Smoking and pancreatic cancer

摘要 胰腺癌(PC)是一种潜伏发展、致死率高的疾病。人类的生存 在5年内，PC患者的比例低于5%。前列腺癌的病因学与 遗传基因突变和多态(遗传易感性)、与生活方式有关的因素，如 高卡路里摄入量、高脂肪饮食和吸烟。尽管流行病学证据表明 吸烟与胰腺恶性肿瘤的关系及吸烟的分子后果 吸烟和尼古丁(香烟烟雾的重要成分)会导致癌症 胰腺不清楚。最近，我们观察到吸入香烟烟雾会导致慢性 伴有胰腺结构纤维化和瘢痕形成的胰腺炎症过程。此外，我们 在烟雾处理的大鼠中发现了与胰腺功能相关的基因表达的变化。 在平行研究中，我们在组织学可识别的导管内病变中检测到MUC4粘蛋白，称为 胰腺上皮内瘤变(Panins)和MUC4的表达呈进行性升高 具有致瘤和恶性表型。MUC4的致癌潜力也被观察到 NIH3T3小鼠成纤维细胞。有趣的是，我们的研究还揭示了MUC4调节 HER2转录后机制的表达(S)。这项研究的总体目标是 建议调查吸烟对发病和死亡的病理影响 PC的进展和建立香烟烟雾的调节机制(S)- 诱导MUC4表达及其在致病过程中的作用。具体来说，我们的目标是建立 香烟烟雾和尼古丁在胰腺癌病因学中的作用及其调控机制 尼古丁诱导MUC4表达的机制(S)。我们假设吸烟 有助于胰腺癌的发展，而MUC4是胰腺癌的重要组成部分 疾病过程。为了检验我们的假设，我们提出了三个具体目标。在目标1中，我们将调查 香烟烟雾/尼古丁通过多种功能对胰腺癌生长的影响 已建立的胰腺癌细胞系和体外培养的人胰腺癌的检测 级数模型。目标2将描述参与调节的信号通路的影响 尼古丁单独以及与其他MUC4诱导剂协同作用对MUC4表达的影响。在目标3中，我们 将在不同的小鼠模型中进行研究，这些模型自发地发展为癌前和 观察吸烟和尼古丁对胰腺恶性病变的影响 胰腺癌发生的早期事件。我们还将在MUC4中生成一个鼠标模型-空 背景明确MUC4在恶性疾病发生和发展中的作用。已被占用 总之，这些研究将确定香烟烟雾和尼古丁在糖尿病病因中的因果作用。 致命的胰腺癌。项目叙事 拟议的研究调查旨在了解香烟的病理后果。 吸烟在胰腺癌发生发展中的作用及吸烟诱导作用的建立 MUC4在致病过程中的表达。在初步研究中，我们已经表明，吸烟 吸入诱导体内慢性胰腺炎症过程及胰腺癌的治疗 尼古丁诱导体外细胞表达粘蛋白MUC4--一种在大部分胰腺中异常表达的粘蛋白 癌症，它也具有转化的特性。建议的研究结果将确立 香烟烟雾和尼古丁在致死性胰腺癌病因学中的作用机制。

ABSTRACT 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. Project Narrative 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.