Inhibition of CCCTC Binding Factor-Programmed Cell Death Ligand 1 Axis Suppresses Emergence of Chemoresistance Induced by Gastric Cancer-Derived Mesenchymal Stem Cells

Abstract

BackgroundGastric cancer (GC) is the third leading cause of cancer-associated deaths worldwide. Stromal cells, especially mesenchymal stem cells (MSCs), play significant roles in the development of therapy resistance depending on their paracrine function. The PD-1/PD-L1 crosstalk between cancer and immune cells has been well studied. Emerging evidence suggests that PD-L1 also contributes to tumor resistance to therapy.MethodsCell survival and apoptosis were assessed using CCK-8, colony formation, and flow cytometry assays. Protein alterations were analyzed via Western blot. Gene knockdown and overexpression were achieved with siRNA/shRNA and lentiviral infection, respectively. Drug effects on tumors in vivo were assessed with xenografts in nude mice. In addition, GC patient samples after chemotherapy treatment were collected to observe the relationship between chemotherapy effect and CTCF or PD-L1.ResultsIn response to 5-fluorouracil or paclitaxel treatment, GCMSC-CM enhanced the cell viability and decreased the apoptosis rate. Furthermore, blocking PD-L1 or CTCF in GC cells prevented GCMSC-induced drug resistance accompanied by a decline in cell stemness. Consistent with these in vitro observations, mice treated with GCMSC-CM showed a lower sensitivity to 5-fluorouracil. In addition, high expression of CTCF and PD-L1 was associated with poor chemotherapy progression in the clinic.ConclusionStudy results demonstrate a mechanism where GCMSC-CM promotes GC chemoresistance by upregulating CTCF-PD-L1 and provide strong evidence in support of targeting CTCF-PD-L1 signaling as a strategy to prevent resistance in the clinic.

Targeting the KLF5-EphA2 axis can restrain cancer stemness and overcome chemoresistance in basal-like breast cancer

“…In this study, we found that the knockdown of KLF5 or EphA2 could improve the drug sensitivity of BLBC cells to the chemotherapeutic agents PTX and DDP ( Figure S4 ), suggesting that this may be related to KLF5- and EphA2-mediated BLBC stemness. Numerous studies have confirmed the close correlation between tumor cell stemness and chemoresistance in glioma, colorectal cancer, breast cancer, leukemia, and oral cancer 53 - 56 . In addition, studies have shown that knockdown of KLF5 could reduce cellular resistance to adriamycin in mesenchymal thyroid cancer, while high expression of KLF5 in colorectal cancer predicted poorer neoadjuvant chemotherapy outcomes 26 .…”

Gastric cancer mesenchymal stem cells promote tumor glycolysis and chemoresistance by regulating B7H3 in gastric cancer cells

“…For example, Honglei Wu et al suggested that MSC‐induced lncRNA HCP5 drove fatty acid oxidation through miR‐3619‐5p/AMPK/PGC1α/CEBPB axis, promoting GC stemness and drug resistance 34 . Our previous study demonstrated that GCMSC‐CM promoted chemotherapy resistance in GC by upregulating CTCF‐PD‐L1 35 . Additionally, Jiewei Xu et al reported that the SNHG1‐miR‐216b‐5p‐HK2 axis plays an important role in the resistance of GC cells to PTX 36 .…”

“…34 Our previous study demonstrated that GCMSC-CM promoted chemotherapy resistance in GC by upregulating CTCF-PD-L1. 35 Additionally, Jiewei Xu et al reported that the SNHG1-miR-216b-5p-HK2 axis plays an important role in the resistance of GC cells to PTX. 36 Hence, we suspected that HK2, a key glycolytic enzyme upregulated by GCMSCs-CM, was able to regulate cellular chemotherapy efficacy.…”