Hepatitis A virus receptor blocks cell differentiation and is overexpressed in clear cell renal cell carcinoma

Centre d'Investigacions en Bioquímica i Biologia Molecular (CIBBIM), Hospital Universitari Vall d'Hebron, Barcelona. Spain.
Kidney International (Impact Factor: 8.56). 06/2004; 65(5):1761-73. DOI: 10.1111/j.1523-1755.2004.00601.x
Source: PubMed


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.
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.
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.
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.

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Available from: Juan Morote, Dec 07, 2014
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    • "Apoptotic Cells through Human TIM-1 Some human kidney cell lines show natural surface expression of TIM-1. We confirmed that 769P cells (Vila et al., 2004), derived from a renal clear-cell carcinoma, express TIM-1 on their cell surface by using hTIM-1 antibody 3D1 (Figure 6A). In contrast, 769P cells did not express TIM-4. "
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    • "TIM-1 has been usurped by the hepatitis A virus (HAV) for cell entry in monkeys and humans (Feigelstock et al., 1998; Kaplan et al., 1996). HAVCR1/TIM-1 is an important asthma determinant gene in humans (McIntire et al., 2003) and its expression is upregulated in acute kidney diseases and renal carcinoma (Han and Bonventre, 2004; Vila et al., 2004). The TIM gene family is located in a genomic locus linked to autoimmune disease and asthma both in mouse and humans (Kuchroo et al., 2006). "
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