Oncogenic activation of glypican-3 by c-Myc in human hepatocellular carcinoma
Oncogenic activation of glypican-3 by c-Myc in human hepatocellular carcinoma
复制标题
c-Myc 在人肝细胞癌中对 Glypican-3 的致癌激活
DOI：
10.1002/hep.25891
复制
发表时间：
2012-10-01
期刊：
影响因子：
13.5
通讯作者：
Chen, Dexi
中科院分区：
文献类型：
--
作者：
Li, Li;Jin, Ronghua;Chen, Dexi
磷脂酰肌醇蛋白聚糖-3（GPC-3）是一种硫酸乙酰肝素蛋白聚糖，在细胞生长和分化中具有重要作用，并且其在肿瘤发生中的功能是组织依赖性的。在肝细胞癌（HCC）中，GPC 3的过表达已被证明是一个可靠的诊断指标。然而，调控GPC 3表达和功能的机制仍不清楚。癌蛋白c-Myc是一种转录因子，在超过50%的人类肿瘤中发挥重要作用。我们在这里报告说，GPC 3是一个转录靶点的c-Myc和c-Myc的表达也受到GPC 3的调节，从而形成一个正反馈信号环。在荧光素酶报告基因实验中，我们发现过表达c-Myc可以诱导GPC 3启动子依赖的荧光素酶活性。此外，突变分析确定了GPC 3启动子内的c-Myc结合位点。外源性过表达c-Myc增加了GPC 3的内源性信使RNA（mRNA）和蛋白水平。染色质免疫沉淀实验揭示了c-Myc与内源性GPC 3启动子的结合，表明c-Myc可以直接转录激活GPC 3。有趣的是，GPC 3也可以提高c-Myc表达。GPC 3的过表达增加了c-Myc蛋白水平，而GPC 3的敲低降低了c-Myc表达水平。最后，c-Myc水平的升高与人HCC样品中GPC 3的过表达相关。结论：这些数据为GPC 3和c-Myc在HCC发生发展中的作用提供了新的机制见解。（肝脏学2012）
Glypican-3 (GPC3) is a heparan sulfate proteoglycan that has an important role in cell growth and differentiation, and its function in tumorigenesis is tissue-dependent. In hepatocellular carcinoma (HCC), the overexpression of GPC3 has been demonstrated to be a reliable diagnostic indicator. However, the mechanisms that regulate the expression and function of GPC3 remain unclear. The oncoprotein c-Myc is a transcription factor that plays a significant role in more than 50% of human tumors. We report here that GPC3 is a transcriptional target of c-Myc and that the expression of c-Myc is also regulated by GPC3, thus forming a positive feedback signaling loop. We found that the overexpression of c-Myc could induce GPC3 promoter-dependent luciferase activity in luciferase reporter experiments. Furthermore, mutational analysis identified c-Myc-binding sites within the GPC3 promoter. The exogenous overexpression of c-Myc increased the endogenous messenger RNA (mRNA) and protein levels of GPC3. Chromatin immunoprecipitation experiments revealed the binding of c-Myc to the endogenous GPC3 promoter, indicating that c-Myc can directly transcriptionally activate GPC3. Interestingly, GPC3 can also elevate c-Myc expression. Overexpression of GPC3 increased c-Myc protein levels, whereas the knockdown of GPC3 reduced c-Myc expression levels. Lastly, the elevated levels of c-Myc correlate with the overexpression of GPC3 in human HCC samples. Conclusion: These data provide new mechanistic insight into the roles of GPC3 and of c-Myc in the development of HCC. (HEPATOLOGY 2012)