Distinct microRNA expression signatures are associated with melanoma subtypes and are regulated by HIF1A

Abstract

Summary The complex genetic changes underlying metastatic melanoma need to be deciphered to develop new and effective therapeutics. Previously, genome-wide microarray analyses of human melanoma identified two reciprocal gene expression programs, including transcripts regulated by either transforming growth factor, beta 1 (TGFβ1) pathways or microphthalmia-associated transcription factor (MITF)/SRY-box containing gene 10 (SOX10) pathways. We extended this knowledge by discovering that melanoma cell lines with these two expression programs exhibit distinctive microRNA (miRNA) expression patterns. We also demonstrated that hypoxia-inducible factor 1 alpha (HIF1A) is increased in TGFβ1 pathway-expressing melanoma cells and that HIF1A upregulates miR-210, miR-218, miR-224, and miR-452. Reduced expression of these four miRNAs in TGFβ1 pathway-expressing melanoma cells arrests the cell cycle, while their overexpression in mouse melanoma cells increases the expression of the hypoxic response gene Bnip3. Taken together, these data suggest that HIF1A may regulate some of the gene expression and biological behavior of TGFβ1 pathway-expressing melanoma cells, in part via alterations in these four miRNAs.

MicroRNA-210-mediated proliferation, survival, and angiogenesis promote cardiac repair post myocardial infarction in rodents

“…Similarly, earlier studies indicate that master hypoxamiR-210 (miR-210) has cell proliferative potential [15, 17–19, 21]. On the contrary, miR-210 knockdown using siRNA could lead to cell cycle arrest [16, 21]. However, to this date, there is no report on miR-210 mediated induction of adult CM mitosis.…”

MicroRNA-224: as a potential target for miR-based therapy of cancer

“…The activation of TGF-β1 can induce upregulation of miR-224 through accelerating phosphorylation of the downstream effectors Smad2/3 in granulosa cell (GC) [12]. Hypoxia-inducible factor 1 alpha (HIF1A) is increased in TGF-β1 pathway-expressing melanoma cells and that HIF1A upregulates the expression of miR-224 [13]. On the contrary, the expression of miR-224 was reported to be suppressed by the tumor suppressor gene p53 and NF-κB p65 subunit in follicular granulosa cell.…”

Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

“…HIF1α is the master regulator of hypoxia, which promotes an invasive phenotype [230]. Notably, HIF1α upregulates miR-210 expression in melanoma [231] (Figure 7). MiR-210 is significantly enhanced in melanoma cell lines as compared with melanocytes and in patient-derived tumor samples as compared with melanocytic nevi [232].…”

“…As for a huge number of tumor-promoting genes, also for miRNAs, the regulation by dysregulated transcription factors plays an important role for aberrant miRNA expression ( Figure 9). A prominent example of a miRNA regulated by specific transcription factors is miR-210, which is regulated by binding of HIF1α by a specific response element in the miRNA-precursor sequence in melanoma [221,231] and also in HCC [215]. Furthermore, when melanoma cells become metastatic, the transcription factor ETS-1 gets phosphorylated and promotes transcription of miR-222 [265].…”