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. It is one of the fastest increasing malignancies and it represents a particular problem among immunosuppressed individuals. MicroRNAs (miRNAs) are short non-coding RNAs that regulate the expression of protein-coding genes at the posttranscriptional level. Here we identify miR-130a to be downregulated in cSCC compared with healthy skin and with precancerous lesions (actinic keratosis) and demonstrate that it is regulated at the transcriptional level by HRAS and MAPK-signaling. We report that miR-130a suppresses the growth of cSCC xenografts in mice. We demonstrate that overexpression of miR-130a suppresses long-term capacity of growth, cell motility and invasion ability in human cSCC cell lines. Mechanistically, miR-130a directly targets Activin A receptor, type I (ACVR1/ALK2) and changes in miR-130a levels result in the diminished activity of BMP/SMAD1 pathway via ACVR1. These data reveal a link between activated MAPK-signaling and decreased expression of miR-130a, which acts as a tumor suppressor miRNA in cSCC and contributes to a better understanding of molecular processes in malignant transformation of epidermal keratinocytes.