Smad3 Suppresses Epithelial Cell Migration and Proliferation via the Clock Gene Dec1, Which Negatively Regulates the Expression of Clock Genes Dec2 and Per1
Smad3 Suppresses Epithelial Cell Migration and Proliferation via the Clock Gene Dec1, Which Negatively Regulates the Expression of Clock Genes Dec2 and Per1
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DOI：
10.1016/j.ajpath.2019.01.006
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发表时间：
2019-04-01
影响因子：
6
通讯作者：
Muragaki, Yasuteru
中科院分区：
文献类型：
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作者：
Sato, Fuyuki;Otsuka, Tsuyoshi;Muragaki, Yasuteru
Smad3具有昼夜节律表达，然而，Smad3是否影响时钟基因的表达知之甚少。在这里，我们研究了Smad3和时钟基因Dec1，Dec2和Pet-1之间的调节机制。与对照组小鼠相比，Smad3基因敲除小鼠的自发活动幅度降低，视交叉上核、肝、肾和舌中Dec1的表达降低。相反，与对照小鼠相比，Dec2和Per1表达增加。在Smad3基因敲除小鼠中，免疫组织化学染色显示，Dec1表达下降，而Dec2和Perl表达增加，在肾脏和肝脏的内皮细胞。在NIH3T3细胞中，Smad3过表达增加Decl的表达，但降低Dec2和Pert的表达。在使用Smad3敲除小鼠的伤口愈合实验中，Dec1表达在鳞状上皮的基底细胞中减少，促进粘膜的伤口愈合。最后，Smad3敲除的鳞状细胞癌细胞的迁移和增殖被Dec1过表达抑制，但被Dec2过表达促进。Dec1过表达降低E-钙粘蛋白和增殖细胞核抗原的表达，而这些表达水平增加Dec2过表达。这些结果表明Smad3与昼夜节律相关，并通过Dec1，Dec2和Per1表达调节细胞迁移和增殖。
Smad3 has circadian expression; however, whether Smad3 affects the expression of clock genes is poorly understood. Here, we investigated the regulatory mechanisms between Smad3 and the clock genes Dec1, Dec2, and Pet-1. In Smad3 knockout mice, the amplitude of locomotor activity was decreased, and Dec1 expression was decreased in the suprachiasmatic nucleus, Liver, kidney, and tongue compared with control mice. Conversely, Dec2 and Per1 expression was increased compared with that of control mice. In Smad3 knockout mice, immunohistochemical staining revealed that Dec1 expression decreased, whereas Dec2 and Perl expression increased in the endothelial cells of the kidney and liver. In NIH3T3 cells, Smad3 overexpression increased Decl expression, but decreased Dec2 and Pert expression. In a wound-healing experiment that used Smad3 knockout mice, Dec1 expression decreased in the basal cells of squamous epithelium, promoting wound healing of the mucosa. Finally, the migration and proliferation of Smad3 knockdown squamous carcinoma cells was suppressed by Dec1 overexpression but was promoted by Dec2 overexpression. Dec1 over expression decreased E-cadherin and proliferating cell nuclear antigen expression, whereas these expression levels were increased by Dec2 overexpression. These results suggest Smad3 is relevant to circadian rhythm and regulates cell migration and proliferation through Decl, Dec2, and Per1 expression.