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The atypical Rho GTPase RhoBTB2 is required for expression of the chemokine CXCL14 in normal and cancerous epithelial cells

Oncogene volume 27, pages 6856–6865 (2008)Cite this article

Abstract

The Rho family of small GTPases control cell migration, cell invasion and cell cycle. Many of these processes are perturbed in cancer and several family members show altered expression in a number of tumor types. RhoBTB2/DBC2 is an atypical member of this family of signaling proteins, containing two BTB domains in addition to its conserved Rho GTPase domain. RhoBTB2 is mutated, deleted or silenced in a large percentage of breast and lung cancers; however, the functional consequences of this loss are unclear. Here we use RNA interference in primary human epithelial cells to mimic the loss of RhoBTB2 seen in cancer cells. Through microarray analysis of global gene expression, we show that loss of RhoBTB2 results in downregulation of CXCL14—a chemokine that controls leukocyte migration and angiogenesis, and whose expression is lost through unknown mechanisms in a wide range of epithelial cancers. Loss of RhoBTB2 expression correlates with loss of CXCL14 secretion by head and neck squamous cell carcinoma cell lines, whereas reintroduction of RhoBTB2 restores CXCL14 secretion. Our studies identify CXCL14 as a gene target of RhoBTB2 and support downregulation of CXCL14 as a functional outcome of RhoBTB2 loss in cancer.

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Acknowledgements

We thank Ian Paterson for providing the HNSCC cell lines and Adrian Thrasher for the provision of lentiviral reagents. We particularly thank James Doherty, who provided initial analysis of the microarray data. This work was supported by a grant awarded to HM by Cancer Research UK.

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Authors and Affiliations

  1. Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, UK

    C M McKinnon, K A Lygoe, L Skelton & H Mellor

  2. Cancer Research UK, London, UK

    R Mitter

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  1. C M McKinnon
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  2. K A Lygoe
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  3. L Skelton
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  4. R Mitter
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  5. H Mellor
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Correspondence to H Mellor.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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McKinnon, C., Lygoe, K., Skelton, L. et al. The atypical Rho GTPase RhoBTB2 is required for expression of the chemokine CXCL14 in normal and cancerous epithelial cells. Oncogene 27, 6856–6865 (2008). https://doi.org/10.1038/onc.2008.317

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  • DOI: https://doi.org/10.1038/onc.2008.317

Keywords

  • Rho GTPase
  • BTB domain
  • microarray
  • cancer
  • tumor microenvironment
  • chemokine

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