Abstract
BackgroundHepatocellular carcinoma (HCC) is one of the most aggressive malignancies. Increasing evidence revealed that long noncoding RNAs (lncRNAs) were frequently involved in various malignancies. Here, we explored the clinical significances, roles, and mechanisms of lncRNA ADORA2A antisense RNA 1 (ADORA2A-AS1) in HCC.MethodsThe clinical significances of ADORA2A-AS1 in HCC were analyzed using RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) project. The expressions of ADORA2A-AS1, Fascin Actin-Bundling Protein 1 (FSCN1), Matrix Metallopeptidase 2 (MMP2), and Baculoviral IAP Repeat Containing 7 (BIRC7) in HCC tissues and cells were measured by qRT-PCR. Cell Counting Kit-8 (CCK-8), 5-ethynyl-2’-deoxyuridine (EdU), caspase-3 activity assay, transwell migration and invasion assays, and xenograft growth and metastasis experiments were performed to evaluate the roles of ADORA2A-AS1 in HCC. RNA pull-down, RNA immunoprecipitation, qRT-PCR, Western blot, and RNA stability assay were performed to elucidate the mechanisms of ADORA2A-AS1 in HCC.ResultsADORA2A-AS1 was identified as an HCC-related lncRNA, whose low expression was correlated with advanced stage and poor outcome in HCC. Gain- and loss-of functional experiments demonstrated that ADORA2A-AS1 inhibited HCC cell proliferation, induced cell apoptosis, repressed cell migration and invasion, and repressed xenograft growth and metastasis in vivo. Mechanistically, ADORA2A-AS1 competitively bound HuR (Hu Antigen R), repressed the binding of HuR to FSCN1 transcript, decreased FSCN1 transcript stability, and downregulated FSCN1 expression. The expression of FSCN1 was negatively correlated with ADORA2A-AS1 in HCC tissues. Through downregulating FSCN1, ADORA2A-AS1 repressed AKT pathway activation. Functional rescue assays showed that blocking of FSCN1/AKT axis abrogated the roles of ADORA2A-AS1 in HCC.ConclusionLow-expression ADORA2A-AS1 is correlated with poor survival of HCC patients. ADORA2A-AS1 exerts tumor-suppressive roles in HCC via binding HuR and repressing FSCN1/AKT axis.
Highlights
Liver cancer is one of the most aggressive malignancies, whose mortality nearly matches the incidence, with estimated 905,677 new cases and 830,180 deaths in 2020 globally [1]
The results revealed that low ADORA2A-AS1 expression was associated with worse overall survival of Hepatocellular carcinoma (HCC) patients (Figure 1A)
In this HCC cohort, low ADORA2A-AS1 expression was found to be correlated with bad encapsulation, microvascular invasion, and advanced Barcelona Clinic Liver Cancer (BCLC) stage (Table 1)
Summary
Liver cancer is one of the most aggressive malignancies, whose mortality nearly matches the incidence, with estimated 905,677 new cases and 830,180 deaths in 2020 globally [1]. Long noncoding RNA (lncRNA) is the most numerous, which has over 200 nucleotides in length [11, 12]. Many lncRNAs were documented to play critical roles in various pathophysiological processes including cancers [17,18,19,20,21,22,23]. These cancer-related lncRNAs exert multiple oncogenic or tumorsuppressive functions, such as cellular proliferation, apoptosis, migration, invasion, drug resistance, and metastasis [24,25,26]. Increasing evidence revealed that long noncoding RNAs (lncRNAs) were frequently involved in various malignancies. We explored the clinical significances, roles, and mechanisms of lncRNA ADORA2A antisense RNA 1 (ADORA2A-AS1) in HCC
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