p19Arf inhibits the invasion of hepatocellular carcinoma cells by binding to C-terminal binding protein.
The INK4A/ARF tumor suppressor locus is frequently inactivated in hepatocellular carcinoma (HCC), yet the consequences of this remain unknown. We recently described a HCC mouse model in which loss of the Ink4a/Arf locus accelerates the development of metastasis and enhances tumor cell migration and invasion in cell culture assays. We show here that knockdown of p19Arf in an HCC cell line increases invasion in cell culture assays. Furthermore, reintroduction of p19(Arf) into HCC cell lines lacking Ink4a/Arf inhibits tumor cell invasion, without affecting cell proliferation, or cell transformation as measured by soft agar colony formation. Inhibition of cell invasion by p19(Arf) was dependent on its C-terminal binding protein (CtBP) interaction domain but independent of Mdm2 binding and nucleolar localization. Indeed, RNA interference-mediated knockdown of CtBP1 or CtBP2 decreased cell invasion, and ectopic expression of CtBP2 enhanced tumor cell migration and invasion. Thus, our data indicate a novel role for the Arf tumor suppressor protein in regulating phenotypes associated with tumor progression and metastasis in HCC cells.
Chen
Ya-Wen
YW
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Paliwal
Seema
S
Draheim
Kyle
K
Grossman
Steven R
SR
Lewis
Brian C
BC
D041721:3T3-L1 Cells; D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016147:Genes, Tumor Suppressor / Q000502:physiology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein