Serum- and Glucocorticoid-induced Kinase Sgk1 Directly Promotes the Differentiation of Colorectal Cancer Cells and Restrains Metastasis.
Serum- and Glucocorticoid-induced Kinase Sgk1 Directly Promotes the Differentiation of Colorectal Cancer Cells and Restrains Metastasis.
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DOI：
10.1158/1078-0432.ccr-18-1033
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发表时间：
2019-01-15
期刊：
影响因子：
--
通讯作者：
Tomlinson I
中科院分区：
文献类型：
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作者：
Lee LYW;Woolley C;Starkey T;Biswas S;Mirshahi T;Bardella C;Segditsas S;Irshad S;Tomlinson I
决定肠细胞分化的分子事件知之甚少，也不清楚它主要是被动事件还是主动过程。在临床上，更好地了解这一过程非常重要，因为在结直肠癌（CRC）中，肿瘤的分化程度与患者的生存率相关。SGK1先前已被鉴定为主要在分化的肠细胞中表达的基因。在结直肠癌（CRC）中，与正常组织相比，SGK1显著下调。利用诱导型SGK1病毒过表达系统诱导CRC细胞系中SGK1的再表达。对这些CRC细胞系进行转录组学和表型分析，并在小鼠和人类队列中进行验证。我们证明，SGK1是上调响应，并在肠细胞分化的重要控制器。SGK1在CRC细胞系中的再表达导致原位异种移植模型中分化、迁移率降低和转移抑制的特征。这些作用可能部分由SGK1诱导的PKP3表达和MYC降解增加介导。我们的研究结果表明，SGK1是一个重要的介质分化的大肠癌细胞，并可能抑制大肠癌转移。
The molecular events that determine intestinal cell differentiation are poorly understood and it is unclear whether it is primarily a passive event or an active process. It is clinically important to gain a greater understanding of the process, since in colorectal cancer (CRC), the degree of differentiation of a tumour is associated with patient survival. SGK1 has previously been identified as a gene that is principally expressed in differentiated intestinal cells. In colorectal cancer (CRC), there is marked downregulation of SGK1 compared to normal tissue. An inducible SGK1 viral overexpression system was utilised to induce re-expression of SGK1 in CRC cell lines. Transcriptomic and phenotypic analyses of these CRC lines was performed and validation in mouse and human cohorts was performed. We demonstrate that SGK1 is upregulated in response to, and an important controller of, intestinal cell differentiation. Re-expression of SGK1 in CRC cell lines results in features of differentiation, decreased migration rates, and inhibition of metastasis in an orthotopic xenograft model. These effects may be mediated in part by SGK1-induced PKP3 expression and increased degradation of MYC. Our results suggest that SGK1 is an important mediator of differentiation of colorectal cells and may inhibit CRC metastasis.