miR-let-7b and miR-let-7c suppress tumourigenesis of human mucosal melanoma and enhance the sensitivity to chemotherapy

Mucosal melanomawith poor prognosis is a common histopathologic subtype of melanomaamong Chinese and other Asian peoples. Regulated microRNAs (miRNAs) have been reported as oncogenes or tumour suppressors in melanoma. However, the roles of specific miRNAs in mucosal melanomaremain largely unknown. Here, we aimed to assess the biological functions, molecular mechanisms and clinical potential of miR-let-7b and miR-let-7c in mucosal melanoma. The expression of miR-let-7b and miR-let-7c in mucosal melanomawas determined by quantitative polymerase chain reaction (qPCR). Cutoff scores for miR-let-7b and miR-let-7c expressions were calculated through receiver operating characteristic (ROC) curve analysis in 106 mucosal melanomapatients according to recurrence. Correlations of miR-let-7b and miR-let-7c expression with clinicopathological characteristics, disease-free survival (DFS) and clinical benefits after treatment were then statistically analysed. The biological functions and molecular mechanisms of miR-let-7b and miR-let-7c were studied in vitro and in vivo. The expression of miR-let-7b and miR-let-7c was decreased in 94 cases (88.7%) and 89 cases (84.0%) of 106 mucosal melanomapatients compared with mucosalnevi. A correlation was observed between the expression of miR-let-7b, miR-let-7c and DFS after surgery. In addition, overexpression of miR-let-7b or miR-let-7c inhibited mucosal melanomacell growth, migration, invasion and metastasis and induced cell apoptosis and cell cycle arrest in vitro and in vivo. Mechanistically, miR-let-7b and miR-let-7c directly targeted metadherin ( MTDH) and calumenin (CALU) and suppressed phospho-ERK in mucosal melanomacells. MTDHand CALU reversed the partial functionof miR-let-7b and miR-let-7c in vitro. Furthermore, progression-free survival (PFS) of mucosal melanomapatients upon temozolomide-based and paclitaxel-based chemotherapy was related to miR-let-7b and miR-let-7c expression. Overexpression of miR-let-7b or miR-let-7c in patient-derived xenograft (PDX) models and certain mucosal melanomacells had better growth inhibition after temozolomideand paclitaxel treatment. MTDHreversed the sensitivity of miR-let-7b and miR-let-7c to paclitaxel in vitro. Our results suggested that miR-let-7b and miR-let-7c inhibited the recurrence of mucosal melanomathrough inhibiting cell growth, migration, invasion and metastasis, inducing cell apoptosis and cell cycle arrest by targeting MTDHand CALU. In addition, miR-let-7b and miR-let-7c increased sensitivity to chemotherapeutic agents by targeting MTDH.