Your browser doesn't support javascript.
loading
p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression.
Amelio, Ivano; Mancini, Mara; Petrova, Varvara; Cairns, Rob A; Vikhreva, Polina; Nicolai, Sara; Marini, Alberto; Antonov, Alexey A; Le Quesne, John; Baena Acevedo, Juvenal D; Dudek, Kate; Sozzi, Gabriella; Pastorino, Ugo; Knight, Richard A; Mak, Tak W; Melino, Gerry.
Afiliação
  • Amelio I; Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom; ia348@mrc-tox.cam.ac.uk gm614@mrc-tox.cam.ac.uk.
  • Mancini M; Biochemistry Laboratory, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS), 00167 Rome, Italy.
  • Petrova V; Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom.
  • Cairns RA; The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 2C1.
  • Vikhreva P; Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom.
  • Nicolai S; Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom.
  • Marini A; Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom.
  • Antonov AA; Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom.
  • Le Quesne J; Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom.
  • Baena Acevedo JD; Department of Cancer Studies, University of Leicester, LE1 9HN Leicester, United Kingdom.
  • Dudek K; Department of Genetics, University of Leicester, LE1 9HN Leicester, United Kingdom.
  • Sozzi G; Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom.
  • Pastorino U; Tumour Genomics, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, 20133 Milan, Italy.
  • Knight RA; Thoracic Surgery, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, 20133 Milan, Italy.
  • Mak TW; Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom.
  • Melino G; The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 2C1.
Proc Natl Acad Sci U S A ; 115(46): E10869-E10878, 2018 11 13.
Article em En | MEDLINE | ID: mdl-30381462
ABSTRACT
Mutations in the TP53 gene and microenvironmentally driven activation of hypoxia-inducible factor-1 (HIF-1) typically occur in later stages of tumorigenesis. An ongoing challenge is the identification of molecular determinants of advanced cancer pathogenesis to design alternative last-line therapeutic options. Here, we report that p53 mutants influence the tumor microenvironment by cooperating with HIF-1 to promote cancer progression. We demonstrate that in non-small cell lung cancer (NSCLC), p53 mutants exert a gain-of-function (GOF) effect on HIF-1, thus regulating a selective gene expression signature involved in protumorigenic functions. Hypoxia-mediated activation of HIF-1 leads to the formation of a p53 mutant/HIF-1 complex that physically binds the SWI/SNF chromatin remodeling complex, promoting expression of a selective subset of hypoxia-responsive genes. Depletion of p53 mutants impairs the HIF-mediated up-regulation of extracellular matrix (ECM) components, including type VIIa1 collagen and laminin-γ2, thus affecting tumorigenic potential of NSCLC cells in vitro and in mouse models in vivo. Analysis of surgically resected human NSCLC revealed that expression of this ECM gene signature was highly correlated with hypoxic tumors exclusively in patients carrying p53 mutations and was associated with poor prognosis. Our data reveal a GOF effect of p53 mutants in hypoxic tumors and suggest synergistic activities of p53 and HIF-1. These findings have important implications for cancer progression and might provide innovative last-line treatment options for advanced NSCLC.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteína Supressora de Tumor p53 / Carcinoma Pulmonar de Células não Pequenas / Fator 1 Induzível por Hipóxia / Neoplasias Pulmonares Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteína Supressora de Tumor p53 / Carcinoma Pulmonar de Células não Pequenas / Fator 1 Induzível por Hipóxia / Neoplasias Pulmonares Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2018 Tipo de documento: Article