Cuadros T.,Vall dHebron Research Institute |
Trilla E.,Servicio de Urologia |
Sarro E.,Vall dHebron Research Institute |
Vila M.R.,Vall dHebron Research Institute |
And 11 more authors.
Renal cell carcinoma (RCC), the third most prevalent urological cancer, claims more than 100,000 lives/year worldwide. The clear cell variant (ccRCC) is the most common and aggressive subtype of this disease. While commonly asymptomatic, more than 30% of ccRCC are diagnosed when already metastatic, resulting in a 95% mortality rate. Notably, nearly one-third of organ-confined cancers treated by nephrectomy develop metastasis during follow-up care. At present, diagnostic and prognostic biomarkers to screen, diagnose, and monitor renal cancers are clearly needed. The gene encoding the cell surfacemoleculeHAVCR1/KIM-1 is a suggested susceptibility gene for ccRCC and ectodomain shedding of this molecule may be a predictive biomarker of tumor progression. Microarray analysis of 769-P ccRCC-derived cells where HAVCR/KIM-1 levels have been upregulated or silenced revealed relevant HAVCR/KIM-1-related targets, some of which were further analyzed in a cohort of 98 ccRCC patients with 100 month follow-up. Wefound that HAVCR/KIM-1 activates the IL-6/STAT-3/HIF-1A axis in ccRCCderived cell lines, which depends on HAVCR/KIM-1 shedding. Moreover, we found that pSTAT-3 S727 levels represented an independent prognostic factor for ccRCC patients. Our results suggest that HAVCR/KIM-1 upregulation in tumors might represent a novel mechanism to activate tumor growth and angiogenesis and that pSTAT-3 S727 is an independent prognostic factor for ccRCC. © 2013 American Association for Cancer Research. Source
Iglesias-Serret D.,Unitat de Bioquimica |
Pique M.,Unitat de Bioquimica |
Barragan M.,Unitat de Bioquimica |
Cosialls A.M.,Unitat de Bioquimica |
And 6 more authors.
Aspirin and other non-steroidal anti-inflammatory drugs induce apoptosis in most cell types. In this study we examined the mechanism of aspirin-induced apoptosis in human leukemia cells. We analyzed the role of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) pathways. Furthermore, we studied the changes induced by aspirin in some genes involved in the control of apoptosis at mRNA level, by performing reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA), and at protein level by Western blot. Our results show that aspirin induced apoptosis in leukemia Jurkat T cells independently of NF-κB. Although aspirin induced p38 MAPK and c-Jun N-terminal kinase activation, selective inhibitors of these kinases did not inhibit aspirin-induced apoptosis. We studied the regulation of Bcl-2 family members in aspirin-induced apoptosis. Aspirin increased the mRNA levels of some pro-apoptotic members, such as BIM, NOXA, BMF or PUMA, but their protein levels did not change. In contrast, aspirin decreased the protein levels of Mcl-1. Interestingly, in the presence of aspirin the protein levels of Noxa remained high. This alteration of the Mcl-1/Noxa balance was also found in other leukemia cell lines and primary chronic lymphocytic leukemia cells (CLL). Furthermore, in CLL cells aspirin induced an increase in the protein levels of Noxa. Knockdown of Noxa or Puma significantly attenuated aspirin-induced apoptosis. These results indicate that aspirin induces apoptosis through alteration of the Mcl-1/Noxa balance. © 2009 Springer Science+Business Media, LLC. Source