Identification and Functional Evaluation of miR-4633-5p as a Biomarker and Tumor Suppressor in Metastatic Melanoma

Background/Aims: Sinonasal mucosal melanoma (SMM) is a rare but extremely aggressive disease. Interestingly, however, as lethal as SMM, a few patients could survive for over 5 years without metastasis. However, biomarkers for metastatic SMM are lacking. Methods: Laser-capture microdissection combined with microRNA microarray and RT-qPCR was performed in formalin-fixed paraffin-embedded tissue samples from SMM patients whose follow-up studies were carried out in parallel. In vitro cell proliferation and invasion assays, gelatin zymography, western blot analysis and RT-qPCR were performed in melanoma cell lines. Results: In the discovery stage, miR-4633-5p expressed differentially in sinonasal mucosal melanoma patients with short and long disease-specific survival. Subsequent large-sample validation revealed that expression of miR-4633-5p was lower in metastatic SMM than in non-metastatic patients (P< 0.001). Moreover, miR-4633-5plow was able to identify metastatic SMM with specificity of 100% (5/5) and sensitivity of 87.5% (21/24). Multivariate analysis further pinpointed miR-4633-5p as an independent marker for metastasis (relative risk: 54.22, P< 0.001). In vitro, overexpression of miR-4633-5p suppressed the growth and invasiveness of melanoma cells through inhibiting activation of Akt pathway and secretion of MMP2, while knockdown of miR-4633-5p reversed the inhibitory effects. Conclusion: Our findings underpin miR-4633-5p as a predictive biomarker in metastatic SMM and a pivotal tumor suppressor that negatively regulates the invasive growth of melanoma cells. Quantitative detection of miR-4633-5p can diagnostically predict the risk of metastasis in SMM patients, which, in turn, may lead to more personalized treatment with better prognosis