目的：初步探讨舒尼替尼诱导高、低表达ABCG2(ATPbinding cassette superfamily G member 2)分子的耐药鼻咽癌CNE2/DDP细胞（简称ABCG2highCNE2/DDP细胞、ABCG2lowCNE2/DDP细胞）中NKG2D配体（natural killer group 2 member D ligands，NKG2DLs）表达的分子机制。方法：Caspase8活化试剂盒和线粒体膜电位法分别检测NK细胞处理后ABCG2highCNE2/DDP细胞和ABCG2lowCNE2/DDP细胞caspase8活化水平和线粒体膜电位。RTPCR检测舒尼替尼处理前后两种CNE2/DDP细胞DNA损伤修复系统相关信号分子mRNA的表达。结果：CNE2/DDP细胞+NK细胞组中两种CNE2/DDP细胞caspase8活性均明显增强；舒尼替尼处理后的ABCG2low CNE2/DDP细胞+NK细胞组和ABCG2highCNE2/DDP细胞＋NK细胞组中caspase8的活性是处理前的2～2.5倍（P<0.01）。舒尼替尼预处理后，CNE2/DDP细胞和NK细胞共培养体系中两种CNE2/DDP细胞的线粒体膜电位分别为(76.58±2.32)%和(73.11±1.93)%，较舒尼替尼处理前明显降低（P<0.05）。舒尼替尼可上调两种CNE2/DDP细胞中ATR、CHK1和CHK2 mRNA的表达，并诱导P53和NFκB mRNA的表达。结论：舒尼替尼可能通过激活DNA损伤修复系统相关信号分子和NFκB的表达，诱导耐药鼻咽癌CNE2/DDP细胞NKG2DLs的表达，同时经由死亡受体信号通路和线粒体信号通路增强NK细胞诱导的肿瘤细胞凋亡。

Objective: To investigate the mec hanism by which unitinib induces upregulation of NKG2D ligands(NKG2DLs) expressions in nasopharyngeal carcinoma CNE2/DDP cells with high or low ABCG2 expression (ABCG2highCNE2/DDP cells or ABCG2lowCNE2/DDP cells). Methods: Caspase8 activity and mitochondrial membrane potential were detected by caspase8 activity kit and mitochondrial membrane potential assay kit in ABCG2highCNE2/DDP cells or ABCG2low CNE2/DDP cells after cocultured with NK cells. Expressions of signal molecules involved in DNA damage and repair system were detected by RTPCR in ABCG2highCNE2/DDP cells and ABCG2lowCNE2/DDP cells before and after sunitinib treatment. Results: Caspase8 activities in ABCG2highCNE2/DDP cells and ABCG2lowCNE2/DDP cells were ignificantly increased after cocultured with in NK cells. After treatment with sunitinib, caspase8 activities in the co culture system were 1-1.5 times higher than those in the untreated ABCG2high and ABCG2lowCNE2/DDP cells (P<0.01). Sunitinib inhibited mitochondrial membrane potentials of ABCG2high and ABCG2lowCNE2/DDP cells in NK cell coculture systems, with the potentials in two kinds of sunitinibtreated CNE2/DDP cells decreased to (76.58±2.32)% and (73.11±1.93)%, respectively, which were markedly lower than those in the untreated ABCG2high and ABCG2low CNE2/DDP cells (P<0.05). Sunitinib could increase mRNA expressions of ATR, CHK1 and CHK2 in ABCG2high and ABCG2 lowCNE2/DDP cells, and induce P53 and NFκB mRNA expressions. Conclusion: Sunitinib can upregulate NKG2DLs expressions in CNE2/DDP cells by activating signaling molecules related to DNA damage and repair system and NFκB, and enhance NK cellinduced apoptosis of tumor cells through death receptor and mitochondrial pathways.

国家自然科学基金资助项目（No. 30973454）；广东省自然科学基金重点项目（No. 9251051501000007）