期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：49
页码：E6744-E6751
DOI：10.1073/pnas.1520390112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceActivating mutations in the B-Raf proto-oncogene serine/threonine kinase (BRAF) gene occur in many tumor types, the highest incidence being in malignant melanoma and papillary thyroid carcinoma. In patients with BRAF mutations tumor progression is more rapid than in patients without these mutations. Therapeutic strategies presently aim at inhibiting BRAF resulting in slower tumor progression; however, lasting remission is rarely accomplished. In this paper we identify the oncomiR-3151 as a downstream effector of mutated BRAF. MicroRNA-3151 (miR-3151) targets TP53 and other members of the TP53 pathway resulting in its inhibition. Simultaneous inhibition of BRAF and miR-3151 potentiates the effects on tumor cell growth. These data establish a link between mutated BRAF and the TP53 pathway, allowing novel therapeutic approaches to be considered. The B-Raf proto-oncogene serine/threonine kinase (BRAF) gene is the most frequently mutated gene in malignant melanoma (MM) and papillary thyroid cancer (PTC) and is causally involved in malignant cell transformation. Mutated BRAF is associated with an aggressive disease phenotype, thus making it a top candidate for targeted treatment strategies in MM and PTC. We show that BRAF mutations in both MM and PTC drive increased expression of oncomiR-3151, which is coactivated by the SP1/NF-{kappa}B complex. Knockdown of microRNA-3151 (miR-3151) with short hairpin RNAs reduces cell proliferation and increases apoptosis of MM and PTC cells. Using a targeted RNA sequencing approach, we mechanistically determined that miR-3151 directly targets TP53 and other members of the TP53 pathway. Reducing miR-3151s abundance increases TP53s mRNA and protein expression and favors its nuclear localization. Consequently, knockdown of miR-3151 also leads to caspase-3-dependent apoptosis. Simultaneous inhibition of aberrantly activated BRAF and knockdown of miR-3151 potentiates the effects of sole BRAF inhibition with the BRAF inhibitor vemurafenib and may provide a novel targeted therapeutic approach in BRAF-mutated MM and PTC patients. In conclusion, we identify miR-3151 as a previously unidentified player in MM and PTC pathogenesis, which is driven by BRAF-dependent and BRAF-independent mechanisms. Characterization of TP53 as a downstream effector of miR-3151 provides evidence for a causal link between BRAF mutations and TP53 inactivation.
