Role of serine protease KLK7 in pancreatic cancer

描述（由申请人提供）： 胰腺癌的特征是邻近结构的局部浸润、神经周围浸润、淋巴结和肝脏的早期转移以及强烈的促纤维增生性基质反应。然而，我们对这种疾病的高度侵袭性的理解严重不足。最近，我们有了新的发现，激肽释放酶7（KLK 7）在胰腺导管腺癌（PDAC）中过表达。使用一系列体外实验，我们已经进一步证明KLK 7可以直接和间接参与促进胰腺肿瘤侵袭周围组织的能力的过程，包括E-钙粘蛋白的脱落、纤连蛋白的切割、与玻连蛋白的粘附的丧失、桥粒芯蛋白-2的降解和proMMP-9的活化。在初步研究中，为了检查KLK 7在胰腺肿瘤中表达的功能意义，我们已经在源自皮下接种于免疫缺陷小鼠的胰腺癌细胞系的肿瘤异种移植物中利用了shRNA介导的KLK 7抑制。KLK 7抑制导致肿瘤生长急剧减少;从而提供了令人信服的证据表明胰腺中KLK 7的异常表达在胰腺肿瘤发生中发挥着重要作用。基于我们发表的和初步的研究结果，我们假设KLK 7在胰腺癌中异常表达是由于启动子甲基化改变，这导致蛋白水解活性的不适当诱导，促进肿瘤侵袭和转移，并增强胰腺肿瘤生长。我们将通过以下具体目标来测试这些假设：1）使用胰腺癌实验模型来检查抑制KLK 7表达对胰腺肿瘤发育、生长和侵袭的影响。2)检查调节胰腺癌中KLK 7表达的机制。3)检查KLK 7蛋白水解活性在胰腺癌细胞中的下游作用。这些研究将有助于填补我们对胰腺癌中发展的失调细胞过程的知识不足，这些细胞过程产生高度侵袭性的肿瘤和极差的患者结局，并可能为靶向KLK 7表达和/或其蛋白水解活性的新型治疗干预提供见解，从而为这种毁灭性疾病提供新的治疗方法。

DESCRIPTION (provided by applicant): Pancreatic cancer is characterized by local invasion of adjacent structures, perineural invasion, early metastases to lymph nodes and liver, and an intense desmoplastic stromal reaction. Our understanding of the highly invasive nature of this disease, however, is severely deficient. Recently, we have made the novel finding that kallikrein 7 (KLK7) is overexpressed in pancreatic ductal adenocarcinomas (PDAC). Using a series of in vitro experiments, we have further demonstrated that KLK7 may participate both directly and indirectly in processes that facilitate the ability of pancreatic tumors to invade surrounding tissues including the shedding of E-cadherin, cleavage of fibronectin, loss of adhesion to vitronectin, degradation of desmoglein-2, and activation of proMMP-9. In preliminary studies, to examine the functional significance of KLK7 expression in pancreatic tumors, we have utilized shRNA-mediated suppression of KLK7 in tumor xenografts derived from pancreatic cancer cell lines inoculated subcutaneously in immunodeficient mice. KLK7 suppression resulted in a dramatic decrease in tumor growth; thus providing compelling evidence that aberrant expression of KLK7 in the pancreas plays an important role in pancreatic tumorigenesis. Based on our published and preliminary findings, we hypothesize that KLK7 is aberrantly expressed in pancreatic adenocarcinomas due to altered promoter methylation, which results in inappropriate induction of proteolytic activity that facilitates tumor invasion and metastasis and enhances pancreatic tumor growth. We will test these hypotheses through the following specific aims: 1) Examine the effects of suppression of KLK7 expression on pancreatic tumor development, growth, and invasion using experimental models of pancreatic cancer. 2) Examine the mechanism(s) regulating KLK7 expression in pancreatic cancer. 3) Examine downstream effects of KLK7 proteolytic activity in pancreatic cancer cells. These studies will help fill the deficits in our knowledge regarding the deregulated cellular processes that develop in pancreatic cancer that produces highly aggressive tumors and extremely poor patient outcomes and may provide insights into novel therapeutic interventions that target either KLK7 expression and/or its proteolytic activity leading to new treatments for this devastating disease.