LncRNAs play essential roles in tumorigenesis and tumor progression. Pseudogene UBE2CP3 is an antisense intronic lncRNA. However, the biological function of UBE2CP3 in gastric cancer (GC) remains unknown. In this study, we revealed that lncRNA UBE2CP3 was aberrantly upregulated in multiple independent gastric cancer cohorts, and its overexpression was clinically associated with poor prognosis in GC. UBE2CP3 was mainly located in cytoplasm and promoted migratory and invasive capacities of GC cells in vitro and in vivo. Mechanismly, a novel dysregulated ceRNA network UB2CP3/miR-138-5p/ITGA2 was identified in GC by transcriptome sequencing. Furthermore, rescue assay further confirmed that UBE2CP3 mainly promoted GC progression through miR-138-5p/ITGA2 axis. More importantly, our data proved that UBE2CP3/IGFBP7 could form an RNA duplex, thereby directly interacting with the ILF3 protein. In turn, this RNA-RNA interaction between IGFBP7 mRNA and UBE2CP3 mediated by ILF3 protein plays an essential role in protecting the mRNA stability of UBE2CP3. In addition, transcription factor ELF3 was identified to be a direct repressor of lncRNA UBE2CP3 in GC. Taken together, overexpression of UBE2CP3 promotes tumor progression via cascade amplification of ITGA2 upregulation in GC. Our finding has revealed that the dysregulation of UBE2CP3 is probably due to the downregulation of ELF3 and/or the overexpression of IGFBP7 mRNA in GC. Our findings reveal, for the first time, that UBE2CP3 plays crucial a role in GC progression by modulating miR-138-5p/ITGA2 axis, suggesting that UBE2CP3 may serve as a potential therapeutic target in GC.

Deregulated lncRNAs play critical roles in tumorigenesis and tumor progression. NR2F1-AS1 is an antisense lncRNA of NR2F1. However, the biological function of NR2F1-AS1 in gastric cancer (GC) remains largely unclear. In this study, we revealed that NR2F1-AS1 and NR2F1 were both positively correlated with the degree of malignancy and predicted poor prognosis in two independent GC cohorts. Besides, NR2F1-AS1 and NR2F1 can respond to Epithelial-to-mesenchymal transition (EMT) signaling in GC, since their expression was increased by TGF-beta treatment and decreased after stable overexpression of OVOL2 in GC cell lines. NR2F1-AS1 and NR2F1 were highly co-expressed in pan-tissues and pan-cancers. Depletion of NR2F1-AS1 compromised the expression level of NR2F1 in GC cells. Furthermore, NR2F1-AS1 knockdown inhibited the proliferation, migration, invasion and G1/S transition of GC cells. More importantly, transcriptome sequencing revealed a novel ceRNA network composed of NR2F1-AS1, miR-29a-3p, and VAMP7 in GC. The overexpression of VAMP7 predicted poor prognosis in GC. Rescue assay confirmed that NR2F1-AS1 promotes GC progression through miR-29a-3p/VAMP7 axis. Our finding highlights that the aberrant expression of NR2F1-AS1 is probably due to the abnormal EMT signaling in GC. LncRNA NR2F1-AS1 plays crucial roles in GC progression by modulating miR-29a-3p/VAMP7 axis, suggesting that NR2F1-AS1 may serve as a potential therapeutic target in GC.

We previously reported that IGFBP7 plays a role in maintaining mRNA stability of oncogenic lncRNA UBE2CP3 by RNA-RNA interaction in gastric cancer (GC). Clinical cohort studies had implied an oncogenic role of IGFBP7 in GC. However, the molecular mechanism of IGFBP7 in GC progression remains unknown. In this study, clinical analysis based on two independent cohorts showed that IGFBP7 was positively associated with poor prognosis and macrophage infiltration in GC. Loss-of-function studies confirmed the oncogenic properties of IGFBP7 in regulating GC cell proliferation and invasion. Mechanismly, IGFBP7 was highly expressed in cancer-associated fibroblasts (CAF) and mesenchymal cells, and was induced by epithelial-to-mesenchymal transition (EMT) signaling, since its expression was increased by TGF-beta treatment and reduced by overexpression of OVOL2 in GC. RNA sequencing, qRT-PCR, ELISA assay showed that IGFBP7 positively regulated FGF2 expression and secretion in GC. Transcriptome analysis revealed that FGFR1 was downregulated in M1 polarization but upregulated in M2 polarization. Exogenous recombinant IGFBP7 treatment in macrophages and GC cells further identified that IGFBP7 promotes tumor associated macrophage (TAM) polarization via FGF2/FGFR1/PI3K/AKT axis. Our finding here represented the first evidence that IGFBP7 promotes GC by enhancing TAM/M2 macrophage polarization through FGF2/FGFR1/PI3K/AKT axis.

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