miR-146a Exerts Differential Effects on Melanoma Growth and Metastatization

Abstract

Malignant melanoma is the most aggressive form of skin cancer; therefore, it is crucial to disclose its underlying molecular mechanisms. MicroRNAs (miRNAs) are small endogenous noncoding RNAs able to posttranscriptionally downregulate the expression of direct target genes. Using a melanoma progression model, miR-146a was identified as a key double-acting player in melanoma malignancy. In fact, miR-146a is able to enhance tumor growth, while it suppresses dissemination. It was determined that miR-146a coordinated melanoma cell growth by its direct targets lunatic fringe (LFNG) and NUMB, which operate on the NOTCH/PTEN/Akt pathway; while inhibition of metastasis formation was linked to decreased expression of ITGAV and ROCK1. Relevantly, miR-146a expression correlated with melanoma recurrence and was enriched in both patient-derived melanoma and cutaneous metastasis specimens, while its direct targets were depleted. However, miR-146a levels drop in circulating tumor cells (CTCs), suggesting the necessity for miR-146a expression to fluctuate during tumor progression in order to favor tumor growth and allow dissemination. This study reconciles the contradictory biologic functions of miR-146a in melanoma progression and unravels distinct molecular mechanisms that need to be considered for therapeutic interventions.

Targeting of miR‐31/96/182 to the Numb gene during head and neck oncogenesis

“…Numb has been shown to be targeted by miR‐146 family members and by miR‐34a in previous studies . Reporter assays in this study specifically show that Numb is targeted by miR‐31, miR‐96 , and miR‐182 both individually and concordantly.…”

“…14,[40][41][42][43] It is well known that miR-146 family members are able to target the Numb gene and these interactions are involved in driving tissue differentiation and disease pathogenesis. 14,36,[44][45][46] In this study, we show that there is concordant upregulation of miR-31, miR-96, and miR-182 in HNSCC. Furthermore, Numb isoforms 1 to 4 possess similar activity and are able to suppress in vitro transformation.…”

“…Although the PTB and PRR are disrupted in a number of the Numb isoforms, which are created by alternative splicing, suppressor activity by a number of Numb isoforms has been reported for multiple types of malignancies, including HNSCC . It is well known that miR‐146 family members are able to target the Numb gene and these interactions are involved in driving tissue differentiation and disease pathogenesis . In this study, we show that there is concordant upregulation of miR‐31, miR‐96 , and miR‐182 in HNSCC.…”

miR‐146a‐5p: Expression, regulation, and functions in cancer

“…Further work supported these findings, and concluded lunatic fringe (LFNG) was also a direct target gene in melanoma cells. Melanoma recurrence correlated with miR‐146a levels (Raimo et al, ). Other investigators confirmed using transwell assays that miR‐146a could also promote malignant melanoma migration and invasion.…”

MicroRNAs in melanoma development and resistance to target therapy

“…Its upregulation during melanoma progression triggers tumor growth through inhibition of lunatic fringe (LFNG) and NUMB and activation of the NOTCH/PTEN/AKT pathway. In contrast its downregulation in Circulating Tumor Cells (CTC), suppresses tumor dissemination through modulation of the expression of ITGAV and ROCK1 [62, 63]. miR-638 is able to promote melanoma metastasis since it is overexpressed in metastatic lesions compared to primary melanomas [64].…”