Concern about health risks associated with rising obesity has become nearly universal, with the mean body mass index (BMI) and the prevalence of obese and overw

Chemotherapy is an important treatment modality for gastric cancer (GC); however, it usually fails because of drug resistance, especially multidrug resistance (MDR). Previously, we found a novel subset of MDR-associated microRNAs (miRNAs) through high-throughput functional screening. In this report, we investigated the exact roles and mechanisms of miR-23b-3p in the MDR of GC. Using gain or loss-of-function in in vitro and in vivo experiments, we found that overexpression of miR-23b-3p reversed cancer cell resistance to multiple chemotherapeutics in vitro and sensitize tumors to chemotherapy in vivo. Reporter gene assay and western blot analysis showed that ATG12 and HMGB2 were the direct targets of miR-23b-3p. Meanwhile, ATG12 and HMGB2 were positively associated with the occurrence of autophagy. Reducing the expression of these target genes by siRNA or inhibition of autophagy both sensitized GC cells to chemotherapy. These findings suggest that a miR-23b-3p/ATG12/HMGB2/autophagy-regulatory loop has a critical role in MDR in GC. In addition, miR-23b-3p could be used as a prognostic factor for overall survival in GC. In conclusion, our data demonstrated that miR-23b-3p inhibited autophagy mediated by ATG12 and HMGB2 and sensitized GC cells to chemotherapy, and suggested the potential application of miR-23b-3p in drug resistance prediction and treatment.

Multidrug resistance remains a major obstacle to successful treatment for patients with gastric cancer (GC). Recently, glycosylation has been demonstrated to play a vital role in the acquisition of multidrug resistance. As a potent inhibitor of glycosylation, tunicamycin (Tu) has shown marked antitumor activities in various cancers. In the present study, we attempted to determine the exact effect of Tu on the chemoresistance of GC. The cytotoxic effects of drugs on GC cells were evaluated by cell viability assays, and apoptosis was detected by flow cytometry. PCR, western blot analysis, immunofluorescence staining and canonical inhibitors were employed to identify the underlying mechanisms of the specific effects of Tu on multidrug-resistant (MDR) GC cells. For the first time, we found that MDR GC cells were more sensitive to Tu-induced cell death than the parental cells and that the increased sensitivity might correlate with basal endoplasmic reticulum (ER) stress. In addition, Tu dramatically increased chemotherapy-induced apoptosis by evoking ER stress in GC cells, particularly MDR cells. Further study indicated that these effects were highly dependent on glycosylation inhibition by Tu, rather than its role as a canonical ER stress inducer. Besides, autophagy was markedly triggered by Tu, and blocking autophagy enhanced the combined effects of Tu and chemotherapy on MDR GC cells. Our results suggest that tumor-targeted glycosylation inhibition may be a feasible strategy to reverse chemoresistance in GC patients.

Multidrug resistance (MDR) is usually correlated with the poor prognosis of gastric cancer. In this study, we revealed a total of 11 microRNAs (miRNA) that regulated MDR of gastric cancer via high-throughput functional screening, and miR-508-5p reversed MDR most efficiently among these candidate miRNAs. The overexpression of miR-508-5p was sufficient to reverse cancer cell resistance to multiple chemotherapeutics in vitro and sensitize tumours to chemotherapy in vivo. Further studies showed that miR-508-5p could directly target the 3′-untranslated regions of ABCB1 and Zinc ribbon domain-containing 1 (ZNRD1), and suppress their expression at the mRNA and protein levels. Meanwhile, the suppression of ZNRD1 led to a decrease in ABCB1. These findings suggest that a miR-508-5p/ZNRD1/ABCB1 regulatory loop has a critical role in MDR in gastric cancer. In addition, miR-508-5p could be used as a prognostic factor for overall survival in gastric cancer. These data reveal an important role for miR-508-5p in the regulation of MDR in gastric cancer, and suggest the potential application of miR-508-5p in drug resistance prediction and treatment.

Metastasis is the primary cause of death in patients with advanced cancer. Recently, a high-fat diet was shown to specifically promote the metastatic potential of specific cancer cells in a CD36-dependent manner. However, the molecular basis of the fatty acid (FA)-induced upregulation of CD36 has remained unclear. Methods: RT-qPCR, FACS analysis, immunoblotting and immunohistochemistry, as well as retrieving TCGA database, were carried out to quantitate CD36 expression in gastric cancer (GC) tissues and cell lines. Transwell assay and xenografts were used to assess cell metastasis abilities in vitro and in vivo after indicated treatment. Luciferase reporter assay was carried out to evaluate the changes in signaling pathways when O-GlcNAcylation level was increased in GC cells and in vitro O-GlcNAcylation assay was utilized for wild and mutant types of CD36 protein to explore the potential O-GlcNAcylation sites. Results: High CD36 expression is a predictor of poor survival and promotes metastasis of GC cells and the use of neutralizing antibodies to block CD36 inhibits GC metastasis in mice. FA or a HFD promotes the metastatic potential of GC cells by upregulating CD36 via increasing the O-GlcNAcylation level. Increased O-GlcNAcylation levels promote the transcription of CD36 by activating the NF-κB pathway and also increase its FA uptake activity by directly modifying CD36 at S468 and T470. Conclusion: FA-induced hyper-O-GlcNAcylation promotes the transcription and function of CD36 by activating the NF-κB pathway and directly modifying CD36 at S468 and T470, which drives GC metastasis.