miR-550a-3p is a prognostic biomarker and exerts tumor-suppressive functions by targeting HSP90AA1 in diffuse malignant peritoneal mesothelioma

Abstract

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and rapidly lethal tumor, poorly responsive to conventional treatments. In this regards, the identification of molecular alterations underlying DMPM onset and progression might be exploited to develop novel therapeutic strategies. Here, we focused on miR-550a-3p, which we found downregulated in 45 DMPM clinical samples compared to normal tissues and whose expression levels were associated with patient outcome. Through a gain-of-function approach using miRNA mimics in 3 DMPM cell lines, we demonstrated the tumor-suppressive role of miR-550a-3p. Specifically, miRNA ectopic expression impaired cell proliferation and invasiveness, enhanced the apoptotic response, and reduced the growth of DMPM xenografts in mice. Antiproliferative and proapoptotic effects were also observed in prostate and ovarian cancer cell lines following miR-550a-3p ectopic expression. miR-550a-3p effects were mediated, at least in part, by the direct inhibition of HSP90AA1 and the consequent downregulation of its target proteins, the levels of which were rescued upon disruption of miRNA-HSP90AA1 mRNA pairing, partially abrogating miR-550a-3p-induced cellular effects. Our results show that miR-550a-3p reconstitution affects several tumor traits, thus suggesting this approach as a potential novel therapeutic strategy for DMPM.

Diagnostic and Therapeutic Pathway in Diffuse Malignant Peritoneal Mesothelioma

“…Other potential druggable targets were disclosed by investigating the dysregulation of the RTK signaling pathway involving EGFR, PDGFRA, and PDGFRB [19]. More recently, other insights were achieved regarding the role of microRNAs in DMPM pathophysiology, particularly miR-550a-3p [20], miR-34a [21], and miR-3805-p [22]. The epithelial-mesenchymal and mesenchymal-epithelial reverse transitions may be associated with the ability of epithelioid DMPM cells to spread peritoneally and promote drug-resistant phenotypes [23].…”