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  2. 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

  • Cell Signal. 2023 Feb 24;110639. doi: 10.1016/j.cellsig.2023.110639.
Qianqian Wang 1 Chao Huang 1 Deqiang Wang 2 Zhixin Tao 1 Hao Zhang 1 Yuanyuan Zhao 1 Mei Wang 1 Chenglin Zhou 3 Juan Xu 3 Bo Shen 4 Wei Zhu 5
Affiliations

Affiliations

  • 1 School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
  • 2 Department of Oncology, Affiliated Hospital of Jiangsu University, Institute of Digestive Diseases, Jiangsu University, Zhenjiang, Jiangsu, China.
  • 3 Department of Laboratory Medicine, Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, Jiangsu, China.
  • 4 Department of Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, China. Electronic address: shenbo987@njmu.edu.cn.
  • 5 School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China. Electronic address: zhuwei@ujs.edu.cn.
Abstract

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.

Keywords

Cisplatin resistance; Gastric cancer; HSP90; Mesenchymal stem cells; PD-L1; Rad51.

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