Department of digestive medicine, Linyi Central Hospital, Linyi, Shandong, China.
Department of Laboratory, Linyi Central Hospital, Linyi, Shandong, China.
J Pharm Pharmacol. 2020 Jun;72(6):807-815. doi: 10.1111/jphp.13243. Epub 2020 Mar 19.
Cancer stem cells (CSCs) have been identified to correlate with the initiation and metastasis of tumours, and DNA damage-inducible transcript 3 (DDIT3) is associated with the poor prognosis in gastric cancer (GC). However, whether DDIT3 mediates CSCs stemness in GC is still unclear.
Microarray analysis and Gene Ontology (GO) were conducted to identify the differentially expressed genes in GC tissues from GC patients. The interaction between DDIT3 and CEBPβ was determined using immunoprecipitation (IP) analysis.
Herein, microarray analysis showed that DDIT3 expression is increased in GC tissues. qRT-PCR confirmed that DDIT3 is significantly increased in GC tissues and cancer cell lines compared with healthy tissues and normal cell lines, individually. Genetic overexpression of DDIT3 enhanced GC cell proliferation, colony-forming ability, sphere formation and CSCs stemness. Mechanistically, DDIT3 directly up-regulated the expression of transcription factor CEBPβ, leading to the increased expression of CSCs markers SOX2, NANOG, OCT4 and CD133 in gastric CSCs. Genetic downregulation of CEBPβ significantly abolishes DDIT3-mediated increased cell proliferation, colony-forming ability, sphere formation and CSCs stemness.
Our results demonstrated that DDIT3 promotes CSCs stemness by up-regulating CEBPβ in GC that provides novel targets for the further GC therapy.
癌症干细胞（CSCs）已被鉴定与肿瘤的发生和转移相关，而 DNA 损伤诱导转录物 3（DDIT3）与胃癌（GC）的预后不良相关。然而，DDIT3 是否介导 GC 中的 CSCs 干性仍不清楚。
通过基因芯片分析和基因本体论（GO）分析，鉴定 GC 患者 GC 组织中差异表达的基因。通过免疫沉淀（IP）分析确定 DDIT3 与 CEBPβ 之间的相互作用。
在此，基因芯片分析显示 DDIT3 在 GC 组织中表达增加。qRT-PCR 证实，与健康组织和正常细胞系相比，DDIT3 在 GC 组织和癌细胞系中显著增加。DDIT3 的遗传过表达增强了 GC 细胞的增殖、集落形成能力、球体形成和 CSCs 干性。机制上，DDIT3 直接上调转录因子 CEBPβ 的表达，导致胃 CSCs 中 CSCs 标志物 SOX2、NANOG、OCT4 和 CD133 的表达增加。CEBPβ 的遗传下调显著消除了 DDIT3 介导的细胞增殖、集落形成能力、球体形成和 CSCs 干性的增加。
我们的研究结果表明，DDIT3 通过上调 GC 中的 CEBPβ 促进 CSCs 干性，为进一步的 GC 治疗提供了新的靶点。
