Smoking and pancreatic cancer

吸烟与胰腺癌

• 批准号: 8205008
• 负责人: Surinder K. Batra
• 金额: $ 30.8万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8205008
• 关键词: Adhesions; Adhesives; Age; Alabama; American; American Cancer Society; Animals; Biological Assay; Biological Models; Blood; Breathing; British; California; Cancer Cell Growth; Cancer Etiology; Cancer Patient; Cancer cell line; Cancerous; Cell Cycle Progression; Cell Line; Cell Proliferation; Cell model; Cell surface; Cells; Cessation of life; Chronic; Cicatrix; Cigarette; Collaborations; Cotinine; Cytoplasm; Data; Development; Diagnosis; Diet; Disease; Down-Regulation; Ductal; ERBB2 gene; Energy Intake; Epidemiology; Etiology; Event; Exhibits; Fatty acid glycerol esters; Fibroblasts; Fibrosis; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Glycoproteins; Goals; Growth; Heart Diseases; Histologic; Human; ITGB2 gene; In Vitro; Incidence; Inflammation; Inflammatory; Inherited; Interferons; Invasive Lesion; Investigation; Journals; Knock-out; Laboratories; Lesion; Life Style; MADH4 gene; MUC4 mucin; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mediating; Membrane; Metabolic; Modeling; Molecular; Mucins; Mus; Mutation; Nature; Neoplasm Metastasis; Nicotine; Oncogenic; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Patients; Phenotype; Premalignant; Process; Property; Publications; Publishing; Pulmonary Emphysema; Rattus; Reporting; Research; Research Personnel; Research Proposals; Risk; Risk Factors; Role; San Francisco; Serum; Signal Pathway; Signal Transduction; Smoke; Smoking; Smoking and Health Research; Structure; Surgeon; Survival Rate; Testing; Time; Tobacco use; Tretinoin; United States; Universities; anticancer research; apomucin; body system; cancer cell; carcinogenesis; cell motility; cell transformation; chronic pancreatitis; cigarette smoke-induced; cigarette smoking; cigarette smoking; gain of function; in vivo; intraepithelial; malignant phenotype; migration; mortality; mouse model; neoplastic; neoplastic cell; outcome forecast; overexpression; pancreatic cancer cells; pancreatic neoplasm; pancreatic tumorigenesis; premature; smoke inhalation; tumor progression; tumorigenic; uptake

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.

抽象的 胰腺癌（PC）是一种阴险进展和高致死性的疾病。生存 在5年期间，PC患者不到5％。 PC的病因与 遗传基因突变和多态性（遗传敏感性），与生活方式相关的因素，例如 高热量摄入量，高脂饮食和吸烟。尽管流行病学证据表明 吸烟与胰腺恶性肿瘤的关联，香烟的分子后果 吸烟和尼古丁（香烟烟雾的重要组成部分）导致癌的形式 胰还不清楚。最近，我们观察到香烟吸入诱发慢性 胰腺炎症过程，纤维化和胰腺结构的疤痕。此外，我们 发现胰腺作用的基因表达改变了经烟雾处理的大鼠的功能。 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 胰腺内肿瘤（PANINS），MUC4的表达逐渐增加 带有.tumorigenic和恶性表型。在 NIH3T3小鼠成纤维细胞。有趣的是，我们的研究还揭示了MUC4调节 通过转录后机制的HER2表达。这项研究的总体目标 提案是研究吸烟在开始的病理后果和 PC的进展并建立烟雾烟雾的基础调节机制 - 诱导MUC4表达及其在致病过程中的作用。具体来说，我们旨在建立 香烟烟和尼古丁在胰腺癌病因中的作用并揭示调节性 尼古丁诱导的MUC4表达的机制。我们假设吸烟 有助于胰腺癌的发展，而MUC4是 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AIM 1中，我们将调查 香烟烟/尼古丁对胰腺癌生长的影响通过执行各种功能 在已建立的胰腺癌细胞系和体外人类胰腺癌中进行测定 进程模型。 AIM 2将描述与中介作用有关的信号传导途径 单独使用MUC4表达的尼古丁并与MUC4的其他诱导剂合作。在AIM 3中，我们 将在不同的小鼠模型中进行研究，这些模型会自发发展前机构和 恶性胰腺病变，以检查香烟 - 烟和尼古丁在增强中的作用 胰腺癌发生的早期事件。我们还将在MUC4-NULL中生成鼠标模型 背景是定义MUC4在恶性疾病开始和进展中的作用。拍摄 这些研究将共同​​确定香烟 - 烟和尼古丁在病因中的因果作用 致命的胰腺癌。项目叙述 拟议的研究调查旨在了解香烟的病理后果 吸烟以发展胰腺癌并确定香烟烟雾引起的作用 在致病过程中MUC4表达。在初步研究中，我们已经证明了香烟烟雾 吸入在体内诱导慢性胰腺炎症过程和胰腺癌治疗 尼古丁体外细胞诱导MUC4表达，MUC4表达是一种异常表达的粘蛋白，在大多数胰腺中 癌症，也具有转化特性。拟议研究的结果将确定 香烟烟和尼古丁在致命胰腺癌病因中的机械作用。

项目成果

Nicotine, IFN-γ and retinoic acid mediated induction of MUC4 in pancreatic cancer requires E2F1 and STAT-1 transcription factors and utilize different signaling cascades.

• DOI: 10.1186/1476-4598-11-24
• 发表时间: 2012-04-26
• 期刊: Molecular cancer
• 影响因子: 37.3
• 作者: Kunigal S;Ponnusamy MP;Momi N;Batra SK;Chellappan SP
• 通讯作者: Chellappan SP