title: A novel KLF6-Rho GTPase axis regulates hepatocellular carcinoma cell migration and dissemination.
abstract: The presence of invasion into the extra-hepatic portion of the portal vein or the development of distant metastases renders hepatocellular carcinoma (HCC) patients ineligible for the only potential curative options for this malignancy-tumor resection or organ transplantation. Gene expression profiling of murine HCC cell lines identified KLF6 as a potential regulator of HCC cell migration. KLF6 knockdown increases cell migration, consistent with the correlation between decreased KLF6 mRNA levels and the presence of vascular invasion in human HCC. Concordantly, single-copy deletion of Klf6 in a HCC mouse model results in increased tumor formation, increased metastasis to the lungs and decreased survival, indicating that KLF6 suppresses both HCC development and metastasis. By combining gene expression profiling and chromatin immunoprecipitation coupled to deep sequencing, we identified novel transcriptional targets of KLF6 in HCC cells including VAV3, a known activator of the RAC1 small GTPase. Indeed, RAC1 activity is increased in KLF6-knockdown cells in a VAV3-dependent manner, and knockdown of either RAC1 or VAV3 impairs HCC cell migration. Together, our data demonstrate a novel function for KLF6 in constraining HCC dissemination through the regulation of a VAV3-RAC1 signaling axis.
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: L G
authors.initials: LG
authors.lastname: Ahronian
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.|Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.|Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Zhu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Maioli, Taiwan.
authors.forename: Y-W
authors.initials: YW
authors.lastname: Chen
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Maioli, Taiwan.
authors.forename: H-C
authors.initials: HC
authors.lastname: Chu
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Klimstra
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.|Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.|Cancer Center, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Lewis
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009479:Neuropeptides / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics*; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000235:genetics*
chemical_list: C491358:Klf6 protein, mouse; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D009479:Neuropeptides; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; C484602:Rac1 protein, mouse; C496622:Vav3 protein, mouse; D020830:rac1 GTP-Binding Protein