Aspects of MUC13 Mucin in Cancer

描述（由申请人提供）：我们实验室最近发表和未发表的研究表明，卵巢癌和胰腺癌中存在一种新型跨膜粘蛋白MUC 13的异常表达。我们还表明，外源性MUC 13表达增强了卵巢癌和胰腺癌细胞系的细胞运动性、侵袭性、增殖和肿瘤发生。这些作用与HER 2和p53表达的调节有关。我们的初步数据支持，我们提出MUC 13的过度表达有助于胰腺癌的发病机制。在这项资助计划中，我们的目标是描述MUC 13粘蛋白在胰腺癌中的功能。我们假设MUC 13的不同结构域在癌细胞中执行特定功能，并且它们的抑制将减少胰腺癌细胞的生长和肿瘤发生。此外，我们假设异常MUC 13表达作为癌蛋白通过EGFR（HER 1，HER 2）的相互作用/稳定化/激活和p53的抑制而起作用。为了验证这些假设，我们提出了三个具体目标。1)探讨胰腺癌细胞中MUC 13不同结构域在MUC 13功能及其调控的信号通路中的作用。2)研究MUC 13对肿瘤发生的作用是否通过EGFR（HER 1，HER 2）和/或肿瘤抑制因子p53介导。在这个目标中，我们建议确定MUC 13是否与EGFR和/或p53物理相互作用，并影响这些蛋白质的表达。3)开发靶向抑制胰腺肿瘤中MUC 13表达和靶向抑制胰腺癌细胞生长的新方法。在此目的中，我们将产生MUC 13 siRNA和奥美昔芬（一种抗癌药物）的PLGA纳米颗粒制剂，其与抗MUC 13 MAb偶联，用于其特异性地在胰腺肿瘤中的持续和靶向递送。总之，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：胰腺癌的生存率非常低，是最致命的恶性肿瘤之一，主要是由于缺乏早期诊断标志物和有关胰腺癌分子机制的信息有限。了解胰腺癌进展的分子机制和识别早期诊断标志物可能会显着减少胰腺癌引起的死亡。

DESCRIPTION (provided by applicant): Recent published and unpublished studies from our laboratory suggest aberrant expression of a novel transmembrane mucin, MUC13, in ovarian and pancreatic cancers.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.