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From the Department of Clinical Medicine,* Division of Gastroenterology, and the Department of Anatomy, University of Rome "La Sapienza," Rome, Italy; the University of Rome "La Sapienza," Polo Pontino, Latina, Italy; the Department of Experimental Medicine, Section of Human and Clinical Anatomy, State University of L’Aquila, L’Aquila, Italy; the Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy; the Divisions of Research and Education¶ and Research,** Central Texas Veterans Health Care System, Temple, Texas; the Departments of Medicine|| and Systems Biology and Translational Medicine, Scott and White and The Texas A&M University System Health Science Center College of Medicine, Temple, Texas; and the Health Science Center Division of Molecular Cardiology, Texas A&M University System, Temple, Texas
We investigated the expression of estrogen receptors (ERs), insulin-like growth factor 1 (IGF-1), and IGF-1R (receptor) in human cholangiocarcinoma and cholangiocarcinoma cell lines (HuH-28, TFK-1, Mz-ChA-1), evaluating the role of estrogens and IGF-1 in the modulation of neoplastic cell growth. ER-
, ER-ß, IGF-1, and IGF-1R were expressed (immunohistochemistry) in all biopsies (18 of 18) of intrahepatic cholangiocarcinoma. ER- was expressed (Western blot) only by the HuH-28 cell line (intrahepatic cholangiocarcinoma), whereas ER-ß, IGF-1, and IGF-1R were expressed in the three cell lines examined. In serum-deprived HuH-28 cells, serum readmission induced stimulation of cell proliferation that was inhibited by ER and IGF-1R antagonists. 17ß-Estradiol and IGF-1 stimulated proliferation of HuH-28 cells to a similar extent to that of MCF7 (breast cancer) but greater than that of TFK-1 and Mz-ChA-1, inhibiting apoptosis and exerting additive effects. These effects of 17ß-estradiol and IGF-1 were associated with enhanced protein expression of ER-, phosphorylated (p)-ERK1/2 and pAKT but with decreased expression of ER-ß. Finally, transfection of IGF-1R anti-sense oligonucleotides in HuH-28 cells markedly decreased cell proliferation. In conclusion, human intrahepatic cholangiocarcinomas express receptors for estrogens and IGF-1, which cooperate in the modulation of cell growth and apoptosis. Modulation of ER and IGF-1R could represent a strategy for the management of cholangiocarcinoma.
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