Abstract
BackgroundCancer incidence and mortality have been increasing in China, making cancer the leading cause of death since 2010 and a major public health concern in the country. Cancer stem cells have been studied in relation to the treatment of different malignancies, including gastric cancer. Anticancer bioactive peptide-3 (ACBP-3) can induce the apoptosis of gastric cancer stem cells (GCSCs) and reduce their tumorigenicity. In the present study, for the first time, we used a miRNA microarray and bioinformatics analysis to identify differentially expressed miRNAs in ACBP-3-treated GCSCs and GCSC-derived tumors in a xenograft model and functionally verified the identified miRNAs. miR-338-5p was selected based on its significant upregulation by ACBP-3 both in cultured GCSCs and in tumor tissues.ResultsmiR-338-5p was downregulated in GCSCs compared with normal gastric epithelial cells, and the ectopic restoration of miR-338-5p expression in GCSCs inhibited cell proliferation and induced apoptosis, which correlated with the upregulation of the pro-apoptotic Bcl-2 proteins BAK and BIM. We also found that ACBP-3-treated GCSCs could respond to lower effective doses of cisplatin (DDP) or 5-fluorouracil (5-FU), possibly because ACBP-3 induced the expression of miR-338-5p and the BAK and BIM proteins and promoted GCSC apoptosis.ConclusionsOur data indicate that miR-338-5p is part of an important pathway for the inhibition of human gastric cancer stem cell proliferation by ACBP-3 combined with chemotherapeutics. ACBP-3 could suppress GCSC proliferation and lower the required effective dose of cisplatin or 5-fluorouracil. Therefore, this study provides not only further evidence for the remarkable anti-tumor effect of ACBP-3 but also a possible new approach for the development of GCSC-targeting therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-016-0112-8) contains supplementary material, which is available to authorized users.
Highlights
Cancer incidence and mortality have been increasing in China, making cancer the leading cause of death since 2010 and a major public health concern in the country
MiR‐338‐5p expression in gastric cancer stem cells (GCSCs) and normal gastric epithelial cells As miR-338-5p demonstrated the highest upregulation by Anticancer bioactive peptide-3 (ACBP-3), it was selected for validation by qRTPCR
Expression of BIM and BAK in GCSCs treated with different drug combinations Given that miR-338-5p overexpression accelerated GCSC apoptosis and that ACBP-3 potently upregulated miR-338-5p levels, we investigated the expression of the pro-apoptotic proteins BIM and BAK in GCSCs treated with ACBP3, DDP and 5-FU, alone or in combination
Summary
Cancer incidence and mortality have been increasing in China, making cancer the leading cause of death since 2010 and a major public health concern in the country. Cancer stem cells have been studied in relation to the treatment of different malignancies, including gastric cancer. Anticancer bioactive peptide-3 (ACBP-3) can induce the apoptosis of gastric cancer stem cells (GCSCs) and reduce their tumorigenicity. Gastric cancer (GC) is one of the major threats to human health worldwide. It is predicted that there will be approximately 4,292,000 newly diagnosed invasive cancer cases in 2015 in China, corresponding to almost 12,000 new cancer diagnoses on. Anticancer bioactive peptide-3 (ACBP-3), a polypeptide isolated from goat liver in our laboratory, has been shown to inhibit proliferation, induce apoptosis, and reduce the tumorigenicity of human GCSCs both in vitro and in vivo. The mechanisms underlying the ACBP-3-mediated suppression of GCSCs remains unknown
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