Abstract
To identify molecules to serve as diagnostic markers for renal cell carcinoma (RCC) and as targets for novel therapeutic drugs, we investigated genome-wide expression profiles of RCCs using a cDNA microarray. We subsequently confirmed that hypoxia-inducible protein-2 (HIG2) was expressed exclusively in RCCs and fetal kidney. Induction of HIG2 cDNA into COS7 cells led to secretion of the gene product into culture medium and resulted in enhancement of cell growth. Small interfering RNA effectively inhibited expression of HIG2 in human RCC cells that endogenously expressed high levels of the protein and significantly suppressed cell growth. Moreover, addition of polyclonal anti-HIG2 antibody into culture medium induced apoptosis in RCC-derived cell lines. By binding to an extracellular domain of frizzled homologue 10 (FZD10), HIG2 protein enhanced oncogenic Wnt signaling and its own transcription, suggesting that this product is likely to function as an autocrine growth factor. ELISA analysis of clinical samples identified secretion of HIG2 protein into the plasma of RCC patients even at an early stage of tumor development, whereas it was detected at significantly lower levels in healthy volunteers or patients with chronic glomerulonephritis. The combined evidence suggests that this molecule represents a promising candidate for development of molecular-targeting therapy and could serve as a prominent diagnostic tumor marker for patients with renal carcinomas.
Highlights
Renal cell carcinoma (RCC), the third most common malignancy of the genitourinary system, accounts for 2% to 3% of all human malignancies
Expression of hypoxia-inducible gene 2 (HIG2) in tumors developed in other tissues, including 16 cell lines derived from colorectal cancers, breast cancers, and hepatocellular carcinomas was absent or hardly detectable by reverse transcription-PCR (RT-PCR) analysis, Figure 1
We have provided substantial evidence here that the product of HIG2, originally identified as a gene induced by hypoxia [13], is likely to function as a crucial growth factor for RCC
Summary
Renal cell carcinoma (RCC), the third most common malignancy of the genitourinary system, accounts for 2% to 3% of all human malignancies. Surgical resection is the most effective treatment for localized RCC tumors, but no satisfactory treatment is available for patients with advanced-stage RCC. RCC tumors are characterized based on histologic features as clear cell (80%), papillary (f10%), chromophobe (
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