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Overexpression of Retinoic Acid Receptor in Hepatocellular Carcinoma¹

Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan [K. S., T. T., M. M.], and Department of Pathogenic Biochemistry, Research Institute for Wakan-Yaku, Toyama Medical and Pharmaceutical University, Toyama 931-0194, Japan [K. M., I. S.]

Purpose: Retinoid analogues have been reported to inhibit the growth of hepatocellular carcinoma (HCC). However, the expression profile of retinoic acid receptors (RARs) in HCC has not been fully clarified. In this study, we investigated the expression of RAR mRNAs and proteins in resected HCC and nontumor liver tissue.

Experimental Design: Reverse transcription-PCR and Western blot analysis were applied to investigate the expression of RAR mRNAs and proteins in 32 resected samples of HCC and 14 samples of nontumor liver tissue. A HCC cell line and primary-cultured hepatocyte were treated with RAR--selective retinoids in vitro to estimate their antiproliferative activity.

Results: The intensities of mRNA and protein for RAR- in HCC tissue were significantly higher than those in nontumor liver tissue (P = 0.002 and P = 0.002, respectively). The intensity ratios of HCC versus nontumor liver for RAR- mRNA and protein were significantly higher than those for RAR-ß and RAR- (mRNA, P = 0.02 and P = 0.006; protein, P = 0.04 and P = 0.007, respectively). There was only one significant correlation between the higher intensity of RAR-ß protein and tumor stage (stage I/II versus stage III/IVA, P = 0.01) among clinicopathological variables in the HCC patients. However, in vitro experiments showed that the growth of a RAR--elevated HCC cell line was potently inhibited by treatment with retinoids at concentrations that did not affect the growth of primary-cultured hepatocytes.

Conclusions: These results imply that RAR- is the dominant receptor in HCC, which suggests that RAR--selective retinoid analogues may be useful for chemotherapy.

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