Mechanisms of Pancreatic Carcinogenesis

 描述（由申请人提供）：胰腺癌是美国癌症相关死亡的第四大常见原因，5年生存率仅为7。高死亡率归因于早期诊断的局限性、侵袭性疾病进展和缺乏有效治疗。超过90%的胰腺癌是具有腺（导管）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（PanIN）是PDAC最重要的前体类型，并且肿瘤发生被认为是从低级别PanIN到高级别PanIN，然后到侵袭性胰腺瘤变的逐步进展。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该进展中发现的最早的突变，并且它们存在于超过90%的PDAC中。患者肿瘤样本中的基因组研究支持KRAS突变是肿瘤发生的主要启动子的模型，而进展为癌症伴随着肿瘤抑制基因中的额外功能丧失突变。Krüppel样因子5（KLF 5）是Krüppel样因子（KLF）家族的一员。KLF 5在调节关键细胞功能方面很重要， 如增殖、分化、迁移和多能性。根据细胞信号 在上下文中，KLF 5可以是肿瘤抑制因子或致癌因子。对胰腺肿瘤与正常组织相比差异表达的微阵列数据的荟萃分析研究显示，KLF 5 mRNA过表达为2.5倍。使用人胰腺癌细胞系的体外研究表明，KLF 5可能在胰腺癌细胞系中具有致癌功能。然而，KLF 5在胰腺癌中的作用还有待研究。我们的初步研究结果表明，Kras突变小鼠的PanIN细胞核中Klf 5的表达量较高，提示KLF 5可能在ADM过程和PanIN形成中起着重要的早期调控作用。我的总体假设是，KLF 5在体内Kras诱导的肿瘤发生中对PanIN的形成至关重要。为了验证这一假设，我提出了以下具体目标：1）研究KLF 5是否是必要的和足够的PanIN在体内形成; 2）阐明KLF 5在Kras诱导的肿瘤发生中的作用的分子机制。本研究旨在探讨KLF 5在ADM和PanIN形成过程中的作用及其分子机制。本研究的结果将为将来研究KLF 5作为胰腺癌的潜在靶点奠定基础。 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.