Aspects of MUC13 Mucin in Cancer

描述(申请人提供)：我们实验室最近发表和未发表的研究表明，一种新的跨膜粘蛋白MUC13在卵巢癌和胰腺癌中异常表达。我们还表明，外源性MUC13表达增强了卵巢和胰腺癌细胞系的细胞运动、侵袭、增殖和肿瘤形成。这些作用与调节HER2和P53的表达有关。根据我们的初步数据，我们认为MUC13的过度表达在胰腺癌的发病机制中起着重要作用。在这项拨款提案中，我们的目标是描绘MUC13粘蛋白在胰腺癌中的功能方面。我们假设MUC13的不同结构域在癌细胞中执行特定的功能，它们的抑制将减少胰腺癌细胞的生长和肿瘤的发生。此外，我们假设MUC13的异常表达通过EGFR(HER1，HER2)的相互作用/稳定/激活和P53的抑制而作为癌蛋白发挥作用。为了检验这些假设，我们提出了三个具体目标。1)探讨不同的MUC13结构域在MUC13调控胰腺癌细胞功能及信号转导通路中的作用。2)探讨MUC13在肿瘤发生中的作用是否通过EGFR(HER1、HER2)和/或抑癌基因P53介导。为此，我们建议确定MUC13是否与EGFR和/或P53物理上相互作用，并影响这些蛋白的表达。3)开发靶向抑制胰腺肿瘤MUC13表达和靶向抑制胰腺癌细胞生长的新方法。在这一目标中，我们将产生PLGA纳米制剂MUC13 siRNA和ormeloxifene(一种抗癌药物)，加上抗MUC13单抗，用于它们在胰腺肿瘤中的持续和靶向递送。综上所述，这些信息将为开发胰腺癌的新治疗策略提供重要的见解。 公共卫生相关性：胰腺癌的存活率非常低，是最致命的恶性肿瘤之一，主要原因是缺乏早期诊断标记物，而且关于胰腺癌周围分子机制的信息有限。了解胰腺癌进展的分子机制，识别早期诊断标记物，可显著降低胰腺癌的死亡率。

DESCRIPTION (provided by applicant): Recent published and unpublished studies from our laboratory suggest aberrant expression of a novel transmembrane mucin, MUC13, in ovarian and pancreatic cancers. We have also shown that exogenous MUC13 expression enhances cellular motility, invasion, proliferation and tumorigenesis of ovarian and pancreatic cancer cell lines. These effects are associated with modulation of HER2 and p53 expression. As supported by our preliminary data, we propose that the overexpression of MUC13 contributes to the pathogenesis of pancreatic cancer. In this grant proposal, our objectives are to delineate the functional aspects of MUC13 mucin in pancreatic cancer. We hypothesize that the different domains of MUC13 execute specific functions in cancer cells and their suppression will diminish pancreatic cancer cell growth and tumorigenesis. Additionally, we hypothesize that the aberrant MUC13 expression operates as an oncoprotein via interaction/stabilization/activation of EGFRs (HER1, HER2) and suppression of p53. To test these hypotheses, we propose three specific aims. 1) To investigate the roles of different MUC13 domains in the function and the signaling pathways modulated by MUC13 in pancreatic cancer cells. 2) To investigate whether the effect of MUC13 on tumorigenesis is mediated through EGFRs (HER1, HER2) and/or the tumor suppressor p53. In this aim we propose to determine if MUC13 physically interacts with EGFRs and/or p53 and influences expression of these proteins. 3) Develop novel methods for targeted repression of MUC13 expression in pancreatic tumors and targeted inhibition of pancreatic cancer cell growth. In this aim we will generate PLGA nanoparticle formulations of MUC13 siRNA and ormeloxifene (an anti- cancer drug), coupled with anti-MUC13 MAbs for their sustained and targeted delivery specifically in pancreatic tumors. Taken together, this information will provide important insights for developing novel therapeutic strategies for pancreatic cancer. PUBLIC HEALTH RELEVANCE: With a very low survival rate, pancreatic cancer is one the most lethal malignancies, primarily due to the lack of early diagnostic markers and limited information regarding the molecular mechanisms surrounding pancreatic cancer. Understanding of the molecular mechanisms of pancreatic cancer progression and the identification of early diagnostic markers may significantly reduce the deaths caused by pancreatic cancer.