Genome-Wide Screen for MicroRNAs Reveals a Role for miR-203 in Melanoma Metastasis

Abstract

Melanoma is one of the deadliest human cancers with limited therapeutic options. MicroRNAs are a class of short noncoding RNAs regulating gene expression at the post-transcriptional level. To identify important miRNAs in melanoma, we compared the miRNome of primary and metastatic melanomas in The Cancer Genome Atlas dataset and found lower miR-203 abundance in metastatic melanoma. Lower level of miR-203 was associated with poor overall survival in metastatic disease. We found that the methylation levels of several CpGs in the MIR203 promoter negatively correlated with miR-203 expression and that treatment with the demethylating agent 5-aza-2-deoxycytidine induced miR-203 expression, which was associated with demethylation of the promoter CpGs, in melanoma cell lines. In vitro, there was a decreased expression of miR-203 in melanoma cell lines in comparison with primary melanocytes. Ectopic overexpression of miR-203 suppressed cell motility, colony formation, and sphere formation as well as the angiogenesis-inducing capacity of melanoma cells. In vivo, miR-203 inhibited xenograft tumor growth and reduced lymph node and lung metastasis. SLUG was shown as a target of miR-203, and knockdown of SLUG recapitulated the effects of miR-203, whereas its restoration was able to reverse the miR-203-mediated suppression of cell motility. These results establish a role for miR-203 as a tumor suppressor in melanoma which suppresses both early and late steps of metastasis. Hence, restoration of miR-203 has therapeutic potential in melanoma.

Predominant Distribution of the RNAi Machinery at Apical Adherens Junctions in Colonic Epithelia Is Disrupted in Cancer

“…In addition, PLEKHA7 re-expression results in the increased levels of miRNAs that we have previously identified to be regulated by PLEKHA7 in Caco2 cells, such as miR-30b, miR-200c, and miR-203a ( Figure 5I) [10,25]. These miRNAs are well-established tumor suppressors and are downregulated in many cancers, including colorectal tumors, as well as in colon cancer cell lines, such as those included in our study [38][39][40][41][42][43][44][45][46][47][48][49][50][51]. Together, these results are in agreement with our previous findings [10,25] and further support a tumor suppressing role for PLEKHA7 in the colonic epithelium, through recruitment and regulation of the RNAi machinery.…”

Downregulation of intratumoral expression of miR-205, miR-200c and miR-125b in primary human cutaneous melanomas predicts shorter survival

“…miR-182, miR-200c and miR-205 expression levels did not correlate with any TCGA transcriptomic subtypes. In an in silico analysis using the TGCA database, Lohcharienkal et al 33 also found a decreased expression of miR-200c and miR-182 in primary vs metastatic melanomas. These findings agree with our observations, since miR-200c and miR-182 expression were significantly decreased in the different stages of melanoma progression.…”

Epigenetic inactivation of miR-203 as a key step in neural crest epithelial-to-mesenchymal transition

“…Based on its their reported functionality, demonstrated target genes and expression pattern during chick development (Darnell et al, 2006), we further focused on miR-203 for in depth analysis. Importantly, miR-203 has been described to act as tumor suppressor (Benaich et al, 2014, Miao et al, 2014, Zhu et al, 2013b), that directly regulates Snail2 expression (Gao et al, 2017, Shi et al, 2015, Zhang et al, 2015, Xiao et al, 2017), whose epigenetic repression causes metastasis in several tumor cells including NCC-derived melanoma (Boldrup et al, 2012, Boll et al, 2013, Chen et al, 2012, Chiang et al, 2011, Ding et al, 2013, Furuta et al, 2010, Huang et al, 2014, Ju et al, 2014, Moes et al, 2012, Zhang et al, 2014, Zhao et al, 2013, Bu and Yang, 2014, Lohcharoenkal et al, 2018). Moreover, the mature miR-203 sequence is highly conserved throughout vertebrates including the basal lamprey (Fig.…”