Ras-Induced miR-146a and 193a Target Jmjd6 to Regulate Melanoma Progression.

Viviana Anelli,Marina Mione,Anita Ordas,Annemarie H Meijer,Manfred Schartl,Victor Gourain,Susanne Kneitz,Leonel Munoz Sagredo

doi:10.3389/fgene.2018.00675

Abstract

Ras genes are among the most commonly mutated genes in human cancer; yet our understanding of their oncogenic activity at the molecular mechanistic level is incomplete. To identify downstream events that mediate ras-induced cellular transformation in vivo, we analyzed global microRNA expression in three different models of Ras-induction and tumor formation in zebrafish. Six microRNAs were found increased in Ras-induced melanoma, glioma and in an inducible model of ubiquitous Ras expression. The upregulation of the microRNAs depended on the activation of the ERK and AKT pathways and to a lesser extent, on mTOR signaling. Two Ras-induced microRNAs (miR-146a and 193a) target Jmjd6, inducing downregulation of its mRNA and protein levels at the onset of Ras expression during melanoma development. However, at later stages of melanoma progression, jmjd6 levels were found elevated. The dynamic of Jmjd6 levels during progression of melanoma in the zebrafish model suggests that upregulation of the microRNAs targeting Jmjd6 may be part of an anti-cancer response. Indeed, triple transgenic fish engineered to express a microRNA-resistant Jmjd6 from the onset of melanoma have increased tumor burden, higher infiltration of leukocytes and shorter melanoma-free survival. Increased JMJD6 expression is found in several human cancers, including melanoma, suggesting that the up-regulation of Jmjd6 is a critical event in tumor progression.The following link has been created to allow review of record GSE37015: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=jjcrbiuicyyqgpc&acc=GSE37015.

Highlights

Activating mutations in the RAS genes or in other members of the ras-signaling pathways are very common in cancer1 and recent deep sequencing data of cancer genomes2 suggest that these mutations are important primers of malignancies
We found six microRNAs, which are upregulated as an early response to oncogenic RAS expression in three different models
As two of these microRNAs target Jmjd6 we investigated the significance of these interactions for melanoma progression

Summary

Introduction

Activating mutations in the RAS genes or in other members of the ras-signaling pathways are very common in cancer and recent deep sequencing data of cancer genomes suggest that these mutations are important primers of malignancies. The oncogenic versions of the human RAS genes (KRAS, HRAS, and NRAS) have been the first and most successful drivers of cancer in transgenic mice (Chin et al, 1999a,b; Johnson et al, 2001; Malumbres and Barbacid, 2003) This ability of ras oncogenes to initiate and maintain cancer has been related to global molecular and epigenetic changes at early stages of transformation. We found that activated Ras signaling promotes the rapid increase of six microRNAS Two of these microRNAs target the same gene, Jmjd, a jumonjiC domain protein with at least two reported functions: histone arginine demethylation (Chang et al, 2007) and mRNA splicing regulation (Webby et al, 2009). Results reported here indicate that Jmjd is a critical player in zebrafish melanoma development and that at least two Ras-induced microRNAs antagonize Jmjd activation

Methods

Results

Conclusion