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MUC13的异常表达。我们还发现，外源性MUC13表达增强了卵巢癌和胰腺癌细胞系的细胞运动、侵袭、增殖和肿瘤发生。这些作用与HER2和p53表达的调节有关。根据我们的初步数据，我们提出MUC13的过表达参与了胰腺癌的发病机制。在这项拨款申请中，我们的目标是描述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MUC13的异常表达作为癌蛋白通过egfr （HER1、HER2）的相互作用/稳定/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MUC13不同结构域在胰腺癌细胞功能中的作用及MUC13调控的信号通路。2)探讨MUC13在肿瘤发生中的作用是否通过EGFRs （HER1、HER2）和/或抑癌基因p53介导。在这个目的中，我们建议确定MUC13是否与egfr和/或p53物理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。在这个目标中，我们将产生MUC13 siRNA和奥美洛昔芬（一种抗癌药物）的PLGA纳米颗粒配方，结合抗MUC13单克隆抗体，以实现其在胰腺肿瘤中的持续和靶向递送。综上所述，这些信息将为开发新的胰腺癌治疗策略提供重要的见解。

DESCRIPTION (provided by applicant): Recent published and unpublished studies from our laboratory suggest aberrant expression of a novel transmembrane mucin, MUC13, in ovarian and pancreatic cancers.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