In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3550-3550
Abstract:
The microRNA miR-211 is an established participant in melanomagenesis, but controversy exists as to whether it acts as a bone fide tumor suppressor or oncogene. Here we ectopically expressed miR-211 in the BRAF v600E-mutant A375 melanoma cell line and examined its effect in xenografts in vivo. The miR-211 ectopic expression promoted aggressive tumor xenograft growth with extensive cell proliferation, and angiogenesis. ChIP-seq and single cell sequencing analysis of xenograft tissues demonstrated that aggressive tumor formation is partly associated with H3K27me3 and H3K4me3, and migration of cells from mouse tissues to tumor locus. Interrogation of xenograft transcriptomics data revealed activation of the ERK5 pathway, itself negatively regulated by miR-211 target genes, BIRC2 and DUSP6, further confirmed as direct miR-211 target genes by RNA immunopurification with RNA-seq (RIP-seq) and site-directed mutagenesis. miR-211 conferred resistance to the BRAF inhibitor vemurafenib, and MEK inhibitor cobimetinib with corresponding increases in ERK5 phosphorylation. The miR-211-ERK5 axis may represent a novel therapeutic target, but however, miR-211 is exquisitely pleiotropic in the complex in vivo tumor environment and its context must be considered carefully in diagnostic and therapeutic development. Citation Format: Bongyong Lee, Anupama Sahoo, Junko Sawada, Dimitrios G. Zisoulis, John Marchica, Sanjay Sahoo, Fabiana I Alves De Lima Layng, Darren Finlay, Joseph Mazar, Piyush Joshi, Masanobu Komatsu, Kristiina Vuori, Garth Powis, Petrus R. de Jong, Animesh Ray, Ranjan J. Perera. microRNA-211 promotes aggressive melanoma growth in vivo by epigenetic modification, and contributes to BRAFV600E inhibitor resistance via ERK5 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3550.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2019-3550
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2019
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Bookmarklink