Activation of the IL-6R/Jak/Stat pathway is associated with a poor outcome in resected pancreatic ductal adenocarcinoma

Denley, S.M., Jamieson, N.B. , McCall, P., Oien, K.C.S. , Morton, J.P. , Carter, C.R., Edwards, J. and McKay, C.J. (2013) Activation of the IL-6R/Jak/Stat pathway is associated with a poor outcome in resected pancreatic ductal adenocarcinoma. Journal of Gastrointestinal Surgery, 17(5), pp. 887-898. (doi: 10.1007/s11605-013-2168-7)

Abstract

<p>Background and Objective: Chronic localized pancreatic inflammation in the form of chronic pancreatitis is an established risk factor for human pancreatic ductal adenocarcinoma (PDAC) development. Constitutive activation of inflammation-related signal transducer and activator of transcription (Stat)3 signaling has been implicated in the development and progression a number of malignancies, including PDAC. Although, the Janus Kinase (Jak)/Stat pathway is a potential drug target, clinicopathological, molecular, and prognostic features of Stat3-activated PDAC remain uncertain. Our aim was to determine the clinicopathological impact of this inflammatory pathway in resectable PDAC.</p> <p>Methods: Using a tissue microarray-based cohort of PDAC from 86 patients undergoing pancreaticoduodenectomy with curative intent and complete clinicopathological data available, we evaluated expression of the interleukin-6 receptor (IL-6R)/Jak/Stat pathway by immunohistochemistry. IL-6R, Jak, phospho (p)-Jak, Stat3, pStat3Tyr705, and pStat3Ser727 were assessed in PDAC and pancreatic intraepithelial neoplasia. A Cox regression multivariate analysis model was used to determine factors influencing survival. Activation of the IL-6R/Jak/Stat3 pathway was compared with the systemic inflammatory response as measured by serum C-reactive protein levels.</p> <p>Results: High Jak was associated with reduced overall survival in multivariate analysis when compared with those with moderate or low expression (p = 0.036; hazard ratio (HR) = 1.68) as was pStat3Tyr705 (p <0.001; HR = 2.66) independent of lymph node status and tumor grade. Patients with a combination of pJakhigh/pStat3Tyr705 high expression had an especially poor prognosis (median survival of 8.8 months; 95 % CI, 4.4–13.2). While the IL-6R/Jak/Stat pathway did not correlate with serum C-reactive protein levels, high pStat3 expression was associated with a reduction in the density of the local tumoral immune response.</p> <p>Conclusion: Activation of the Jak/Stat3 pathway via phosphorylation was associated with adverse outcome following resection of PDAC with curative intent supporting potential roles for pJak and pStat3 as prognostic biomarkers markers and therapeutic targets.</p>

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jamieson, Professor Nigel and Carter, Mr Ross and Edwards, Professor Joanne and McCall, Dr Pamela and Oien, Professor Karin and Morton, Professor Jen
• Authors: Denley, S.M., Jamieson, N.B., McCall, P., Oien, K.C.S., Morton, J.P., Carter, C.R., Edwards, J., and McKay, C.J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Gastrointestinal Surgery
• ISSN: 1091-255X
• ISSN (Online): 1873-4626