miR-139 is a Tumor Suppressor microRNA with a Guanine-rich Precursor Terminal Loop

MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression that modulate cancer-related processes, including cell growth, proliferation, differentiation, and invasion. While numerous oncogenic (oncomiRs) and tumor suppressor (TS) miRNAs have been characterized, structural features distinguishing these groups are not fully understood. This study investigates whether guanine (G) enrichment in precursor miRNA (pre-miRNA) terminal loop (TL) regions across the human miRNome is associated with tumor-suppressive activity in lung cancer.

We analyzed 955 human pre-miRNA TL region sequences to quantify G residue enrichment. G-rich TL miRNAs were identified using a G-enrichment score, with G-free TL miRNAs as controls. Functional annotations were compiled from 831 published studies. Publicly available transcriptomic and proteomic datasets were analyzed to assess miRNA expression and target regulation in lung adenocarcinoma (LUAD).

G-rich TL miRNAs (n=42) exhibited higher TS-to-oncomiR ratios than G-free control miRNAs. The enrichment of TS miRNAs among G-rich TL miRNAs was significantly stronger in lung cancer compared to the pan-cancer background (Breslow-Day test, p = 0.027). miR-139, a TS miRNA with a G-rich TL region, was consistently downregulated in LUAD at all stages, accompanied by increased expression of its validated oncogenic target, CCNB1.

The association between G-rich TL regions and TS function suggests that TL G content may affect miRNA processing efficiency, stability, and functional activity in lung cancer. The inverse expression patterns of miR-139 and CCNB1 in LUAD are consistent with a potential functional contribution of this structural feature to disease progression.

G-rich TL architecture is associated with TS miRNA function, particularly in lung cancer. miR-139, a TS miRNA characterized by a G-rich TL region, exemplifies this relationship by targeting the oncogene CCNB1. These findings underscore the potential relevance of TL sequence composition in miRNA-mediated tumor suppression and support its consideration in future research strategies aimed at restoring vulnerable TS miRNAs.