Abstract
BackgroundHepatocellular carcinoma (HCC) is the most common malignant liver tumor with poor clinical outcomes. Increasing amount of long non-coding RNAs (lncRNAs) have been revealed to be implicated in the carcinogenesis and progression of HCC. However, the expressions, clinical significances, and roles of most lncRNAs in HCC are still unknown.MethodsThe expression of lncRNA MCM3AP antisense RNA 1 (MCM3AP-AS1) in HCC tissues and cell lines was detected by qRT-PCR and fluorescence in situ hybridization. Immunoblotting, CCK-8, EdU, colony formation and flow cytometry were performed to investigate the role of MCM3AP-AS1 in HCC cell proliferation, cell cycle and apoptosis in vitro. A subcutaneous tumor mouse model was constructed to analyze in vivo growth of HCC cells after MCM3AP-AS1 knockdown. The interactions among MCM3AP-AS1, miR-194-5p and FOXA1 were measured by RNA pull-down, RNA immunoprecipitation and luciferase reporter assay.ResultsWe revealed a novel oncogenic lncRNA MCM3AP-AS1, which is overexpressed in HCC and positively correlated with large tumor size, high tumor grade, advanced tumor stage and poor prognosis of HCC patients. MCM3AP-AS1 knockdown suppressed HCC cell proliferation, colony formation and cell cycle progression, and induced apoptosis in vitro, and depletion of MCM3AP-AS1 inhibited tumor growth of HCC in vivo. Mechanistically, MCM3AP-AS1 directly bound to miR-194-5p and acted as competing endogenous RNA (ceRNA), and subsequently facilitated miR-194-5p’s target gene forkhead box A1 (FOXA1) expression in HCC cells. Interestingly, FOXA1 restoration rescued MCM3AP-AS1 knockdown induced proliferation inhibition, G1 arrest and apoptosis of HCC cells.ConclusionsOur results recognized MCM3AP-AS1 as a novel oncogenic lncRNA, which indicated poor clinical outcomes in patients with HCC. MCM3AP-AS1 exerted an oncogenic role in HCC via targeting miR-194-5p and subsequently promoted FOXA1 expression. Our findings suggested that MCM3AP-AS1 could be a potential prognostic biomarker and therapeutic target for HCC.
Highlights
Hepatocellular carcinoma (HCC) is the most common malignant liver tumor with poor clinical outcomes
2% of the human genome accounts for protein coding genes, while about 70% of the genome is identified as non-coding RNAs due to the great progressions of genome and transcriptome sequencing [5]. ncRNAs are further grouped into long ncRNAs and small ncRNAs depending on their transcript size [6]
We find that long non-coding RNAs (lncRNAs) TUSC7 is down-regulated in HCC and indicates poor prognosis of patients, and it inhibits epithelial-mesenchymal transition (EMT) and HCC metastasis by acting as miR-10a sponge and subsequently leads to Eph tyrosine kinase receptor A4 (EphA4) upregulation [25]
Summary
Hepatocellular carcinoma (HCC) is the most common malignant liver tumor with poor clinical outcomes. Increasing amount of long non-coding RNAs (lncRNAs) have been revealed to be implicated in the carcinogenesis and progression of HCC. High expression of lncRNA linc00210 is detected in liver cancer and contributes to tumor progression by driving the activation of Wnt/β-catenin pathway in a catenin beta interacting protein 1 (CT NNBIP1)-dependent manner [22]. Forkhead box A2 (FOXA2)-induced lncRNA-NEF is frequently down-regulated in HCC, and suppresses epithelial-mesenchymal transition (EMT) and tumor metastasis by antagonizing Wnt/β-catenin pathway [23]. LncRNA-MUF is found to be highly expressed in HCC and facilitates hepatocarcinogenesis via directly regulating Annexin A2 (ANXA2)/Wnt/β-catenin signaling and miR-34a/Snail1/ EMT axis [24]. We investigate the expression and function of lncRNA CASC2 in HCC and reveal that CASC2 exerts an anti-metastatic role by targeting miR-367/F-box and WD repeat domain containing 7 (FBXW7) axis [26]. Several lncRNAs have been reported to participate in the tumorigenesis and progression of HCC, the expressions and roles of most lncRNAs in HCC are still unclear
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