Abstract
BackgroundDysregulation of long non-coding RNAs (lncRNAs) is responsible for cancer initiation and development, positioning lncRNAs as not only biomarkers but also promising therapeutic targets for cancer treatment. A growing number of lncRNAs have been reported in hepatocellular carcinoma (HCC), but their functional and mechanistic roles remain unclear.MethodsGene Set Enrichment Analysis was used to investigate the molecular mechanism of UPK1A antisense RNA 1 (UPK1A-AS1). Cell Counting Kit-8 assays, EdU assays, flow cytometry, western blotting, and xenograft assays were used to confirm the role of UPK1A-AS1 in the proliferation of HCC cells in vitro and in vivo. Bioinformatics analyses and quantitative polymerase chain reaction (qRT-PCR) were performed to explore the interplay between UPK1A-AS1 and enhancer of zeste homologue 2 (EZH2). RNA immunoprecipitation (RIP), RNA pull-down assays, western blotting, and qRT-PCR were conducted to confirm the interaction between UPK1A-AS1 and EZH2. The interaction between UPK1A-AS1 and miR-138-5p was examined by luciferase reporter and RIP assays. Finally, the expression level and prognosis value of UPK1A-AS1 in HCC were analyzed using RNA sequencing data from The Cancer Genome Atlas datasets.ResultsWe showed that UPK1A-AS1, a newly identified lncRNA, promoted cellular proliferation and tumor growth by accelerating cell cycle progression. Cell cycle-related genes, including CCND1, CDK2, CDK4, CCNB1, and CCNB2, were significantly upregulated in HCC cells overexpressing UPK1A-AS1. Furthermore, overexpression of UPK1A-AS1 could protect HCC cells from cis-platinum toxicity. Mechanistically, UPK1A-AS1 interacted with EZH2 to mediate its nuclear translocation and reinforce its binding to SUZ12, leading to increased H27K3 trimethylation. Targeting EZH2 with specific small interfering RNA impaired the UPK1A-AS1-mediated upregulation of proliferation and cell cycle progression-related genes. Moreover, miR-138-5p was identified as a direct target of UPK1A-AS1. Additionally, UPK1A-AS1 was significantly upregulated in HCC, and the upregulation of UPK1A-AS1 predicted poor prognosis for patients with HCC.ConclusionsOur study revealed that UPK1A-AS1 promotes HCC development by accelerating cell cycle progression through interaction with EZH2 and sponging of miR-138-5p, suggesting that UPK1A-AS1 possesses substantial potential as a novel biomarker for HCC prognosis and therapy.
Highlights
Dysregulation of long non-coding RNAs is responsible for cancer initiation and development, positioning Long non-coding RNA (lncRNA) as biomarkers and promising therapeutic targets for cancer treatment
Upregulation of UPK1A-AS1 promotes proliferation of hepatocellular carcinoma (HCC) cells Detection of UPK1A-AS1 expression in HCC cell lines suggested that UPK1A-AS1 was highly expressed in HCC cells compared to the human hepatocyte cell line L02 (Supplementary Figure 1A)
To investigate the molecular mechanism of UPK1A-AS1, we conducted Gene Set Enrichment Analysis (GSEA) of The Cancer Genome Atlas (TCGA) cohort and found that high UPK1A-AS1expressing groups were enriched for cell cycle-related gene sets (Fig. 1a), suggesting that UPK1A-AS1 may have a role in cell proliferation
Summary
Dysregulation of long non-coding RNAs (lncRNAs) is responsible for cancer initiation and development, positioning lncRNAs as biomarkers and promising therapeutic targets for cancer treatment. LncRNAs have been regarded as potential biomarkers and therapeutic targets for cancers, including HCC [11]. Our previous findings showed that MIR22HG, a highly conserved lncRNA, was downregulated and predicted poor prognosis in patients with HCC [15]. These findings indicate that lncRNAs are critically involved in the development and progression of HCC and may serve as biomarkers for HCC diagnosis and prognosis
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