SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial-mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway.
SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial-mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway.
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DOI：
10.1016/j.canlet.2012.02.035
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发表时间：
2012-09-28
期刊：
影响因子：
9.7
通讯作者：
Wang, Zheng
中科院分区：
文献类型：
--
作者：
Li, Xuqi;Ma, Qingyong;Xu, Qinhong;Liu, Han;Lei, Jianjun;Duan, Wanxing;Bhat, Kruttika;Wang, Fengfei;Wu, Erxi;Wang, Zheng
在我们之前的研究中，我们发现阻断SDF-1/CXCR 4信号通路可以抑制胰腺癌细胞的体外迁移和侵袭。然而，SDF-1/CXCR 4介导的侵袭的下游调控机制仍不清楚。本文报道了SDF-1/CXCR 4在胰腺癌中的作用以及SDF-1/CXCR 4介导胰腺癌侵袭的可能机制。我们发现，在胰腺癌中，SDF-1/CXCR 4轴与非经典Hedgehog（Hh）通路之间存在串扰。此外，我们的数据表明，CXCR 4的配体，SDF-1诱导CXCR 4阳性胰腺癌侵袭，上皮间质转化（EMT）过程，并激活非经典Hh通路。此外，我们还证明了Smoothened（SMO）抑制剂cyclopamine和Gli-1特异性siRNA可有效抑制由SDF-1/CXCR 4轴激活引起的胰腺癌侵袭和EMT。总的来说，这些数据表明，SDF-1/CXCR 4通过以配体非依赖性方式增加SMO的转录来调节非经典Hh途径。综上所述，SDF-1/CXCR 4轴可能代表了预防胰腺癌进展的有希望的治疗靶点。
In our previous study, we found that blockade of SDF-1/CXCR4 signaling inhibits pancreatic cancer cell migration and invasion in vitro. However, the mechanism governing the downstream regulation of SDF-1/CXCR4-mediated invasion remains unclear. Here we report the role of SDF-1/CXCR4 in pancreatic cancer and the possible mechanism of SDF-1/CXCR4-mediated pancreatic cancer invasion. We show that there is a cross-talk between SDF-1/CXCR4 axis and non-canonical Hedgehog (Hh) pathway in pancreatic cancer. Furthermore, our data demonstrate that the ligand of CXCR4, SDF-1 induces CXCR4-positive pancreatic cancer invasion, epithelial–mesenchymal transition (EMT) process and activates the non-canonical Hh pathway. Moreover, we also demonstrate that the invasion of a pancreatic cancer and EMT resulting from the activation of SDF-1/CXCR4 axis is effectively inhibited by Smoothened (SMO) inhibitor cyclopamine and siRNA specific to Gli-1. Collectively, these data demonstrate that SDF-1/CXCR4 modulates the non-canonical Hh pathway by increasing the transcription of SMO in a ligand-independent manner. Taken together, SDF-1/CXCR4 axis may represent a promising therapeutic target to prevent pancreatic cancer progression.
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