Mi-RNA-888-5p Is Involved in S-Adenosylmethionine Antitumor Effects in Laryngeal Squamous Cancer Cells

SIMPLE SUMMARY: Laryngeal Squamous Cell Carcinoma (LSCC) is a leading cause of cancer-related death with a strong interest in identifying and developing new treatments. MicroRNAs (miRNAs) have emerged as one of the most important determinants of neoplastic transformation and progression. miRNA modulation causes significant antitumor effects both in vitro and in vivo and miRNA regulation by natural compounds, represents a promising approach in the field of cancer research. S-Adenosylmethionine (AdoMet), a natural compound and a nutritional supplement, is well known for its antiproliferative and pro-apoptotic effects in many kinds of human tumors. Here, we report that AdoMet induces ER-stress and autophagy paralleled by miR-888-5p downregulation and MYCBP and CDH1 increased expression in Laryngeal Squamous Cancer Cells (LSCC). This study contributes to understanding the mechanisms by which AdoMet exerts its effects in LSCC, suggesting the use of AdoMet as an attractive miRNA-mediated chemopreventive and therapeutic strategy against cancer. ABSTRACT: (1) Purpose: The methyl donor S-Adenosylmethionine (AdoMet) has been widely explored as a therapeutic compound, and its application-alone or in combination with other molecules-is emerging as a potential effective strategy for the treatment and chemoprevention of tumours. In this study, we investigated the antitumor activity of AdoMet in Laryngeal Squamous Cell Carcinoma (LSCC), exploring the underlying mechanisms. (2) Results: We demonstrated that AdoMet induced ROS generation and triggered autophagy with a consistent increase in LC3B-II autophagy-marker in JHU-SCC-011 and HNO210 LSCC cells. AdoMet induced ER-stress and activated UPR signaling through the upregulation of the spliced form of XBP1 and CHOP. To gain new insights into the molecular mechanisms underlying the antitumor activity of AdoMet, we evaluated the regulation of miRNA expression profile and we found a downregulation of miR-888-5p. We transfected LSCC cells with miR-888-5p inhibitor and exposed the cells to AdoMet for 48 and 72 h. The combination of AdoMet with miR-888-5p inhibitor synergistically induced both apoptosis and inhibited cell migration paralleled by the up-regulation of MYCBP and CDH1 genes and of their targets. (3) Conclusion: Overall, these data highlighted that epigenetic reprogramming of miRNAs by AdoMet play an important role in inhibiting apoptosis and migration in LSCC cell lines.