Cancer stem cells in Epstein‐Barr virus‐associated gastric carcinoma
Cancer stem cells in Epstein‐Barr virus‐associated gastric carcinoma
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DOI：
10.1111/cas.14435
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发表时间：
2020-04
期刊：
影响因子：
5.7
通讯作者：
Mariko Yasui;A. Kunita;S. Numakura;H. Uozaki;T. Ushiku;M. Fukayama
中科院分区：
文献类型：
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作者：
Mariko Yasui;A. Kunita;S. Numakura;H. Uozaki;T. Ushiku;M. Fukayama
肿瘤干细胞（cancer stem cells，CSCs）在肿瘤的发生、发展过程中起着决定性的作用。为了研究Epstein巴尔病毒（EBV）相关癌（EBVaGC）中的CSC，我们在EBV感染的胃癌细胞系（TMK 1和NUGC 3）中筛选了先前报道的胃癌干细胞标志物，并将CD 44 v6 v9双阳性细胞鉴定为候选CSC。从EBVaGC细胞系（SNU 719）细胞和EBV感染的TMK 1细胞中分选出CD 44 v6/v9+/+细胞，与相应的CD 44 v6/v9−/−细胞相比，这些细胞群在SCID小鼠中显示出高球体形成能力和肿瘤形成。球体形成能力依赖于核因子-κB（NF-κB）信号通路，这通过BAY 11 - 7082下球体形成能力的降低得到证实。小干扰RNA敲低潜伏膜蛋白2A（LMP 2A），EB病毒感染的潜伏基因产物之一，减少SNU 719细胞中球状体的形成。转染LMP 2A基因可增加TMK 1细胞的成球能力，这是通过NF-κB信号传导介导的。总之，这些结果表明，CD 44 v6 v9 +/+细胞是EBVaGC中通过LMP 2A/NF-κB途径维持的CSC。未来的研究应调查CD 44 v6/v9+/+细胞在正常和肿瘤性胃上皮细胞，以预防和治疗这种特定亚型的胃癌感染EBV。
Cancer stem cells (CSCs) play a decisive role in the development and progression of cancer. To investigate CSCs in Epstein‐Barr virus (EBV)‐associated carcinoma (EBVaGC), we screened previously reported stem cell markers of gastric cancer in EBV‐infected gastric cancer cell lines (TMK1 and NUGC3) and identified CD44v6v9 double positive cells as candidate CSCs. CD44v6/v9+/+ cells were sorted from EBVaGC cell line (SNU719) cells and EBV‐infected TMK1 cells and these cell populations showed high spheroid‐forming ability and tumor formation in SCID mice compared with the respective CD44v6/v9−/− cells. Sphere‐forming ability was dependent on the nuclear factor‐κB (NF‐κB) signaling pathway, which was confirmed by decrease of sphere formation ability under BAY 11‐7082. Small interfering RNA knockdown of latent membrane protein 2A (LMP2A), one of the latent gene products of EBV infection, decreased spheroid formation in SNU719 cells. Transfection of the LMP2A gene increased the sphere‐forming ability of TMK1 cells, which was mediated through NF‐κB signaling. Together, these results indicate that CD44v6v9+/+ cells are CSCs in EBVaGC that are maintained through the LMP2A/NF‐κB pathway. Future studies should investigate CD44v6/v9+/+ cells in normal and neoplastic gastric epithelium to prevent and treat this specific subtype of gastric cancer infected with EBV.