Inducible nitric oxide synthase enhances disease aggressiveness in pancreatic cancer
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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
S. Perwez Hussain, email: email@example.com
Keywords: NOS2, NO, PDAC, KPC mouse model
Received: February 12, 2016 Accepted: June 12, 2016 Published: June 29, 2016
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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