Role of Gastrokine 2 in pancreatic cancer development

摘要 胰腺导管腺癌（PDAC）是最致命的成人癌症之一，5年生存率为 只有11%，是美国男性和女性癌症相关死亡的五大主要原因之一。 States.这些可怕的统计数字突出表明，需要更好地了解促进人权的机制。 胰腺癌的发生和发展。最近的研究已经开始表明，上皮化生 胰腺癌的分化可显著影响疾病进展。我们的初步数据来自 正在进行的研究细胞因子IL-12/IL-23在胰腺癌细胞分化中的作用的研究显示， 侵袭性上皮细胞向间充质样表型的获得与同时发生的胃上皮细胞的丧失有关。 谱系基因，包括Gastrokine 2（Gkn 2）。Gkn 2在正常胃上皮细胞中大量表达， 在胃上皮细胞内环境稳定中起抗炎作用。最近，Gkn 2和它的家族成员Gkn 1 已经显示在胰腺癌的化生上皮细胞中从头上调。但 胃动素在胰腺肿瘤发生中的功能作用仍不清楚。本提案的目标是 阐明胰腺肿瘤中从头Gkn 2表达的动力学、细胞来源和驱动因素，以及 以确定Gkn 2在胰腺癌发展中的功能作用。为了实现这些目标，在目标1中， 我们将确定Gkn 2阳性细胞的表达模式和细胞身份，以及了解如何 致癌Kras和/或Src信号传导可能有助于胰腺上皮细胞中Gkn 2的表达。在 目的2，我们将研究Gkn 2在胰腺肿瘤生长、肿瘤细胞分化和肿瘤细胞凋亡中的作用。 入侵具体来说，我们将利用可逆的Gkn 2敲低系统来确定其对细胞增殖的贡献。 胰腺癌中Kras转化上皮细胞的生长和分化。我们的研究计划将 利用最先进的模型，以提供一个胃的身份基因程序如何出现早期的理解 在转化的胰腺上皮中，并作为癌症侵袭性进展的潜在障碍。

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest adult cancers with a 5-year survival rate of only 11% and is one of the top five leading causes of cancer-related deaths for men and women in the United States. These dire statistics underscore the need for a better understanding of the mechanisms that promote pancreatic cancer initiation and progression. Recent studies have begun to show that metaplastic epithelial differentiation in pancreatic cancer can significantly impact disease progression. Our preliminary data from ongoing studies investigating the role of cytokines IL-12/IL-23 in pancreatic cancer cell differentiation showed that gain of aggressive epithelial to mesenchymal-like phenotype is associated with the concurrent loss of gastric lineage genes, including Gastrokine 2 (Gkn2). Gkn2 is abundantly expressed by normal stomach epithelial cells, plays an anti-inflammatory role in gastric epithelial homeostasis. Recently, Gkn2 and its family member Gkn1 have been shown to be de novo upregulated in metaplastic epithelial cells in pancreatic cancer. However, the functional roles of gastrokines in pancreatic tumorigenesis remain unclear. The goals of this proposal are to elucidate the kinetics, cellular source, and driver(s) of de novo Gkn2 expression in pancreatic neoplasia, as well as determine the functional role of Gkn2 in pancreatic cancer development. To achieve these goals, in Aim 1, we will determine the expression pattern and cellular identity of Gkn2-positive cells, as well as understand how oncogenic Kras and/or Src signaling may contribute to the expression of Gkn2 in pancreatic epithelial cells. In Aim 2, we will investigate the functional role of Gkn2 in pancreatic tumor growth, tumor cell differentiation, and invasion. Specifically, we will utilize reversible Gkn2 knockdown systems to determine its contribution to the growth and differentiation of Kras-transformed epithelial cells in pancreatic cancer. Our proposed research will utilize state-of-the art models to provide an understanding of how a gastric identity gene program emerges early in transformed pancreatic epithelium and acts as a potential impediment to the aggressive progression of cancer.