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Carcinogenesis Advance Access originally published online on October 5, 2009
Carcinogenesis 2009 30(11):1841-1847; doi:10.1093/carcin/bgp198
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

ELR+ CXC chemokines and oncogenic Ras-mediated tumorigenesis

Kevin M. O'Hayer1, Donita C. Brady1 and Christopher M. Counter*,1,2

1 Department of Pharmacology and Cancer Biology
2 Department of Radiation Oncology, DUMC, Durham, NC 27710, USA

* To whom correspondence should be addressed. Tel: +919 684 9890; Fax: +919 684 8958; Email: count004{at}mc.duke.edu

The small GTPase Ras is mutated to remain in the active oncogenic state in one-third of human cancers, thereby promoting tumorigenesis. It has recently come to light that one consequence of oncogenic Ras signaling is secretion of cytokines vascular endothelial growth factor (VEGF), interleukin 6 (IL6), hCXCL1 (Gro-{alpha}) and hCXCL8 (IL8). As the latter two belong to the ELR+ Cys-X-Cys (CXC) chemokine family, we investigated whether the entire family of ELR+ CXC chemokines plays a role in oncogenic Ras-mediated tumorigenesis. We now demonstrate that oncogenic Ras induced the expression and secretion of the ELR+ CXC chemokine family in different tumorigenic human cells and that these chemokines are elevated in tumor specimens. Moreover, genetic ablation of the common receptor for these chemokines, mCXCR2, reduced oncogenic Ras-driven tumorigenesis in mice. Taken together, we suggest that oncogenic Ras induces the secretion of the ELR+ CXC chemokine family to promote tumorigenesis. This chemokine signature may identify the presence of Ras activation in cancer and perhaps even serve as targets for oncogenic Ras-driven tumor cells.

Abbreviations: CXC, Cys-X-Cys; DMBA, dimethylbenzanthracene; ELISA, enzyme-linked immunosorbent assay; GTP, guanosine triphosphate; HEK, human embryonic kidney; IL, interleukin; mRNA, messenger RNA; RT–PCR, reverse transcription–polymerase chain reaction; shRNA, short hairpin RNA; TPA, 12-O-tetradecanoylphorbol 13-acetate; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; VEGF, vascular endothelial growth factor

Received October 1, 2008; revised July 3, 2009; accepted July 25, 2009.


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