Clarification of control mechanisms for adhesion molecules and metastasis/invasion mechanisms by cytokines to contribute to cure pancreatic cancer

我们已经表明，上调il -1 α表达仅是肝转移性胰腺癌细胞系的特征。此外，我们证实，与低转移胰腺癌细胞系相比，IL-1 α表达增加是肝转移胰腺癌细胞系的一个特征，并且IL-1 α通过IL-1受体I型（IL-1RI）增强了胰腺癌细胞系的粘附分子表达和转移潜能。本研究的目的是确定整合素和细胞内信号转导在胰腺癌细胞增殖、粘附和侵袭能力中的作用。现将目前取得的成果报告如下。与转移性胰腺癌细胞共培养时，HUVEC的增殖和管的形成都得到了强烈的增强，在il -1 α存在的情况下，HUVEC的增殖和管的形成也得到了类似程度的增强。相反，IL-1ra阻断IL-1alpha可抑制HUVEC增殖和血管生成2。研究了NF-kappaB在信号转导通路中的作用。(1)蛋白酶体抑制剂能呈剂量依赖性地抑制胰腺癌细胞株的增殖，并抑制Ikappa-B显性阴性载体转染的胰腺癌细胞的增殖能力。GDNF刺激后，侵袭细胞数量增加，NF-kappaB活性增加。然而，当蛋白酶体抑制剂或Ikappa-B显性负载体存在时，两者都被显著抑制，后者阻断NF-kappaB的核定位。此外，GDNF刺激后，两者的活性均未发生变化。(2)信号转导抑制剂，如ERK-1/2和p38 MAPK抑制剂，可以阻止转录因子AP-1的激活。这表明AP-1是MAPK通路的下游靶点，ERK-1/2和p38 MAPK可能通过激活AP-1介导il -1诱导的胰腺癌细胞增殖和侵袭能力的增强。少

We have shown that up-regulated IL-1alpha expression is a feature only of liver-metastatic pancreatic cancer cell lines. Furthermore, we confirmed that increased IL-1alpha expression is a feature of liver-metastatic pancreatic cancer cell lines, in contrast to low-metastatic pancreatic cancer cell lines, and that IL-1alpha enhances adhesion molecule expression and metastatic potential in pancreatic cancer cell lines via IL-1 receptor type I(IL-1RI). The aims of this study were to identify the role of integrins and intracellular signaling transduction for pancreatic cancer cell proliferative, adhesive, and invasive capabilities.We report the results that we acquired till now as follows.1.Both HUVEC proliferation and tube formation were strongly enhanced by co-culture with metastatic pancreatic cancer cells and were enhanced to a similar extent by culture in the presence of IL-1alpha. In contrast, blockade of IL-1alpha by IL-1ra inhibited HUVEC proliferation and angiogenesis.2.The role o … More f NF-kappaB in signaling transduction pathways was investigated.(1)Proliferation of pancreatic cancer cell lines was decreased by a proteasome inhibitor in a dose-dependent manner, and the proliferative capabilities of Ikappa-B dominant negative vector-transfected pancreatic cancer cells were also inhibited. The invaded cell number and the NF-kappaB activity were increased by GDNF stimulation. However, in the presence of a proteasome inhibitor or Ikappa-B dominant negative vector, which blocks the nuclear localization of NF-kappaB, both were significantly suppressed. Furthermore, reduced activity of both remained unchanged by GDNF stimulation.(2)Treatment with signaling transduction inhibitors, such as ERK-1/2 and p38 MAPK inhibitors, prevented the activation of transcription factor AP-1. It can be suggested that AP-1 is a downstream target of MAPK pathways and that ERK-1/2 and p38 MAPK may mediate the IL-1alpha-induced enhancements of proliferative and invasive capabilities of pancreatic cancer cells through AP-1 activation. Less