Local estrogen formation by nontumoral, cirrhotic, and malignant human liver tissues and cells.
We have investigated the activity and expression of aromatase enzyme in nontumoral, cirrhotic, and malignant human liver tissues and cells using both chromatographic and reverse transcription (RT)-PCR analyses. After 24- and 72-h incubation of tissue minces or hepatic cell lines with either testosterone or androstenedione as androgen precursor, human hepatocellular carcinoma (HCC) tissues and HepG2 hepatoma cells showed elevated aromatase activity, with estrogen formation rates being 20 and >95%, respectively, as opposed to nontumoral hepatic tissues and nonmalignant Chang liver (CL) cells, where no aromatase activity could be detected. Cirrhotic samples exhibited intermediate enzyme activity. Notably, exposure of HepG2 cells to the aromatase inhibitor Letrozole resulted in a striking decrease of estrogen formation, which became virtually absent at a Letrozole dose of 0.4 nM. RT-PCR analysis revealed markedly lower aromatase mRNA in both CL cells and nontumoral liver tissues, as compared with HepG2 cells and HCC samples. Cirrhotic specimens displayed variable transcript levels, in turn comparable with those observed in nontumoral or HCC tissues. Exon-specific RT-PCR showed prominent expression of exon I.3A-containing message and exon I.4-containing message in CL and HepG2 cells, as in nontumoral and HCC tissues, respectively. The present evidence implies that locally elevated estrogen formation in malignant human liver tissues and cells may have a role in the development and/or maintenance of human HCC, eventually leading to develop alternative strategies for treatment of HCC patients using antiaromatase agents.
Castagnetta
Luigi A M
LA
Department of Experimental Oncology and Clinical Application, University Medical School, Palermo, Italy.
Agostara
Biagio
B
Montalto
Giuseppe
G
Polito
Lucia
L
Campisi
Ildegarda
I
Saetta
Annalisa
A
Itoh
Toru
T
Yu
Bin
B
Chen
Shiuan
S
Carruba
Giuseppe
G
D000728:Androgens / Q000378:metabolism; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004967:Estrogens / Q000096:biosynthesis*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D000728:Androgens; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D004967:Estrogens; D001141:Aromatase