Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner.
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 信号通过配体独立的方式调节缺氧诱导的胰腺癌细胞上皮间质转化和侵袭。
DOI：
10.1186/1476-4598-12-66
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发表时间：
2013-06-20
期刊：
影响因子：
37.3
通讯作者：
Wu E
中科院分区：
文献类型：
--
作者：
Lei J;Ma J;Ma Q;Li X;Liu H;Xu Q;Duan W;Sun Q;Xu J;Wu Z;Wu E
缺氧在肿瘤的上皮间质转化（EMT）和侵袭中起着至关重要的作用。然而，尚不清楚缺氧如何导致这些事件。我们研究Hedgehog（Hh）信号在缺氧诱导的胰腺癌EMT和侵袭中的作用。胰腺癌细胞在受控低氧条件（3%O2）或常氧条件下培养。采用HIF-1α siRNA、SMO拮抗剂cyclopamine和GLI 1 siRNA抑制HIF-1α转录或Hh信号激活。采用实时荧光定量PCR、Western blot和侵袭实验检测缺氧和Hh信号对癌细胞EMT和侵袭能力的影响。在这里，我们表明，非经典的Hh信号是必需的，作为一个重要的作用，在胰腺癌细胞中缺氧诱导的EMT和侵袭开关。此外，我们的数据表明，缺氧诱导EMT过程以及入侵，并激活非经典的Hh通路，而不影响音刺猬同源物（SHH）的表达。此外，这些影响是可逆的HIF-1α siRNA干扰与不变SHH和patched 1（PTCH 1）水平。此外，我们的数据表明，Smoothened（SMO）拮抗剂cyclopamine和GLI 1 siRNA可有效抑制缺氧诱导的侵袭和EMT过程。此外，GLI 1干扰抑制EMT进程，显著抑制波形蛋白表达，而通过环巴胺抑制SMO不能降低波形蛋白水平。这些数据表明，缺氧可以触发其他因子（如TGF-β，KRAS或RTK）绕过SMO直接激活GLI 1。我们的研究结果表明，Hh信号调节缺氧诱导的胰腺癌EMT和侵袭的配体独立的方式。因此，Hh信号传导可能代表用于预防胰腺癌进展的有希望的治疗靶点。
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. 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. 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. 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.
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影响因子：
9.7
作者：
Li, Xuqi;Ma, Qingyong;Xu, Qinhong;Liu, Han;Lei, Jianjun;Duan, Wanxing;Bhat, Kruttika;Wang, Fengfei;Wu, Erxi;Wang, Zheng
通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
11.2
作者：
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