Oncotarget

Research Papers:

Inducible nitric oxide synthase enhances disease aggressiveness in pancreatic cancer

Jian Wang, Peijun He, Matthias Gaida, Shouhui Yang, Aaron J. Schetter, Jochen Gaedcke, B. Michael Ghadimi, Thomas Ried, Harris Yfantis, Dong Lee, Jonathan M. Weiss, Jimmy Stauffer, Nader Hanna, H. Richard Alexander and S. Perwez Hussain _

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Oncotarget. 2016; 7:52993-53004. https://doi.org/10.18632/oncotarget.10323

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Abstract

Jian Wang1, Peijun He1, Matthias Gaida2, Shouhui Yang1 Aaron J. Schetter3, Jochen Gaedcke4, B. Michael Ghadimi4, Thomas Ried5, Harris Yfantis6, Dong Lee6, Jonathan M. Weiss7, Jimmy Stauffer8, Nader Hanna9, H. Richard Alexander9, S. Perwez Hussain1

1Pancreatic Cancer Unit, Laboratory of Human Carcinogenesis, CCR, NCI, Bethesda, MD, USA

2Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany

3US Food and Drug Administration, Silver spring, MD, USA

4Department of General, Visceral and Pediatric Surgery, University Medicine, Göttingen, Germany

5Genetics Branch, CCR, NCI, Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA

6Pathology and Laboratory Medicine, Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA

7Cancer and Inflammation Program, CCR, NCI Frederick, MD, USA

8Laboratory of Cell and Developmental Signaling, NCI Frederick, MD, USA

9Division of Surgical Oncology, University of Maryland School of Medicine, Baltimore, MD, USA

Correspondence to:

S. Perwez Hussain, email: [email protected]

Keywords: NOS2, NO, PDAC, KPC mouse model

Received: February 12, 2016     Accepted: June 12, 2016     Published: June 29, 2016

ABSTRACT

Pancreatic cancer is one of the most lethal malignancies and is refractory to the available treatments. Pancreatic ductal adenocarcinoma (PDAC) expresses high level of inducible nitric oxide synthase (NOS2), which causes sustained production of nitric oxide (NO). We tested the hypothesis that an aberrantly increased NO-release enhances the development and progression of PDAC. Enhanced NOS2 expression in tumors significantly associated with poor survival in PDAC patients (N = 107) with validation in independent cohorts. We then genetically targeted NOS2 in an autochthonous mouse model of PDAC to examine the effect of NOS2-deficiency on disease progression and survival. Genetic ablation of NOS2 significantly prolonged survival and reduced tumor severity in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice. Primary tumor cells isolated from NOS2-deficient KPC (NKPC) mice showed decreased proliferation and invasiveness as compared to those from KPC mice. Furthermore, NKPC tumors showed reduced expression of pERK, a diminished inactivation of Forkhead box transcription factor O (FOXO3), a tumor suppressor, and a decrease in the expression of oncomir-21, when compared with tumors in KPC mice. Taken together, these findings showed that NOS2 is a predictor of prognosis in early stage, resected PDAC patients, and provide proof-of-principle that targeting NOS2 may have potential therapeutic value in this lethal malignancy.


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