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Background Metastasis remains the main cause of cancer-related death for gastric cancer (GC) patients, but the mechanisms are poorly understood. Using The Cancer Genome Atlas (TCGA) data base and bioinformatics analyses, we identified C12orf59 might act as a potential oncogenic protein in GC. Methods We investigate the expression pattern and clinical significance of C12orf59 in two independent cohorts of GC samples. In the training cohort, we used the X-tile program software to generate the optimal cutoff value for C12orf59 expression in order to classify patients accurately according to clinical outcome. In the validation cohort, this derived cutoff score was applied to exam the association of C12orf59 expression with survival outcome. A series of in vivo and in vitro assays were then performed to investigate the function of C12orf59 in GC. Results C12orf59 was significantly upregulated, and associated with poor survival outcome in two cohorts of GC samples. Gain- and loss of- function studies demonstrated C12orf59 promotes GC cell invasive and metastatic capacity both in vitro and in vivo, and induces epithelial–mesenchymal transition and angiogenesis. Mechanically, C12orf59 exerts oncogenic functions by up-regulating CDH11 expression via NF-κB signaling. Interesting, CDH11 could in turn promote NF-κB bind to C12orf59’s promoter and form a positive feedback loop to sustain the metastatic ability of GC cells. Additionally, downregulation of miR-654-5p is another important mechanism for C12orf59 overexpression in GC. Conclusion Our finding suggested the newly identified C12orf59/NF-κB/CDH11 feedback loop may represent a new strategy for GC treatment. Electronic supplementary material The online version of this article (10.1186/s13046-019-1114-2) contains supplementary material, which is available to authorized users.

Figure S2. Suppression or overexpression of C12orf59 did not alter the GC cellular growth rate. (DOCX 155 kb)

Figure S1. TCGA data analysis of C12orf59 expression pattern and prognostic value in GC tissues. a. Expression of C12orf59 mRNA level in 68 paired GC and adjacent normal tissues from TCGA database. The mean level of C12orf59 expression in the GC tissues was significantly higher than in normal tissues (*P

Figure S3. The microvessel density (MVD), as indicated by CD31 staining was noticeably stronger in GC samples with C12orf59 high expression compared with GC samples with C12orf59 low expression in the training cohort of 170 samples. *P

Table S1. List of genes differentially expressed in MKN-45 cells after C12orf59 knockdown using a Human Tumor Metastasis Real-time PCR Array. (DOCX 24 kb)

Figure S4. Restoration of CDH11 in GC cells enhanced the in vivo metastasis ability. Representative hematoxylin and eosin (H&E) staining depicting metastatic tumors in the lung of nude mice that originated from MKN-45/shC12orf59/CDH11 and MKN-45/shC12orf59/control cells injected via the tail vein (left). Number of metastatic nodules formed in the lung of mice 6 weeks after tail vein injection of MKN-45/shC12orf59/CDH11 or MKN-45/shC12orf59/control cells. Six mice per group; **P

Figure S6. miR-654-5p inhibited GC cell invasion and metastatic ability in vitro. a. Overexpression of miR-654-5p dramatically reduced the migratory ability of GC cells in the wound-healing assay. b. Overexpression of miR-654-5p resulted in a decrease in the migratory and invasive abilities of GC cells as determined by Transwell analysis. *P

The clinicopathologic characteristics of the 112 GC patients who received surgery followed by adjuvant chemotherapy in this study. (DOC 40 kb)

Background The development of chemoresistance and metastasis are the leading causes of death for gastric cancer (GC) patients, however, the molecular mechanisms involved remain unclear. Dysregulation of miRNAs is associated with a variety of disease, including GC. Recently, microarray profiling analysis revealed that miR-939 was dysregulated in human GC samples, but the role of miR-939 in GC has not been intensively investigated. Methods In the present study, we firstly examined the expression pattern of miR-939 in two independent cohorts of clinical GC samples: one cohort of 112 GC patients with stage I-III disease who underwent surgery followed by adjuvant chemotherapy; and another cohort of 110 GC patients with stage IV disease who received palliative chemotherapy. A series of in vivo and in vitro assays were then performed to investigate the function of miR-939 in GC. Results We detected that reduced expression of miR-939 was associated with chemoresistance and increased risk of tumor recurrence in GC patients. Further function study demonstrated that overexpression of miR-939 suppressed GC cell growth, and enhanced 5-fluorouracil-induced chemosensitivity by compromising cellular growth and inducing apoptosis in vitro and in vivo. Moreover, miR-939 repressed the migration and invasion of GC cells in vitro, and diminished the occurrence of lung metastasis in vivo. We further identified solute carrier family 34 member 2 (SLC34A2) was a novel target of miR-939. Mechanistically, we elucidated that miR-939 exerted its function mainly through inhibiting SLC34A2/Raf/MEK/ERK pathway, which is activated in GC. Multivariate analysis identified miR-939, SLC34A2, and their combination as independent indicators for poor prognosis and tumor recurrence in GC patients. Conclusion Our data indicate that miR-939 acts as a tumor suppressor miRNA in GC, and miR-939/SLC34A2 axis represents a novel therapeutic strategy for future GC treatment. Electronic supplementary material The online version of this article (doi:10.1186/s12943-017-0586-y) contains supplementary material, which is available to authorized users.