Smoking and pancreatic cancer

描述（申请人提供）：胰腺癌（PC）是一种发展隐匿、致死率高的疾病。PC患者的5年生存率低于5%。前列腺癌的病因与遗传基因突变和多态性（遗传易感性）、生活方式相关因素（如高热量摄入、高脂肪饮食和吸烟）有关。尽管流行病学证据表明吸烟与胰腺恶性肿瘤有关，但吸烟和尼古丁（香烟烟雾的重要成分）导致胰腺癌变的分子后果尚不清楚。最近，我们观察到香烟烟雾吸入可诱导胰腺结构纤维化和瘢痕形成的慢性胰腺炎症过程。此外，我们还发现吸烟大鼠胰腺功能相关基因的表达发生了改变。在平行研究中，我们在组织学上可识别的导管内病变胰腺上皮内瘤变（PanINs）中检测到MUC4粘蛋白，MUC4的表达随着致瘤性和恶性表型的增加而逐渐增加。在NIH3T3小鼠成纤维细胞中也观察到MUC4的致癌潜能。有趣的是，我们的研究还揭示了MUC4通过转录后机制调节HER2的表达。本研究计划的总体目标是研究吸烟对PC发生和发展的病理影响，并建立吸烟诱导MUC4表达的调控机制及其在发病过程中的作用。具体来说，我们的目标是确定吸烟和尼古丁在胰腺癌病因学中的作用，并揭示尼古丁诱导MUC4表达的调控机制。我们假设吸烟有助于胰腺癌的发展，而MUC4是疾病过程中的一个重要组成部分。为了验证我们的假设，我们提出了三个具体目标。在Aim 1中，我们将通过在已建立的胰腺癌细胞系和体外人类胰腺癌进展模型中进行各种功能测定来研究香烟烟雾/尼古丁对胰腺癌生长的影响。目的2将描述介导尼古丁单独或与其他MUC4诱导剂合作对MUC4表达影响的信号通路。在Aim 3中，我们将在自发发展为恶性和恶性胰腺病变的不同小鼠模型中进行研究，以检查香烟烟雾和尼古丁在增强胰腺癌早期事件中的作用。我们还将在MUC4缺失的背景下建立小鼠模型，以确定MUC4在恶性疾病的发生和进展中的作用。综上所述，这些研究将确定吸烟和尼古丁在致死性胰腺癌病因学中的因果作用。公共卫生相关性：拟议的研究调查旨在了解吸烟对胰腺癌发展的病理后果，并确定吸烟诱导的MUC4表达在发病过程中的作用。在初步研究中，我们发现吸入香烟烟雾在体内诱导慢性胰腺炎症过程，在体外用尼古丁治疗胰腺癌细胞诱导MUC4表达，这是一种在大多数胰腺癌中异常表达的粘蛋白，它也具有转化特性。拟议研究的结果将确定香烟烟雾和尼古丁在致死性胰腺癌病因学中的机制作用。

DESCRIPTION (provided by applicant): Pancreatic cancer (PC) is a disease of insidious progression and high lethality. The survival of patients with PC is less than 5% over the period of 5 years. The etiology of PC is associated with inherited gene mutations and polymorphisms (genetic susceptibility), lifestyle-related factors, such as high caloric intake, high-fat diet and smoking. Despite epidemiological evidence suggesting an association of cigarette smoking with pancreatic malignancy, the molecular consequences of cigarette smoking and nicotine (an important constituent of cigarette smoke) leading to cancerous form of the pancreas are not clear. Recently, we have observed that cigarette smoke inhalation induces a chronic pancreatic inflammatory process with fibrosis and scarring of pancreatic structures. Furthermore, we have found altered expression of genes involved in the function of the pancreas in smoke-treated rats. In parallel studies, we detected MUC4 mucin in histologically identifiable intra-ductal lesions known as Pancreatic Intraepithelial Neoplasias (PanINs), and the expression of MUC4 increased progressively with tumorigenic and malignant phenotype. The oncogenic potential of MUC4 was also observed in the NIH3T3 mouse fibroblast cells. Interestingly, our studies have also revealed that MUC4 regulates the expression of HER2 by post-transcriptional mechanism(s). The overall objective of this research proposal is to investigate the pathological consequences of cigarette smoking toward the initiation and progression of PC and to establish the regulatory mechanism(s) underlying the cigarette smoke-induced MUC4 expression and its role in the pathogenic process. Specifically, we aim to establish the role of cigarette smoke and nicotine in the etiology of pancreatic cancer and unravel the regulatory mechanism(s) underlying nicotine-induced MUC4 expression. We hypothesize that cigarette smoking contributes to the development of pancreatic cancer, and that MUC4 is an important component in the disease process. To test our hypothesis, we propose three specific aims. In Aim 1, we will investigate the effect of cigarette-smoke/nicotine on pancreatic cancer growth by performing various functional assays in established pancreatic cancer cell lines and in an in-vitro human pancreatic cancer progression model. Aim 2 will delineate the signaling pathways implicated in mediating the effect of nicotine on MUC4 expression alone and in collaboration with other inducers of MUC4. In Aim 3, we will carry out studies in different mouse models that spontaneously develop pre-malignant and malignant pancreatic lesions to examine the effect of cigarette-smoke and nicotine in potentiating the early events of pancreatic carcinogenesis. We will also generate a mouse model in MUC4-null background to define the role of MUC4 in malignant disease initiation and progression. Taken together, these studies will establish the causal role of cigarette-smoke and nicotine in the etiology of lethal pancreatic cancer. PUBLIC HEALTH RELEVANCE: The proposed research investigations are aimed at understanding the pathological consequences of cigarette smoking toward the development of pancreatic cancer and establishing the role of cigarette smoke-induced MUC4 expression in the pathogenic process. In preliminary studies, we have shown that cigarette smoke inhalation induces a chronic pancreatic inflammatory process in vivo and the treatment of pancreatic cancer cells in vitro with nicotine induces MUC4 expression, an aberrantly expressed mucin in majority of pancreatic cancer, which also possess transforming properties. The outcome of the proposed studies will establish the mechanistic role of cigarette smoke and nicotine in the etiology of lethal pancreatic cancer.