Cocarcinogenic Effects of Intrahepatic Bile Acid Accumulation in Cholangiocarcinoma Development
Cocarcinogenic Effects of Intrahepatic Bile Acid Accumulation in Cholangiocarcinoma Development
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DOI：
10.1158/1541-7786.mcr-13-0503
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发表时间：
2014-01-01
影响因子：
5.2
通讯作者：
Macias, Rocio I. R.
中科院分区：
文献类型：
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作者：
Lozano, Elisa;Sanchez-Vicente, Laura;Macias, Rocio I. R.
在临床上发现胆汁淤积之前，胆汁酸在肝胆管肿瘤病变中的蓄积可能发生。这是否有利于肝内胆管细胞癌的发展已在这项研究中进行了调查。急诊将RecA基因启动子克隆到Luc 2的上游，通过激活SOS基因检测其体外直接遗传毒性。该试验证明胆汁酸不能诱导DNA损伤。DNA损伤剂顺铂的遗传毒性作用既不增强，也不妨碍肝毒性和肝保护甘氨鹅去氧胆酸和甘氨熊去氧胆酸，分别。相反，硫代乙酰胺代谢物，而不是硫代乙酰胺本身，诱导DNA损伤。因此，硫代乙酰胺被用来诱导大鼠肝癌，导致30周后可见的肿瘤。在胆管结扎（BDL）动物中研究了胆汁酸蓄积对初始癌变阶段（8周）的影响。血清胆汁酸测量和肝脏特异性健康和肿瘤标志物的测定显示，早期硫代乙酰胺治疗诱导高胆固醇血症，以及胆管中肿瘤标志物Neu的上调，BDL增强。胆汁酸蓄积与白细胞介素（IL）-6表达增加和法尼醇X受体（FXR）下调有关。胆管增殖和凋亡激活，具有相反的模式（BDL >硫代乙酰胺+ BDL >>硫代乙酰胺vs.硫代乙酰胺>硫代乙酰胺+ BDL > BDL）。总之，胆汁酸的肝内蓄积不直接诱导致癌作用，但由于刺激胆管增殖、增强炎症和减少FXR依赖性化学保护而促进共致癌作用。
Bile acid accumulation in liver with cholangiolar neoplastic lesions may occur before cholestasis is clinically detected. Whether this favors intrahepatic cholangiocarcinoma development has been investigated in this study. The E. coli RecA gene promoter was cloned upstream from Luc2 to detect in vitro direct genotoxic ability by activation of SOS genes. This assay demonstrated that bile acids were not able to induce DNA damage. The genotoxic effect of the DNA-damaging agent cisplatin was neither enhanced nor hindered by the hepatotoxic and hepatoprotective glycochenodeoxycholic and glycoursodeoxycholic acids, respectively. In contrast, thioacetamide metabolites, but not thioacetamide itself, induced DNA damage. Thus, thioacetamide was used to induce liver cancer in rats, which resulted in visible tumors after 30 weeks. The effect of bile acid accumulation on initial carcinogenesis phase (8 weeks) was investigated in bile duct ligated (BDL) animals. Serum bile acid measurement and determination of liver-specific healthy and tumor markers revealed that early thioacetamide treatment induced hypercholanemia together with upregulation of the tumor marker Neu in bile ducts, which were enhanced by BDL. Bile acid accumulation was associated with increased expression of interleukin (IL)-6 and downregulation of farnesoid X receptor (FXR). Bile duct proliferation and apoptosis activation, with inverse pattern (BDL > thioacetamide + BDL >> thioacetamide vs. thioacetamide > thioacetamide + BDL > BDL), were observed. In conclusion, intrahepatic accumulation of bile acids does not induce carcinogenesis directly but facilitates a cocarcinogenic effect due to stimulation of bile duct proliferation, enhanced inflammation, and reduction in FXR-dependent chemoprotection.