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Oncotarget. 2016 Feb 9;7(6):7280-96. doi: 10.18632/oncotarget.6906.

CXCR2 signaling regulates KRAS(G¹²D)-induced autocrine growth of pancreatic cancer.

Author information

1
Department of Pathology and Microbiology, 985900 Nebraska Medical Center, Omaha, NE, USA.
2
Department of Biochemistry and Molecular Biology, 985870 Nebraska Medical Center, Omaha, NE, USA.
3
Eppley Institute, 985950 Nebraska Medical Center, Omaha, NE, USA.

Abstract

Pharmacological inhibition of RAS, the master regulator of pancreatic ductal adenocarcinoma (PDAC), continues to be a challenge. Mutations in various isoforms of RAS gene, including KRAS are known to upregulate CXC chemokines; however, their precise role in KRAS-driven pancreatic cancer remains unclear. In this report, we reveal a previously unidentified tumor cell-autonomous role of KRAS(G12D)-induced CXCR2 signaling in mediating growth of neoplastic PDAC cells. Progressively increasing expression of mCXCR2 and its ligands was detected in the malignant ductal cells of Pdx1-cre;LSL-Kras(G12D) mice. Knocking-down CXCR2 in KRAS(G12D)-bearing human pancreatic duct-derived cells demonstrated a significant decrease in the in vitro and in vivo tumor cell proliferation. Furthermore, CXCR2 antagonists showed selective growth inhibition of KRAS(G12D)-bearing cells in vitro. Intriguingly, both genetic and pharmacological inhibition of CXCR2 signaling in KRAS(G12D)-bearing pancreatic ductal cells reduced the levels of KRAS protein, strongly implying the presence of a KRAS-CXCR2 feed-forward loop. Together, these data demonstrate the role of CXCR2 signaling in KRAS(G12D)-induced growth transformation and progression in PDAC.

KEYWORDS:

CXCR2; ERK; KRAS(G12D); PDAC; autocrine growth

PMID:
26771140
PMCID:
PMC4872785
DOI:
10.18632/oncotarget.6906
[Indexed for MEDLINE]
Free PMC Article

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