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Oncogenic activation of glypican‐3 by c‐Myc in human hepatocellular carcinoma
Author(s) -
Li Li,
Jin Ronghua,
Zhang Xiaoli,
Lv Fudong,
Liu Lifeng,
Liu Daojie,
Liu Kai,
Li Ning,
Chen Dexi
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25891
Subject(s) - glypican 3 , chromatin immunoprecipitation , gene knockdown , biology , carcinogenesis , microbiology and biotechnology , immunoprecipitation , transcription factor , promoter , cancer research , luciferase , messenger rna , gene expression , hepatocellular carcinoma , gene , biochemistry , transfection
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. (H EPATOLOGY 2012)