Inducible nitric oxide synthase enhances disease aggressiveness in pancreatic cancer.

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

doi:10.18632/oncotarget.10323

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.

Highlights

Pancreatic cancer is a highly lethal malignancy with median survival of less than 6 months, and ranks as the 4th leading cause of cancer-related death in the United States
Analysis of the pancreatic cancer cohorts in The Cancer Genome Atlas (TCGA) and Oncomine database [Collision cohort [14]] showed that a higher tumor NOS2 expression associates with poorer survival in patients with Pancreatic ductal adenocarcinoma (PDAC) (Kaplan-Meier analysis, Log-rank test p = 0.041 and p = 0.022) (Supplementary Figure S1), which is consistent with the findings in our test cohort of 107 resected patients
These findings showed that NOS2 is a candidate prognostic marker in early stage PDAC patients undergoing surgical resection, and NOS2/nitric oxide (NO) signaling may play a role in enhanced disease progression

Summary

Introduction

Pancreatic cancer is a highly lethal malignancy with median survival of less than 6 months, and ranks as the 4th leading cause of cancer-related death in the United States. An estimated 53,070 new cases of pancreatic cancer will be diagnosed and 41,780 deaths occur in 2016 alone due to this malignancy [1]. Pancreatic ductal adenocarcinoma (PDAC) is the most common form, which accounts for more than 90% of all the pancreatic cancer cases. The lack of early detection markers and ineffective treatment in advanced disease have led to a consistent rise in both incidence and mortality in pancreatic cancer, which is estimated to become the second leading cause of cancerrelated death by 2030 [2]. The recent advances in our understanding www.impactjournals.com/oncotarget of the complex pancreatic cancer biology and tumor architecture have started to emerge as opportunities to design improved treatments

Methods

Results

Conclusion