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CAF promotes chemoresistance through NRP2 in gastric cancer.

Authors
  • Yang, Yanpeng1
  • Ma, Yongchen2
  • Yan, Shen3
  • Wang, Pengyuan1
  • Hu, Jianwen1
  • Chen, Shanwen1
  • Zhu, Jing1
  • Wang, Jingui1
  • Chen, Guowei1
  • Liu, Yucun4
  • 1 Department of Gastroenterology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, China. , (China)
  • 2 Department of Endoscopic Center, Peking University First Hospital, Beijing, China. , (China)
  • 3 Department of Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, China. , (China)
  • 4 Department of Gastroenterology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, China. [email protected] , (China)
Type
Published Article
Journal
Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association
Publication Date
May 01, 2022
Volume
25
Issue
3
Pages
503–514
Identifiers
DOI: 10.1007/s10120-021-01270-w
PMID: 34826008
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Fibroblasts are the predominant cell type in the stroma of tumor, and cancer-associated fibroblasts (CAFs) promote cancer chemoresistance by secreting various bioactive molecules. However, the differential expression between CAFs and normal fibroblasts (NFs) and how can CAFs uniquely impact cancer cells are still unexplored. Primary CAFs and NFs were cultured from gastric cancer specimens, and their variant expression was analyzed by RNA-sequencing. Chemoresistance was evaluated by measuring cell viability, apoptosis, and 3D-coculture techniques. CAFs were isolated from gastric cancers and defined by specific cell-surface markers. CAFs decreased the sensitivity of gastric cancer cells to 5-FU. RNA-sequencing showed that CAFs expressed a higher level of NRP2 than NFs. And the high expression of NRP2 was correlated with worse oncological outcomes in gastric cancer patients. Further study showed that the knockdown of NRP2 eradicated the resistance to 5-FU. And the secretion of stromal cell-derived factor-1 (SDF-1) was reduced following NRP2 knockdown. Furthermore, we found that the increased sensitivity to 5-FU was induced by DNA damage. And this process was mediated by predominant effectors of the Hippo pathway, YAP/TAZ. The present study indicated that CAFs within gastric cancers promote chemoresistance through the expression of NRP2. The secretion of SDF-1 that mediated by VEGF/NRP2 signaling in CAFs and the activation of Hippo pathway in cancer cells in large part participated in this project. © 2021. The Author(s).

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