Nicotine in Pancreatic Cancer: Molecular Mechanisms

尼古丁在胰腺癌中的作用：分子机制

基本信息

批准号：
7571613
负责人：
HWYDA A ARAFAT
金额：
$ 17.38万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7571613
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 Operative Surgical Procedures PTK2 gene Pancreas Pancreatic Ductal Adenocarcinoma Pathology Pathway interactions Patients Phenotype Play Population Production Proliferation Marker Protein Binding Protein Kinase C Proteins Proto-Oncogene Proteins c-akt 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 therapeutic intervention novel therapeutics osteopontin outcome forecast overexpression pancreatic juice pre-clinical prevent protein expression public health relevance research study smoking cessation tumor tumor growth tumor progression tumorigenic

项目摘要

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个主要原因。 2007年，美国的新PDA病例数量估计为37,180。不幸的是，大多数人会死于这种疾病。这种类型的癌症在抽烟的人中发病率最高。尼古丁是香烟烟雾的重要组成部分，已被证明可以激活几种癌症中促进生长的途径。但是，尼古丁促进PDA的侵略性的手段知之甚少。因此，迫切需要剖析尼古丁启动以介导PDA进展的基本分子机制。在此探索性应用中，我们建议研究尼古丁诱导的分子和细胞变化所涉及的信号传导途径，从而导致胰腺癌进展。我们建议关注骨桥蛋白（OPN）在胰腺癌细胞中关于恶性肿瘤的起始和进展的相互作用。 OPN是一种分泌的糖基化蛋白，可变的丝氨酸磷酸化，结合整联蛋白和某些CD44变体，触发一系列调节细胞运动，存活和增殖的细胞内信号事件。我们的初步结果为PDA，Nicotine和OPN之间的复杂关系提供了新颖而有趣的见解。在胰腺癌细胞中添加尼古丁会引起OPN mRNA和蛋白质表达的显着增加。此外，暴露于香烟烟雾的大鼠显示胰腺OPN mRNA和蛋白质表达中的剂量依赖性上调。对PDA患者的癌症组织的分析表明，胰腺ACINI和恶性管中存在大量OPN。尚不清楚OPN在介导尼古丁在胰腺癌中的致瘤作用中的作用（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研究尼古丁刺激并被OPN激活的下游信号通路以促进致癌。我们将解决涉及SRC，FAK，PKC和AKT/PI 3激酶的OPN下游单途径的参与，以调节胰腺癌细胞的迁移和增殖。在人PDA组织中，OPN的表达将与血管生成和增殖标记相关，并且在原发性和转移性部位的吸烟者和非吸烟者的患者中，将比较其表达水平。我们假设尼古丁通过增强OPN表达和随后激活下游信号传导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型的治疗方法，可减少胰腺癌细胞肿瘤性，并抑制手术切除后的转移和复发，尤其是在吸烟的人群中。我们的研究将介绍新的机械见解，并更好地理解尼古丁作为胰腺癌发展和发展的主要危险因素的作用。公共卫生相关性：在这项探索性研究中，我们提议辨别尼古丁诱导的OPN有助于PDA进展的分子和细胞过程。强大的研究人员和临床医生将进行拟议的研究：Drs。胰腺癌和外科肿瘤学中的查尔斯·约（Charles Yeo），骨桥蛋白信号传导和癌症转移中的戴维·丹纳特（David Denhardt），以及我们在胰腺病理学和胰腺骨桥蛋白的信号传导和调节方面的专业知识。我们研究的数据可能导致新的机械见解，迄今为止，尼古丁和OPN之间的功能联系尚不清楚。阐明这些机制将更好地理解尼古丁作为胰腺癌中的主要危险因素。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Osteopontin splice variant as a potential marker for metastatic disease in pancreatic adenocarcinoma.

骨桥蛋白剪接变体作为胰腺腺癌转移性疾病的潜在标志物。

DOI：
10.1111/jgh.12561
发表时间：
2014
期刊：
Journal of gastroenterology and hepatology
影响因子：
4.1
作者：
Siddiqui,AliA;Jones,Elizabeth;Andrade,Darren;Shah,Apeksha;Kowalski,ThomasE;Loren,DavidE;Chipitsyna,Galina;Arafat,HwydaA
通讯作者：
Arafat,HwydaA

RAN GTPase and Osteopontin in Pancreatic Cancer.

DOI：
10.4172/2165-7092.1000113
发表时间：
2013-04-01
期刊：
Pancreatic disorders & therapy
影响因子：
0
作者：
Saxena S;Gandhi A;Lim PW;Relles D;Sarosiek K;Kang C;Chipitsyna G;Sendecki J;Yeo CJ;Arafat HA
通讯作者：
Arafat HA

Serum monocyte chemoattractant protein-1 in pancreatic cancer.