Leptin enhances cholangiocarcinoma cell growth.
Leptin enhances cholangiocarcinoma cell growth.
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DOI：
10.1158/0008-5472.can-07-6682
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发表时间：
2008-08-15
期刊：
影响因子：
11.2
通讯作者：
Benedetti A
中科院分区：
文献类型：
--
作者：
Fava G;Alpini G;Rychlicki C;Saccomanno S;DeMorrow S;Trozzi L;Candelaresi C;Venter J;Di Sario A;Marzioni M;Bearzi I;Glaser S;Alvaro D;Marucci L;Francis H;Svegliati-Baroni G;Benedetti A
胆管癌是一种侵袭性很强的恶性肿瘤，预后很差。由于调控胆管癌细胞生长的分子机制尚不清楚，因此缺乏有效的治疗策略。此外，缺乏用于研究恶性胆管细胞病理生理机制的体内实验动物模型。瘦素是一种调节热量平衡的激素，肥胖患者体内的瘦素增加，会刺激几种癌症的生长，比如肝细胞癌。这项研究的目的是确定瘦素是否刺激胆管癌的生长。我们测定了正常和恶性人胆管细胞中瘦素受体的表达。然后研究瘦素对肝内胆管癌（HuH-28）细胞增殖、迁移和凋亡的影响，以及细胞内通路。此外，在实验中，肥胖的fa/fa Zucker大鼠（一种遗传上存在瘦素受体缺陷的动物物种）和它们的窝鼠通过长期喂食硫乙酰胺（一种强致癌物）诱导了胆管癌。24周后，评估瘦素对胆管癌发展和生长的影响。正常和恶性人胆管细胞表达瘦素受体。瘦素通过细胞外信号调节激酶1/2的转录3依赖性激活的信号转导和激活因子，在体外增加胆管癌细胞的增殖和转移潜能。瘦素能促进胆管癌细胞的生长和迁移，并具有抗凋亡作用。此外，瘦素功能的丧失减少了胆管癌的发生和生长。硫乙酰胺诱导的实验性癌变模型是研究胆管癌病理生物学的一种有效的、可重复的方法。调节瘦素介导的信号可以被认为是预防和治疗胆管癌的有效工具。
Cholangiocarcinoma is a strongly aggressive malignancy with a very poor prognosis. Effective therapeutic strategies are lacking because molecular mechanisms regulating cholangiocarcinoma cell growth are unknown. Furthermore, experimental in vivo animal models useful to study the pathophysiologic mechanisms of malignant cholangiocytes are lacking. Leptin, the hormone regulating caloric homeostasis, which is increased in obese patients, stimulates the growth of several cancers, such as hepatocellular carcinoma. The aim of this study was to define if leptin stimulates cholangiocarcinoma growth. We determined the expression of leptin receptors in normal and malignant human cholangiocytes. Effects on intrahepatic cholangiocarcinoma (HuH-28) cell proliferation, migration, and apoptosis of the in vitro exposure to leptin, together with the intracellular pathways, were then studied. Moreover, cholangiocarcinoma was experimentally induced in obese fa/fa Zucker rats, a genetically established animal species with faulty leptin receptors, and in their littermates by chronic feeding with thioacetamide, a potent carcinogen. After 24 weeks, the effect of leptin on cholangiocarcinoma development and growth was assessed. Normal and malignant human cholangiocytes express leptin receptors. Leptin increased the proliferation and the metastatic potential of cholangiocarcinoma cells in vitro through a signal transducers and activators of transcription 3–dependent activation of extracellular signal-regulated kinase 1/2. Leptin increased the growth and migration, and was antiapoptotic for cholangiocarcinoma cells. Moreover, the loss of leptin function reduced the development and the growth of cholangiocarcinoma. The experimental carcinogenesis model induced by thioacetamide administration is a valid and reproducible method to study cholangiocarcinoma pathobiology. Modulation of the leptin-mediated signal could be considered a valid tool for the prevention and treatment of cholangiocarcinoma.