title: HAVCR/KIM-1 activates the IL-6/STAT-3 pathway in clear cell renal cell carcinoma and determines tumor progression and patient outcome.
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 surface molecule HAVCR1/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. We found that HAVCR/KIM-1 activates the IL-6/STAT-3/HIF-1A axis in ccRCC-derived 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.
authors.affiliation: Authors' Affiliations: Fisiopatología Renal, CIBBIM; Statistics and Bioinformatics Unit (UEB), Vall d'Hebron Institute of Research; Servicio de Urología, Hospital Vall d'Hebron; Servicio de Anatomía Patológica, Hospital Vall d'Hebrón; Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica, Facultat de Biociències; Departament de Bioquimica i Biologia Molecular, Unitat de Bioquímica de Medicina, Universitat Autònoma de Barcelona, Bellaterra; and Instituto Reina Sofía de Investigación Nefrológica, Fundación Renal Íñigo Álvarez de Toledo, Spain.
authors.forename: Thaïs
authors.initials: T
authors.lastname: Cuadros
authors.forename: Enric
authors.initials: E
authors.lastname: Trilla
authors.forename: Eduard
authors.initials: E
authors.lastname: Sarró
authors.forename: Maya R
authors.initials: MR
authors.lastname: Vilà
authors.forename: Jordi
authors.initials: J
authors.lastname: Vilardell
authors.forename: Inés
authors.initials: I
authors.lastname: de Torres
authors.forename: Mayte
authors.initials: M
authors.lastname: Salcedo
authors.forename: Joan
authors.initials: J
authors.lastname: López-Hellin
authors.forename: Alex
authors.initials: A
authors.lastname: Sánchez
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramón y Cajal
authors.forename: Emilio
authors.initials: E
authors.lastname: Itarte
authors.forename: Juan
authors.initials: J
authors.lastname: Morote
authors.forename: Anna
authors.initials: A
authors.lastname: Meseguer
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D057809:HEK293 Cells; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C491143:HAVCR1 protein, human; C497442:HIF1A protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C508600:IL6 protein, human; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D011991:Receptors, Virus; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human