Background Cisplatin (CDDP) treatment is one of the most predominant chemotherapeutic strategies for patients with gastric cancer (GC). A better understanding of the mechanisms of CDDP resistance can greatly improve therapeutic efficacy in patients with GC. Circular RNAs (circRNAs) are a class of noncoding RNAs whose functions are related to the pathogenesis of cancer, but, in CDDP resistance of GC remains unknown. Methods circAKT3 (hsa_circ_0000199, a circRNA originating from exons 8, 9, 10, and 11 of the AKT3 gene) was identified by RNA sequencing and verified by quantitative reverse transcription PCR. The role of circAKT3 in CDDP resistance in GC was assessed both in vitro and in vivo. Luciferase reporter assay, biotin-coupled RNA pull-down and fluorescence in situ hybridization (FISH) were conducted to evaluate the interaction between circAKT3 and miR-198. Functional experiments were measured by western blotting, a cytotoxicity assay, clonogenic assay and flow cytometry. Results The expression of circAKT3 was higher in CDDP-resistant GC tissues and cells than in CDDP-sensitive samples. The upregulation of circAKT3 in GC patients receiving CDDP therapy was significantly associated with aggressive characteristics and was an independent risk factor for disease-free survival (DFS). Our data indicated that circAKT3 promotes DNA damage repair and inhibits the apoptosis of GC cells in vivo and in vitro. Mechanistically, we verified that circAKT3 could promote PIK3R1 expression by sponging miR-198. Conclusions circAKT3 plays an important role in the resistance of GC to CDDP. Thus, our results highlight the potential of circAKT3 as a therapeutic target for GC patients receiving CDDP therapy. Electronic supplementary material The online version of this article (10.1186/s12943-019-0969-3) contains supplementary material, which is available to authorized users.

BackgroundGastric carcinoma (GC) is a common and lethal malignancy, and epithelial-mesenchymal transition (EMT) is believed to contribute to invasive and metastatic tumor growth. Aquaporin 3 (AQP3) is overexpressed in human GC tissues, while human epidermal growth factor (EGF) and hepatocyte growth factor, which can induce EMT, are able to up-regulate AQP3 expression, subsequently promoting GC cell migration and proliferation. The purpose of this study was to investigate the effects of AQP3 on EMT in human GC.MethodsAQP3 and EMT-related proteins were detected by immunohistochemistry in human GC specimens and their clinical significance evaluated. AQP3 knockdown was attempted using small interfering RNAs, while EGF was used to up-regulate AQP3 expression. Western blotting, real-time quantitative polymerase chain reaction assays and immunofluorescence were used to evaluate changes in expression of AQP3 and EMT-related proteins in the SGC7901 and MGC803 human GC cell lines.ResultsAQP3 up-expression was associated with EMT-related proteins in human GC specimens, which correlated with poor prognosis for GC. AQP3 modulated GC cell proliferation, migration and invasion in vitro, and induced E-cadherin repression. AQP3 also up-regulated the expression of vimentin and fibronectin in vitro. The PI3K/AKT/SNAIL signaling pathway was likely involved in the induction of EMT by AQP3 in GC.ConclusionsAQP3 promotes EMT in human cases of GC, allowing us to understand the mechanisms of AQP3 in GC progression, thus providing a potential strategy for its treatment.

Cisplatin (CDDP) resistance is a major clinical problem associated with poor prognosis in gastric cancer (GC) patients. In this study, we performed integrated analysis of TCGA data from microRNAs (miRNAs) expression matrix of GC patients who received CDDP-based chemotherapy with GEO dataset which contains differential miRNAs expression profiles in CDDP-resistant and -sensitive cell lines. We identified miR-148a-3p downregulation as a key step involved in CDDP resistance. Using a cohort consisting 105 GC patients who received CDDP-based therapy, we found that miR-148a-3p downregulation was associated with a decrease in patients’ disease-free survival (DFS, P=0.0077). A series of experiment data demonstrated that: 1) miR-148a-3p was downregulated in CDDP-resistant GC cell lines; 2) miR-148a-3p reconstitution sensitized CDDP-resistant cells to CDDP treatment through promoting mitochondrial fission and decreasing AKAP1 expression level; 3) AKAP1 played a novel role in CDDP resistance by inhibiting P53-mediated DRP1 dephosphorylation; 4) miR-148a-3p reconstitution in CDDP-resistant cells inhibits the cyto-protective autophagy by suppressing RAB12 expression and mTOR1 activation. Taken together, our study demonstrates that miR-148a-3p could be a promising prognostic marker or therapeutic candidate for overcoming CDDP resistance in GC.