Transposable Element-Derived miR-28-5p and miR-708-5p: Exploring Potential Roles in Lung Cancer

<b>Background:</b> Transposable elements are normally silenced by epigenetic mechanisms; however, during malignant transformation, epigenetic alterations enable transposons to produce functional molecules like miRNAs. Among these, LINE-2 (L2) elements can generate miRNAs capable of regulating key genes, including tumor suppressors. Two L2-derived miRNAs, miR-28 and miR-708, have been linked to lung cancer, yet the mechanisms underlying their dysregulation remain poorly understood. Our study reveals how genomic context contributes to aberrant gene expression through comprehensive bioinformatic analyses. <b>Methods:</b> Using bioinformatics analysis, we evaluated the expression of miR-28 and miR-708 in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) datasets from TCGA. Further, we assessed the expression and methylation status of miR-28 and miR-708 host genes, <i>LPP</i> and <i>TENM4</i>, respectively, using computational tools. Finaly, we searched for potential candidate tumor suppressor genes targeted by miR-28 and miR-708, which are downregulated in LUAD and LUSC. <b>Results:</b> We found that intragenic L2-derived miR-28 and miR-708 are significantly upregulated in LUAD and LUSC. While <i>TENM4</i> gene also displays a marked increase in expression in LUAD and LUSC, in tumor versus normal tissue, this difference is less obvious for the <i>LPP</i> gene. We suggest that such dysregulations in expression might be linked to specific methylation patterns of their genomic locations. Furthermore, we emphasize that miR-28 and miR-708 might contribute to lung cancer pathogenesis by targeting key tumor suppressor genes. <b>Conclusions:</b> Alterations in the methylation status of L2-miRNAs genomic loci might result in elevated levels of miRNAs and subsequent targeting of tumor suppressor genes with potential implications in lung cancer pathogenesis.