LncRNA MALAT1 Inhibits Apoptosis and Promotes Invasion by Antagonizing miR-125b in Bladder Cancer Cells.
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ABSTRACT:
SUBMITTER: Xie H
PROVIDER: S-EPMC5688934 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Octamer-binding transcription factor 4 (OCT4) is a key regulatory gene that maintains the pluripotency and self-renewal properties of embryonic stem cells. Although there is emerging evidence that it can function as oncogene in several cancers, the role in mediating cervical cancer remains unexplored. Here we found that OCT4 protein expression showed a pattern of gradual increase from normal cervix to cervical carcinoma in situ and then to invasive cervical cancer. Overexpression of OCT4 in two types of cervical cancer cells promotes the carcinogenesis, and inhibits cancer cell apoptosis. OCT4 induces upregulation of miR-125b through directly binding to the promoter of miR-125b-1 confirmed by chromatin immunoprecipitation analysis. MiRNA-125b overexpression suppressed apoptosis and expression of BAK1 protein. In contrast, miR-125b sponge impaired the anti-apoptotic effect of OCT4, along with the upregulated expression of BAK1. Significantly, Luciferase assay showed that the activity of the wild-type BAK1 3'-untranslated region reporter was suppressed and this suppression was diminished when the miR-125b response element was mutated or deleted. In addition, we observed negative correlation between levels of BAK1 and OCT4, and positive between OCT4 and miR-125b in primary cervical cancers. These findings suggest an undescribed regulatory pathway in cervical cancer, by which OCT4 directly induces expression of miR-125b, which inhibits its direct target BAK1, leading to suppression of cervical cancer cell apoptosis.
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Project description:MAFG-AS1 is an oncogenic lncRNA in multiple types of cancer. However, its role in bladder cancer (BC) remains unclear. The present study aimed to investigate the function of MAFG-AS1 in BC. BC and paired non-tumor tissues were collected. Two BC cell lines HT01197 and HT-1376 were used. Dual luciferase activity assay, RT-qPCR, western blot, CCK-8, transwell invasion assay, and wound healing assay were performed. We found that MAFG-AS1 was significantly up-regulated in BC tissues and predicted a poor survival rate. MAFG-AS1 interacted with miR-125b-5p. However, the expression levels of MAFG‑AS1 and miR-125b-5p were not obviously correlated in BC tissues, and MAFG‑AS1 and miR-125b-5p did not regulate the expression of each other. Interestingly, we found that SphK1, a downstream target of miR-125b-5p, was negatively correlated with miR-125b-5p, while it was positively correlated with MAFG-AS1 across BC tissues. In addition, overexpression of MAFG‑AS1 upregulated the expression of SphK1 in BC cells, and attenuated the inhibitory effects of miR-125b-5p on the expression of SphK1. Functional assays showed that overexpression of MAFG‑AS1 promoted BC cell proliferation, migration, and invasion, while its effects were attenuated by overexpression of miR-125b-5p. Moreover, overexpression of miR-125b-5p inhibited BC cell proliferation, migration, and invasion, while its effects were alleviated by overexpression of SphK1. Taken together, our findings demonstrated that MAFG-AS1 has an oncogenic role in BC by regulating the miR-125b-5p/SphK1 axis. MAFG-AS1 might serve as a good diagnostic marker and a potential therapeutic target of BC.
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Project description:We aimed to explore the interaction among lncRNA MALAT1, miR-129 and SOX2. Besides, we would investigate the effect of MALAT1 on the proliferation of glioma stem cells and glioma tumorigenesis. Differentially expressed lncRNAs in glioma cells and glioma stem cells were screened out with microarray analysis. The targeting relationship between miR-129 and MALAT1 or SOX2 was validated by dual-luciferase reporter assay. The expressions of MALAT1, miR-129 and SOX2mRNA in both glioma non-stem cells and glioma stem cells were examined by qRT-PCR assay. The impact of MALAT1 and miR-129 on glioma stem cell proliferation was observed by CCK-8 assay, EdU assay and sphere formation assay. The protein expression of SOX2 was determined by western blot. The effects of MALAT1 and miR-129 on glioma tumour growth were further confirmed using xenograft mouse model. The mRNA expression of MALAT1 was significantly up-regulated in glioma stem cells compared with non-stem cells, while miR-129 was significantly down-regulated in glioma stem cells. MALAT1 knockdown inhibited glioma stem cell proliferation via miR-129 enhancement. Meanwhile, miR-129 directly targeted at SOX2 and suppressed cell viability and proliferation of glioma stem cells by suppressing SOX2 expression. The down-regulation of MALAT1 and miR-129 overexpression both suppressed glioma tumour growth via SOX2 expression promotion in vivo. MALAT1 enhanced glioma stem cell viability and proliferation abilities and promoted glioma tumorigenesis through suppressing miR-129 and facilitating SOX2 expressions.
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Project description:Zinc fingers and homeoboxes 1 (ZHX1) is a transcription repressor that has been implicated in the tumorigenesis and progression of diverse tumors. The functional role and regulating mechanism of ZHX1 has not been elucidated in glioblastoma (GBM). Previous reports have suggested that a large number of non-coding RNAs play a vital role in glioma initiation and progression. This study aimed to investigate the functional role and co-regulatory mechanisms of the metastasis-associated lung adenocarcinoma transcript-1 (MALAT1)/ microRNA-199a (miR-199a)/ZHX1 axis in GBM. We analyzed the expression of the MALAT1/miR-199a/ZHX1 axis and its correlation with patients' overall survival using two different glioma gene-expression datasets. A series of in vitro and in vivo studies including dual luciferase reporter assay, fluorescence in situ hybridization (FISH), RNA immunoprecipitation, and pull-down experiments were completed to elucidate the biological significance of the MALAT1/miR-199a/ZHX1 axis in promoting glioma proliferation and progression. Elevated ZHX1 expression correlated with poor prognosis in GBM patients, and in vitro studies demonstrated that ZHX1 attenuated GBM cell apoptosis by downregulation of pro-apoptotic protein (Bax) and upregulation of anti-apoptotic protein (Bcl-2). Furthermore, knockdown of MALAT1 inhibited GBM proliferation and progression in vitro and reduced tumor volume and prolonged survival in an orthotopic GBM murine model. Finally, we demonstrated that MALAT1 promoted ZHX1 expression via acting as a competing endogenous RNA by sponging miR-199a. The MALAT1/miR-199a/ZHX1 axis promotes GBM cell proliferation and progression in vitro and in vivo, and its expression negatively correlates with GBM patient survival. Blocking the MALAT1/miR-199a/ZHX1 axis can serve as a novel therapeutic strategy for treating GBM.
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Project description:BackgroundAlthough miR-125b plays a crucial role in many human cancers. However, its function in heart failure (HF) remains unclear. Our study aimed to investigate its involvement in heart failure.MethodsIn this study, the mouse HF model was successfully constructed through transverse aortic constriction (TAC) operation. Changes in mRNA and protein levels in isolated myocytes and heart tissues were examined using qRT-PCR, Western blot and Immunohistochemical staining and immunofluorescent staining. Changes in cardiac functions were examined using ultrasound. Interactions between miR-125b and BAK1 was analyzed using the luciferase reporter assay. Cardiomyocyte apoptosis was evaluated using the TUNEL staining.ResultsWe found that miR-125b expression was significantly downregulated in myocardial tissues of HF mice. Moreover, miR-125b upregulation in HF mice injected with agomir-125b efficiently ameliorated cardiac function. Further, miR-125b upregulation significantly decreased the protein levels of apoptosis-related makers c-caspase 3 and Bax, while increased Bcl-2 expression. In addition, BAK1 was identified as a direct target of miR-125b. As expected, BAK1 overexpression observably reversed the effect of agomir-125b on cardiac function and on the expression of apoptosis-related makers in the heart tissues of HF mice.ConclusionsTaken together, miR-125b overexpression efficiently attenuated cardiac function injury of HF mice by targeting BAK1 through inhibiting cardiomyocyte apoptosis, suggesting that miR-125b/BAK1 axis might be a potential target for the diagnosis or treatment of HF.
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Project description:Colorectal cancer represents a great burden for patients worldwide. Long noncoding RNA BX357664 is an RNA that was identified by microarray technique in renal cell carcinoma. The function of BX357664 in solid tumors remains largely unknown. The present study aimed to investigate the expression profile and functional role of BX357664 in human colorectal cancer progression. The transcription levels of BX357664 were initially examined in vivo and in vitro. An overexpression plasmid was constructed in order to examine the effects of BX357664 overexpression on cell proliferation, apoptosis, migration and invasion. The results demonstrated that BX357664 was significantly downregulated in clinical colorectal cancer tissues and cell lines. Overexpression of BX357664 decreased cell proliferation rates and cell colony formation capacities in HCT116 and HT-29 cells. Following BX357664 overexpression, HCT116 and HT-29 cells exhibited reduced migration and invasion capacities. Would closure was also blunted by >50% following overexpression of BX357664 in HCT-116 and HT-29 cells. In addition, the cell cycle regulators Cyclin B1, CDC25C and Cyclin D1 as well as the mesenchymal marker N-cadherin were downregulated, whereas the epithelial marker E-cadherin was upregulated by BX357664 overexpression. Finally, HCT116 and HT-29 cell apoptosis was induced and activities of caspase-3 and caspase-9 increased significantly following BX357664 overexpression. The present data suggested that BX257664 negatively regulated cell proliferation and metastasis and promoted cell apoptosis in colorectal cancer. These observations provided novel evidence that BX357664 might serve as a tumor suppressor and a potential therapeutic target in the treatment of colorectal cancer in the clinic.
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Project description:MicroRNAs (miRNAs) are strongly associated to the progression of hepatocellular carcinoma (HCC), which presents a high potential for diagnosis and treatment; however, the role of miRNAs is still largely unknown. The aim of the present study was to examine the expression and the biological role of miRNA (miR)-206 in the development of HCC, and to identify the underlying molecular mechanism. Results from this study show that miR-206 was significantly downregulated in HCC tissues and cell lines. It was observed that low expression of miR-206 was linked to advanced TNM stage, tumor nodularity and venous infiltration in patients with HCC; low miR-206 expression was associated with shorter survival times. miR-206 overexpression using miR-206 mimics notably decreased the proliferative ability and increased apoptosis of MHCC97-H and HCCLM3 HCC cell lines. Overexpression of miR-206 suppressed invasiveness associated with reduced epithelial-mesenchymal transition. Moreover, the c-Met oncogene, which is upregulated in HCC tissues, was negatively associated with the expression of miR-206. Notably, it was shown that miR-206 may exert its antitumor effect through suppressing c-Met/Akt/mTOR signaling. Low expression of miR-206 was shown to be regulated by lncRNA MALAT1 in HCC. Collectively, this study presented evidence that miR-206 was controlled by lncRNA MALAT1 and partially suppressed the proliferation and invasion of HCC through the c-Met/Akt/mTOR signaling pathway. According to these results, understanding MALAT1/miR-206-dependent regulation may lead to potential approaches for diagnosis and prospective treatment of HCC.
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Project description:ObjectiveThe study aimed to explore the correlations of long non-coding RNA MALAT1 (lncRNA MALAT1) and its targets microRNA (miR)-125b, miR-133, miR-146a, and miR-203 with acute exacerbation risk, inflammation, and disease severity of chronic obstructive pulmonary disease (COPD).MethodsPlasma samples were obtained from 120 acute exacerbation COPD (AECOPD) patients, 120 stable COPD patients, and 120 healthy controls (HCs). RT-qPCR was conducted to detect lncRNA MALAT1 expression and its target miRNAs, and ELISA was performed to detect the inflammatory cytokines.ResultsLncRNA MALAT1 was highest in AECOPD patients followed by stable COPD patients and then HCs, which distinguished AECOPD patients from HCs (AUC: 0.969, 95% CI: 0.951-0.987) and stable COPD patients (AUC: 0.846, 95% CI: 0.798-0.894). Furthermore, lncRNA MALAT1 positively correlated with GOLD stage in both AECOPD and stable COPD patients. Regarding inflammatory cytokines, lncRNA MALAT1 positively correlated with tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-8, IL-17, and IL-23 in both AECOPD and stable COPD patients. Besides, lncRNA MALAT1 negatively correlated with miR-125b, miR-146a, and miR-203 in AECOPD patients and reversely correlated with miR-125b and miR-146a in stable COPD patients. Notably, miR-125b, miR-133, miR-146a, and miR-203 were the lowest in AECOPD patients, followed by stable COPD patients, and then HCs; miR-125b, miR-133, miR-146a, and miR-203 negatively correlated with inflammation and GOLD stage in AECOPD and stable COPD patients.ConclusionLncRNA MALAT1 exhibits clinical implications in acute exacerbation risk prediction and management of COPD via the inner-correlation with its targets miR-125b, miR-146a, and miR-203.
| S-EPMC7521228 | biostudies-literature
Project description:Metastasis contributes to the poor prognosis of colorectal cancer, the causative factor of which is not fully understood. Previously, we found that miR-125b (Accession number: MIMAT0000423) contributed to cetuximab resistance in colorectal cancer (CRC). In this study, we identified a novel mechanism by which miR-125b enhances metastasis by targeting cystic fibrosis transmembrane conductance regulator (CFTR) and the tight junction-associated adaptor cingulin (CGN) in CRC. We found that miR-125b expression was upregulated in primary CRC tumors and metastatic sites compared with adjacent normal tissues. Overexpression of miR-125b in CRC cells enhanced migration capacity, while knockdown of miR-125b decreased migration and invasion. RNA-sequencing (RNA-seq) and dual-luciferase reporter assays identified CFTR and CGN as the target genes of miR-125b, and the inhibitory impact of CFTR and CGN on metastasis was further verified both in vitro and in vivo. Moreover, we found that miR-125b facilitated the epithelial-mesenchymal transition (EMT) process and the expression and secretion of urokinase plasminogen activator (uPA) by targeting CFTR and enhanced the Ras Homolog Family Member A (RhoA)/Rho Kinase (ROCK) pathway activity by targeting CGN. Together, these findings suggest miR-125b as a key functional molecule in CRC and a promising biomarker for the diagnosis and treatment of CRC.
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Project description:BackgroundMetastasis is a major factor weakening the long-term survival of breast cancer patients. Increasing evidence revealed that long non-coding RNAs (lncRNAs) were involved in the occurrence and development of breast cancer. In this study, we aimed to investigate the role of LGALS8-AS1 in the metastatic progression of breast cancer cells and its potential mechanisms.ResultsThe lncRNA LGALS8-AS1 was highly expressed in breast cancer and associated with poor survival. LGALS8-AS1 functioned as an oncogenic lncRNA that promoted the metastasis of breast cancer both in vitro and in vivo. It upregulated SOX12 via competing as a competing endogenous RNA (ceRNA) for sponging miR-125b-5p and acted on the PI3K/AKT signaling pathway to promote the metastasis of breast cancer. Furthermore, SOX12, in turn, activated LGALS8-AS1 expression via direct recognition of its sequence binding enrichment motif on the LGALS8-AS1 promoter, thereby forming a positive feedback regulatory loop.ConclusionThis study manifested a novel mechanism of LGALS8-AS1 facilitating the metastasis of breast cancer. The LGALS8-AS1/miR-125b-5p/SOX12 reciprocal regulatory loop dyscrasia promoted the migration and invasion of breast cancer cells. This signaling axis could be applicable to the design of novel therapeutic strategies against this malignancy.
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