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1.
Oncogene ; 36(10): 1339-1350, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27669434

RESUMO

KRas is mutated in a significant number of human cancers and so there is an urgent therapeutic need to target KRas signalling. To target KRas in lung cancers we used a systems approach of integrating a genome-wide miRNA screen with patient-derived phospho-proteomic signatures of the KRas downstream pathway, and identified miR-193a-3p, which directly targets KRas. Unique aspects of miR-193a-3p biology include two functionally independent target sites in the KRas 3'UTR and clinically significant correlation between miR-193a-3p and KRas expression in patients. Rescue experiments with mutated KRas 3'UTR showed very significantly that the anti-tumour effect of miR-193a-3p is via specific direct targeting of KRas and not due to other targets. Ex vivo and in vivo studies utilizing nanoliposome packaged miR-193a-3p demonstrated significant inhibition of tumour growth, circulating tumour cell viability and decreased metastasis. These studies show the broader applicability of using miR-193a-3p as a therapeutic agent to target KRas-mutant cancer.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias/genética , Neoplasias/patologia , Células Neoplásicas Circulantes/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Interferência de RNA , Regiões 3' não Traduzidas , Ciclo Celular , Linhagem Celular Tumoral , Bases de Dados Genéticas , Genes Reporter , Humanos , Metástase Neoplásica , Células Neoplásicas Circulantes/patologia , RNA Mensageiro/genética
3.
Oncogene ; 35(6): 691-701, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-25639871

RESUMO

The myc oncogene is overexpressed in almost half of all breast and ovarian cancers, but attempts at therapeutic interventions against myc have proven to be challenging. Myc regulates multiple biological processes, including the cell cycle, and as such is associated with cell proliferation and tumor progression. We identified a protein signature of high myc, low p27 and high phospho-Rb significantly correlated with poor patient survival in breast and ovarian cancers. Screening of a miRNA library by functional proteomics in multiple cell lines and integration of data from patient tumors revealed a panel of five microRNAs (miRNAs) (miR-124, miR-365, miR-34b*, miR-18a and miR-506) as potential tumor suppressors capable of reversing the p27/myc/phospho-Rb protein signature. Mechanistic studies revealed an RNA-activation function of miR-124 resulting in direct induction of p27 protein levels by binding to and inducing transcription on the p27 promoter region leading to a subsequent G1 arrest. Additionally, in vivo studies utilizing a xenograft model demonstrated that nanoparticle-mediated delivery of miR-124 could reduce tumor growth and sensitize cells to etoposide, suggesting a clinical application of miRNAs as therapeutics to target the functional effect of myc on tumor growth.


Assuntos
Neoplasias da Mama/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Regulação Neoplásica da Expressão Gênica , Genes myc , MicroRNAs/fisiologia , Neoplasias Ovarianas/genética , Proteína do Retinoblastoma/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Fosfoproteínas/metabolismo , Proteômica/métodos , Proteína do Retinoblastoma/metabolismo , Transcriptoma , Células Tumorais Cultivadas
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