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

Warangkana Lohcharoenkal, Kunal Das Mahapatra, Lorenzo Pasquali, Caitrin Crudden, Lara Kular, Yeliz Z. Akkaya Ulum, Lingyun Zhang, Ning Xu Landén, Leonard Girnita, Maja Jagodic, Mona Ståhle, Enikö Sonkoly, Andor Pivarcsi*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)882-892
Number of pages11
JournalJournal of Investigative Dermatology
Volume138
Issue number4
DOIs
Publication statusPublished - Apr 2018

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