Dexeus University Institute
Dexeus University Institute
Guo T.,Dalian Medical University |
Zhao S.,Dalian Medical University |
Wang P.,Dalian Medical University |
Xue X.,Dalian Medical University |
And 11 more authors.
Oncotarget | Year: 2017
Aberrant overexpression of the transcription/translation factor Y-box-binding protein (YB-1) is associated with poor prognosis of lung adenocarcinoma, however the underlying mechanism by which YB-1 acts has not been fully elucidated. Here, we reported that inhibition of YB-1 diminished proliferation, migration and invasion of lung adenocarcinoma cells. Interestingly, we identified metastasis associated in colon cancer-1 (MACC1) as a target of YB-1. Depletion of YB-1 markedly decreased MACC1 promoter activity and suppressed the MACC1/c-Met signaling pathway in lung adenocarcinoma cells. Additionally, chromatin immunoprecipitation (ChIP) assay demonstrated that YB-1 bound to the MACC1 promoter. Moreover, YB-1 was positively correlated with MACC1, and both proteins were over-expressed in lung adenocarcinoma tissues. The Cox-regression analysis indicated that high YB-1 expression was an independent risk factor for prognosis in enrolled patients. Furthermore, depletion of YB-1 attenuated tumorigenesis in a xenograft mouse model and reduced MACC1 expression in tumor tissues. Collectively, our data suggested that targeting YB-1 suppressed lung adenocarcinoma progression through the MACC1/c- Met pathway and that the high expression of YB-1/MACC1 is a potential prognostic marker in lung adenocarcinoma. © Guo et al.
Campelo R.G.,University of La Coruña |
Massuti B.,University of Alicante |
Mosquera J.,University of La Coruña |
Rosell R.,Hospital Germans Trias i Pujol |
Rosell R.,Dexeus University Institute
Translational Lung Cancer Research | Year: 2014
Lung cancer is a leading cause of cancer death and probably one of the most challenging cancers to treat. Platinum-based chemotherapy remains as the standard of treatment for most of advanced nonsmall cell lung cancer (NSCLC) patients, and although therapeutic improvements have been achieved in the last years, the benefits are quite modest. One of the most important advances in NSCLC care has been the identification of oncogenic mutations that contribute to the pathogenesis of lung cancer, suggesting that some tumors can rely on a specific gene for their survival and proliferation, and the subsequent development of drugs targeted to these specific alterations. Activating mutations of the epidermal growth factor receptor (EGFR) have been the first molecular event that can be targeted with specific drugs in NSCLC. The discovery of the first reversible EGFR small-molecule inhibitors (TKIs) in the past decade, has changed the history of lung cancer treatment. EGFR inhibition has emerged to be an important strategy in the treatment of NSCLC. However, all patients will eventually present progression of disease because of both primary and acquired resistance to EGFR TKIs. In the future, a better understanding of the tumor heterogeneity as well as tumor resistance mechanisms will evolve more rational therapies and potential combinations of different targeted therapies. © Translational lung cancer research. All rights reserved.
Rosell R.,Hospital Germans Trias I Pujol |
Rosell R.,Dexeus University Institute |
Molina M.A.,Dexeus University Institute |
Costa C.,Dexeus University Institute |
And 30 more authors.
Clinical Cancer Research | Year: 2011
Purpose: Advanced non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations (deletion in exon 19 or L858R) show an impressive progression-free survival of 14 months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. We hypothesized that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways. Experimental Design: We assessed the T790M mutation in pretreatment diagnostic specimens from 129 erlotinib-treated advanced NSCLC patients with EGFR mutations. The expression of eight genes and two proteins involved in DNA repair and four receptor tyrosine kinases was also examined. Results: The EGFR T790M mutation was observed in 45 of 129 patients (35%). Progression-free survival was 12 months in patients with and 18 months in patients without the T790M mutation (P = 0.05). Progression-free survival was 27 months in patients with low BRCA1 mRNAlevels, 18 months in those with intermediate levels, and 10 months in those with high levels (P = 0.02). In the multivariate analysis, the presence of the T790M mutation (HR, 4.35; P = 0.001), intermediate BRCA1 levels (HR, 8.19; P < 0.0001), and high BRCA1 levels (HR, 8.46; P < 0.0001) emerged as markers of shorter progression-free survival. Conclusions: Low BRCA1 levels neutralized the negative effect of the T790M mutation and were associated with longer progression-free survival to erlotinib. We advocate baseline assessment of the T790M mutation and BRCA1 expression to predict outcome and provide alternative individualized treatment to patients based on T790M mutations and BRCA1 expression. ©2011 AACR.