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E2F1 somatic mutation within miRNA target site impairs gene regulation in colorectal cancer

Lopes-Ramos, Camila M ; Barros, Bruna P ; Koyama, Fernanda C ; Carpinetti, Paola A ; Pezuk, Julia ; Doimo, Nayara T S ; Habr-Gama, Angelita ; Perez, Rodrigo O ; Parmigiani, Raphael B Navarro, Alfons

PloS one, 2017-07, Vol.12 (7), p.e0181153-e0181153 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
E2F1 somatic mutation within miRNA target site impairs gene regulation in colorectal cancer
Autor: Lopes-Ramos, Camila M ; Barros, Bruna P ; Koyama, Fernanda C ; Carpinetti, Paola A ; Pezuk, Julia ; Doimo, Nayara T S ; Habr-Gama, Angelita ; Perez, Rodrigo O ; Parmigiani, Raphael B
Navarro, Alfons
Assuntos: 3' Untranslated Regions ; Activation ; Aged ; Alterations ; Apoptosis ; Binding Sites ; Biology and life sciences ; Cancer ; Cell cycle ; Cell growth ; Chromosome 5 ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - genetics ; Deactivation ; E2F1 gene ; E2F1 Transcription Factor - chemistry ; E2F1 Transcription Factor - genetics ; Female ; Gene amplification ; Gene expression ; Gene Expression Regulation, Neoplastic ; Gene regulation ; Gene sequencing ; Genetic aspects ; Genetic Predisposition to Disease ; Genetic regulation ; High-Throughput Nucleotide Sequencing - methods ; Humans ; Inactivation ; Male ; Medical research ; Melanoma ; Metastasis ; MicroRNA ; MicroRNAs ; MicroRNAs - metabolism ; Middle Aged ; miRNA ; Mutation ; Proteins ; Ribonucleic acid ; RNA ; Sequence Analysis, DNA - methods ; Skin cancer ; Target recognition ; Tissues ; Transcription factors ; Tumor suppressor genes ; Tumorigenesis ; Up-Regulation
É parte de: PloS one, 2017-07, Vol.12 (7), p.e0181153-e0181153
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Current address: Idengene Medicina Diagnóstica LTDA, São Paulo City, São Paulo, Brazil
Competing Interests: The authors have declared that no competing interests exist.
Descrição: Genetic studies have largely concentrated on the impact of somatic mutations found in coding regions, and have neglected mutations outside of these. However, 3' untranslated regions (3' UTR) mutations can also disrupt or create miRNA target sites, and trigger oncogene activation or tumor suppressor inactivation. We used next-generation sequencing to widely screen for genetic alterations within predicted miRNA target sites of oncogenes associated with colorectal cancer, and evaluated the functional impact of a new somatic mutation. Target sequencing of 47 genes was performed for 29 primary colorectal tumor samples. For 71 independent samples, Sanger methodology was used to screen for E2F1 mutations in miRNA predicted target sites, and the functional impact of these mutations was evaluated by luciferase reporter assays. We identified germline and somatic alterations in E2F1. Of the 100 samples evaluated, 3 had germline alterations at the MIR205-5p target site, while one had a somatic mutation at MIR136-5p target site. E2F1 gene expression was similar between normal and tumor tissues bearing the germline alteration; however, expression was increased 4-fold in tumor tissue that harbored a somatic mutation compared to that in normal tissue. Luciferase reporter assays revealed both germline and somatic alterations increased E2F1 activity relative to wild-type E2F1. We demonstrated that somatic mutation within E2F1:MIR136-5p target site impairs miRNA-mediated regulation and leads to increased gene activity. We conclude that somatic mutations that disrupt miRNA target sites have the potential to impact gene regulation, highlighting an important mechanism of oncogene activation.
Editor: United States: Public Library of Science
Idioma: Inglês

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E2F1 somatic mutation within miRNA target site impairs gene regulation in colorectal cancer

Lopes-Ramos, Camila M ; Barros, Bruna P ; Koyama, Fernanda C ; Carpinetti, Paola A ; Pezuk, Julia ; Doimo, Nayara T S ; Habr-Gama, Angelita ; Perez, Rodrigo O ; Parmigiani, Raphael B Navarro, Alfons

United States: Public Library of Science

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