Transcribed ultraconserved region 339 promotes carcinogenesis by modulating tumor suppressor microRNAs

Abstract

The transcribed ultraconserved regions (T-UCRs) encode long non-coding RNAs implicated in human carcinogenesis. Their mechanisms of action and the factors regulating their expression in cancers are poorly understood. Here we show that high expression of uc.339 correlates with lower survival in 210 non-small cell lung cancer (NSCLC) patients. We provide evidence from cell lines and primary samples that TP53 directly regulates uc.339. We find that transcribed uc.339 is upregulated in archival NSCLC samples, functioning as a decoy RNA for miR-339-3p, -663b-3p, and -95-5p. As a result, Cyclin E2, a direct target of all these microRNAs is upregulated, promoting cancer growth and migration. Finally, we find that modulation of uc.339 affects microRNA expression. However, overexpression or downregulation of these microRNAs causes no significant variations in uc.339 levels, suggesting a type of interaction for uc.339 that we call “entrapping”. Our results support a key role for uc.339 in lung cancer.

Circular RNA ATXN7 promotes the development of gastric cancer through sponging miR-4319 and regulating ENTPD4

“…Up to now, the biological function and mechanism of circRNAs still need to be explored in malignancies progression [19]. Highly conserved sequences and particular covalently closed circular construction formed the feature of circRNAs [20]. It was reported that cir-cRNAs might be the underlying biomarkers to diagnose and cure a series of diseases due to the considerable functions they exerted on the development of diverse diseases, such as cancers [21,22].…”

Decrypting noncoding RNA interactions, structures, and functional networks

“…Recently, a new type of RNA:RNA interaction was described involving a T-UCR. The transcript of uc.339 harbors three IEs for miR-339-3p, miR-663b-3p, and miR-95-5p; of note, the uc.339 interaction with these miRNAs leads to up-regulation of their common target CCNE2, the cyclin E2 that plays a role in cell cycle G1/S transition and promotes lung carcinogenesis (Vannini et al 2017), overriding a canonical competing endogenous RNA (ceRNA)-type of interaction (Poliseno et al 2010;Cesana et al 2011) in which overexpression of the lncRNA or of the miRNAs down-regulates the interacting counterpart. Conversely, while up-regulation of uc.339 reduces the levels of miR-339, miR-663b, and miR-95, modulation (both up-and down-) of these three miR-NAs does not significantly affect the expression levels of the uc.339 transcript.…”

“…These sequences represent a particular type of SE. The disruption of the TREs impairs the binding of miR-339, miR-663b, and miR-95 to uc.339 (Vannini et al 2017). TREs are likely to be present in other lncRNAs and mRNA.…”

Targeting Epigenetic Dependencies in Solid Tumors: Evolutionary Landscape Beyond Germ Layers Origin

“…For example, non-coding RNA such as microRNAs, small RNA molecules of~22 bp, display a pleiotropic activity by canonically binding thousands of complementary mRNA transcripts and, in turn, perturbing their stability and subsequent translation [35,36]. Other involved mechanisms are the long non-coding RNAs (lnRNAs) that may serve as adaptors to drive epigenetic modulators or may sequestrate epigenetic complexes or transcription factors away from the chromatin [37,38] (Figure 1).…”