Expression of Wild-Type and Variant Estrogen Receptor Alpha in Liver Carcinogenesis and Tumor Progression

Although estrogen receptors (ERs) are expressed in human hepatocellular carcinoma (HCC), several clinical trials have failed to demonstrate the efficacy of antiestrogen treatment in HCC patients. Recently, the identification of several ER splicing variants has enlightened the complex nature of estrogen signaling in peripheral tissues; this may help understanding estrogen role in either nontumoral or malignant nonclassical target organs, including liver. In this work we have investigated mRNA expression of wild-type and splice variants of ER alpha in nontumoral, cirrhotic, and malignant human liver, as well as in HCC cell lines, using an exon-specific reverse transcription polymerase chain reaction (RT-PCR). In particular, ER alpha 66 was detected in nontumoral and, to a lesser extent, in cirrhotic liver tissues, whereas its expression decreased or became undetectable in HCC tissues and cell lines. The ER alpha 46 splicing variant was detected ubiquitously in all samples; interestingly, however, the ER alpha 36 variant was inversely expressed with respect to ER alpha 66, being highest in HepG2 cells, intermediate in Huh7 cells, and lowest in HA22T cells. It is noteworthy that aromatase was correspondingly expressed with ER alpha 36 and inversely related to ER alpha 66. This observation suggests that a switch from ER alpha 66 to a predominant expression of ER alpha 36 may be associated with development and/or progression of human HCC.