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

有报道称，Hedgehog （HH）信号激活的配体（Shh）依赖性参与了胰腺癌的发生和发展，但Shh在包括胰腺癌在内的任何癌症中过度发展的机制尚不清楚。在本主题中，我们分析了胰腺癌中核因子- kb （NF-κB）活性与Shh表达水平的相关性，因为NF-κB通常在胰腺癌引起的阻塞性胰腺炎中被激活。我们发现NF-κB p65与Shh在手术切除的胰腺标本（包括慢性胰腺炎和胰腺腺癌标本）中的表达呈正相关。PDTC、诱饵ODN或显性阴性的NF-κB抑制胰腺癌细胞Shh mRNA的组成性表达。反之，il - 1-β、TNF-a和LPS三种炎症刺激诱导Shh过表达，导致Hh通路激活，这与阻断NF-κB抑制这些刺激诱导的Shh过表达一致。重要的是，nf - kb诱导的HH信号激活增强了胰腺癌细胞的增殖。此外，抑制Hh通路和NF-κB可抑制增强的细胞侵袭。我们的数据表明，NF-κB激活是控制胰腺癌中Shh过表达的机制之一，NF-κB激活部分通过HH信号通路加速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.