Molecular and cellular pathobiology HAVCR/KIM-1 activates the IL-6/STAT-3 pathway in clear cell renal cell carcinoma and determines tumor progression and patient outcome

Thaïs Cuadros, Enric Trilla, Eduard Sarro, Maya R. Vila, Jordi Vilardell, Ines De Torres, Mayte Salcedo, Joan Lopez-Hellin, Alex Sanchez, Santiago Ramon Y. Cajal, Emilio Itarte, Juan Morote, Anna Meseguer

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50 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)1416-1428
JournalCancer Research
Volume74
DOIs
Publication statusPublished - 1 Mar 2014

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