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Insulin‐like growth factor 2 mRNA‐binding protein 1 (IGF2BP1) is an important protumorigenic factor in hepatocellular carcinoma
Author(s) -
Gutschner Tony,
Hämmerle Monika,
Pazaitis Nikolaos,
Bley Nadine,
Fiskin Evgenij,
Uckelmann Hannah,
Heim Andreas,
Groβ Matthias,
Hofmann Nina,
Geffers Robert,
Skawran Britta,
Longerich Thomas,
Breuhahn Kai,
Schirmacher Peter,
Mühleck Britta,
Hüttelmaier Stefan,
Diederichs Sven
Publication year - 2014
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.26997
Subject(s) - biology , rna binding protein , oncogene , cancer research , carcinogenesis , gene knockdown , messenger rna , growth factor , insulin like growth factor binding protein , epigenetics , hepatocellular carcinoma , pten , microbiology and biotechnology , gene , apoptosis , cell cycle , insulin like growth factor , genetics , pi3k/akt/mtor pathway , receptor
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. (H epatology 2014;59:1900–1911)