Mechanisms of Pancreatic Carcinogenesis

 描述(申请人提供)：胰腺癌是美国癌症相关死亡的第四大常见原因，5年存活率仅为7。高死亡率归因于早期诊断的局限性、疾病的积极进展以及缺乏有效的治疗。胰腺癌90%以上为腺(导)分化的浸润性恶性肿瘤，称为胰腺导管腺癌(PDAC)。胰腺上皮内瘤变(Panins)是PDAC最重要的前体类型，肿瘤的发生被认为是一个从低级别Panins到高级别Panins再到侵袭性胰腺肿瘤的逐步发展过程。柯尔斯滕鼠肉瘤病毒癌基因同源突变(KRAS)是在这一进展中发现的最早的突变之一，它们存在于90%以上的PDAC中。对患者肿瘤样本的基因组研究支持这一模型，即KRAS突变是肿瘤发生的主要启动者，而进展为癌症伴随着肿瘤抑制基因的额外功能缺失突变。KRüppel-like factor5(KLF5)是Krüppel-like factor5(KLF5)转录因子家族的成员。KLF5在细胞关键功能的调节中起重要作用 如增殖、分化、迁移和多能性。取决于细胞信号 背景，KLF5既可以是肿瘤抑制因子，也可以是致癌因子。对胰腺肿瘤与正常组织差异表达基因芯片数据的荟萃分析研究表明，KLF5基因的过度表达是正常组织的2.5倍。使用人胰腺癌细胞系进行的体外研究表明，KLF5可能在胰腺癌细胞系中具有致癌功能。然而，KLF5在体内胰腺癌中的作用还有待研究。我的初步数据显示，Kras突变小鼠的Panins有核KLF5的高表达，这表明KLF5可能在调节ADM过程和Panin的形成中发挥关键的早期作用。我的主要假设是，KLF5在Kras诱导的体内肿瘤形成中对Panin的形成至关重要。为了验证这一假说，我提出了以下具体目标：1)研究KLF5是否是体内Panin形成的必要条件和充分条件；2)阐明KLF5在Kras诱导的肿瘤发生中作用的分子机制。通过这项研究，我希望研究KLF5在ADM和Panin形成过程中的作用和分子机制。本研究的结果将为KLF5作为胰腺潜在靶点的未来研究奠定基础 癌症治疗。

 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.