Oncotarget

Research Papers:

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

Abhilasha Purohit, Michelle Varney, Satyanarayana Rachagani, Michel M. Ouellette, Surinder K. Batra and Rakesh K. Singh _

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Oncotarget. 2016; 7:7280-7296. https://doi.org/10.18632/oncotarget.6906

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Abstract

Abhilasha Purohit1, Michelle Varney1, Satyanarayana Rachagani2, Michel M. Ouellette3, Surinder K. Batra1,2,3, Rakesh K. Singh1

1Department of Pathology and Microbiology, 985900 Nebraska Medical Center, Omaha, NE, USA

2Department of Biochemistry and Molecular Biology, 985870 Nebraska Medical Center, Omaha, NE, USA

3Eppley Institute, 985950 Nebraska Medical Center, Omaha, NE, USA

Correspondence to:

Rakesh K. Singh, e-mail: rsingh@unmc.edu

Keywords: KRAS(G12D), PDAC, CXCR2, autocrine growth, ERK

Received: August 05, 2015     Accepted: November 25, 2015     Published: January 13, 2016

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.


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