Hepatitis A virus receptor blocks cell differentiation and is overexpressed in clear cell renal cell carcinoma.
BACKGROUND
The molecular mechanisms underlying tumorigenesis and progression of clear cell renal cell carcinoma (ccRCC) are not well understood. We aimed to identify new molecular markers to provide insight into these processes.


METHODS
This work reports on the identification of human hepatitis A virus cellular receptor 1 (hHAVcr-1) as a differentially expressed gene in ccRCC using RNA-based arbitrarily primed polymerase chain reaction (RAP-PCR). Results were further confirmed by Northern and Western blot assays. Carcinoma 769-P and normal HK-2 cells derived from proximal tubule epithelial cells, grown under different culture conditions, were used to understand the putative role of hHAVcr-1 in renal malignancy. hHAVcr-1 stable transfected clones and dipeptidyl peptidase IV (DPPIV) assays allowed assessing its involvement in cell differentiation.


RESULTS
The hHAVcr-1 is overexpressed in eight out of 13 ccRCC and its expression neglected in benign oncocytomas. In culture, hhavcr-1 is dramatically overexpressed in normal and tumor cell lines that, having acquired the fully differentiated phenotype, are induced to de-differentiate by means of phorbol ester phorbol 12-myristate-13-acetate (PMA) treatment. Similarly, differentiation prevention by addition of PMA to confluent cells also increases hhavcr-1 expression. hHAVcr-1 stable transfected 769-P cells proved that hhavcr-1 itself blocks differentiation. Since hhavcr-1 is expressed at higher levels in tumor cells, we used an African green monkey cell model to show that immunotoxins directed against the monkey homologue of hhavcr-1 could kill kidney cells.


CONCLUSIONS
Our results showed that hHAVcr-1 blocks differentiation of proximal tubule epithelial cells and that it could be used as a target for therapy of kidney carcinomas.
Vilà
Maya R
MR
Centre d'Investigacions en Bioquímica i Biologia Molecular (CIBBIM), Hospital Universitari Vall d'Hebron, Barcelona. Spain.
Kaplan
Gerardo G
GG
Feigelstock
Dino
D
Nadal
Margarita
M
Morote
Joan
J
Porta
Ruth
R
Bellmunt
Joaquim
J
Meseguer
Anna
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D002454:Cell Differentiation; D002455:Cell Division; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D000072596:Hepatitis A Virus Cellular Receptor 1; D030041:Hepatitis A virus / Q000472:pathogenicity; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics* / Q000502:physiology*
D004273:DNA, Neoplasm; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011991:Receptors, Virus