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

• Published in: European journal of cancer (1990) Vol. 49; no. 8; pp. 2034 - 2047
• Main Authors: Cuadros, Thaïs, Trilla, Enric, Vilà, Maria Rosa, de Torres, Inés, Vilardell, Jordi, Messaoud, Nabil Ben, Salcedo, Mayte, Sarró, Eduard, López-Hellin, Joan, Blanco, Albert, Mir, Carmen, Ramón y Cajal, Santiago, Itarte, Emilio, Morote, Juan, Meseguer, Anna
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.05.2013; Elsevier
• Subjects: Adult; Aged; Aged, 80 and over; Binding Sites - genetics; Biological and medical sciences; Biomarker; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting, Western; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; Clear cell renal cell carcinoma (ccRCC); Disease Progression; Female; Genetic Predisposition to Disease - genetics; HEK293 Cells; Hematology, Oncology and Palliative Medicine; Hepatitis A virus; Hepatitis A Virus Cellular Receptor 1; hHAVcr-1; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Kidney - metabolism; Kidney - pathology; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Kidney tumours; KIM-1; Male; Medical sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Microscopy, Fluorescence; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Multivariate Analysis; Mutation; Pharmacology. Drug treatments; Prognosis; Receptors, Virus - genetics; Receptors, Virus - metabolism; Retrospective Studies; Tumors; Tumour progression; KIM-1; Tumour progression; hHAVcr-1; Kidney tumours; Biomarker; Clear cell renal cell carcinoma (ccRCC); Hepatitis A virus; Picornaviridae; Kidney tumor; Biological marker; Hepatic disease; Genetic determinism; Viral hepatitis A; Cancerology; Tumor progression; Predisposition; Grawitz tumor; Cell; Biological receptor; Kidney disease; Transmembrane protein; Urinary system disease; Mesonephroma; Malignant tumor; Hepatovirus; Infection; Virus; Clear cell carcinoma; Viral disease; Kidney cancer; Digestive diseases; Cancer
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2012.12.020

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.