Clarification of control mechanisms for metastasis/invasion in pancreatic cancer

我们曾报道神经营养因子GDNF在胰腺癌细胞侵袭能力中起重要作用。此外，我们还证实IL-1α的高表达是肝转移胰腺癌细胞系的一个特征，IL-1受体I型(IL-1RI)通过增强胰腺癌细胞系中黏附分子整合素的表达和转移潜能。本研究的目的是确定GDNF和炎性细胞因子在胰腺癌细胞增殖、黏附和侵袭能力中的作用。GDNF和IL-1α通过激活转录因子如核因子-kB和AP-1，显著增强a6β1和a5β1-整合素的表达。在所有胰腺内神经中，GDNF均呈强阳性表达。在胰腺癌组织中，RET的表达强于正常导管细胞，且与胰腺癌切除及淋巴侵犯后的生存率显著相关。ILK活性的改变控制了p38MAPK的磷酸化，从而调节了胰腺癌细胞的黏附和侵袭。过表达的ILK通过激活GSK-3强烈增强p38MAPK的磷酸化，从而促进胰腺癌细胞的侵袭能力。免疫组织化学分析显示，ILK的强表达与胰腺癌患者预后不良有统计学意义的相关性。胰腺癌细胞中FAK的激活与RAS/ERK信号通路的激活有关，通过siRNA抑制FAK的表达可以抑制这些信号通路的激活，这与抑制胰腺癌细胞的黏附和侵袭能力是一致的。

We previously reported that the neurotrophic factor, GDNF, has an important role in the invasive capability of pancreatic cancer cells. Furthermore, we confirmed that increased IL-lalpha expression is a feature of liver-metastatic pancreatic cancer cell lines and that IL-lalpha enhances adhesion molecule integrins 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 GDNF and inflammatory cytokines for pancreatic cancer cell proliferative, adhesive, and invasive capabilities.We report the results that we acquired till now as follows.1. GDNF and IL-lalpha significantly enhanced the expression of a6β1 and a5β1-integrins through the activation of transcription factors such as NF-kB and AP-1.2. In all intrapancreatic nerves GDNF was expressed strongly. In pancreatic cancer tissues, the expression of RET was stronger than that seen in normal ductal cells and was significantly related to the survival rate after resection and lymphatic invasion.3. Alteration of ILK kinase activity controlled p38 MAPK phosphorylation with subsequent regulation of pancreatic cancer cell adhesion and invasion. Overexpressed ILK enhances the p38 MAPK phosphorylation strongly through GSK-3 activation which promotes aggressive capabilities of pancreatic cancer cells. In immunohistochemical analysis, statistically significant association between strong expression of ILK and poor prognosis of pancreatic cancer patients were observed.4. FAK activation correlated with the activation of Ras/ERK signaling pathways in pancreatic cancer cells and activation of these signaling pathways can be inhibited by knockdown of FAK expression with siRNA, consistent with the inhibition of adhesive and invasive capabilities of pancreatic cancer cells.