Regulation of Melanoma Progression through the TCF4/miR-125b/NEDD9 Cascade

Abstract

Melanoma progression from a primary lesion to a distant metastasis is a complex process associated with genetic alterations, epigenetic modifications, and phenotypic switches. Elucidation of these phenomena may indicate how to interfere with this fatal disease. The role of microRNAs as key negative regulators of gene expression, controlling all cellular processes including cell migration and invasion, is now being recognized. Here, we used in silico analysis of microRNA expression profiles of primary and metastatic melanomas and functional experiments to show that microRNA-125b (miR-125b) is a determinant candidate of melanoma progression: (i) miR-125b is more strongly expressed in aggressive metastatic than primary melanomas, (ii) there is an inverse correlation between the amount of miR-125b and overall patient survival, (iii) invasion/migration potentials in vitro are inversely correlated with the amount of miR-125b in a series of human melanoma cell lines, and (iv) inhibition of miR-125b reduces migratory and invasive potentials without affecting cell proliferation in vitro. Furthermore, we show that neural precursor cell expressed developmentally down-regulated protein 9 (i.e., NEDD9) is a direct target of miR-125b and is involved in modulating melanoma cell migration and invasion. Also, transcription factor 4, associated with epithelial-mesenchymal transition and invasion, induces the transcription of miR-125b-1. In conclusion, the transcription factor 4/miR-125b/NEDD9 cascade promotes melanoma cell migration/invasion.

Melanoma Suppressor Functions of the Carcinoma Oncogene FOXQ1

“…This was in agreement with previous reports on β-catenin invasion-inhibiting activity in melanoma cells (Domingues et al, 2017; Domingues et al, 2014; Rambow et al, 2016). On the other hand, co-expression of FOXQ1 and EβP negated each other invasion-suppressing activities (Figure 5G).…”

<p>The Emerging Roles of miR-125b in Cancers</p>

“…These signals promote cancer metastasis by regulating migration, invasion, and infiltration. 76 Interestingly, miR-125b can bind within the coding sequence (CDS) of c-Jun mRNA and thus regulate c-Jun protein expression. 41 In ovarian cancer, SET, EIF4EBP1, and BCL3 are the targets of miR-125b.…”

The Non-Coding Landscape of Cutaneous Malignant Melanoma: A Possible Route to Efficient Targeted Therapy

“…miR-100, miR-125a and miR-125b also impair immunotherapy by favouring myeloid cell differentiation and polarization towards an immunosuppressive phenotype [ 130 ]. Furthermore, these miRNAs decrease drug sensitivity to BRAF inhibitors [ 117 , 118 ], promoting tumour cell proliferation, survival and invasion [ 58 , 117 ]. In BRAFi-resistant melanoma cell lines, the expression of miR-200c is significantly decreased, however its restoration prevents the establishment of drug resistance by targeting several transcriptional repressors involved in EMT [ 124 ].…”

“…The MET-like process of malignant melanocytes is favoured by miR-125b overexpression, who directly targets a transcript of NEDD9 (neural precursor cell expressed developmentally down-regulated protein 9) [ 58 , 59 ], and whose in vitro inhibition was found to decrease the invasive potential of aggressive melanoma cells [ 58 ]. Other miRNAs (miR-34b, miR-34c, and miR-199a-3p) also contribute to this mesenchymal movement by targeting the mRNA of tyrosine-protein kinase Met (c-MET), whose increased expression facilitates melanoma cell migration and metastasis [ 60 , 61 ].…”