@article {Jia856, author = {Yongning Jia and Ziyu Li and Xiaojing Cheng and Xiaojiang Wu and Fei Pang and Jinyao Shi and Shen Li and Xiaolong Li and Ying Hu and Lianhai Zhang and Jiafu Ji}, title = {Depletion of death-associated protein-3 induces chemoresistance in gastric cancer cells through the β-catenin/LGR5/Bcl-2 axis}, volume = {67}, number = {5}, pages = {856--861}, year = {2019}, doi = {10.1136/jim-2018-000934}, publisher = {BMJ Publishing Group Limited}, abstract = {Previously, we demonstrated that death-associated protein-3 (DAP3) loss drives chemoresistance in gastric cancer cells. In the present study, we aimed to determine the underlying molecular mechanism. The effect of DAP3 silencing on β-catenin signaling was assessed. The direct mediator of DAP3 silencing-induced chemoresistance was identified. Depletion of DAP3 stimulates nuclear accumulation of β-catenin and enhances β-catenin-dependent transcriptional activity in gastric cancer cells. However, the protein kinase B , , extracellular regulated protein kinase and signal transducer and activator of transcription 3 signaling pathways remain unaffected by DAP3 loss. We found that the downstream target gene LGR5 (leucine-rich G-protein coupled receptor 5) is upregulated in DAP3-depleted gastric cancer cells. Moreover, knockdown of LGR5 resensitizes DAP3-depleted gastric cancer cells to 5-fluorouracil (5-FU) and oxaliplatin. We also observed that ectopic expression of LGR5 reduces apoptosis in gastric cancer cells on treatment with 5-FU and oxaliplatin, which is accompanied by prevention of caspase-3 cleavage. The antiapoptotic protein Bcl-2 is identified as a key mediator of LGR5-induced apoptosis resistance in gastric cancer cells. The present findings indicate that DAP3 deficiency-induced chemoresistance in gastric cancer is at least partially mediated through the β-catenin/LGR5/Bcl-2 axis. Targeting LGR5 may provide a novel strategy to overcome chemoresistance in DAP3-deficient gastric cancer cells.}, issn = {1081-5589}, URL = {http://hw-f5-jim.highwire.org/content/67/5/856}, eprint = {http://hw-f5-jim.highwire.org/content/67/5/856.full.pdf}, journal = {Journal of Investigative Medicine} }