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.
OBJECTIVE
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.
Fisiopatología Renal, CIBBIM, VHIR, Spain.
Thaïs
T
Cuadros
Enric
E
Trilla
Maria Rosa
MR
Vilà
Inés
I
de Torres
Jordi
J
Vilardell
Nabil Ben
NB
Messaoud
Mayte
M
Salcedo
Eduard
E
Sarró
Joan
J
López-Hellin
Albert
A
Blanco
Carmen
C
Mir
Santiago
S
Ramón y Cajal
Emilio
E
Itarte
Juan
J
Morote
Anna
A
Meseguer
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001665:Binding Sites / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D057809:HEK293 Cells; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D011379:Prognosis; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies
D014408:Biomarkers, Tumor; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D008562:Membrane Glycoproteins; D011991:Receptors, Virus