Sonic hedgehog signaling pathway mediates development of hepatocellular carcinoma
Sonic hedgehog signaling pathway mediates development of hepatocellular carcinoma
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音猬因子信号通路介导肝细胞癌的发生发展。
DOI：
10.1007/s13277-016-5463-6
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发表时间：
2016-12-01
期刊：
影响因子：
--
通讯作者：
Wang, Dong
中科院分区：
文献类型：
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作者：
Cai, Heng;Li, Hongxing;Wang, Dong
尽管在人肝细胞癌（HCC）患者和大多数HCC细胞系中已经证实了音刺猬（Shh）信号通路的异常激活，但是Shh通路促进HCC发展的机制仍然不确定。使用二乙基亚硝胺（DEN）诱导的肝癌模型，模拟从肝损伤，异常肝细胞增殖，肝硬化到肝细胞癌变的过程，我们通过检测Shh，patched-1（Ptch），smoothened（SMO）和胶质瘤相关癌基因-1（Gli 1）基因的表达来研究Shh通路的异常激活。在此过程中，CDK 1和cyclin B1蛋白的表达，这是两个组件的M期促进因子（MPF）控制G2/M转换，也被检查，以探讨Shh激活和细胞周期进程之间的潜在关系。Shh、Ptch和Gli 1蛋白阳性细胞主要分布于增生结节、癌结节、小叶间胆管上皮和癌前组织。Shh、Ptch和Gli 1蛋白的阳性表达率从正常组织开始到最终癌变的过程中呈逐渐增加的趋势。细胞周期蛋白B1和细胞周期蛋白依赖性激酶1在DEN诱导大鼠中的表达水平高于正常大鼠，主要分布于肝门脉区、增生结节、癌结节和癌前组织。结果提示，肝癌发生过程中Shh信号通路被激活，激活的Shh信号通路通过增加cyclin B1和CDK 1蛋白的表达，促进细胞G2/M期转换，促进细胞增殖，最终导致肝癌的发生。更好地了解肝癌中Shh信号通路可能有助于开发抑制细胞增殖和促进细胞周期阻滞的新治疗策略。
Although abnormal activation of the sonic hedgehog (Shh) signaling pathway has been demonstrated in human hepatocellular carcinoma (HCC) patients and in most HCC cell lines, the mechanism by which the Shh pathway promotes the development of HCC remains uncertain. Using a liver cancer model induced by diethylnitrosamine (DEN) which mimics the process from liver injury, abnormal hepatocyte proliferation, and hepatocirrhosis to hepatocyte canceration, we investigated the abnormal activation of the Shh pathway by examining the expression of Shh, patched-1 (Ptch), smoothened (SMO), and glioma-associated oncogene-1 (Gli1) genes. During this process, the expression of CDK1 and cyclin B1 protein, which are two components of the M-phase promoting factor (MPF) controlling G2/M transition, was also examined to explore the potential relationship between Shh activation and cell cycle progression. We observed that the cells with Shh, Ptch, and Gli1 protein expression were mainly distributed in hyperplastic nodule, cancerous node, the epithelia of interlobular bile duct, and precancerous tissues. A gradually increasing tendency of the positive expression rate of Shh, Ptch, and Gli1 proteins in the process from the beginning normal tissue to the final cancer formation was revealed. The cyclin B1 and CDK1 expression level was higher in the DEN-induced rats as compared with normal rats, and their expression was mainly distributed in the portal area of the liver, hyperplastic nodule, cancerous node, and precancerous tissues. Our results suggested that the Shh signaling pathway is activated during liver carcinogenesis, and activated Shh signaling promotes the cell proliferation by facilitating the G2/M transition through increasing the expression of cyclin B1 and CDK1 protein, which eventually results in the development of liver cancer. Better understanding of the Shh signaling pathway in HCC may contribute to the development of novel therapeutic strategies in inhibiting cell proliferation and promoting cell cycle arrest.