Pancreatic Ductal Adenocarcinoma (PDAC) is among the most malignant cancers, with 5-year survival of 6%. Chronic inflammation is associated with increased risk of PDAC. Nitric oxide (NO) is an important mediator of inflammatory responses and plays a role in tumorigenesis. The principal source of an increased and sustained level of NO is inducible nitric oxide synthase (NOS2). In this study, we’ve tested the hypothesis that NO enhances tumor progression in pancreatic cancer. We found that higher NOS2 expression in tumors was associated with poor survival in resected PDAC patients (p = 0.011). We then investigated the role of NO by deleting NOS2 gene in a genetically engineered mouse model of pancreatic cancer (KPC mice) with pancreas-specific activation of mutant KRAS and P53, which faithfully recapitulates the development and progression of human pancreatic cancer. NOS2-deficient KPC mice showed longer survival compared to the KPC littermates with wildtype NOS2 (p<0.01). Compared to tumors from KPC mice, KPC/NOS2−/− tumors were less vascularized (p<0.001) and with less macrophage recruitment (p<0.005), indicated by decreased expression of CD31 and F4/80 respectively. NOS2 deficiency led to attenuated proliferation and invasion, and enhanced apoptosis indicated by high level of cleaved caspase-3 (p = 0.02). Consistent with the less malignant phenotype, NOS2 deficiency reduced nuclear pERK accumulation (P = 0.034) and the subsequent phosphorylation of FOXO3 (p = 0.026). Further investigation showed a positive correlation between NOS2 expression and pFOXO level in human PDAC specimen (p = 0.005). In addition, NOS2 deficiency reduced the expression of a well known oncogenic microRNA, miR21 (p = 0.001). In summary, NOS2 gene expression in tumors is a candidate prognostic marker in resected pancreatic cancer patients, and NOS2/NO signaling may contribute to the pancreatic tumor progression by inactivating FOXO3 in KPC mice. In this ongoing study, we are further investigating the mechanistic role of NO in disease progression.
Citation Format: Jian Wang, Peijun He, Matthias M. Gaida, Shouhui Yang, Aaron Schetter, Jochen Gaedcke, Michael Ghadimi, Thomas Ried, Harris G. Yfantis, Dong H. Lee, Jonathan M. Weiss, Nadar Hanna, H. Richard Alexander, S. Perwez Hussain. Nitric oxide signaling pathway as a pathogenic driver in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 923. doi:10.1158/1538-7445.AM2015-923