Development of pancreatic cancer therapy and prevention using morphogen as a target signaling pathway

已有报道Hedgehog(Hedgehog，HH)信号激活配体(Shh)依赖参与胰腺癌的发生发展，但Shh在包括胰腺癌在内的任何肿瘤中过度发展的机制尚不清楚。由于胰腺癌引起的梗阻性胰腺炎往往会激活核因子-κB，因此，本课题分析了胰腺癌组织中核因子-KB(NF-κB)活性与Shh表达水平的相关性。我们发现在手术切除的胰腺组织中，包括慢性胰腺炎和胰腺癌组织中，NF-κB p65和Shh的表达呈正相关。PDTC、诱骗寡核苷酸和显性阴性的NF-κB抑制胰腺癌细胞Shhκ的组成性表达。反之，IL-1-β、肿瘤坏死因子-α和脂多糖三种炎性刺激诱导Shh过表达，激活HH通路，与阻断NF-κB抑制这些刺激诱导的Shh过表达一致。重要的是，核因子-KB诱导的HH信号激活促进了胰腺癌细胞的增殖。此外，抑制HH途径和抑制NF-κB可抑制增强的细胞侵袭。我们的研究结果提示，NF-κB的激活是控制胰腺癌Shh过表达的机制之一，而NF-κB的激活部分通过HH信号通路促进了胰腺癌细胞的增殖和侵袭。

It has been reported that Hedgehog (HH) signal activation of ligand (Shh) dependence participates in pancreas carcinogenesis and development, but Shh is not clarified about mechanism developing excessively in any cancers including pancreatic cancer. In this theme, we analyzed the correlation between activity of nuclear factor-KB (NF-κB) and expression level of Shh in pancreatic cancer, because NF-κB is usually activated by obstructive pancreatitis caused by pancreatic cancer. We found a positive correlation between NF-κB p65 and Shh expression in surgically resected pancreas specimens, including specimens of chronic pancreatitis and pancreatic adenocarcinoma. Suppression of NF-κB by PDTC, decoy ODN or dominant-negativeNF-κB suppressed constitutive expression of Shh mRNA in pancreatic cancer cells. Vice versa, three inflammatory stimuli including IL1-β, TNF-a and LPS induced overexpression of Shh, resulting in activation of the Hh pathway, consistent with that blockade of NF-κB suppressed overexpression of Shh induced by these stimuli. Importantly, NF-KB-induced HH signal activation enhanced cell proliferation in pancreatic cancer cells. In addition, inhibition of the Hh pathway as well as NF-κB suppressed the enhanced cell invasion. Our data suggest that NF-κB activation is one of the mechanisms controling Shh overexpression in pancreatic cancer and that proliferation and invasion of pancreatic cancer cells is accelerated by NF-κB activation in part through HH signaling pathway.