Hepatocyte RXRalpha deficiency in matured and aged mice: impact on the expression of cancer-related hepatic genes in a gender-specific manner.

Background: The occurrence of liver cancer is higher in males than in females, and the incidence increases during aging. Signaling pathways regulated by retinoid x receptor alpha (RXRalpha) are involved in hepatocellular carcinogenesis. The phenotype of hepatocyte RXRalpha deficient mice is different between genders. To explore the impact of hepatocyte RXRalpha deficiency on gender-dependent hepatic gene expression, we compared the expression profiles of cancer-related genes in 6 and 24 month old male and female mice.

Results: In 6 month old mice, male mutant mice showed more cancer-related genes with alteration in mRNA levels than females did (195 vs. 60). In aged mice (24 month), female mutant mice showed greater deviation in mRNA expression levels of cancer-related genes than their male counterparts (149 vs. 82). The genes were classified into five categories according to their role in carcinogenesis: apoptosis, metastasis, cell growth, stress, and immune respnse. In each category, dependent upon age and gender, the genes as well as the number of genes with altered mRNA levels due to RXRalpha deficiency varies.

Conclusion: The change in hepatic cancer-related gene expression profiles due to RXRalpha deficiency was gender- and age-dependent. The alteration of mRNA levels of cancer-related genes implied that aberrant RXRalpha signaling could potentially increase the risk of liver cancer and that retinoid signaling might contribute to gender- and age-associated liver cancer incidence.