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首页> 外文期刊>Molecular Cancer >Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner
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Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner

机译：刺猬信号通过配体非依赖性调节缺氧诱导胰腺癌细胞上皮向间质转化和侵袭

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Background Hypoxia plays a vital role in cancer epithelial to mesenchymal transition (EMT) and invasion. However, it is not quite clear how hypoxia may contribute to these events. Here we investigate the role of Hedgehog (Hh) signaling in hypoxia induced pancreatic cancer EMT and invasion. Methods Pancreatic cancer cells were cultured under controlled hypoxia conditions (3% O2) or normoxic conditions. HIF-1α siRNA , cyclopamine (a SMO antagonist) and GLI1 siRNA were used to inhibit HIF-1α transcription or Hh signaling activation. The effect of hypoxia and Hh signaling on cancer cell EMT and invasion were evaluated by Quantitative real-time PCR analysis, Western blot analysis and invasion assay. Results Here, we show that non-canonical Hh signaling is required as an important role to switch on hypoxia-induced EMT and invasion in pancreatic cancer cells. Moreover, our data demonstrate hypoxia induces EMT process as well as invasion, and activates the non-canonical Hh pathway without affecting sonic hedgehog homolog (SHH) expression. Moreover, these effects are reversible upon HIF-1α siRNA interference with unchanged SHH and patched1 (PTCH1) level. Furthermore, our data demonstrate that hypoxia induced invasion and EMT process are effectively inhibited by Smoothened (SMO) antagonist cyclopamine and GLI1 siRNA . In addition, GLI1 interference inhibited EMT progress with significantly suppressed vimentin expression, whereas inhibition of SMO through cyclopamine could not reduce vimentin level. This data indicate that hypoxia could trigger other factors (such as TGF-β , KRAS or RTK) bypassing SMO to activate GLI1 directly. Conclusions Our findings suggest that Hh signaling modulates hypoxia induced pancreatic cancer EMT and invasion in a ligand-independent manner. Thus, Hh signaling may represent a promising therapeutic target for preventing pancreatic cancer progression.
机译：背景低氧在癌上皮向间质转化（EMT）和侵袭中起着至关重要的作用。但是，目前尚不清楚缺氧如何导致这些事件。在这里，我们研究了刺猬（Hh）信号在缺氧诱导的胰腺癌EMT和侵袭中的作用。方法在控制的低氧条件（3％O2）或常氧条件下培养胰腺癌细胞。使用HIF-1αsiRNA，环巴胺（一种SMO拮抗剂）和GLI1 siRNA来抑制HIF-1α转录或Hh信号激活。通过实时定量PCR分析，蛋白质印迹分析和侵袭分析评估缺氧和Hh信号传导对癌细胞EMT和侵袭的影响。结果在这里，我们显示非规范Hh信号作为在缺氧诱导的EMT和胰腺癌细胞侵袭中的重要作用是必需的。此外，我们的数据表明缺氧诱导EMT过程以及入侵，并激活非规范的Hh途径，而不会影响声猬因子（SHH）的表达。此外，在HIF-1αsiRNA干扰且SHH和patched1（PTCH1）水平不变的情况下，这些作用是可逆的。此外，我们的数据表明，Smoothened（SMO）拮抗剂环巴胺和GLI1 siRNA可有效抑制缺氧诱导的侵袭和EMT过程。此外，GLI1干扰抑制EMT进展，同时显着抑制波形蛋白表达，而通过环巴胺抑制SMO不能降低波形蛋白水平。该数据表明低氧可能会触发其他因素（例如TGF-β，KRAS或RTK）绕过SMO直接激活GLI1。结论我们的发现表明Hh信号以配体独立的方式调节低氧诱导的胰腺癌EMT和侵袭。因此，Hh信号传导可能代表了预防胰腺癌进展的有希望的治疗靶标。

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