The ELF3-regulated lncRNA UBE2CP3 is over-stabilized by RNA–RNA interactions and drives gastric cancer metastasis via miR-138-5p/ITGA2 axis

Abstract

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.

LncRNA RP11-89 facilitates tumorigenesis and ferroptosis resistance through PROM2-activated iron export by sponging miR-129-5p in bladder cancer

“…Recent studies have shown that lncRNAs regulate many important cancer phenotypes through controlling different cancer-related pathways [ 31 , 32 ]. For example, Li et al reported that lncRNA UBE2CP3 targets miR-138-5p to regulate gastric cancer progression via EMT process [ 33 ]. In this research, we demonstrated that lncRNA RP11-89 could play a regulatory role in bladder cancer ferroptosis and progression directly via a novel ceRNA network of RP11-89/miR-129-5p/PROM2 axis.…”

p53-Induced LINC00893 Regulates RBFOX2 Stability to Suppress Gastric Cancer Progression

“…It has also been widely proved that there is a close connection between lncRNAs and gastric cancer metastasis. Some of them are reported to promote the metastasis of gastric cancer, such as lncRNA UBE2CP3, HOTAIR and GMAN (Wei et al, 2020; Xu et al, 2020 ; Li et al, 2021 ). Meanwhile, lncRNAs such as lnc-CTSLP4 and lnc-LEMGC can inhibit the metastasis of gastric cancer through different ways ( Pan et al, 2021 ; Zhang et al, 2022 ).…”

The SNAI2-ELF3-AS1 Feedback Loop Drives Gastric Cancer Metastasis and Regulates ELF3 Expression At Transcriptional and Post-Transcriptional Levels

“…Our previously published study had implied that transcription factor ELF3 plays tumor-suppressive roles in GC. (11,13) Herein, we further con rmed that ELF3 protein and ELF3 mRNA were signi cantly downregulated in GC (Fig. 3H-J).…”

“…(31) Similarly, Li et al have reported that the antisense intronic lncRNA UBE2CP3 and IGFBP7 mRNA can form an RNA duplex, which could strengthen UBE2CP3 mRNA stability in GC. (11) Herein, we also found that the rst exon of ELF3-AS1 could bind with the overlapping regions of the rst exon of ELF3-201 transcripts to form double-stranded RNA molecules, which interacted with ILF2/ILF3 complex. However, whether the ILF2/ILF3 complex can regulate the SNAI2 signaling by regulating the stability of ELF3-AS1 transcripts remains to be further studied.…”