A Novel miR-451a isomiR, Associated with Amelanotypic Phenotype, Acts as a Tumor Suppressor in Melanoma by Retarding Cell Migration and Invasion

Abstract

miRNAs are key regulatory small non-coding RNAs involved in critical steps of melanoma tumorigenesis; however, the relationship between sequence specific variations at the 5′ or 3′ termini (isomiR) of a miRNA and cancer phenotype remains unclear. Deep-sequencing and qRT-PCR showed reduced expression of miR-144/451a cluster and most abundant isomiR (miR451a.1) in dysplastic nevi, in-situ and invasive melanomas compared to common nevi and normal skin (n = 101). miRNA in situ hybridization reproducibly confirmed lost miR-451a.1 in melanoma compared to nevus cells or adjacent keratinocytes. Significantly higher expression of miR-451a.1 was associated with amelanotic phenotype in melanomas (n = 47). In contrast, miR-451a was associated with melanotic phenotype, absent pagetoid scatter of intraepidermal melanocytes, superficial spreading histological subtype and tumor inflammation. Sequencing miRNAs from cultured melanocytes with cytoplasmic melanin gradient (light, medium to dark) showed absent miR-451a while revealing other melanin-associated miRNAs, e.g. miR-30b, miR-100 and miR-590 in darkly and let-7a, let-7i and let-7f in lightly to moderately pigmented cultured melanocytes. Ectopic expression of miR-144/451a in melanoma cell lines resulted in markedly higher levels of mature miR-451a.1 than miR451a or miR-144; and significantly retarded cell migration and inhibited invasion in a glucose-sensitive manner. Surprisingly, these effects were not mediated by calcium binding protein 39 (CAB39), a proven miR451a gene target. miR-144/miR-451a cluster is a novel miRNA locus with tumor suppressive activity in melanoma.

Circulating microRNA/isomiRs as novel biomarkers of esophageal squamous cell carcinoma

“…Isoforms of miR differ slightly from mature miR by base length and sequence and are referred to as isomiR. Although the function of isomiR is not completely understood, they are known to play an important role in cancer development [18,19]. IsomiRs also exist in the blood with high stability, similarly to mature miRs.…”

Identification of microRNAs associated with invasive and aggressive phenotype in cutaneous melanoma by next-generation sequencing

“…18 miR-211 functions as a metabolic switch 19 and as a potent tumor suppressor in vitro influencing gene pathways involved in cell invasion. [20][21][22] It is located within the noncoding sequence (intron 6) of Melastatin-1 (MLSN-1) gene, 20 which is expressed at high levels in melanocytic nevi but significantly reduced in metastatic melanomas with variable expression in primary lesions. 23 Loss of MLSN-1 mRNA is predictive of significantly reduced disease-free survival of melanoma patients.…”

Biogenesis and biological implications of isomiRs in mammals- a review

“…Babapoor and team [44] identified isomiR sequence of miRNAs that were deregulated in cutaneous melanomaand found that miR-451a was functioning as a tumor suppressor in gastrointestinal cancer cells and glioma cells. They concluded that miR-451a was involved in melanoma progression while the mature form of this isomiR, miR-451a.1 was associated with amelanotic melanoma [44]. Zhang and coworkers [45] developed a new method to discover the catalogue of isomiRs in association with cancer progression in human.…”