Mechanisms of Pancreatic Carcinogenesis

胰腺癌发生机制

基本信息

批准号：
9120096
负责人：
Ping He
金额：
$ 3.12万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9120096
关键词：
Acinar Cell Adopted Cancer Biology Cancer Etiology Cancer Patient Cancer cell line Carcinoma Cell Line Cell Nucleus Cell physiology Cessation of life Characteristics DNA Binding Domain Data Disease Disease Progression Ductal Early Diagnosis Elements Excision Family Future Genomics Homologous Gene Human Immunohistochemistry In Vitro Investigation KRAS2 gene Lead Learning Lesion Malignant Neoplasms Malignant neoplasm of pancreas Mediating Messenger RNA Meta-Analysis Metaplasia Microscopic Modeling Molecular Mus Mutation Normal tissue morphology Nuclear Oncogenic Operative Surgical Procedures Outcome Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pancreatitis Pathway interactions Patients Play Prevalence Process Proteins Rattus Regulation Resected Resistance Rest Risk Factors Role SEER Program Sampling Signal Transduction Staging Survival Rate System Systemic Therapy Testing Time Tissue Microarray Tissues Transgenic Mice Tumor Suppressor Genes Tumor Suppressor Proteins United States Viral Oncogene Work Zinc Fingers base cancer therapy carcinogenesis differential expression effective therapy human disease improved in vivo inhibitor/antagonist knock-down loss of function mutation member migration mortality mouse model mutant new therapeutic target novel overexpression pancreatic cancer cells pancreatic neoplasm pancreatic tumorigenesis pluripotency public health relevance sarcoma targeted treatment three dimensional cell culture transcription factor tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth most common cause of cancer-associated deaths in the U.S with a 5-year survival rate of only 7. High mortality rate is attributed to limitations in early diagnosis, aggressive disease progression, and lack of effective treatments. More than 90% of pancreatic cancer are invasive malignant neoplasms with glandular (ductal) differentiation, termed pancreatic ductal adenocarcinoma (PDAC). Pancreatic intraepithelial neoplasia (PanINs) are the most important type of precursors to PDAC, and tumorigenesis is believed to be a stepwise progression from low-grade PanINs to high-grade PanINs and then to invasive pancreatic neoplasia. Constitutively active mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) are some of the earliest mutations found in this progression, and they are present in over 90% of PDAC. Genomic studies in patient tumor sample support the model that mutation in KRAS is a major initiator of tumorigenesis while progression to carcinoma is accompanied by additional loss-of-function mutations in tumor suppressor genes. Krüppel-like factor 5 (KLF5) is a member in the Krüppel-like factor (KLF) family of transcription factors. KLF5 is important in the regulation of key cellular functions such as proliferation, differentiation, migration, and pluripotency. Depending on the cellular signaling context, KLF5 can be either a tumor suppressor or an oncogenic factor. Meta-analysis study of microarray data on differential expression of pancreatic tumor compared to normal tissue show a 2.5-fold overexpression in KLF5 mRNA. In vitro studies using human pancreatic cancer cell lines have shown that KLF5 may have oncogenic functions in pancreatic cancer cell lines. However, the role of KLF5 in pancreatic cancer in vivo has yet to be studied. My preliminary data show that PanINs from mice with mutant Kras have high expression of nuclear Klf5, which suggests that KLF5 may play a crucial and early role in regulating ADM process and PanIN formation. My overarching hypothesis is that KLF5 is critical for the formation of PanIN in Kras-induced tumorigenesis in vivo. To test this hypothesis, I propose the following Specific Aims: 1) To investigate whether KLF5 is necessary and sufficient for PanIN formation in vivo; 2) To elucidate the molecular mechanisms underlying the role of KLF5 in Kras-induced tumorigenesis. Through the proposed study, I wish to investigate the role and molecular mechanism of KLF5 as a crucial factor in process of ADM and PanIN formation during early tumorigenesis. The result of this study will be the basis for future investigations of KLF5 as a potential target for pancreatic cancer treatment.

描述（由适用提供）：胰腺癌是美国癌症相关死亡的第四大原因，5年生存率仅为7。高死亡率归因于早期诊断，攻击性疾病进展和缺乏有效治疗的局限性。超过90％的胰腺癌是具有腺体（导管）分化的侵入性恶性肿瘤，称为胰腺导管腺癌（PDAC）。胰腺内肿瘤（Panins）是PDAC的最重要类型的前体类型，肿瘤发生被认为是从低级Panins到高级Panins，然后是侵入性胰腺肿瘤的逐步发展。 Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）中的组成性活性突变是在此进展中发现的一些最早的突变，它们存在于PDAC的90％以上。患者肿瘤样品中的基因组研究支持了KRAS中突变是肿瘤发生的主要起始，而向癌的进展是通过肿瘤抑制基因的额外功能突变来实现的。 Krüppel样因子5（KLF5）是Krüppel样因子（KLF）转录因子家族的成员。 KLF5在调节关键细胞功能的调节中很重要作为增殖，分化，迁移和多能性。取决于细胞信号上下文，KLF5可以是肿瘤抑制因子或致癌因子。与正常组织相比，有关胰腺肿瘤差异表达的微阵列数据的荟萃分析显示，KLF5 mRNA的过表达为2.5倍。使用人胰腺癌细胞系的体外研究表明，KLF5在胰腺癌细胞系中可能具有致癌功能。但是，KLF5在体内胰腺癌中的作用尚未研究。我的初步数据表明，来自突变体KRA的小鼠的Panins对核KLF5的表达很高，这表明KLF5可能在注册ADM过程和Panin形成中起着至关重要的早期作用。我的总体假设是，KLF5对于在体内引起的KRAS诱导的肿瘤发生中的Panin形成至关重要。为了检验这一假设，我提出了以下特定目的：1）研究KLF5是否需要且足够的panin形成； 2）阐明KLF5在KRAS诱导的肿瘤发生中的作用的分子机制。通过拟议的研究，我希望将KLF5的作用和分子机制研究为早期肿瘤发生过程中ADM和Panin形成过程中的关键因素。这项研究的结果将是KLF5未来投资的基础，作为胰腺的潜在目标癌症治疗。