title: Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an important protumorigenic factor in hepatocellular carcinoma.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Helmholtz-University-Group "Molecular RNA Biology & Cancer," German Cancer Research Center DKFZ & Institute of Pathology, University Hospital Heidelberg, Germany.
authors.forename: Tony
authors.initials: T
authors.lastname: Gutschner
authors.forename: Monika
authors.initials: M
authors.lastname: Hämmerle
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Pazaitis
authors.forename: Nadine
authors.initials: N
authors.lastname: Bley
authors.forename: Evgenij
authors.initials: E
authors.lastname: Fiskin
authors.forename: Hannah
authors.initials: H
authors.lastname: Uckelmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Heim
authors.forename: Matthias
authors.initials: M
authors.lastname: Groβ
authors.forename: Nina
authors.initials: N
authors.lastname: Hofmann
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.forename: Britta
authors.initials: B
authors.lastname: Skawran
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Britta
authors.initials: B
authors.lastname: Mühleck
authors.forename: Stefan
authors.initials: S
authors.lastname: Hüttelmaier
authors.forename: Sven
authors.initials: S
authors.lastname: Diederichs
mesh_terms: D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000473:pathology; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: C406144:IGF2BP1 protein, human; D019394:Ki-67 Antigen; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins