低氧/低氧诱导因子-1α通过TGF-β1诱导人肝内胆管上皮细胞上皮间质转化

目的：探讨低氧/低氧诱导因子-1α（HIF-1α）对人肝内胆管上皮细胞（HIBEC）上皮-间质转化（EMT）的诱导作用及其分子机制。方法：HIBEC在1%氧浓度的低氧环境中培养，分析细胞迁移、侵袭能力的变化，以及EMT相关标志E-钙黏蛋白和S100A4的表达水平。以HIF-1α的siRNA和转化生长因子-β1（TGF-β1）抑制剂LY364947分别沉默或抑制HIF-1α和TGF-β1，再重复上述实验。结果：与常氧培养相比较，低氧条件下，HIBEC的细胞迁移和侵袭能力明显增强，上皮细胞标志物E-钙黏蛋白表达明显下降，间质细胞标志物S100A4表达明显升高（P＜0.05）。以HIF-1α的siRNA和TGF-β1分别沉默或抑制HIF-1α和TGF-β1后，上述低氧引起的HIBEC生物学变化均受到明显抑制（P＜0.05）。结论：低氧可以通过活化HIF-1α诱导HIBEC发生EMT，这种诱导作用主要是通过TGF-β1完成的。

The mechanism of epithelial-mesenchymal transition of human intrahepatic biliary epithelial cells induced by hypoxia/hypoxic inducible factor-1α through tgf-β1

Objective: To investigate the role of hypoxia/hypoxic inducible factor-1α (HIF-1α) in inducing epithelial-mesenchymal transition of human intrahepatic biliary epithelial cells (HIBEC) as well as its molecular mechanisms. Methods: Under the condition of hypoxia (1% O2), HIBECs were cultured in vitro and analyzed for mobility, invasiveness and expression levels of EMT-related markers including E-cadherin and S100A4. The above-mentioned experiments were repeated with HIF-1α silenced by siRNA and transforming growth factor β1 (TGF-β1) inhibited by inhibitor LY364947. Results: Under the condition of hypoxia, in contrast to normoxia, HIBECs showed markedly enhanced mobility and invasiveness as well as significant downregulation of E-cadherin and upregulation of S100A4. After HIF-1α silence or TGF-β1 inhibition, above-mentioned biological changes of HIBECs were significantly inhibited under hypoxia. Conclusion: Hypoxia can induce EMT of HIBECs by activating HIF-1α. TGF-β1 plays an important role in hypoxia/HIF-1α-induced EMT of HIBECs.