Nicotine in Pancreatic Cancer: Molecular Mechanisms

尼古丁在胰腺癌中的作用：分子机制

• 批准号: 7454098
• 负责人: HWYDA A ARAFAT
• 金额: $ 22.24万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7454098
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acinus organ component; Addictive Behavior; Address; Adenocarcinoma Cell; Adult; Behavior; Binding; Biological Assay; CD44 gene; Cancer Model; Cancer cell line; Cell Proliferation; Cell Surface Receptors; Cell Survival; Cell physiology; Cell-Matrix Junction; Cells; Cigarette; Clinical Research; Complex; Data; Development; Disease; Dose; Down-Regulation; Duct (organ) structure; Epidemiologic Studies; Event; Excision; Family; Focal Adhesions; Foundations; Functional disorder; Future; Genes; Genetic Transcription; Growth; Human; Immunohistochemistry; In Vitro; Incidence; Integrin Binding; Integrins; Knowledge; Lead; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Messenger RNA; Molecular; Monoclonal Antibodies; Nature; Neoplasm Metastasis; Nicotine; Numbers; Operative Surgical Procedures; PTK2 gene; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathology; Pathway interactions; Patients; Personal Satisfaction; Phenotype; Play; Polymerase Chain Reaction; Population; Production; Proliferation Marker; Protein Binding; Protein Kinase C; Protein Overexpression; Proteins; Proto-Oncogene Proteins c-akt; Public Health; Rattus; Receptor Protein-Tyrosine Kinases; Recurrence; Regulation; Research; Research Personnel; Risk; Risk Factors; Role; SRC gene; Series; Serine; Serum; Signal Pathway; Signal Transduction; Simulate; Site; Small Interfering RNA; Smoke; Smoker; Smoking; Surgical Oncology; Time; Tissues; Tumorigenicity; United States; Up-Regulation; Variant; Western Blotting; angiogenesis; base; cancer cell; cancer type; carcinogenesis; cell behavior; cell motility; cigarette smoking; cigarette smoking; citrate carrier; extracellular; inhibitor/antagonist; insight; member; migration; mortality; non-smoker; novel; novel strategies; novel therapeutics; osteopontin; outcome forecast; pancreatic juice; pre-clinical; prevent; protein expression; research study; smoking cessation; tumor; tumor growth; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of adult cancer mortality in the United States. In 2007, the number of new PDA cases in the United States is estimated at 37,180. Unfortunately, most will die of this disease. This type of cancer has the highest incidence in people who smoke cigarettes. Nicotine is an important component of cigarette smoke and has been shown to activate growth-promoting pathways in several cancers. However, the means through which nicotine contributes to the aggressive nature of PDA is poorly understood. There is, therefore, an urgent need to dissect the basic molecular mechanisms that are initiated by nicotine to mediate PDA progression. In this exploratory application we propose to study the signaling pathways involved in the nicotine-induced molecular and cellular changes that lead to pancreatic cancer progression. We propose to focus on the interactions of osteopontin (OPN) in pancreatic cancer cells with regard to the initiation and progression of malignancy. OPN is a secreted glycosylated protein, variably serine-phosphorylated, that binds integrins and certain CD44 variants, triggering a cascade of intracellular signaling events regulating cell motility, survival and proliferation. Our preliminary results provide novel and intriguing insights into a complex relationship among PDA, nicotine, and OPN. Addition of nicotine to pancreatic cancer cells induced a significant increase in OPN mRNA and protein expression. Moreover, rats that were exposed to cigarette smoke show a dose-dependent upregulation in pancreatic OPN mRNA and protein expression. Analysis of cancer tissue from PDA patients showed the presence of significant amounts of OPN in the pancreatic acini and in the malignant ducts. It is unknown what role, if any, OPN plays in mediating the tumorigenic effects of nicotine in pancreatic cancer. Thus, in the proposed studies we will utilize pancreatic cancer cell lines to investigate the downstream signaling pathways that are stimulated by nicotine and activated by OPN to promote carcinogenesis. We will address the involvement of OPN downstream singling pathways that involve Src, FAK, PKC, and AKT/PI 3-kinase in modulating migration and proliferation of pancreatic cancer cells. In human PDA tissue, the expression of OPN will be correlated with angiogenesis and proliferation markers and its expression levels will be compared in patients who are smokers and non-smokers in primary and metastatic sites. We hypothesize that nicotine mediates its carcinogenic effects in pancreatic cancer through enhancement of OPN expression and subsequent activation of downstream signaling events. We further propose that blocking OPN expression and/or function may represent a novel therapeutic approach to reduce pancreatic cancer cell tumorigenicity and inhibit metastasis and recurrence after surgical resection, especially in the cigarette-smoking population. Our studies will introduce novel mechanistic insights and a better understanding of the role of nicotine as a major risk factor in the development and progression of pancreatic cancer. PUBLIC HEALTH RELEVANCE: In this exploratory study, we are proposing to discern the molecular and cellular processes through which nicotine-induced OPN contributes to the progression of PDA. A powerful team of researchers and clinicians will conduct the proposed studies: Drs. Charles Yeo in pancreatic cancer and surgical oncology, David Denhardt, in osteopontin signaling and cancer metastasis, and our expertise in pancreatic pathology and osteopontin signaling and regulation in the pancreas. Data from our studies are likely to lead to novel mechanistic insights and as yet, an unknown functional link between nicotine and OPN. Unraveling these mechanisms will lead to better understanding of the role of nicotine as a major risk factor in pancreatic cancer.

描述（由申请人提供）：胰腺导管腺癌（PDA）是美国成人癌症死亡率的第四大原因。 2007 年，美国新发 PDA 病例数估计为 37,180 例。不幸的是，大多数人会死于这种疾病。这种类型的癌症在吸烟者中发病率最高。尼古丁是香烟烟雾的重要成分，已被证明可以激活多种癌症的生长促进途径。然而，人们对尼古丁如何导致 PDA 的攻击性却知之甚少。因此，迫切需要剖析尼古丁引发介导 PDA 进展的基本分子机制。在这个探索性应用中，我们建议研究尼古丁诱导的导致胰腺癌进展的分子和细胞变化所涉及的信号通路。我们建议重点关注骨桥蛋白（OPN）在胰腺癌细胞中与恶性肿瘤的发生和进展有关的相互作用。 OPN 是一种分泌性糖基化蛋白，具有不同程度的丝氨酸​​磷酸化，可结合整合素和某些 CD44 变体，引发一系列细胞内信号传导事件，调节细胞运动、存活和增殖。我们的初步结果为 PDA、尼古丁和 OPN 之间的复杂关系提供了新颖而有趣的见解。向胰腺癌细胞中添加尼古丁可诱导 OPN mRNA 和蛋白质表达显着增加。此外，暴露于香烟烟雾的大鼠胰腺 OPN mRNA 和蛋白质表达呈剂量依赖性上调。对 PDA 患者癌症组织的分析表明，胰腺腺泡和恶性导管中存在大量 OPN。目前尚不清楚 OPN 在介导尼古丁对胰腺癌的致瘤作用中起什么作用（如果有的话）。因此，在拟议的研究中，我们将利用胰腺癌细胞系来研究尼古丁刺激并被 OPN 激活以促进癌发生的下游信号通路。我们将探讨涉及 Src、FAK、PKC 和 AKT/PI 3 激酶的 OPN 下游单信号通路在调节胰腺癌细胞迁移和增殖中的作用。在人PDA组织中，OPN的表达将与血管生成和增殖标志物相关，并且将比较吸烟者和非吸烟者的原发部位和转移部位的表达水平。我们假设尼古丁通过增强 OPN 表达和随后激活下游信号事件来介导其在胰腺癌中的致癌作用。我们进一步提出，阻断 OPN 表达和/或功能可能代表一种新的治疗方法，以减少胰腺癌细胞的致瘤性并抑制手术切除后的转移和复发，特别是在吸烟人群中。我们的研究将引入新的机制见解，并更好地理解尼古丁作为胰腺癌发生和进展的主要危险因素的作用。公共健康相关性：在这项探索性研究中，我们建议了解尼古丁诱导的 OPN 促进 PDA 进展的分子和细胞过程。一个强大的研究人员和临床医生团队将进行拟议的研究：博士。 Charles Yeo 在胰腺癌和外科肿瘤学方面，David Denhardt 在骨桥蛋白信号传导和癌症转移方面，以及我们在胰腺病理学和骨桥蛋白信号传导和胰腺调节方面的专业知识。我们的研究数据可能会带来新的机制见解，以及尼古丁和 OPN 之间未知的功能联系。揭开这些机制将有助于更好地理解尼古丁作为胰腺癌主要危险因素的作用。