Overexpression of retinoic acid receptor alpha in hepatocellular carcinoma.

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-alpha-selective retinoids in vitro to estimate their antiproliferative activity.

RESULTS

The intensities of mRNA and protein for RAR-alpha 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-alpha mRNA and protein were significantly higher than those for RAR-beta and RAR-gamma (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-beta 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-alpha-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-alpha is the dominant receptor in HCC, which suggests that RAR-alpha-selective retinoid analogues may be useful for chemotherapy.