LINC00052 upregulates EPB41L3 to inhibit migration and invasion of hepatocellular carcinoma by binding miR-452-5p.
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ABSTRACT:
SUBMITTER: Zhu L
PROVIDER: S-EPMC5609956 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hepatocellular carcinoma (HCC) has a high recurrence rate, and patients exhibit poor survival mainly because intrahepatic metastasis is common. We previously reported that let-7c down-regulation is significantly associated with poor differentiation level in HCC. In the present study, we demonstrate that miR-199a-5p and let-7c are frequently down-regulated in HCC cells and tissues, and low expression of miR-199a-5p is correlated with tumor size, liver envelope invasion. Furthermore, miR-199a-5p and let-7c cooperatively inhibit HCC cell migration and invasion in vitro. MAP4K3 is identified as the direct target of miR-199a-5p and let-7c and this regulation is further confirmed by luciferase reporter assays and Western blotting. In addition, MAP4K3 functions as a metastasis promoter since the results demonstrate that MAP4K3 could promote HCC cell migration and invasion. We also find that miR-199a-5p and let-7c increase the sensitivity of HCC cells to sorafenib.We report that miR-199a-5p and let-7c cooperatively and efficiently inhibit HCC cell migration and invasion by targeting the metastasis promoter MAP4K3 and MAP4K3-mediated drug sensitization, suggesting that the use of miRNAs and sorafenib in combination therapy may be a powerful approach to the treatment of HCC.
| S-EPMC5355128 | biostudies-literature
Project description:BACKGROUND:The implication of miR-452-5p and its prospective machinery in hepatocellular carcinoma (HCC) remains largely unknown. For this reason, this study aimed to inspect the clinical implication of miR-452-5p expression in HCC tissues with multiple detection approaches, to analyze its potential function via in silico methods, and to validate this using a dual-luciferase reporter assay. METHODS:The assessment of the expression level of miR-452-5p in HCC was conducted via four methods: 1) in-house real-time quantitative PCR (RT-qPCR), 2) miRNA-sequencing (miRNA-seq) from The Cancer Genome Atlas (TCGA), 3) miRNA microarrays from the Gene Expression Omnibus (GEO), and 4) comprehensive meta-analyses calculating the standard mean difference (SMD) and summary of receiver operator characteristic (sROC). Following the target prediction, one of the potential targets of miR-452-5p was validated through a dual-luciferase reporter assay. RESULTS:MiR-452-5p was consistently elevated in HCC tissues via various detection methods, including in-house RT-qPCR, miRNA-seq, and miRNA microarrays. The final SMD was 0.842 for 820 cases of HCC samples. Simultaneously, the area under curve (AUC) of the sROC was 0.80 (0.76-0.83). The 1,135 predicted targets of miR-452-5p were enriched in the pathways of cytokine-cytokine receptor interaction, carbon metabolism, and complement and coagulation cascades. Among these predicted targets, CDKN1B was verified to be a real target of miR-452-5p. CONCLUSION:The overexpression of miR-452-5p may play a pivotal role in the carcinogenesis of HCC via targeting multiple signaling pathways and genes. The function and molecular machinery of miR-452-5p in HCC requires further in-depth exploration.
| S-EPMC6949781 | biostudies-literature
Project description:BackgroundAbundant evidence has manifested that long noncoding RNAs (lncRNAs) are closely implicated in human cancers, including hepatocellular carcinoma (HCC). Remarkably, lncRNA FAM83H antisense RNA 1 (FAM83H-AS1) has been reported to be a tumor-propeller in multiple cancers. However, its effect on HCC progression remains unknown.MethodsFAM83H-AS1 expression was analyzed by RT-qPCR. Colony formation, EdU, and flow cytometry as well as transwell assays were implemented to analyze the biological functions of FAM83H-AS1 on HCC progression. Luciferase reporter, RIP and RNA pull-down assays were implemented to detect the interaction among FAM83H-AS1, microRNA-485-5p (miR-485-5p), and myocyte enhancer factor 2D (MEF2D) in HCC cells.ResultsFAM83H-AS1 expression in HCC cells was markedly elevated. FAM83H-AS1 accelerated cell proliferation, migration and invasion whereas inhibiting cell apoptosis in HCC. Besides, we confirmed that FAM83H-AS1 acts as a miR-485-5p sponge in HCC cells. Additionally, MEF2D was verified to be a direct target of miR-485-5p. FAM83H-AS1 could upregulate MEF2D expression via sponging miR-485-5p. Further, rescue experiments testified that MEF2D upregulation or miR-485-5p downregulation offset the repressive effect of FAM83H-AS1 depletion on HCC cell progression.ConclusionsFAM83H-AS1 facilitates HCC malignant progression via targeting miR-485-5p/MEF2D axis, suggesting that FAM83H-AS1 may be a promising biomarker for HCC treatment in the future.
| S-EPMC8650424 | biostudies-literature
Project description:Despite the rapidly identified numbers of lncRNA in humans, exploration of the molecular mechanisms of lncRNA is lagging, because the molecular mechanisms of lncRNA can be various and complex in different conditions. In this study, we found a new molecular mechanism for a versatile molecule, MIR22HG. MIR22HG is an lncRNA that contributes to the initiation and progression of many human cancers, including hepatocellular carcinoma (HCC). We report that MIR22HG was downregulated in 120 HCC samples compared with adjacent nontumor liver tissues. More interestingly, decreased expression of MIR22HG in HCC could predict poor prognosis of HCC patients. Knockdown of MIR22HG promoted the growth, migration and invasion of HCC cells. In exploring the molecular mechanism of MIR22HG, we found that MIR22HG functioned as a tumor suppressor in hepatocellular carcinomas, in part through serving as a competing endogenous RNA to modulate the miRNA-10a-5p level. Moreover, NCOR2 was verified to act as the downstream target gene of MIR22HG/miR-10a-5p. In addition, the MIR22HG/miRNA-10a-5p/NCOR2 axis inhibited the activation of the Wnt/β-catenin pathway. Together, our results demonstrated that MIR22HG inhibited HCC progression in part through the miR-10a-5p/NCOR2 signaling axis and might act as a new prognostic biomarker for HCC patients.
| S-EPMC6398879 | biostudies-other
Project description:BackgroundHepatocellular carcinoma (HCC) cell-derived exosomes have shown effects on inducing M2 macrophage polarization and promoting HCC progression. MiR-452-5p was reported by recent studies to promote malignancy progression as an exosomal microRNA that secreted by HCC cells, of which the underlying mechanism remains unclear. Here, we further explored how miR-452-5p functions in HCC.MethodsMiR-452-5p expressions in HCC cells was examined by in situ hybridization. Next, HCC cell lines were transfected with the mimics or the inhibitor of miR-452-5p. Transfected cells' biological behavior were analyzed by CCK-8, flow cytometry, and Transwell assay. Then, exosomes were purified from miR-452-5p inhibited or overexpressed HCC cells and cocultured with macrophages to examine the role of miR-452-5p in macrophage polarization. To examine the role of exosomal miR-452-5p on macrophage polarization and tumor growth. We also performed the dual-luciferase assay to explore the targeting relationship between miR-452-5p and TIMP3.ResultsThe upregulation of miR-452-5p was identified in HCC. The effects of HCC cell-derived exosomes on accelerating HCC migration and invasion and inducing M2 macrophage polarization were confirmed, which were further enhanced after overexpressing miR-452-5p but neutralized after silencing miR-452-5p. In addition, in vivo experiments demonstrated the effect of miR-452-5p on accelerating HCC growth and metastasis. Also, we identified that TIMP3 overexpression inhibited the promoted cell invasion and migration by HCC cell-derived exosomes.ConclusionExosomal miR-452-5p secreted from HCC cells could induce polarization of M2 macrophage and therefore stimulating HCC progression by targeting TIMP3. Thus, miR-452-5p might be a potential biomarker for HCC prognosis.
| S-EPMC9508462 | biostudies-literature
Project description:ObjectiveDLGAP1-AS2 has been characterized as an oncogenic lncRNA in glioma. Our preliminary microarray analysis revealed the altered expression of DLGAP1-AS2 in hepatocellular carcinoma (HCC), but the role of DLGAP1-AS2 in HCC remains unknown.MethodExpression of DLGAP1-AS2 and miR-154-5p in paired HCC and nontumor tissues from 62 HCC patients was determined by RT-qPCR. The 62 HCC patients were followed up for 5 years to analyze the prognostic value of DLGAP1-AS2 for HCC. DLGAP1-AS2 knockdown and miR-154-5p overexpression was achieved in HCC cells to study the relationship between them. Methylation of miR-154-5p was analyzed by methylation-specific PCR. Cell proliferation was analyzed by CCK-8 assay.ResultsDLGAP1-AS2 was upregulated in HCC and predicted poor survival. miR-154-5p was downregulated in HCC and inversely correlated with DLGAP1-AS2. In HCC cells, DLGAP1-AS2 knockdown resulted in the upregulation of miR-154-5p expression and decreased methylation of miR-154-5p gene. Transwell assay showed that DLGAP1-AS2 knockdown and miR-154-5p overexpression inhibited cell invasion and migration, and the combination of LGAP1-AS2 knockdown and miR-154-5p overexpression showed stronger effects.ConclusionDLGAP1-AS2 knockdown may inhibit HCC cell migration and invasion by regulating miR-154-5p methylation.
| S-EPMC7641292 | biostudies-literature
Project description:BackgroundThioredoxin reductase 1 (TXNRD1) is an antioxidant enzyme reportedly overexpressed in hepatocellular carcinoma (HCC); however, the detailed function and mechanisms of TXNRD1 in HCC remain obscure. In this study, we investigated the miR-125b-5p-specific regulation of TXNRD1 levels and its effect on HCC cells.MethodsWe detected miR-125b-5p levels in human HCC tissue samples through quantitative reverse transcription polymerase chain reaction (qRT-PCR), and in vitro experiments were employed to investigate the effect of miR-125b-5p on HCC cell proliferation, migration, and invasion. Additionally, we examined miR-125b-5p-mediated changes in TXNRD1 levels by qRT-PCR and western blotting, and a dual luciferase-reporter assay was conducted to confirm direct targeting of the 3' untranslated region of TXNRD1 mRNA by miR-125b-5p.ResultsmiR-125b-5p expression was reduced in HCC tissues relative to that in matched para-carcinoma tissues; this finding was verified in HCC cohorts from the Gene Expression Omnibus and The Cancer Genome Atlas. Additionally, low miR-125b-5p expression was associated with poor prognosis in HCC patients, and gene-set enrichment analysis indicated that miR-125b-5p levels were associated with HCC proliferation and metastasis. As predicted, overexpressing miR-125b-5p restrained the proliferation, migration, and invasion of Huh7 and SK-Hep-1 cells and forced expression of the miR-125b-5p-downregulated TXNRD1 mRNA and protein levels in HCC cells. Moreover, dual luciferase-reporter assays revealed that miR-125b-5p targets TXNRD1 to directly regulate its expression, whereas TXNRD1 overexpression abolishes the inhibitory effect of miR-125b-5p on HCC cell proliferation, migration, and invasion.ConclusionsThese results demonstrated miR-125b-5p as a tumor suppressor in HCC through its inhibition of TXNRD1, thereby suggesting it as a potential target for the clinical treatment of HCC.
| S-EPMC6668076 | biostudies-literature
Project description:BackgroundCervical cancer is one most common cancer types among females over the world. While its underlying mechanisms remain unclear. Circ-CCDC66 has been revealed to participate in multiple biological functions, and contribute to various diseases' progression. In the current study, we aimed to demonstrate the role of circ-CCDC66 in cervical cancer progression.MethodsReal-time quantitative PCR (RT-qPCR) was conducted to measure the expression of circ-CCDC66, miR-452-5p, and REXO1 mRNA. Cell fractionation assay and RNA fluorescence in situ hybridization (FISH) were performed to locate circ-CCDC66 in cells. Cell account kit 8 (CCK-8) was used to detect cell proliferation ability. Transwell assay was applied to evaluate cell migration or invasion ability. Bioinformatics analysis, biotinylated RNA pull-down, RNA immunoprecipitation, and dual-luciferase reporter assays were conducted to assess the association between miR-452 and circ-CCDC66 or REXO1. Western blot was applied to measure the protein expression of REXO1. The animal tumor model was used to assess the effect of circ-CCDC66 in vivo.ResultsThe expression of circ-CCDC66 was upregulated in cervical cancer tumor tissues in comparison with normal tissues, and correlated with later tumor stage and larger tumor size. Downregulated circ-CCDC66 inhibited cervical cancer cell proliferation, migration, and invasion. Circ-CCDC66 was an efficient molecular sponge for miR-452-5p, and negatively regulated miR-452-5p expression. MiR-452-5p directly targeted to REXO1. Circ-CCDC66 regulated REXO1 expression to modulate cervical cancer progression via miR-452-5p. Moreover, downregulated circ-CCDC66 was found to suppress tumor growth in vivo.ConclusionOur results demonstrated the role of circ-CCDC66/miR-452-5p/REXO1 axis in cervical cancer progression, we might provide novel therapeutic targets for cervical cancer clinical intervention.
| S-EPMC7789749 | biostudies-literature
Project description:UnlabelledTwist1 is well known to induce epithelial-mesenchymal transition (EMT) and promote tumor metastasis. MicroRNAs (miRNAs) are involved in the EMT process and are associated with metastasis in hepatocellular carcinoma (HCC). In the present study, microRNA-26b-5p (miR-26b-5p) expression was consistently and significantly downregulated in HepG2-Twist1 HCC cell lines compared with HepG2-vector cell lines using microarrays (the HepG2-Twist1 cell line can stably express Twist1). miR-26b- 5p downregulation was directly mediated by Twist1 through binding to the promoter region of miR-26b-5p in HepG2-Twist1 cells by ChIP-seq technology. Both gain- and loss-of-function studies showed that miR-26b-5p dramatically suppressed EMT and the invasion ability of HCC cells in vitro. Using mouse models, tumors derived from miR- 26b-5p-overexpressed HCC cells exhibited a significant reduction in tumorigenicity compared with the control group. Subsequent investigation revealed that miR-26b-5p directly inhibited SMAD family member 1 (SMAD1) expression. miR-26b-5p repressed BMP4/Smad1 signaling following SMAD1 inhibition. Overexpression of SMAD1 reversed the function of miR-26b-5p. In human HCC tissues and mouse xenograft tumors, miR-26b-5p levels were inversely correlated with SMAD1 expression as well as metastasis.ConclusionmiR-26b-5p suppresses Twist1-induced EMT, invasion, and metastasis of HCC cells by targeting SMAD1 and BMP4/Smad1 signaling. This suggests a promising application for miR-26b-5p in anti-HCC therapy.
| S-EPMC5029709 | biostudies-literature
Project description:Background: Hepatocellular carcinoma (HCC), a most common malignant tumor, has an unfavorable clinical outcome. Emerging evidence has demonstrated that long noncoding RNAs (lncRNAs) play an important role in the carcinogenesis and progression of HCC. However, the clinical significances and the biological roles of most lncRNAs in HCC remain poorly understood. Methods: The expression levels of lncRNA loc339803 in HCC tissues and cell lines were determined by quantitative real-time polymerase chain reaction (qRT-PCR) assay. The cellular sublocalization of loc339803 was determined by fluorescence in situ hybridization and nuclear and cytoplasmic RNA isolation assay. Western blot, CCK-8, Edu, colony formation, migration and invasion assays were used to investigate the roles of loc339803 in HCC progression in vitro. A mouse model for lung metastasis was constructed to evaluate the role of loc339803 in HCC development in vivo. The correlations among loc339803, miR-30a-5p and SNAIL1 were validated by qRT-PCR and a dual- luciferase reporter assay. Results: The expression of loc339803 was upregulated in HCC tissues and cell lines, and positively correlated with tumor size, advanced tumor stage, higher serum AFP level and poor prognosis of HCC patients. Loc339803 can promote the migration and invasion of HCC cells in vivo and in vitro. Further studies demonstrated that loc339803 functioned as a competing endogenous RNA (ceRNA) by directly binding to miR-30a-5p, thus up-regulating the expression of SNAIL1, a target gene of miR-30a-5p. Moreover, miR-30a-5p upregulation blocked the enhanced migration and invasion of HCC cells induced by loc339803 overexpression. Conclusions: Loc339803 may be oncogenic in HCC and associated with poor clinical outcomes. LncRNA loc339803 might promote the invasion and migration of HCC cells through regulating miR-30a-5p/ SNAIL1 axis.
| S-EPMC7797647 | biostudies-literature