC, as manifested in patients with larger tumors (>2 cm) at (p < 0.001). Therefore, these findings aid our understanding of BC pathogenesis, in the clinical setting, being related in part to the LINC00511/miR axis, which could be a future potential therapeutic target.

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Autoregulatory suppression of c-Myc by miR-185-3p.

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