KLF5 activates lncRNA DANCR and inhibits cancer cell autophagy accelerating gastric cancer progression.
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ABSTRACT:
SUBMITTER: Cheng Z
PROVIDER: S-EPMC8455684 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Long noncoding RNAs (lncRNAs) are associated with various types of cancer. However, the precise roles of many lncRNAs in tumor progression remain unclear. In this study, we found that the expression of the lncRNA TP53TG1 was downregulated in gastric cancer (GC) and it functioned as a tumor suppressor. In addition, low TP53TG1 expression was significantly associated with poor survival in patients with GC. TP53TG1 inhibited the proliferation, metastasis, and cell cycle progression of GC cells, while it promoted their apoptosis. m6A modification sites are highly abundant on TP53TG1, and demethylase ALKBH5 reduces TP53TG1 stability and downregulates its expression. TP53TG1 interacts with cancerous inhibitor of protein phosphatase 2A (CIP2A) and triggers its ubiquitination-mediated degradation, resulting in the inhibition of the PI3K/AKT pathway. These results suggest that TP53TG1 plays an important role in inhibiting the progression of GC and provides a crucial target for GC treatment.
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Project description:Human serum microRNAs (miRNAs) have been shown to serve as disease fingerprints for predicting survival of cancer patients. However, the roles of specific miRNAs involved in gastric cancer (GC) are largely unknown. In this study, miRNA profiling was performed on sera obtained from six patients in good- and poor-survival groups. Expression of miR-423-3p was validated by quantitative RT-PCR in another 67 GC serum samples and paired normal and cancerous gastric tissues. Luciferase reporter assays were used to identify the target gene Bcl-2-interacting mediator of cell death (Bim). As a result, between the good-survival and poor-survival groups, the expression of nine serum miRNAs was altered more than two-fold. Among these, miR-423-3p was significantly increased in the poor-survival group, and its overexpression in GC tissues predicted poor survival in 119 patients with GC. miR-423-3p was found to promote cell proliferation, migration, and invasion in cell lines and animal models. Mechanistically, knockdown of the autophagy-related gene (Atg) 7 rescued the GC-promoting effect of miR-423-3p. In conclusion, miR-423-3p activates oncogenic and Beclin-1-dependent autophagy and promotes GC progression by reducing the expression of Bim. The newly identified miR-423-3p-Bim axis might be a potential therapeutic target in GC.
| S-EPMC5383553 | biostudies-literature
Project description:Background: Long non-coding RNAs (lncRNAs) are deemed to be relevant to the tumorigenesis and development of a variety of tumors, containing gastric cancer (GC). The purpose of our investigations is to explore the character of HCP5 in GC. Methods: HCP5 expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in 62 matched GC tissues and corresponding para-carcinoma tissues. In vitro and in vivo functional assays were subjected to verify the biological effects of HCP5 after alteration of HCP5. Chromatin immunoprecipitation assay (CHIP) assays were conducted to confirm that myocyte enhancer factor 2A (MEF2A) could bind to HCP5 promoter regions and thereby induce HCP5 expression. Analysis of the latent binding of miR-106b-5p to HCP5 and p21 was made by bioinformatics prediction and luciferase reporter assays. Results: Significant downregulation of HCP5 was detected in GC tissues. Negative correlation was determined between HCP5 expression level and tumor size and overall survival in GC patients. HCP5 depletion had a facilitating impact on proliferation, migration and invasion of GC cells. Consistently, overexpression of HCP5 came into an opposite effect. Moreover, we demonstrated that MEF2A could combine with the promoter region of HCP5 and thereby induce HCP5 transcription. Luciferase reporter assays revealed that HCP5 could compete with miR-106b-5p as a competing endogenous RNA (ceRNA) and upregulated p21 expression in GC. Conclusions: MEF2A-mediated HCP5 could exert an anti-tumor effect among the development of GC via miR-106b-5p/p21 axis, which provides a novel target for GC therapy.
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Project description:Objective:This study set out to probe into the effects of long non-coding RNA (LncRNA) differentiation antagonizing non-protein coding RNA (DANCR) on apoptosis and autophagy of breast cancer (BC) cells. Methods:The expression levels of DANCR, miR-758-3p and paired box 6 (PAX6) in BC tissues and cell lines were detected. The transcription and protein levels of PAX6, apoptosis-related factors (caspase-3, caspase-9, Bax/Bcl-2), and autophagy-related factors (LC3B, Atg5, Beclin-1) in BC cells were detected. The cell proliferation, apoptosis, autophagy and the regulatory relationship between genes and target genes were analyzed. Results:DANCR and PAX6 were up-regulated in BC tissues and cell lines, while miR-758-3p was opposite. Down-regulating DANCR inhibited the malignant proliferation of BC cells and also promoted apoptosis and autophagy, which showed that caspase-3, caspase-9, Bax/Bcl-2, LC3B, Atg5 transcription and protein levels increased, while Beclin-1 transcription and protein levels decreased. DANCR regulated miR-758-3p in a targeted manner, and its over-expression could weaken the anti-cancer effect of miR-758-3p on BC cells. In addition, miR-758-3p also directly targeted PAX6, and knocking down its expression could weaken the inhibitory effect of down-regulating PAK6 on BC cell apoptosis and autophagy. We also found that DANCR acted as a competitive endogenous RNA sponge miR-758-3p, thus regulating the PAX6 expression. Conclusion:DANCR-miR-758-3p-PAX6 molecular network plays a key regulatory role in BC cell apoptosis and autophagy, which may provide reference for treating patients.
| S-EPMC7269637 | biostudies-literature
Project description:BackgroundLong noncoding RNAs (lncRNAs) are a new class of cancer regulators. Here, we aimed to investigate the diagnostic and therapeutic values of an lncRNA, differentiation antagonizing noncoding RNA (DANCR), in lung cancer.MethodsReal-time polymerase chain reaction was used to compare DANCR levels in normal and cancerous lung tissues as well as lung cancer cells. Lentiviral transduction was used to induce DANCR overexpression or silencing in vitro, followed by monitoring cell proliferation, colony formation, and changes in microRNA-216a (miR-216a) expression. DANCR-specific small hairpin RNA transduction was used to establish cells with stable DANCR knockdown, and silenced cells were used to initiate lung tumor xenografts, followed by monitoring tumor growth.ResultsDANCR upregulation was seen in lung cancer, particularly in high-grade lung cancer tissues and aggressive cancer cells. Ectopic DANCR expression induced lung cancer cell proliferation and colony formation, whereas DANCR silencing induced opposing effects. The miR-216a level in cancer cells was negatively correlated with DANCR expression. The DANCR knockdown reduced the growth of tumor xenografts in vivo.ConclusionDANCR upregulation is a potential indicator of aggressive lung cancer. Silencing of DANCR has great potential as a potent therapeutic strategy in lung cancer.
| S-EPMC6852365 | biostudies-literature
Project description:Cisplatin (DDP) resistance is a huge obstacle to gastric cancer (GC) treatment. Long non-coding RNAs (lncRNAs) have been manifested to exert pivotal functions in GC development. Herein, we aimed to explore the functional impact of lncRNA small nucleolar RNA host gene 6 (SNHG6) on DDP resistance and progression of GC. Quantitative real-time PCR (qRT-PCR) assay or Western blotting was performed to detect the expression of SNHG6, microRNA(miR)-1297, and epithelial-mesenchymal transition (EMT)-related factors and B-Cell Lymphoma 2 (Bcl-2) in DDP-resistant GC cells. Half inhibition concentration (IC50) to DDP, clonogenicity, apoptosis and invasion were examined via CCK-8 assay, colony formation assay, flow cytometry and Transwell assay, respectively. Target association between miR-1297 and SNHG6 or BCL-2 was demonstrated via dual-luciferase reporter assay or RIP assay. Xenograft models in nude mice were formed to investigate role of SNHG6 in vivo. We found that SNHG6 and BCL-2 were up-regulated, while miR-1297 expression was declined in GC tissues and DDP-resistant cells. Moreover, depletion of SNHG6 or gain of miR-1297 could repress DDP resistance, proliferation and metastasis of DDP-resistant cells, which was weakened by miR-1297 inhibition or BCL-2 overexpression. Besides, SNHG6 positively regulated BCL-2 expression by sponging miR-1297. Furthermore, SNHG6 knockdown repressed GC tumor growth in vivo. In a word, lncRNA SNHG6 knockdown had inhibitory effects on DDP resistance and progression of GC by sponging miR-1297, highlighting its potential in GC treatment.
| S-EPMC8661508 | biostudies-literature
Project description:Osteoporosis is a progressive bone disease caused by impaired function of endogenous bone marrow-derived mesenchymal stem cells (BMSCs). Herein, we investigated the mechanism of lncRNA SNHG14 in osteoporosis progression. BMSCs were isolated from BALB/c mice. The osteogenic ability of BMSCs was assessed by Alkaline phosphatase (ALP) and Alizarin Red S Staining (ARS) staining. The interaction between miR-493-5p and SNHG14 or myocyte enhancer factor 2 C (Mef2c) was confirmed by dual-luciferase reporter assay. Bone histomorphometry changes were evaluated to analyze SNHG14'roles in osteoporosis in vivo. Our results illustrated SNHG14 and Mef2c levels were increased in a time-dependent manner in BMSCs, and miR-493-5p expression was decreased. SNHG14 knockdown inhibited osteogenic differentiation of BMSCs, and SNHG14 upregulation had the opposite effect. SNHG14 overexpression elevated bone mineral density and bone trabecular number, and alleviated osteoporosis progression in vivo. Mechanically, miR-493-5p was a target of SNHG14, and miR-493-5p targeted the Mef2c gene directly. SNHG14 overexpression reversed the inhibition of miR-493-5p on the osteogenic ability of BMSCs, and miR-493-5p silencing accelerated BMSCs osteogenesis by activating Mef2c-mediated autophagy to accelerate BMSCs osteogenesis. In short, SNHG14 activated autophagy via regulating miR-493-5p/Mef2c axis to alleviate osteoporosis progression, which might provide a new molecular target for osteoporosis treatment.
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Project description:Gliomas are the most fatal malignant cerebral tumors. Temozolomide (TMZ), as the primary chemotherapy drug, has been widely used in clinics. However, resistance of TMZ still remains to poor defined. LncRNAs have been reported to play crucial roles in progression of various cancers and resistance of multiple drugs. However, the biological function and underlying mechanisms of most lncRNAs in glioma still remains unclear. Based on the TCGA database, a total of 94 differentially expressed lncRNAs, including 16 up-regulated genes and 78 downregulated genes were identified between gliomas and normal brain tissues. Subsequently, lncRNA DLEU1, HOTAIR, and LOC00132111 were tested to be significantly related to overall survival (OS) between high- and low-expression groups. Additionally, we verified that lncRNA DLEU1 was high expressed in 108 gliomas, compared with 19 normal brain tissues. And high expression of lncRNA DLEU1 predicted a poor prognosis (HR = 1.703, 95%CI: 1.133-2.917, p-value = 0.0159). Moreover, functional assays revealed that knockdown of lncRNA DLEU1 could suppress the proliferation by inducing cell cycle arrest at G1 phase and reducing the S phase by down-regulating the CyclinD1 and p-AKT, as the well as migration and invasion by inhibiting the epithelial-mesenchymal transition (EMT) markers, such as ZEB1, N-cadherin, β-catenin and snail in glioma cells. Furthermore, silencing lncRNA DLEU1 suppressed TMZ-activated autophagy via regulating the expression of P62 and LC3, and promoted sensitivity of glioma cells to TMZ by triggering apoptosis. Conclusively, our study indicated that lncRNA DLEU1 might perform as a prognostic potential target and underlying therapeutic target for sensitivity of glioma to TMZ.
| S-EPMC7756250 | biostudies-literature
Project description:BackgroundGastric cancer (GC) is one of the most common cancers worldwide and the majority of GC patients are diagnosed at advanced stages due to the lack of early detection biomarkers. LncRNAs have been shown to play important roles in various diseases and could be predictive biomarkers and therapeutic targets. Our study demonstrated that low expression of lncRNA APTR could promote gastric cancer progression.MethodsDifferentiated expressed lncRNAs were identified through analyzing TCGA paired GC RNA sequencing data. LncRNA APTR's clinical relevance was analyzed using the TCGA dataset and GEO datasets. APTR expression in patient samples was detected through qPCR. The proliferation, colony formation, and migration of GC cells were tested. Bioinformatic analyses were performed to explore APTR-affected signaling pathways in GC.ResultsLncRNA APTR is lower expressed in gastric tumor samples and low expression of APTR predicts a poor diagnosis and outcome in GC patients. Silencing APTR promotes gastric cancer proliferation and invasiveness. APTR expression is negatively correlated with inflammatory signaling in the gastric tumor microenvironment.ConclusionOur study showed that low expression of lncRNA APTR in gastric cancer is correlated with tumorigenesis and poor diagnosis and prognosis, which is a potential biomarker for gastric cancer patients' diagnosis and treatment.
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Project description:Tumor necrosis factor receptor superfamily member 11B (TNFRSF11B) has been studied to be involved in the development and progression of several human malignancies. However, little is unveiled regarding the complex mechanisms of TNFRSF11B in human gastric cancer (GC). The clinical significance of TNFRSF11B was assessed in 70 and 160 GC tissues using immunohistochemistry method and gene microarray analysis, respectively. The biological function of TNFRSF11B was studied in vitro and in vivo assays. Immunofluorescence assay was used to evaluate the expression of ?-catenin in the nucleus. The expression of ?-catenin and related protein was determined by Western blot. The interaction between TNFRSF11B and GSK3? was detected by co-immunoprecipitation. We demonstrated that TNFRSF11B was highly expressed in the cytoplasm of GC and associated with the patient poor outcome. Our studies showed that TNFRSF11B in GC cells significantly promoted cell proliferation, migration, invasion in vitro and tumorigenic ability in vitro and in vivo. Meanwhile, TNFRSF11B inhibited GC cell apoptosis. The proportion of nuclear active ?-catenin showed positively correlation with TNFRSF11B expression. TNFRSF11B directly combined with GSK-3? upregulating its phosphorylation, and increased expression of ?-catenin and its downstream effectors. Collectively, these findings demonstrate that TNFRSF11B promote the aggressive phenotypes of GC cells and activated Wnt/?-catenin signaling. Accordingly, TNFRSF11B had potential as a biomarker and inhibition of TNFRSF11B expression might offer a new therapeutic target for GC patients.
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