Chronic alcohol exposure promotes HCC stemness and metastasis through β-catenin/miR-22-3p/TET2 axis.
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ABSTRACT:
SUBMITTER: Chen D
PROVIDER: S-EPMC8202861 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe mechanism underlying breast cancer stem cell (BCSCs) characteristics remains to be fully elucidated. Accumulating evidence implies that long noncoding RNAs (lncRNAs) play a pivotal role in regulating BCSCs stemness.MethodsLncRNA LUCAT1 expression was assessed in breast cancer tissues (n = 151 cases) by in situ hybridization. Sphere-formation assay and colony formation assay were used to detect cell self-renewal and proliferation, respectively. RNA immunoprecipitation, RNA pull down and luciferase reporter assays were used to identify LUCAT1 and TCF7L2 as the direct target of miR-5582-3p. The activity of the Wnt/β-catenin pathway was analyzed by TOP/FOP-Flash reporter assays, western blot and immunohistochemistry (IHC).ResultsThis study found LUCAT1 expression was related to tumor size (p = 0.015), lymph node metastasis (p = 0.002) and TNM staging (p < 0.001). High LUCAT1 expression indicated a shorter overall survival (p = 0.006) and disease-free survival (p = 0.011). Furthermore, LUCAT1 was more expressed in BCSCs than in breast cancer cells (BCCs) by lncRNA microarray chips. LUCAT1 up-regulation promoted proliferation of BCCs, while LUCAT1 down-regulation inhibited self-renewal of BCSCs. MiR-5582-3p was directly bound to LUCAT1 and TCF7L2 and negatively regulated their expression. LUCAT1 affected Wnt/β-catenin pathway.ConclusionsLUCAT1 might be a significant biomarker to evaluate prognosis in breast cancer. LUCAT1 increased stem-like properties of BCCs and stemness of BCSCs by competitively binding miR-5582-3p with TCF7L2 and enhancing the Wnt/β-catenin pathway. The LUCAT1/miR-5582-3p/TCF7L2 axis provides insights for regulatory mechanism of stemness, and new strategies for clinical practice.
| S-EPMC6626338 | biostudies-literature
Project description:Long noncoding RNAs (lncRNAs) play the critical biological role in many malignant tumours. MIR4435-2HG has been proven to be a novel oncogenic lncRNA. However, the exact role and mechanism of MIR4435-2HG in hepatocellular carcinoma (HCC) remain unclear. Here, we found that MIR4435-2HG is overexpressed in HCC tissue compared to normal controls and that high level of MIR4435-2HG indicates a poorer prognosis in HCC patients. MIR4435-2HG enhances the growth and metastasis ability of HCC cells. MIR4435-2HG promotes the expression of YWHAZ by sponging miR-22-3p to liberate YWHAZ mRNA transcripts. MIR4435-2HG facilitates the proliferation and metastasis of HCC by modulating the miR-22-3p/YWHAZ axis. These results demonstrated the role and mechanism of MIR4435-2HG in malignant progression of HCC. MIR4435-2HG may be used as the prognostic marker and treatment target for the patient with HCC.
| S-EPMC7653602 | biostudies-literature
Project description:BackgroundTreating advanced colon cancer remains challenging in clinical settings because of the development of drug resistance and distant metastasis. Mechanisms underlying the metastasis of colon cancer are complex and unclear.MethodsComputational analysis was performed to determine genes associated with the exosomal long noncoding (lncRNA) plasmacytoma variant translocation 1 (PVT1)/vascular endothelial growth factor A (VEGFA) axis in patients with colon cancer. The biological importance of the exosomal lncRNA PVT1/VEGFA axis was examined in vitro by using HCT116 and LoVo cell lines and in vivo by using a patient-derived xenograft (PDX) mouse model through knockdown (by silencing of PVT1) and overexpression (by adding serum exosomes isolated from patients with distant metastasis (M-exo)).ResultsThe in silico analysis demonstrated that PVT1 overexpression was associated with poor prognosis and increased expression of metastatic markers such as VEGFA and epidermal growth factor receptor (EGFR). This finding was further validated in a small cohort of patients with colon cancer in whom increased PVT1 expression was correlated with colon cancer incidence, disease recurrence, and distant metastasis. M-exo were enriched with PVT1 and VEGFA, and both migratory and invasive abilities of colon cancer cell lines increased when they were cocultured with M-exo. The metastasis-promoting effect was accompanied by increased expression of Twist1, vimentin, and MMP2. M-exo promoted metastasis in PDX mice. In vitro silencing of PVT1 reduced colon tumorigenic properties including migratory, invasive, colony forming, and tumorsphere generation abilities. Further analysis revealed that PVT1, VEGFA, and EGFR interact with and are regulated by miR-152-3p. Increased miR-152-3p expression reduced tumorigenesis, where increased tumorigenesis was observed when miR-152-3p expression was downregulated.ConclusionExosomal PVT1 promotes colon cancer metastasis through its association with EGFR and VEGFA expression. miR-152-3p targets both PVT1 and VEGFA, and this regulatory pathway can be explored for drug development and as a prognostic biomarker.
| S-EPMC8315867 | biostudies-literature
Project description:Objective:The aim of this study was to investigate the role of XPD in migration and invasion of hepatocellular carcinoma (HCC) cells. Methods:The expression of XPD and miR-29a-3p was examined by western blot and qRT-PCR, cell proliferation was detected by MTT assay, cell migration was detected by transwell assay. TargetScan was used to predict potential targets of miR-29a-3p. Results:In this study, we found that the expression of XPD and miR-29a-3p was downregulated in HCC samples and HCC cell lines. XPD suppressed proliferation and migration of HCC cell via regulating miR-29a-3p expression. Target prediction analysis and dual-luciferase reporter assay confirmed Mdm2 and PDGF-B were direct targets of miR-29a-3p, and miR-29a-3p suppressed proliferation and migration of HCC cells via regulating the expression of Mdm2 or PDGF-B. Conclusions:Our data indicated that XPD suppressed cell proliferation and migration via miR-29a-3p-Mdm2/PDGF-B axis in HCC.
| S-EPMC6321695 | biostudies-other
Project description:Increasing evidence suggests that global downregulation of miRNA expression is a hallmark of human cancer, potentially due to defects in the miRNA processing machinery. In this study, we found that the protein expression of Argonaute 2 (AGO2), a key regulator of miRNA processing, was downregulated in colorectal cancer (CRC) tissues, which was also consistent with the findings of the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Furthermore, the correlation between the levels of AGO2 and epithelial-mesenchymal transition (EMT) markers (E-cadherin and vimentin) indicated that reduced levels of AGO2 promoted EMT in CRC. Low expression of AGO2 was an indicator of a poor prognosis among CRC patients. Knockdown of AGO2 in CRC cells promoted migration, invasion and metastasis formation in vitro and in vivo but had no influence on proliferation. To provide detailed insight into the regulatory roles of AGO2, we performed integrated transcriptomic, quantitative proteomic and microRNA sequencing (miRNA-seq) analyses of AGO2 knockdown cells and the corresponding wild-type cells and identified neuropilin 1 (NRP1) as a new substrate of AGO2 via miR-185-3p. Our data provided evidence that knockdown of AGO2 resulted in a reduction of miR-185-3p expression, leading to the upregulation of the expression of NRP1, which is a direct target of miR-185-3p, and elevated CRC cell metastatic capacity. Inhibition of NRP1 or treatment with a miR-185-3p mimic successfully rescued the phenotypes of impaired AGO2, which suggested that therapeutically targeting the AGO2/miR-185-3p/NRP1 axis may be a potential treatment approach for CRC.
| S-EPMC8042018 | biostudies-literature
Project description:Accumulating evidences revealed that long noncoding RNAs (lncRNAs) have been participated in cancer malignant progression, including glioblastoma multiforme (GBM). Despite much studies have found the precise biological role in the regulatory mechanisms of GBM, however the molecular mechanisms, particularly upstream mechanisms still need further elucidated. RT-QPCR, cell transfection, western blotting and bioinformatic analysis were executed to detect the expression of EGR1, HNF1A-AS1, miR-22-3p and ENO1 in GBM. Cell proliferation assay, colony formation assay, wound healing, migration and invasion assays were performed to detect the malignant characters of GBM cells. The molecular regulation mechanism was confirmed by luciferase reporter assay, ChIP and RIP. Finally, orthotopic mouse models were established to examine the effect of HNF1A-AS1 in vivo. In the current study, we analyzed clinical samples to show that the HNF1A-AS1 expression is upregulated and associated with poor patient survival in GBM. Functional studies revealed that HNF1A-AS1 knockdown markedly inhibits malignant phenotypes of GBM cells, whereas overexpression of HNF1A-AS1 exerts opposite effect. Mechanistically, the transcription factor EGR1 forced the HNF1A-AS1 expression by directly binding the promoter region of HNF1A-AS1. Furthermore, combined bioinformatics analysis with our mechanistic work, using luciferase reporter assays and RIP, we first demonstrated that HNF1A-AS1 functions as a competing endogenous RNA (ceRNA) with miR-22-3p to regulate ENO1 expression in GBM cells. HNF1A-AS1 directly binds to miR-22-3p and significantly inhibits miR-22-3p expression, while ENO1 expression was increased. miR-22-3p inhibitor offsets the HNF1A-AS1 silencing induced suppression in malignant behaviors of GBM cells. ENO1 was verified as a direct target of miR-22-3p and its expression levels was negatively with the prognosis in GBM patients. Taken together, our study illuminated the definite mechanism of HNF1A-AS1 in promoting GBM malignancy, and provided a novel therapeutic target for further clinical application.
| S-EPMC8590016 | biostudies-literature
Project description:BackgroundDiabetic cardiomyopathy (DCM) is one of the serious complications of the accumulated cardiovascular system in the long course of diabetes. To date, there is no effective treatment available for DCM. Circular RNA (circRNA) is a novel r2egulatory RNA that participates in a variety of cardiac pathological processes. However, the regulatory role of circular RNA MAP3K5 (circMAP3K5) in DCM is largely unclear.Methods and resultsMicroarray analysis of DCM rats' heart circular RNAs was performed and the highly species-conserved circRNA mitogen-activated protein kinase kinase kinase 5 (circMAP3K5) was identified, which participates in DCM processes. High glucose-provoked cardiotoxicity leads to the up-regulation of circMAP3K5, which mechanistically contributes to cardiomyocyte cell death. Also, in high glucose-induced H9c2 cardiomyocytes, the level of apoptosis was significantly increased, as well as the expression of circMAP3K5. In contrast, the depletion of circMAP3K5 could reduce high glucose-induced apoptosis in cardiomyocytes. In terms of mechanism, circMAP3K5 acts as a miR-22-3p sponge and miR-22-3p directly target death-associated protein kinase 2 (DAPK2) in H9c2 cardiomyocytes, where in circMAP3K5 upregulates DAPK2 expression by targeting miR-22-3p. Moreover, we also found that miR-22-3p inhibitor and pcDNA DAPK2 could antagonize the protective effects brought by the depletion of circMAP3K5.ConclusionCircMAP3K5 is a highly conserved noncoding RNA that is upregulated during DCM process. We concluded that circMAP3K5 promotes high glucose-induced cardiomyocyte apoptosis by regulating the miR-22-3p/DAPK2 axis. The results of this study highlight a novel and translationally important circMAP3K5-based therapeutic approach for DCM.
| S-EPMC10809294 | biostudies-literature
Project description:To explore the effect of fetal-lethal non-coding developmental regulatory RNA (FENDRR) in the initiation and progression of gastric cancer (GC). We detected the levels of FENDRR, microRNA-214-3p (miR-214-3p), and ten-eleven-translocation (TET2) in GC tissues and GC cell lines. In addition, we evaluated the location of FENDRR in GC cell lines by fluorescence in situ hybridization (FISH). Cell proliferation and apoptosis were measured by CCK-8 and Hoechst staining assays. Methylation-specific PCR assay (MSP) was used to evaluate the methylation status of ras-association domain family 1A (RASSF1A). We also observed the direct binding of miR-214-3p on FENDRR by dual-luciferase activity assay in GC cells. FENDRR and TET2 expressions were significantly down-regulated and miR-214-3p was up-regulated in gastric cancer tissues compared to adjacent unaffected tissues. In addition, RASSF1A was hypermethylated in gastric cancer tissues compared to adjacent tissues. The expressions of all the three indicators were influenced by differentiation of tumor, TNM stage of tumors, and lymph node metastasis in patients with GC. A gastric cancer cell line with low FENDRR expression compared to a high FENDRR expressing cell line showed again increased miR-214-3p expression, decreased TET2 and RASSF1A expressions, and RASSF1A hypermethylation, resulting in decreased apoptosis and increased proliferation. Furthermore, we observed a negative correlation between FENDRR and miR-214-3p in GC. The FENDRR/miR-214-3P/TET2 axis plays a critical role in GC progress via methylation of RASSF1A.
| S-EPMC6220211 | biostudies-literature
Project description:Abnormal energy metabolism is one of the characteristics of tumours. In the last few years, more and more attention is being paid to the role and regulation of tumour aerobic glycolysis. Cancer cells display enhanced aerobic glycolysis, also known as the Warburg effect, whereby tumour cells absorb glucose to produce a large amount of lactic acid and energy under aerobic conditions to favour tumour proliferation and metastasis. In this study, we report that the haploinsufficient tumour suppressor ASPP2, can inhibit HCC growth and stemness characteristics by regulating the Warburg effect through the WNT/β-catenin pathway. we performed glucose uptake, lactate production, pyruvate production, ECAR and OCR assays to verify ASPP2 can inhibit glycolysis in HCC cells. The expression of ASPP2 and HK2 was significantly inversely correlated in 80 HCC tissues. Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance. This ASPP2-induced inhibition of glycolysis metabolism depends on the WNT/β-catenin pathway. ASPP2-regulated Warburg effect is associated with tumour progression and provides prognostic value. and suggest that may be promising as a new therapeutic strategy in HCC.
| S-EPMC9983321 | biostudies-literature
Project description:The Wnt/?-catenin pathway is constitutively active and promotes multiple tumor processes, including breast cancer metastasis. However, the underlying mechanism by which the Wnt/?-catenin pathway is constitutively activated in breast cancer metastasis remains unclear. Inhibition of Wnt antagonists is important for Wnt/?-catenin signaling activation, and post-transcriptional regulation of these antagonists by microRNAs (miRNAs) might be a possible mechanism underlying signaling activation. Regulation of nuclear pre-mRNA domain-containing 1A (RPRD1A) is a known inhibitor of cell growth and Wnt/?-catenin signaling activity, but the function and regulatory mechanism of RPRD1A in breast cancer have not been clarified. The aim of this study was to understand how regulators of the Wnt/?-catenin pathway may play a role in the metastasis of this cancer. Methods: RPRD1A expression and its association with multiple clinicopathological characteristics was analyzed immunohistochemically in human breast cancer specimens. miR-454-3p expression was analyzed using real-time PCR. RPRD1A or miR-454-3p knockdown and overexpression were used to determine the underlying mechanism of their functions in breast cancer cells. Xenografted tumor model, 3D invasive culture, cell migration and invasion assays and sphere formation assay were used to determine the biofunction of RPRD1A and miR-454-3p in breast cancer. Electrophoretic mobility shift assay (EMSA), luciferase reporter assay, and RNA immunoprecipitation (RIP) were performed to study the regulation and underlying mechanisms of RPRD1A and miR-454-3p expression and their correlation with the Wnt/?-catenin pathway in breast cancer. Results: The Wnt/?-catenin signaling antagonist RPRD1A was downregulated and its upstream regulator miR-454-3p was amplified and overexpressed in metastatic breast cancer, and both were correlated with overall and relapse-free survival in breast cancer patients. The suppression by miR-454-3p on RPRD1A was found to activate Wnt/?-catenin signaling, thereby promoting metastasis. Simultaneously, three other negative regulators of the Wnt/?-catenin pathway, namely, AXIN2, dickkopf WNT signaling pathway inhibitor (DKK) 3 and secreted frizzled related protein (SFRP) 1, were also found to be targets of miR-454-3p and were involved in the signaling activation. miR-454-3p was found to be involved in early metastatic processes and to promote the stemness of breast cancer cells and early relapse under both in vitro and in vivo conditions. Conclusions: The findings indicate that miR-454-3p-mediated suppression of Wnt/?-catenin antagonist RPRD1A, as well as AXIN2, DKK3 and SFRP1, sustains the constitutive activation of Wnt/?-catenin signaling; thus, miR-454-3p and RPRD1A might be potential diagnostic and therapeutic targets for breast cancer metastasis.
| S-EPMC6376193 | biostudies-literature