title: MicroRNA-3151 inactivates TP53 in BRAF-mutated human malignancies.
abstract: 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-κB 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-3151's abundance increases TP53's 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.
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Malori A
authors.initials: MA
authors.lastname: Lankenau
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Ravi
authors.initials: R
authors.lastname: Patel
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Sophia E
authors.initials: SE
authors.lastname: Maharry
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Hoag
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Megan
authors.initials: M
authors.lastname: Duggan
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Walker
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Joseph
authors.initials: J
authors.lastname: Markowitz
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210 albert.delachapelle@osumc.edu ann-kathrin.eisfeld@osumc.edu.
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Eisfeld
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210 albert.delachapelle@osumc.edu ann-kathrin.eisfeld@osumc.edu.
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D021581:Active Transport, Cell Nucleus; D002277:Carcinoma / Q000235:genetics*; D002291:Carcinoma, Papillary; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics*; D035683:MicroRNAs / Q000502:physiology*; D009154:Mutation; D016328:NF-kappa B / Q000502:physiology; D000090063:Proto-Oncogene Mas; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013449:Sulfonamides / Q000627:therapeutic use; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D000077484:Vemurafenib
chemical_list: D007211:Indoles; C000715470:MAS1 protein, human; C000593307:MIRN3151 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D000090063:Proto-Oncogene Mas; D013449:Sulfonamides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; PTC; TP53; melanoma; microRNA