Mechanism of RelA activation in Pancreatic cancer

描述(申请人提供)：最近，一种人类胰腺癌的进展模型被提出，其基础是在胰腺导管病变中发现的特定突变，称为胰腺上皮内肿瘤。我们试图阐明这些基因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在人胰腺癌的侵袭、血管生成和转移表型中所起作用的潜在分子机制。 我们首次报道了约67%(16/24)的人胰腺癌和9/11的人胰腺癌细胞系中有核因子-kappaB的结构性激活，但在正常胰腺组织或永生化/非致癌的胰腺上皮细胞中不存在。我们正在进行的研究表明，胰腺癌中的核因子-kappaB活性与转移的发生有关。我们发现突变的IkappaBalpha(S32，36A)可以抑制胰腺癌细胞在裸小鼠原位移植模型中的肝转移，提示其在胰腺癌转移中起关键作用。我们发现了几个与胰腺癌转移相关的RrelA下游靶基因，如尿激酶型纤溶酶原激活物(UPA)、血管内皮生长因子(VEGF)和bclxl。对转基因小鼠胚胎成纤维细胞的分析表明，MAP3K信号级联激活了IkappaB激酶(IKK)和核因子-kappaB，以响应生长因子和细胞因子。然而，在胰腺癌中，核因子-kappaB被结构性激活的机制仍有待阐明。在本研究中，我们将验证一种假设，即EGF受体的过度表达和IL-1α的自分泌诱导胰腺癌细胞结构性RELA/NF-kappaB的激活，以及EGF和IL-α介导的RAS/MAPK信号级联调节IKK和NF-kappaB的活性。这些研究将确定在人胰腺癌的进展过程中，核因子-kappaB如何在EGF和IL-1α的作用下被激活。我们的发现将为更好地理解诱导胰腺癌转移表型所需的特定基因改变，以及设计和开发这种疾病潜在治疗策略的分子基础。

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.