目的：探讨不同分子靶向药物对高表达与低表达ATP结合转运蛋白G超家族成员2（ATPbinding cassette superfamily G member 2，ABCG2）的人耐药鼻咽癌CNE2/DDP细胞（分别简写为ABCG2highCNE2/DDP和ABCG2lowCNE2/DDP）表面NKG2D配体（natural killer group 2 member D ligands, NKG2DLs）表达的诱导作用及其对NK细胞杀伤敏感性的影响。方法：免疫磁珠法分选ABCG2 highCNE2/DDP、ABCG2lowCNE2/DDP细胞及NK细胞。流式细胞术检测分选细胞的纯度和不同分子靶向药物（硼替佐米、索拉非尼、舒尼替尼）处理前后ABCG2highCNE2/DDP和ABCG2lowCNE2/DDP细胞NKG2DLs的表达率。LDH释放法检测不同药物处理前后ABCG2highCNE2/DDP和ABCG2lowCNE2/DDP细胞对NK细胞杀伤的敏感性。结果：ABCG2 highCNE2/DDP和ABCG2lowCNE2/DDP细胞表面ABCG2的表达率分别为（91.40±2.32）%和（1.70±0.24）%。分选后NK细胞中CD3-CD16+CD56+细胞的比例达90%以上。药物处理前，ABCG2highCNE2/DDP和ABCG2lowCNE2/DDP细胞MICA、MICB、ULBP1、ULBP2和ULBP3呈弱表达；经不同分子靶向药物处理后，5种NKG2DLs的表达率均明显上升(P<001)，以舒尼替尼处理后NKG2DLs的表达率升高最明显。随着NKG2DLs表达的上调，ABCG2highCNE2/DDP和ABCG2lowCNE2/DDP细胞对NK细胞杀伤的敏感性也随之升高。结论：不同分子靶向药物可诱导耐药鼻咽癌CNE2/DDP细胞NKG2DLs的表达，以舒尼替尼的诱导作用最强，且肿瘤细胞NKG2DLs的表达与其对NK细胞杀伤敏感性之间存在线性关系。

Objective:To investigate molecular targeted agentinduced expressions of natural killer group 2 member D ligands (NKG2D ligands, NKG2DLs) in multidrug resistant nasopharyngeal carcinoma cell line CNE2/DDP with high or low ATPbinding cassette superfamily G member 2 expression (ABCG2 highCNE2/DDP cells or ABCG2lowCNE2/DDP cells) and its effects on their cytotoxic sensitivities to NK cells. Methods: ABCG2highCNE2/DDP cells, ABCG2lowCNE2/DDP cells and NK cells were isolated by magnetic activated cell sorting. Purity of the isolated cells and expression rates of NKG2DLs on ABCG2highCNE2/DDP and ABCG2lowCNE2/DDP cells before and after treatment with different molecular targeted agents (bortezomib, sorafenib, sunitinib) were examined by flow cytometry (FCM). Cytotoxic sensitivities of ABCG2highCNE2/DDP and ABCG2 lowCNE2/DDP cells were measured by LDH releasing assay. Results: Expression rates of ABCG2 on ABCG2 highCNE2/DDP and ABCG2lowCNE2/DDP cells were (91.40±2.32)% and (1.70±024)%, respectively. More than 90% of the isolated NK cells were CD3-CD16+CD56+ cells. Expressions of 5 types of NKG2DLs (MICA, MICB, ULBP1, ULBP2 and ULBP3) on untreated ABCG2highCNE2/DDP and ABCG2lowCNE2/DDP cells were relatively low, but their expressions were significantly upregulated after treatment with different molecular targeted agents (bortezomib, sorafenib, sunitinib), with the highest NKG2DLs expressions found in the sunitinibtreated group cells. In addition, cytotoxic sensitivities of ABCG2highCNE2/DDP and ABCG2lowCNE2/DDP cells to NK cells were increased with the upregulated expressions of NKG2DLs. Conclusion: Different molecular targeted agents can upregulate NKG2DLs expressions in human multidrug resistant nasopharyngeal carcinoma cells, with sunitinib showing the highest induction ability. A linear correlation exists between NKG2DLs expressions and tumor cell cytotoxic sensitivities to NK cells.

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）