Insulin-Like Growth Factor 2 mRNA-Binding Protein 1 (IGF2BP1) Is an Important Protumorigenic Factor in Hepatocellular Carcinoma

作者：Tony Gutschner, Monika Hämmerle, Nikolaos Pazaitis, Nadine Bley, Evgenij Fiškin, Hannah J. Uckelmann, Andreas Heim, Matthias Groβ, Nina Hofmann, Robert Geffers, Britta Skawran, Thomas Longerich, Kai Breuhahn, Peter Schirmacher, Britta Mühleck, Stefan Hüttelmaier, Sven Diederichs · 发表于：Hepatology · 年份：2014 · DOI：10.1002/hep.26997 · 被引用次数：199 · 研究领域：RNA Research and Splicing、RNA modifications and cancer、Growth Hormone and Insulin-like Growth Factors

UNLABELLED: Hepatocarcinogenesis is a stepwise process. It involves several genetic and epigenetic alterations, e.g., loss of tumor suppressor gene expression (TP53, PTEN, RB) as well as activation of oncogenes (c-MYC, MET, BRAF, RAS). However, the role of RNA-binding proteins (RBPs), which regulate tumor suppressor and oncogene expression at the posttranscriptional level, are not well understood in hepatocellular carcinoma (HCC). Here we analyzed RBPs induced in human liver cancer, revealing 116 RBPs with a significant and more than 2-fold higher expression in HCC compared to normal liver tissue. We focused our subsequent analyses on the Insulin-like growth factor 2 messenger RNA (mRNA)-binding protein 1 (IGF2BP1) representing the most strongly up-regulated RBP in HCC in our cohort. Depletion of IGF2BP1 from multiple liver cancer cell lines inhibits proliferation and induces apoptosis in vitro. Accordingly, murine xenograft assays after stable depletion of IGF2BP1 reveal that tumor growth, but not tumor initiation, strongly depends on IGF2BP1 in vivo. At the molecular level, IGF2BP1 binds to and stabilizes the c-MYC and MKI67 mRNAs and increases c-Myc and Ki-67 protein expression, two potent regulators of cell proliferation and apoptosis. These substrates likely mediate the impact of IGF2BP1 in human liver cancer, but certainly additional target genes contribute to its function. CONCLUSION: The RNA-binding protein IGF2BP1 is an important protumorigenic factor in liver carcin...