title: Estrogens and insulin-like growth factor 1 modulate neoplastic cell growth in human cholangiocarcinoma.
abstract: 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-alpha, ER-beta, IGF-1, and IGF-1R were expressed (immunohistochemistry) in all biopsies (18 of 18) of intrahepatic cholangiocarcinoma. ER-alpha was expressed (Western blot) only by the HuH-28 cell line (intrahepatic cholangiocarcinoma), whereas ER-beta, 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. 17beta-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 17beta-estradiol and IGF-1 were associated with enhanced protein expression of ER-alpha, phosphorylated (p)-ERK1/2 and pAKT but with decreased expression of ER-beta. 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.
authors.affiliation: Department of Clinical Medicine, Division of Gastroenterology, University of Rome, via R. Rossellini 51, 00137 Rome, Italy. domenico.alvaro@uniroma1
authors.forename: Domenico
authors.initials: D
authors.lastname: Alvaro
authors.forename: Barbara
authors.initials: B
authors.lastname: Barbaro
authors.forename: Antonio
authors.initials: A
authors.lastname: Franchitto
authors.forename: Paolo
authors.initials: P
authors.lastname: Onori
authors.forename: Shannon S
authors.initials: SS
authors.lastname: Glaser
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
authors.forename: Luca
authors.initials: L
authors.lastname: Marucci
authors.forename: Paola
authors.initials: P
authors.lastname: Sterpetti
authors.forename: Stefano
authors.initials: S
authors.lastname: Ginanni-Corradini
authors.forename: Andrea
authors.initials: A
authors.lastname: Onetti Muda
authors.forename: David E
authors.initials: DE
authors.lastname: Dostal
authors.forename: Adriano
authors.initials: A
authors.lastname: De Santis
authors.forename: Adolfo F
authors.initials: AF
authors.lastname: Attili
authors.forename: Antonio
authors.initials: A
authors.lastname: Benedetti
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis; D047629:Estrogen Receptor beta / Q000096:biosynthesis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D016376:Oligonucleotides, Antisense; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051058:Oncogene Protein v-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3