These authors contributed equally to this work.
Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an important protumorigenic factor in hepatocellular carcinoma
Article first published online: 1 APR 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 59, Issue 5, pages 1900–1911, May 2014
How to Cite
Gutschner, T., Hämmerle, M., Pazaitis, N., Bley, N., Fiskin, E., Uckelmann, H., Heim, A., Groβ, M., Hofmann, N., Geffers, R., Skawran, B., Longerich, T., Breuhahn, K., Schirmacher, P., Mühleck, B., Hüttelmaier, S. and Diederichs, S. (2014), Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an important protumorigenic factor in hepatocellular carcinoma. Hepatology, 59: 1900–1911. doi: 10.1002/hep.26997
Potential conflict of interest: Nothing to report.
Supported by the German Research Foundation (DFG Transregio TRR77, TP B3, B2, B4, B5, B7), the Excellence Cluster CellNetworks, the Helmholtz Society (VH-NG-504), and the Virtual Helmholtz Institute for Resistance in Leukemia. M.H. was supported by a Gerok stipend of the TRR77. N.P. was supported by a stipend of the GRK1591. Funding to S.H. was provided by ProNet-T3 (BMBF) and the GRK1591 (DFG).
- Issue published online: 23 APR 2014
- Article first published online: 1 APR 2014
- Accepted manuscript online: 7 JAN 2014 05:23AM EST
- Manuscript Accepted: 3 JAN 2014
- Manuscript Received: 9 JUL 2013
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 carcinogenesis. Hence, therapeutic targeting of IGF2BP1 may offer options for intervention in human HCC. (Hepatology 2014;59:1900–1911)