Mechanism of RelA activation in Pancreatic cancer

描述（由申请人提供）：最近，基于在称为胰腺上皮内瘤形成的病理学表现越来越明显的胰腺导管病变中鉴定的特异性突变，提出了人胰腺癌的进展模型。我们试图阐明这些遗传改变在启动和维持正常胰腺导管上皮细胞的致瘤表型以及人胰腺癌的侵袭性、血管生成和转移表型中发挥作用的潜在分子机制。 我们首次报道了NF-κ B在约67%（16/24）的人胰腺癌和9/11的人胰腺癌细胞系中被组成性激活的证据，但在正常胰腺组织或永生化/非致瘤性胰腺上皮细胞中没有。我们正在进行的研究表明，NF-κ B在胰腺癌中的活性与转移的发生有关。我们已经表明，抑制组成型RelA活性的突变体IkappaB α（S32，36 A）抑制胰腺癌细胞在原位裸鼠模型中的肝转移，这表明组成型RelA活性在胰腺癌转移中起着关键作用。我们鉴定了几个与胰腺癌转移相关的RelA下游靶基因，如尿激酶纤溶酶原激活物（uPA）、VEGF和bcl-xl。对基因改变的小鼠胚胎成纤维细胞的分析揭示了一个新的发现，即MAP 3 K信号级联激活IkappaB激酶（IKK）和NF-κ B，以响应生长因子和细胞因子。然而，NF-kappaB在胰腺癌中被组成性激活的机制仍有待阐明。在本研究中，我们将验证以下假设：EGF受体的过表达和白细胞介素-1 α（IL-1 α）的自分泌诱导胰腺癌细胞中的组成性RelA/NF-κ B活化，以及EGF和IL-α介导的RAS/MAPK信号级联调节IKK和NF-κ B活性。这些研究将确定NF-kappaB在人胰腺癌进展中如何响应EGF和IL-1 α而被激活。我们的发现将提供一个更好的理解，在演唱会上诱导胰腺癌转移表型和潜在的治疗策略的设计和开发的分子基础所需的特定的遗传改变，这种疾病。

DESCRIPTION (provided by applicant): Recently a progression model for human pancreatic adenocarcinoma has been proposed based on the specific mutations identified in progressively more pathologic-appearing pancreatic ductal lesions termed pancreatic intraepithelial neoplasias. We seek to elucidate the underlying molecular mechanism that these genetic alterations play in initiating and maintaining tumorigenic phenotypes in normal pancreatic ductal epithelial cells, and invasive, angiogenic and metastatic phenotypes in human pancreatic adenocarcinoma. We have reported the first evidence that NF-kappaB, is constitutively activated in approximately 67% (16 of 24) of human pancreatic adenocarcinoma and 9 of 11 human pancreatic cancer cell lines, but not in normal pancreatic tissues or in immortalized/nontumorigenic pancreatic epithelial cells. Our ongoing study suggests that NF-kappaB activity in pancreatic cancer is associated with the occurrence of metastasis. We have shown that inhibition of constitutive RelA activity by a mutant IkappaBalpha (S32, 36A) suppressed liver metastasis of pancreas cancer cells in an orthotopic nude mouse model, suggesting that the constitutive RelA activity plays a key role in pancreas cancer metastasis. We identified several RelA downstream target genes relevant to pancreatic adenocarcinoma metastasis such as urokinase plasminogen activator (uPA), VEGF and bcl-xl. Analysis of genetically altered mouse embryonic fibroblasts reveals a novel finding that MAP3K signaling cascades activate IkappaB kinase (IKK) and NF-kappaB in response to growth factor and cytokine. However, the mechanism by which NF-kappaB is constitutively activated in pancreatic cancer still remains to be elucidated. In this study, we will test the hypothesis that the overexpression of EGF receptor and autocrine of lnterleukin-1alpha (IL-1alpha) induce constitutive RelA/NF-kappaB activation in pancreatic cancer cells and EGF and IL-alpha mediated RAS/MAPK signaling cascades for regulating IKK and NF-kappaB activity. These studies will determine how NF-kappaB is activated in response to EGF and IL-1alpha in the progression of human pancreatic adenocarcinoma. Our finding will provide a better understanding of the specific genetic alterations required in concert to induce metastatic phenotype in pancreatic cancer and the molecular basis for the design and development of potential therapeutic strategies for this disease.