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Cloning and Characterization of a Novel Gene, DRH1, Down-Regulated in Advanced Human Hepatocellular Carcinoma¹

Pathology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan [Y. Y., M. S., G. F., K. K., S. H.], and Third Department of Internal Medicine, Hokkaido University Faculty of Medicine, Sapporo 060-8038, Japan [Y. Y., M. A.]

Few genes related to carcinogenesis and progression of hepatocellular carcinoma (HCC) have been identified to date. In the present study, we report the cloning and characterization of a novel gene, DRH1, which is frequently down-regulated in HCC. The full-length DRH1 clone contains an open reading frame of 1257 nucleotides encoding 419 amino acids. The deduced DRH1 protein shows 41% identity to VDUP1, expression of which is rapidly induced by 1,25-dihydroxyvitamin D₃. The DRH1 gene was localized to chromosome 15, and DRH1 protein was mainly observed in the cytoplasm of transiently transfected cells. Real-time quantitative reverse transcription-PCR analysis showed that the expression level of DRH1 was reduced in 29 of 35 (83%) HCCs compared with corresponding noncancerous liver tissue. The average (mean ± SE) ratio of DRH1 expression level in tumor to corresponding noncancerous tissue was significantly different between well, moderately, and poorly differentiated HCCs (1.15 ± 0.23, 0.69 ± 0.10, and 0.19 ± 0.04, respectively) and between HCCs without and with vascular invasion (0.94 ± 0.16 and 0.46 ± 0.07, respectively). These results indicate that the down-regulation of DRH1 occurs not at an early stage but rather at a late stage of HCC progression. Although the function of DRH1 protein is still unknown, our findings suggest that DRH1 is related to the progression of HCC and may provide a new prognostic factor.

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