缺乏 PPAR/-失活的 SGK-1 与肝癌发生有关。
Lack of PPAR/-Inactivated SGK-1 Is Implicated in Liver Carcinogenesis.
机构信息
Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Shanghai Sixth Hospital, Shanghai, China.
Department of Gastroenterology and Hepatology, Guangzhou First Municipal People's Hospital, Guangzhou Medical University, Guangzhou, China.
出版信息
Biomed Res Int. 2020 Oct 2;2020:9563851. doi: 10.1155/2020/9563851. eCollection 2020.
OBJECTIVE
The present study examined the role of PPAR/ in hepatocellular carcinoma (HCC).
METHODS
The effect of PPAR/ on HCC development was analyzed using PPAR/-overexpressed liver cancer cells and PPAR/-knockout mouse models.
RESULTS
PPAR/ mice were susceptible to diethylnitrosamine- (DEN-) induced HCC (87.5% vs. 37.5%, < 0.05). In addition, PPAR/-overexpressed HepG2 cells had reduced proliferation, migration, and invasion capabilities accompanied by increased apoptosis and cell cycle arrest at the G0/G1 phase. Moreover, differential gene expression profiling uncovered that the levels of serine/threonine-protein kinase (SGK-1) mRNA and its encoded protein were reduced in PPAR/-overexpressed HepG2 cells. Consistently, elevated SGK-1 levels were found in PPAR/ mouse livers as well as PPAR/-knockdown human SMMC-7721 HCC cells. Chromatin immunoprecipitation (ChIP) assays followed by real-time quantitative polymerase chain reaction (qPCR) assays further revealed the binding of PPAR/ to the SGK-1 regulatory region in HepG2 cells.
CONCLUSIONS
Due to the known tumor-promoting effect of SGK1, the present data suggest that PPAR/-deactivated SGK1 is a novel pathway for inhibiting liver carcinogenesis.
目的
本研究探讨了过氧化物酶体增殖物激活受体 γ（PPARγ）在肝细胞癌（HCC）中的作用。
方法
采用过表达 PPARγ 的肝癌细胞和 PPARγ 基因敲除小鼠模型分析 PPARγ 对 HCC 发展的影响。
结果
PPARγ 基因敲除小鼠对二乙基亚硝胺（DEN）诱导的 HCC 更易感（87.5%比 37.5%，P<0.05）。此外，过表达 PPARγ 的 HepG2 细胞增殖、迁移和侵袭能力降低，同时凋亡增加，细胞周期停滞在 G0/G1 期。此外，差异基因表达谱分析发现，过表达 PPARγ 的 HepG2 细胞中丝氨酸/苏氨酸蛋白激酶（SGK-1）mRNA 及其编码蛋白的水平降低。同样，在 PPARγ 基因敲除小鼠的肝脏以及 PPARγ 基因敲低的人 SMMC-7721 HCC 细胞中，SGK-1 水平升高。染色质免疫沉淀（ChIP）分析联合实时定量聚合酶链反应（qPCR）进一步证实了 PPARγ 在 HepG2 细胞中与 SGK-1 调控区的结合。
结论
鉴于 SGK1 的已知促肿瘤作用，本研究数据表明，PPARγ 失活的 SGK1 是抑制肝发生癌变的新途径。
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