MiR-130a Acts as a Tumor Suppressor MicroRNA in Cutaneous Squamous Cell Carcinoma and Regulates the Activity of the BMP/SMAD Pathway by Suppressing ACVR1.

Cutaneous squamous cell carcinoma (cSCC) is a malignant neoplasm of the skin resulting from the accumulation of somatic mutations due to solar radiation. cSCC is one of the fastest increasing malignancies, and it represents a particular problem among immunosuppressed individuals. MicroRNAs are short noncoding RNAs that regulate the expression of protein-coding genes at the post-transcriptional level. In this study, we identify miR-130a to be downregulated in cSCC compared to healthy skin and precancerous lesions (actinic keratosis). Moreoever, we show that its expression is regulated at the transcriptional level by HRAS and MAPK signaling pathway. We demonstrate that overexpession of miR-130a suppresses long-term capacity of growth, cell motility and invasion ability of human cSCC cell lines. We report that miR-130a suppresses the growth of cSCC xenografts in mice. Mechanistically, miR-130a directly targets ACVR1 (ALK2), and changes in miR-130a levels result in the decreased activity of the BMP/SMAD pathway through ACVR1. These data reveal a link between activated MAPK signaling and decreased expression of miR-130a, which acts as a tumor-suppressor microRNA in cSCC and contribute to a better understanding of the molecular processes during malignant transformation of epidermal keratinocytes.