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Dysregulation of non-coding RNAs, including miRNAs and lncRNAs has been reported to play vital roles in gastric cancer (GC) carcinogenesis, but the mechanism involved is largely unknown. Using the cancer genome atlas (TCGA) data set and bioinformatics analyses, we identified miR-532-5p as a potential tumor suppressor in GC, and found that lncRNA LINC01410 might be a negative regulator of miR-532-5p. We then conducted a series of in vivo and in vitro assays to explore the effect of LINC01410 on miR-532-5p-mediated GC malignancy and the underlying mechanism involved. MiR-532-5p overexpression inhibited GC metastasis and angiogenesis in vitro and in vivo, whereas miR-532-5p silencing had the opposite effect. Further study showed that miR-532-5p attenuated NF-κB signaling by directly inhibiting NCF2 expression, while miR-532-5p silencing in GC enhanced NF-κB activity. Furthermore, we demonstrated miR-532-5p down-regulation was caused by aberrantly high expression of LINC01410 in GC. Mechanistically, overexpression of LINC01410 promoted GC angiogenesis and metastasis by binding to and suppressing miR-532-5p, which resulted in up-regulation of NCF2 and sustained NF-κB pathway activation. Interestingly, NCF2 could in turn increase the promoter activity and expression of LINC01410 via NF-κB, thus forming a positive feedback loop that drives the malignant behavior of GC. Finally, high expression of LINC01410, along with low expression of miR-532-5p, was associated with poor survival outcome in GC patients. Our studies uncover a mechanism for constitutive LINC1410-miR-532-5p-NCF2-NF-κB feedback loop activation in GC, and consequently, as a potential therapeutic target in GC treatment.

Cancer stem cells (CSCs)/cancer‐initiating cells (CICs) are suggested responsible for driving cancer resistance to conventional therapies and for cancer recurrence and/or metastasis. CD133 is served as a key biomarker to identify and characterize this subpopulation of cells in hepatocellular carcinoma (HCC). Our previous study indicated that overexpression of eukaryotic initiation factor 5A2 (EIF5A2) promotes HCC cell metastasis and angiogenesis. In this study, we demonstrated that EIF5A2 might play a crucial role in CSCs regulation and investigated its potential molecular mechanisms. Using quantitative real‐time polymerase chain reaction assay, we observed that the expression of EIF5A2 positively correlated with CD133 levels in a cohort of cancerous and noncancerous liver tissues and cells. Next, HCC cells with high expression of EIF5A2 have a strong capacity to form undifferentiated tumor spheres in vitro and show elevated levels of stem cell‐related genes, leading to an increased ability to develop tumors when subcutaneously injected into nude mice. Furthermore, differential microRNA expression was profiling between two EIF5A2‐depleted HCC cell lines and their control one identified a decreased expression of miR‐29b in EIF5A2‐depleted cell lines. Further functional studies illustrated that downregulated miR‐29b level is responsible for EIF5A2‐maintained HCC cell stemness either in vitro or in vivo. Moreover, enforced expression of EIF5A2 in HCC cells largely enhanced the binding of c‐Myc on the promoter of miR‐29b and downregulation of miR‐29b by EIF5A2 was dependent on c‐Myc. Our findings, collectively, reveal that EIF5A2 contributes to the maintenance of CD133+ HCC cells via the c‐Myc/miR‐29b axis. StemCells2018;36:180–191 A schematic model showing the molecular mechanism of eukaryotic initiation factor 5A2 (EIF5A2) regulates CD133 via c‐Myc/miR‐29b pathway in hepatocellular carcinoma cells (HCCs). Upregulation of EIF5A2 enhances the binding of c‐Myc on the promoter of miR‐29b to inhibit its expression, and then upregulating the levels of CD133, thus, HCC cells are prone to maintain their stemness.