miR-342-3p regulates MYC transcriptional activity via direct repression of E2F1 in human lung cancer

Abstract

Accumulating evidence indicates that altered miRNA expression is crucially involved in lung cancer development, though scant information is available regarding how MYC, an archetypical oncogene, is regulated by miRNAs, especially via a mechanism involving MYC cofactors. In this study, we attempted to identify miRNAs involved in regulation of MYC transcriptional activity in lung cancer. To this end, we utilized an integrative approach with combinatorial usage of miRNA and mRNA expression profile datasets of patient tumor tissues, as well as those of MYC-inducible cell lines in vitro. In addition to miRNAs previously reported to be directly regulated by MYC, including let-7 and miR-17-92, our strategy also helped to identify miR-342-3p as capable of indirectly regulating MYC activity via direct repression of E2F1, a MYC-cooperating molecule. Furthermore, miR-342-3p module activity, which we defined as a gene set reflecting the experimentally substantiated influence of miR-342-3p on mRNA expression, was found to be inversely correlated with MYC activity reflected by MYC module activity in three independent datasets of lung adenocarcinoma patients obtained from the Director's Challenge Consortium of the United States (P = 1.94 × 10(-73)), the National Cancer Center of Japan (P = 9.05 × 10(-34)) and the present study (P = 1.17 × 10(-19)). Our integrative approach appears to be useful to elucidate inter-regulatory relationships between miRNAs and protein coding genes of interest, even those present in patient tumor tissues, which remains a challenge to better understand the pathogenesis of this devastating disease.

Coordination of Myeloid Differentiation with Reduced Cell Cycle Progression by PU.1 Induction of MicroRNAs Targeting Cell Cycle Regulators and Lipid Anabolism

“…Notably, E2f1 is targeted by miR-342-3p, miR-342-5p, miR-449a-5p, and miR-1298-5p. E2f1 has miR-342-3p binding sites at positions 262 to 268 and at positions 284 to 290 of the 3= untranslated region (UTR) (32). STRING analysis also suggested that E2F2 and E2F3 were targeted by induced miRNAs (Fig.…”

Predictive relevance of miR‑34a, miR‑224 and miR‑342 in patients with advanced squamous cell carcinoma of the lung undergoing palliative chemotherapy

“…Xie et al (21) demonstrated that miR-342 was downregulated in NSCLC and acted as a tumor suppressor through the repression of RAP2B, member of RAS oncogene family. Similarly, Tai et al (22) identified that miR-342 was capable of indirectly regulating MYC activity via the direct repression of E2F transcription factor 1. Takahashi et al (23) investigated how cigarette smoking altered plasma miRNA profiles; they identified that there was a decrease in plasma miR-342 in subjects who quit smoking, compared with smokers.…”

Predictive microRNAs for lymph node metastasis in endoscopically resectable submucosal colorectal cancer

“…E2F1 overexpression was reported to be correlated with LNM and distant metastasis in CRC [22]. In addition, E2F1 and RAP2B were reported to promote progression and metastasis of lung cancer and their expressions was downregulated by miR-342-3p in lung cancer [26, 28]. We also showed that miR-3621 was upregulated in LNM-positive CRCs and its expression level was positively correlated with RAP2B expression.…”