Aromatase in nontumoral and malignant human liver tissues and cells

We have investigated activity and expression of key steroids enzymes, including aromatase, in nontumoral, cirrhotic, and malignant human liver tissues and cells. Following 24 and 72 h incubation of malignant human liver cell lines HepG2, HuH7, and HA22T cells with testosterone (T) used as androgen precursor, we observed an increasingly high proportion of T oxidation to androstenedione, with aromatase being the prevalent enzyme activity in HepG2 and HuH7 cells at 72 h, while no aromatase could be detected in HA22T cells. On the other hand, balance of 5alpha- and 5beta-pathways was largely in favor of the 5alpha-pathway in HA22T cells and in favor of the 5beta-pathways in HuH7 cells. In in vivo studies conducted in nontumoral, cirrhotic, and malignant human liver tissue samples, aromatase activity was, respectively, undetectable, moderate, and elevated. RT-PCR analysis revealed high, intermediate, and very low levels of aromatase expression in HepG2, HuH7, and HA22T cells, respectively. Interestingly, both amphiregulin, a member of the EGF family of EGFR ligands, and an estrogen receptor (ER)-alpha, the hERalpha46, exhibited a corresponding figure of expression, being very high in HepG2 cells and markedly lower in HA22T and HuH7 cells. We propose here that locally elevated estrogen formation, brought about by high aromatase expression and activity, may result in the promotion of liver tumor cell growth through the induction of AREG via an ER-mediated mechanism.