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

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.

SUBMITTER: Purohit A

PROVIDER: S-EPMC4872785 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Purohit Abhilasha A Varney Michelle M Rachagani Satyanarayana S Ouellette Michel M MM Batra Surinder K SK Singh Rakesh K RK

Oncotarget 20160201 6

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 express ...[more]

PMID: 26771140

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

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

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