Abstract
Chemotherapy is the first-tier treatment regime for gastric cancer (GC) patients at advance stages. Mesenchymal stem cell (MSC) cam affect drug-resistance of GC cells in tumor microenvironment, but the detailed mechanism remains poorly understood. Present study aimed to investigate the regulation of MSC-induced long non-coding RNA (lncRNA) in GC. Dysregulated lncRNAs in GC were analyzed based on GEO data. Stemness and drug-resistance of GC cells were detected by sphere formation, colony formation, CCK-8, and flow cytometry analyses. MicroRNA (miRNA)-related pathways were analyzed by online KEGG analysis tool DAVID6.8. Molecular interactions were determined by luciferase reporter assay, pulldown, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and co-immunoprecipitation (CoIP). Results revealed that MSC co-culture improved stemness and drug-resistance of GC cells. LncRNA histocompatibility leukocyte antigen complex P5 (HCP5) was induced in GC cells by MSC co-culture, contributing to stemness and drug-resistance. Mechanistically, HCP5 sequestered miR-3619-5p and upregulated PPARG coactivator 1 alpha (PPARGC1A), increasing transcription complex Peroxisome proliferator activated receptor (PPAR) coactivator‐1α (PGC1α)/CEBPB and transcriptionally inducing carnitine palmitoyltransferase 1 (CPT1), which prompted the fatty acid oxidation (FAO) in GC cells. In conclusion, MSC-induced lncRNA HCP5 drove FAO through miR-3619-5p/AMPK/PGC1α/CEBPB axis to promote stemness and chemo-resistance of GC, indicating that targeting HCP5 was a novel approach to enhancing the efficacy of chemotherapy in GC.
Highlights
Gastric cancer (GC) has long been the uppermost cause of tumor-associated mortality[1,2]
Flow cytometry analysis showed that rate of CD133+ and CD44+ GC cells increased under the co-culture with Mesenchymal stem cell (MSC) (Fig. 1c)
Apoptosis of GC cells was suppressed by MSCs co-culture, and the inductive effect of oxaliplatin and 5-Fu on GC cell apoptosis was abrogated by MSCs co-culture (Fig. 1e)
Summary
Gastric cancer (GC) has long been the uppermost cause of tumor-associated mortality[1,2]. Resistance to drugs largely limits the efficacy of chemotherapy in GC5. A better grasp of Studies have attached great importance of tumor microenvironment to cancer cell resistance to drugs[6,7]. Tumor microenvironment consists of diverse types of nonmalignant cells, such as mesenchymal stromal cells (MSCs)[8]. Through secreting a series of cytokines, MSCs pose impacts on proliferation, metastasis, as well as angiogenesis of cancer cells[9,10]. MSCs are demonstrated as contributors of tissue regeneration responding to therapy[11,12].
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