不同亚型的弥漫大B细胞淋巴瘤对含有阿霉素(Dox)的R-CHOP治疗反应不一致，其中涉及的机制尚不明确。我们发现Dox在GCB-DLBCL中通过DNA损伤应答抗肿瘤，而在ABC-DLBCL中则通过活性氧(ROS)的累积诱导氧化应激杀伤肿瘤细胞，且参与调控细胞内ROS水平的氨基酸转运子xCT主要表达在 ABC-DLBCL。提示我们xCT可能参与介导ABC-DLBCL对Dox的耐药。因此，本研究拟在证实xCT在不同亚型DLBCL表达谱的基础上，分别在体内外通过xCT抑制剂SASP和xCT siRNA/shRNA抑制xCT的功能和表达，评价xCT对ABC-DLBCL细胞GSH合成、ROS水平和Dox耐药的影响及相关氧化应激信号通路，从而获得xCT在ABC-DLBCL中参与调节Dox耐药的依据及机制，明确DLBCL不同亚型对化疗反应不一致的原因，以期提高ABC-DLBCL对R-CHOP治疗的敏感性

DLBCL can be sub-divided into at least 2 distinct subtypes: germinal center B cell like (GCB)and activated B-cell like (ABC)with differentsurvival outcome. Our previsous data showed that Dox-induced cytotoxicity in GCB-DLBCLs is dependent on DNA damage response; however, in ABC-DLBCLs Dox mainly triggers oxidative cell death rather than DNA damage response. xCT is the light-chain subunit of System xc(-). It mediates the exchange of intracellular glutamate for extracellular cystine, the availability of which is rate limiting for GSH synthesis, with the activity of xCT therefore being essential for the GSH-dependent antioxidant system. However the role of xCT in DLBCL therapeutic response has not been explored. In particular, it is unknown whether xCT can privide Dox resistance in ABC-DLBCLs by upregulating antioxidant capacity..In summary, in this project we will evaluate xCT expression in different DLBCL cell lines and determine whether, and if so how, xCT inhibition affects the response of ABC-DLBCLs to Dox-containging therapy.