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.

Cuadros T, Trilla E, Vilà MR, de Torres I, Vilardell J, Messaoud NB, Salcedo M, Sarró E, López-Hellin J, Blanco A, Mir C, Ramón y Cajal S, Itarte E, Morote J, Meseguer A.
Eur J Cancer. 2013 May;49(8):2034-47. doi: 10.1016/j.ejca.2012.12.020. Epub 2013 Jan 23.
https://www.ncbi.nlm.nih.gov/pubmed/?term=Hepatitis+A+virus+cellular+receptor+1%2Fkidney+injury+molecule-1+is+a+susceptibility+gene+for+clear+cell+renal+cell+carcinoma+and+hepatitis+A+virus+cellular+receptor%2Fkidney+injury+molecule-1+ectodomain+shedding+a+predictive+biomarker+of+tumour+progression

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.