Gastric cancer derived mesenchymal stem cells promoted DNA repair and cisplatin resistance through up-regulating PD-L1/Rad51 in gastric cancer
Gastric cancer derived mesenchymal stem cells promoted DNA repair and cisplatin resistance through up-regulating PD-L1/Rad51 in gastric cancer
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胃癌来源的间充质干细胞通过上调胃癌中程序性死亡配体1（PD-L1）/辐射敏感51蛋白（Rad51）促进DNA修复及顺铂耐药 。
DOI：
10.1016/j.cellsig.2023.110639
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发表时间：
2023-03-01
影响因子：
4.8
通讯作者：
Zhu，Wei
中科院分区：
文献类型：
--
作者：
Wang，Qianqian;Huang，Chao;Zhu，Wei
进展期胃癌患者的化疗耐药在很大程度上限制了治疗的有效性，导致疾病复发和预后不良。胃癌间充质干细胞(GCMSC)通过上调程序性死亡配体1(PD-L1)的表达，促进胃癌的侵袭、转移和免疫逃逸。然而，GCMSC介导的PD-L1调控胃癌化疗耐药的机制尚不清楚。在顺铂(DDP)作用下，GCMSC条件培养液(GCMSC-CM)处理的GC细胞具有较高的半数抑制浓度(IC50)和较低的凋亡率，多药耐药基因(MDR1)和RAD51等DNA修复相关基因的表达也较高。PD-L1的下调逆转了GCMSC-CM介导的RAD51的增加，导致GC细胞对DDP的敏感性增加。此外，抑制热休克蛋白90(HSP90)调节PD-L1和RAD51的表达，揭示了HSP90在GCMSC-CM介导的顺铂耐药中的重要作用。与体外观察、患者样本和异种移植模型的分析进一步证实，PD-L1或HSP90的减少削弱了GCMSC-CM介导的顺铂耐受，同时也降低了RAD51和MDR1。结论：GCMSC-CM通过调节PD-L1-RAD51增强了GC细胞对DDP的耐药性。首次报道了GCMSC诱导胃癌细胞对顺铂耐药的这一特殊机制，为顺铂耐药的GC细胞提供了潜在的治疗靶点。
Chemotherapy resistance in advanced gastric cancer (GC) patients has largely limited the effectiveness of therapy, resulting in disease recurrence and poor prognosis. Gastric cancer derived mesenchymal stem cells (GCMSC) are widely believed to promote GC invasion, metastasis and immune escape via up-regulating programmed death ligand 1 (PD-L1). However, the mechanism by which PD-L1 mediated by GCMSC might regulate the chemoresistance is unknown in GC. Herein, higher half maximal inhibitory concentrations (IC50) and less apoptotic rate were observed in GCMSC conditioned medium (GCMSC-CM) treated GC cells exposed to cisplatin (DDP), along with high expression of multi-drug resistance 1 (MDR1) and DNA repair related genes such as Rad51. The knockdown of PD-L1 reversed the increase of Rad51 mediated by GCMSC-CM, resulting in the increased sensitivity of GC cells to DDP. In addition, inhibition of heat shock protein 90 (HSP90) regulated the expression of PD-L1 and Rad51, revealing the important role of HSP90 in GCMSC-CM mediated DDP resistance. Consistent with the observations in vitro, analysis of patient samples and xenograft models further confirmed that reduction of PD-L1 or HSP90 weakened DDP tolerance mediated by GCMSC-CM, along with decrease of Rad51 and MDR1.In conclusion, we demonstrated that GCMSC-CM enhanced DDP resistance in GC cells through regulating PD-L1-Rad51. It is the first to report this particular mechanism of DDP resistance induced by GCMSC in GC, suggesting a potential therapeutic targets for DDP resistant GC cells.