Transforming growth factor-β induces epithelial to mesenchymal transition by down-regulation of claudin-1 expression and the fence function in adult rat hepatocytes
Transforming growth factor-β induces epithelial to mesenchymal transition by down-regulation of claudin-1 expression and the fence function in adult rat hepatocytes
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DOI：
10.1111/j.1478-3231.2007.01631.x
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发表时间：
2008-04-01
影响因子：
6.7
通讯作者：
Sawada, Norimasa
中科院分区：
文献类型：
--
作者：
Kojima, Takashi;Takano, Ken-ichi;Sawada, Norimasa
背景/目的：转化生长因子- β (tgf - β)启动并维持上皮-间质转化（EMT），导致紧密连接的解体和上皮细胞极性的丧失。在tgf - β诱导的EMT过程中，成熟肝细胞中紧密连接蛋白的表达和栅栏功能的变化表明上皮细胞的极性仍然不清楚。方法：本研究采用大鼠肝细胞原代培养法，观察了0.01 ~ 20 ng/ml tgf - β对肝细胞整体紧密连接蛋白claudin-1、claudin -2和occludin表达及栅栏功能的影响。结果：在成年大鼠肝细胞中，tgf - β诱导EMT，表现为smad - interaction protein-1 （SIP1）和Snail上调，E-cadherin下调。低剂量tgf - β开始观察到claudin-1的下调和occludin的上调，而高剂量tgf - β开始观察到claudin-2的上调。此外，tgf - β治疗导致栅栏功能的破坏，这与通过p38丝裂原活化蛋白激酶（MAPK）、磷酸肌醇-3激酶和蛋白激酶C表达的cladin -1密切相关，但与MAPK信号通路无关。结论：在体外成熟肝细胞中，tgf - β通过不同的信号通路下调claudin-1和篱笆功能诱导EMT。
Background/Aims: Transforming growth factor-beta (TGF-beta) initiates and maintains epithelial-mesenchymal transition (EMT), which causes disassembly of tight junctions and loss of epithelial cell polarity. In mature hepatocytes during EMT induced by TGF-beta, changes in the expression of tight junction proteins and the fence function indicated that epithelial cell polarity remains unclear. Methods:In the present study, using primary cultures of adult rat hepatocytes at day 10 after plating, in which epithelial cell polarity is well maintained by tight junctions, we examined the effects of 0.01-20 ng/ml TGF-beta on the expression of the integral tight junction proteins, claudin-1, -2 and occludin, as well as the fence function. Results: In adult rat hepatocytes, TGF-beta induced EMT, which was indicated as upregulation of Smad-interacting protein-1 (SIP1) and Snail and down-regulation of E-cadherin. Down-regulation of claudin-1 and upregulation of occludin were observed beginning from a low dose of TGF-beta, whereas upregulation of claudin-2 was observed at a high dose of TGF-beta. Furthermore, treatment with TGF-beta caused disruption of the fence function, which was closely associated with the expression of claudin-1 via p38 mitogen-activated protein kinase (MAPK), phosphoinositide-3 kinase and protein kinase C but not MAPK signalling pathways. Conclusion: These results suggest that in mature hepatocytes in vitro, TGF-beta induces EMT by down-regulation of claudin-1 and the fence function via distinct signalling pathways.