Hepatitis A virus cellular receptor 1/kidney injury molecule-1 is a susceptibility gene for clear cell renal cell carcinoma and hepatitis A virus cellular receptor/kidney injury molecule-1 ectodomain shedding a predictive biomarker of tumour progression

Thaïs Cuadros, Enric Trilla, Maria Rosa Vilà, Inés De Torres, Jordi Vilardell, Nabil Ben Messaoud, Mayte Salcedo, Eduard Sarró, Joan López-Hellin, Albert Blanco, Carmen Mir, Santiago Ramón Y Cajal, Emilio Itarte, Juan Morote, Anna Meseguer

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15 Citations (Scopus)

Abstract

Aim of the study: To correlate hepatitis A virus cellular receptor (HAVCR)/kidney injury molecule-1 (KIM-1) expression in clear cell renal cell carcinoma (ccRCC) tumours with patient outcome and study the consequences of HAVCR/KIM-1 ectodomain shedding. Methods: HAVCR/KIM-1 expression in ccRCC, oncocytomes, papillary carcinomas and unaffected tissue counterparts was evaluated. Minimal change disease and pre-clamping normal and ccRCC tissue biopsies were included. Tissue microarrays from 98 ccRCC tumours were analysed. Tumour registry data and patient outcome were retrospectivelly collected. Deletions in HAVCR/KIM-1 ectodomain and lentiviral infection of 786-O cells with HAVCR/KIM-1 mutated constructs to determine their subcellular distribution and invasive capacity were performed. Results: HAVCR/KIM-1 was expressed in ccRCC, papillary tumours and in tubule cells of adjacent and distal unaffected counterparts of ccRCC tumours. The latest was not related to ischemic or tumour-related paracrine effects since pre-clamping normal biopsies were positive for HAVCR/KIM-1 and unaffected counterparts of papillary tumours were negative. HAVCR/KIM-1 analyses in patients and the invasive capacity of HAVCR/KIM-1 shedding mutants in cell lines demonstrated that: (i) relative low HAVCR/KIM-1 membrane levels correlate with activated shedding in ccRCC patients and mutant cell lines; (ii) augmented shedding directly correlates with higher invasiveness and tumour malignancy. Concluding statements: Constitutive expression of HAVCR/KIM-1 in kidney might constitute a susceptibility trait for ccRCC tumour development. Enhanced HAVCR/KIM-1 ectodomain shedding promotes invasive phenotype in vitro and more aggressive tumours in vivo. © 2013 Elsevier Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)2034-2047
JournalEuropean Journal of Cancer
Volume49
DOIs
Publication statusPublished - 1 May 2013

Keywords

  • Biomarker
  • Clear cell renal cell carcinoma (ccRCC)
  • KIM-1
  • Kidney tumours
  • Tumour progression
  • hHAVcr-1

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