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A novel KLF6-Rho GTPase axis regulates hepatocellular carcinoma cell migration and dissemination

Oncogene volume 35, pages 4653–4662 (2016)Cite this article

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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.

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Acknowledgements

We thank Genentech for sharing Klf6flox mice; Scott Friedman for providing the Klf6flox mice and sharing data before publication. We thank JiuFeng Cai and Victor Adelanwa for technical assistance; Dr Kerry Burnstein for providing the VAV3 expression constructs; Karl Simin, Leslie Shaw, Scot Wolfe and members of the Lewis lab for helpful discussions and critical review of the manuscript. The assistance of the Memorial Sloan-Kettering Cancer Center Genomics Core and the University of Massachusetts Medical School Genomics and Deep Sequencing core facilities is gratefully acknowledged. This study was supported by NIH grant R01 CA121171 to BCL. The funders played no role in the design, execution or interpretation of the study.

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Authors and Affiliations

  1. Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester,, MA, USA

    L G Ahronian, L J Zhu & B C Lewis

  2. Program in Molecular Medicine, University of Massachusetts Medical School,, Worcester,, MA, USA

    L J Zhu & B C Lewis

  3. Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School,, Worcester,, MA, USA

    L J Zhu

  4. National Institute of Cancer Research, National Health Research Institutes, Maioli, Taiwan

    Y-W Chen & H-C Chu

  5. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York,, NY, USA

    D S Klimstra

  6. Cancer Center, University of Massachusetts Medical School,, Worcester,, MA, USA

    B C Lewis

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  1. L G Ahronian
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Correspondence to B C Lewis.

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Ahronian, L., Zhu, L., Chen, YW. et al. A novel KLF6-Rho GTPase axis regulates hepatocellular carcinoma cell migration and dissemination. Oncogene 35, 4653–4662 (2016). https://doi.org/10.1038/onc.2016.2

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