Activation of the IL-6R/Jak/Stat Pathway is Associated with a Poor Outcome in Resected Pancreatic Ductal Adenocarcinoma
Activation of the IL-6R/Jak/Stat Pathway is Associated with a Poor Outcome in Resected Pancreatic Ductal Adenocarcinoma
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DOI：
10.1007/s11605-013-2168-7
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发表时间：
2013-05-01
影响因子：
3.2
通讯作者：
McKay, Colin J.
中科院分区：
文献类型：
--
作者：
Denley, Simon M.;Jamieson, Nigel B.;McKay, Colin J.
慢性胰腺炎形式的慢性局限性胰腺炎症是人类胰腺导管腺癌（PDAC）发展的既定风险因素。炎症相关的信号转导子和转录激活子（Stat）3信号传导的组成性激活已经涉及许多恶性肿瘤（包括PDAC）的发展和进展。虽然Janus激酶（Jak）/Stat通路是一个潜在的药物靶点，但Stat 3激活的PDAC的临床病理、分子和预后特征仍不确定。我们的目的是确定这种炎症通路在可切除的PDAC.Using组织芯片为基础的队列的PDAC从86例接受胰腺炎切除术的治愈意图和完整的临床病理数据，我们评估白细胞介素-6受体（IL-6 R）/Jak/Stat通路的表达免疫组织化学。在PDAC和胰腺上皮内瘤变中评估IL-6 R、Jak、磷酸（p）-Jak、Stat 3、pStat 3（Tyr 705）和pStat 3（Ser 727）。采用考克斯回归多变量分析模型确定影响生存的因素。通过血清C-反应蛋白水平测定，比较IL-6 R/Jak/Stat 3通路的激活与全身炎症反应，多变量分析显示，与中、低表达pJak的患者相比，高表达pJak的患者总生存率降低（p = 0.036;风险比（HR）= 1.68），pStat 3（Tyr 705）（p < 0.001; HR = 2.66）也是如此，与淋巴结状态和肿瘤分级无关。具有pJak（高）/pStat 3（Tyr 705）（高）表达的组合的患者具有特别差的预后（中位生存期为8.8个月; 95%CI，4.4-13.2）。虽然IL-6 R/Jak/Stat通路与血清C-反应蛋白水平无关，但pStat 3高表达与局部肿瘤免疫应答密度的降低相关，通过磷酸化激活Jak/Stat 3通路与PDAC切除后的不良结局相关，支持pJak和pStat 3作为预后生物标志物和治疗靶点的潜在作用。
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.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, pStat3(Tyr705), and pStat3(Ser727) 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.High pJak 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 pStat3(Tyr705) (p < 0.001; HR = 2.66) independent of lymph node status and tumor grade. Patients with a combination of pJak(high)/pStat3(Tyr705) (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.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.