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Downregulation of microRNA-199b predicts unfavorable prognosis and emerges as a novel therapeutic target which contributes to PP2A inhibition in metastatic colorectal cancer.
Cristóbal, Ion; Caramés, Cristina; Rincón, Raúl; Manso, Rebeca; Madoz-Gúrpide, Juan; Torrejón, Blanca; González-Alonso, Paula; Rojo, Federico; García-Foncillas, Jesús.
Afiliação
  • Cristóbal I; Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz, UAM, University Hospital "Fundacion Jimenez Diaz", E-28040 Madrid, Spain.
  • Caramés C; Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz, UAM, University Hospital "Fundacion Jimenez Diaz", E-28040 Madrid, Spain.
  • Rincón R; Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz, UAM, University Hospital "Fundacion Jimenez Diaz", E-28040 Madrid, Spain.
  • Manso R; Pathology Department, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain.
  • Madoz-Gúrpide J; Pathology Department, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain.
  • Torrejón B; Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz, UAM, University Hospital "Fundacion Jimenez Diaz", E-28040 Madrid, Spain.
  • González-Alonso P; Pathology Department, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain.
  • Rojo F; Pathology Department, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain.
  • García-Foncillas J; Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz, UAM, University Hospital "Fundacion Jimenez Diaz", E-28040 Madrid, Spain.
Oncotarget ; 8(25): 40169-40180, 2017 Jun 20.
Article em En | MEDLINE | ID: mdl-27517624
ABSTRACT
The tumor suppressor microRNA-199b (miR-199b) is a negative SET regulator associated with poor outcome in some human cancers. However, its expression levels as well as potential biological and clinical significance in colorectal cancer (CRC) remain completely unexplored. The PP2A inhibitor SET has shown promising therapeutic and clinical implications in metastatic CRC (mCRC) but the molecular mechanisms underlying SET deregulation are currently unknown. We show here miR-199b downregulation in 4 out of 5 CRC SET-overexpressing cell lines and its inverse correlation with SET overexpression in CRC patients. Moreover, miR-199b led to PP2A activation through a direct SET inhibition, impaired cell viability and enhanced oxaliplatin sensitivity in CRC cells. MiR-199b was found downregulated in 25% of cases, and associated with lymph metastasis (p = 0.049), presence of synchronous metastasis at diagnosis (p = 0.026) and SET overexpression (p < 0.001). Furthermore, low miR-199b levels determined shorter overall (p < 0.001), progression-free survival (p = 0.003) and predicted clinical benefit to oxaliplatin treatment. The miR-199b prognostic impact was particularly evident in both younger and KRAS wild-type subgroups. Multivariate analyses confirmed its independent prognostic impact. Altogether, our results show that miR-199b is a tumor suppressor whose downregulation independently determines worse outcome and emerges as a potential contributing mechanism to inhibit PP2A via SET overexpression in a subgroup of mCRC patients.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Neoplasias Colorretais / Regulação para Baixo / Regulação Neoplásica da Expressão Gênica / MicroRNAs / Proteína Fosfatase 2 / Chaperonas de Histonas Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Oncotarget Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Espanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Neoplasias Colorretais / Regulação para Baixo / Regulação Neoplásica da Expressão Gênica / MicroRNAs / Proteína Fosfatase 2 / Chaperonas de Histonas Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Oncotarget Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Espanha