Alvaro Domenico, Barbaro Barbara, Franchitto Antonio, Onori Paolo, Glaser Shannon S, Alpini Gianfranco, Francis Heather, Marucci Luca, Sterpetti Paola, Ginanni-Corradini Stefano, Onetti Muda Andrea, Dostal David E, De Santis Adriano, Attili Adolfo F, Benedetti Antonio, Gaudio Eugenio
Department of Clinical Medicine, Division of Gastroenterology, University of Rome, via R. Rossellini 51, 00137 Rome, Italy. domenico.alvaro@uniroma1
Am J Pathol. 2006 Sep;169(3):877-88. doi: 10.2353/ajpath.2006.050464.
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.
我们研究了雌激素受体（ERs）、胰岛素样生长因子1（IGF-1）和IGF-1受体（IGF-1R）在人胆管癌及胆管癌细胞系（HuH-28、TFK-1、Mz-ChA-1）中的表达情况，评估雌激素和IGF-1在调节肿瘤细胞生长中的作用。在所有肝内胆管癌活检样本（18例中的18例）中，ER-α、ER-β、IGF-1和IGF-1R均有表达（免疫组织化学法）。仅HuH-28细胞系（肝内胆管癌）表达ER-α（蛋白质印迹法），而ER-β、IGF-1和IGF-1R在所检测的三种细胞系中均有表达。在血清饥饿的HuH-28细胞中，重新加入血清可诱导细胞增殖，而这种增殖受到ER和IGF-1R拮抗剂的抑制。17β-雌二醇和IGF-1对HuH-28细胞增殖的刺激程度与MCF7（乳腺癌）相似，但大于TFK-1和Mz-ChA-1，同时抑制细胞凋亡并发挥相加作用。17β-雌二醇和IGF-1的这些作用与ER-α、磷酸化（p）-ERK1/2和pAKT蛋白表达增强有关，但与ER-β表达降低有关。最后，在HuH-28细胞中转染IGF-1R反义寡核苷酸可显著降低细胞增殖。总之，人肝内胆管癌表达雌激素和IGF-1受体，它们在调节细胞生长和凋亡中协同发挥作用。调节ER和IGF-1R可能是胆管癌治疗的一种策略。
