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

Frontiers in Genetics

Viviana Anelli¹  Leonel Munoz Sagredo³  Manfred Schartl⁴  Anita Ordas⁵  Marina Mione⁵  Victor Gourain⁶  Annemarie H. Meijer⁷  Susanne Kneitz⁸ 

[1] Cibio, University of Trento, Trento, Italy;Comprehensive Cancer Center, University Clinic Würzburg, Würzburg, Germany;Faculty of Medicine, University of Valparaiso, Valparaíso, Chile;;Hagler Institute for Advanced Study and Department of Biology, Texas A&Institute of Biology, Leiden University, Leiden, Netherlands;Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany;M University, College Station, TX, United States;Physiological Chemistry, Biocenter, University of Würzburg, Würzburg, Germany;

关键词: zebrafish;    cancer models;    microRNA;    Jmjd6;    ras;    melanoma;   

DOI  :  10.3389/fgene.2018.00675

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown