Mechanism of RelA activation in Pancreatic cancer

描述（由申请人提供）：最近提出了一种人类胰腺腺癌的进展模型，该模型基于在称为胰腺上皮内瘤变的渐进式胰腺导管病变中发现的特定突变。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类胰腺腺癌的侵袭性、血管生成性和转移性表型中发挥作用的潜在分子机制。

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.