Circular RNA circVAMP3 promotes aerobic glycolysis and proliferation by regulating LDHA in renal cell carcinoma.
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ABSTRACT:
SUBMITTER: Li J
PROVIDER: S-EPMC9079058 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In recent researches, circular RNAs (circRNAs) have been shown to exert critical functions in osteosarcoma biology. Nevertheless, the contribution of circRNAs to osteosarcoma remains largely unclear. Results indicated that expression of circATRNL1 was higher in osteosarcoma tissues and cells. The high-expression of circATRNL1 was significantly correlated with aggressive features and acted as an independent risk factor for osteosarcoma patients' overall survival. Functionally, our findings demonstrate that circATRNL1 promotes the osteosarcoma aerobic glycolysis in vitro. Mechanistically, circATRNL1 up-regulated the expression level of LDHA, which was also targeted by miR-409-3p. Therefore, circATRNL1 exerted the accelerative roles of osteosarcoma aerobic glycolysis through miR-409-3p/LDHA axis. In conclusion, circATRNL1 promoted osteosarcoma progression by enhancing glycolysis via circATRNL1/miR-409-3p/LDHA axis, which may inspire a novel therapeutic target for osteosarcoma.
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Project description:Increasing evidence has indicated the great diagnostic and therapeutic potentials of circular RNAs (circRNAs) in human cancers. Although the biological roles of circRNAs in pancreatic ductal adenocarcinoma (PDAC) have been partially annotated, the potential regulatory mechanism of circRNAs in PDAC tumorigenesis remains poorly understood. Here, our study found that the novel circRNA circSLIT2 was significantly upregulated in PDAC tissues and cells. Clinically, ectopic high-expression of circSLIT2 was correlated with unfavorable prognosis of PDAC patients. Functional experiments demonstrated that circSLIT2 promoted the aerobic glycolysis and proliferation of PDAC cells in vitro, and circSLIT2 knockdown inhibited tumor growth in vivo. Mechanistically, circSLIT2 acted as miRNA sponge to target miR-510-5p/c-Myc axis. Furthermore, c-Myc bound with the promoter region of lactate dehydrogenase A (LDHA) to activate the transcription. Collectively, present findings reveal that circSLIT2/miR-510-5p/c-Myc/LDHA axis participates in the aerobic glycolysis and carcinogenesis of PDAC, and may act as a promising therapeutic target.
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Project description:Interacting with proteins is a crucial way for long noncoding RNAs (lncRNAs) to exert their biological responses. Here we report a high throughput strategy to characterize lncRNA interacting proteins in vivo by combining tobramycin affinity purification and mass spectrometric analysis (TOBAP-MS). Using this method, we identify 140 candidate binding proteins for lncRNA highly upregulated in liver cancer (HULC). Intriguingly, HULC directly binds to two glycolytic enzymes, lactate dehydrogenase A (LDHA) and pyruvate kinase M2 (PKM2). Mechanistic study suggests that HULC functions as an adaptor molecule that enhances the binding of LDHA and PKM2 to fibroblast growth factor receptor type 1 (FGFR1), leading to elevated phosphorylation of these two enzymes and consequently promoting glycolysis. This study provides a convenient method to study lncRNA interactome in vivo and reveals a unique mechanism by which HULC promotes Warburg effect by orchestrating the enzymatic activities of glycolytic enzymes.
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Project description:BackgroundWith the development of RNA-seq technology, tens of thousands of circular RNAs (circRNAs), a novel class of RNAs, have been identified. However, little is known about circRNA formation and biogenesis in hepatocellular carcinoma (HCC).MethodsWe performed ribosomal-depleted RNA-seq profiling of HCC and para-carcinoma tissues and analyzed the expression of a hotspot circRNA derived from the 3'UTR of the stearoyl-CoA desaturase (SCD) gene, termed SCD-circRNA 2.FindingsIt was significantly upregulated in HCC and correlated with poor patient prognosis. Moreover, we observed that the production of SCD-circRNA 2 was dynamically regulated by RNA-binding protein 3 (RBM3). RBM3 overexpression was indicative of a short recurrence-free survival and poor overall survival for HCC patients. Furthermore, by modulating the RBM3 or SCD-circRNA 2 levels, we found that RBM3 promoted the HCC cell proliferation in a SCD-circRNA 2 dependent manner.InterpretationHerein, we report that RBM3 is crucial for the SCD-circRNA 2 formation in HCC cells, which not only provides mechanistic insights into cancer-related circRNA dysregulation but also establishes RBM3 as an oncogene with both therapeutic potential and prognostic value. FUND: This work was supported by the National Key Research and Development Program of China (2016YFC1302303), the National Natural Science Foundation of China (Grant No. 81672345 and 81,402,269). The funders did not have any roles in study design, data collection, data analysis, interpretation, writing of the report.
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Project description:Phospholipase C? (PLC?) and anaerobic glycolysis were determined to be involved in the development of human urinary bladder cancer (UBC), but the mechanisms remain unclear. In the present study, 64 bladder cancer specimens and 42 adjacent tissue specimens were obtained from 64 patients, and immunochemistry indicated that PLC? and lactate dehydrogenase (LDHA) are overexpressed in UBC. PLC? and LDHA were demonstrated to be positively correlated at transcription levels, indicating that one of these two genes may be regulated by another. To elucidate the mechanisms, PLC? was knocked down in T24 cells by short hairpin RNA, and then signal transducer and activator of transcription 3 (STAT3) phosphorylation and LDHA were determined to be downregulated, which indicated that PLC? may serve roles upstream of LDHA through STAT3 to regulate glycolysis in UBC. Furthermore, chromatin immunoprecipitation and luciferase reporter assays were performed to confirm that STAT3 could bind to the promoter of the LDHA gene to enhance its expression. A xenograft tumor mouse model also demonstrated similar results as the in vitro experiments, further confirming the role of PLC? in regulating bladder cell growth in vivo. Collectively, the present study demonstrated that PLC? may regulate glycolysis through the STAT3/LDHA pathway to take part in the development of human UBC.
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Project description:BackgroundCancer cells prefer utilizing aerobic glycolysis in order to exacerbate tumor mass and maintain un-regulated proliferative rates. As a key glycolytic activator, phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) has been implicated in multiple tumor type progression. However, the specific function and clinical significance of PFKFB3 in renal cell carcinoma (RCC) are yet not clarified. This investigation assessed PFKFB3 roles in RCC.MethodsPFKFB3 expression levels were analyzed in clear cell renal cell carcinoma (ccRCC) tissues, together with its relationship with clinical characteristics of ccRCC. Real-time PCR and Western blot assays were employed for determining PFKFB3 expression in different RCC cell lines. Furthermore, we determined the glycolytic activity by glucose uptake, lactate secretion assay and ECAR analysis. CCK-8 assay, clone formation, flow cytometry and EdU assessments were performed for monitoring tumor proliferative capacity and cell-cycle distribution. Furthermore, a murine xenograft model was employed for investigating the effect of PFKFB3 on tumor growth in vivo.ResultsPFKFB3 was significantly up-regulated in RCC specimens and cell lines in comparison to normal control. Overexpression of PFKFB3 was directly correlated to later TNM stages, thus becoming a robust prognostic biomarker for ccRCC cases. Furthermore, PFKFB3 knockdown suppressed cell glycolysis, proliferative rate and cell-cycle G1/S conversion in RCC cells. Importantly, in vivo experiments confirmed that PFKFB3 knockdown delayed tumor growth derived from the ACHN cell line.ConclusionsSuch results suggest that PFKFB3 is a key molecular player in RCC progression via mediating glycolysis / proliferation and provides a potential therapeutic target against RCC.
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Project description:Background:Suppressed gluconeogenesis and increased glycolysis are common in clear cell renal cell carcinoma (ccRCC). Phosphoenolpyruvate carboxykinase 1 (PCK1) is a rate-limiting gluconeogenesis enzyme. However, the role of PCK1 in tumor metabolism and progression remains unclear. Methods:Artificial modulation of PCK1 (down- and upregulation) in two ccRCC cell lines was performed to explore the role of PCK1 in the glycolytic phenotype and in tumor growth and metastasis in vitro and in vivo. Sixty-two patients with ccRCC underwent 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography. The levels of PCK1 and lactate dehydrogenase A (LDHA) in ccRCC tissues and peritumor tissues were investigated with immunohistochemistry. The relationships between 18F-FDG accumulation and the expression of PCK1 and LDHA were analyzed. The mechanisms underlying the regulation of LDHA by PCK1 were analyzed using in vitro molecular techniques. Results:PCK1 suppressed ccRCC cell growth and metastasis in vitro and inhibited tumorigenesis in nude mice by blocking the aerobic glycolysis pathway. Clinically, low levels of PCK1 expression were associated with poor prognosis in patients with ccRCC. The expression level of PCK1 was negatively correlated with tumor progression, the LDHA expression level and 18F-FDG accumulation in primary ccRCC tissue. We also demonstrated that PCK1 reduces the stability of LDHA through posttranslational regulation. Finally, we showed that the effects of PCK1 on glucose metabolism, cell proliferation and metastasis are mediated via the inhibition of LDHA. Conclusion:Our study identified a novel molecular mechanism underlying the Warburg effect. PCK1 may serve as a candidate prognostic biomarker, and targeting the PCK1/LDHA pathway might be a new strategy to selectively inhibit tumor metabolism in human ccRCC.
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Project description:Circular RNAs have been reported to play significant roles in regulating pathophysiological processes while also guiding clinical diagnosis and treatment of hepatocellular carcinoma (HCC). However, only a few circRNAs have been identified thus far. Herein, we investigated the role of a specific closed-loop structure of hsa_circ_101555 that was generated by back-splicing of the host gene casein kinase 1 gamma 1 (CSNK1G1) in the development and proliferation of HCC. We investigated the expression of Hsa_circ_101555 in HCC and normal tissues using bioinformatics. The expression level of hsa_circ_101555 was further detected by fluorescence in situ hybridization and qRT-PCR in ten HCC patients. Transwell, migration, WST-1 assays, and colony formation assays were used to evaluate the role of hsa_circ_101555 in HCC development and proliferation. The regulatory mechanisms of hsa_circ_101555 in miR-145-5p and CDCA3 were determined by dual luciferase reporter assay. A mouse xenograft model was also used to determine the effect of hsa_circ_101555 on HCC growth in vivo. hsa_circ_101555 showed greater stability than the linear RNA; while in vitro and in vivo results demonstrated that hsa_circ_101555 silencing significantly suppressed cell proliferation, migration, and invasion of HCC cells. Rescue experiments further demonstrated that suppression of miR-145-5p significantly attenuated the biological effects of hsa_circ_101555 knockdown in HCC cells. We also identified a putative oncogene CDCA3 as a potential miR-145-5p target. Thus, our results demonstrated that hsa_circ_101555 might function as a competing endogenous RNA of miR-145-5p to upregulate CDCA3 expression in HCC. These findings suggest that hsa_circ_101555 may be a potential therapeutic target for patients with HCC.
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Project description:Circular RNAs (circRNAs) are a class of non-coding RNAs with a loop structure; however, their functions remain largely unknown. Growing evidence suggests that circRNAs play a pivotal role in the progression of malignant diseases. However, the expression profiles and function of circRNAs in hepatocellular carcinoma (HCC) remain unclear. We investigated the expression of microtubule-associated serine/threonine kinase 1 (MAST1) circRNA (circMAST1) in HCC and healthy tissues using bioinformatics, quantitative real-time PCR (qRT-PCR), and fluorescence in situ hybridization. Luciferase reporter assays were performed to assess the interaction between circMAST1 and miR-1299. Proliferation assays, colony formation assays, flow cytometry, transwell assays, and western blotting were also performed. A mouse xenograft model was also used to determine the effect of circMAST1 on HCC growth in vivo. CircMAST1 was upregulated in HCC tissues and cell lines; silencing via small interfering RNA inhibited migration, invasion, and proliferation of HCC cell lines in vitro as well as tumor growth in vivo. Furthermore, the expression of circMAST1 was positively correlated with catenin delta-1 (CTNND1) and negatively correlated with microRNA (miR)-1299 in HCC clinical samples. Importantly, circMAST1 sponged miR-1299 to stabilize the expression of CTNND1 and promoted tumorigenic features in HCC cell lines. We found that circMAST1 may serve as a novel biomarker for HCC. Moreover, circMAST1 elicits HCC progression by sponging miRNA-1299 and stabilizing CTNND1. Our data provide potential options for therapeutic targets in patients with HCC.
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Project description:Aerobic glycolysis is the main pathway for energy metabolism in cancer cells. It provides energy and biosynthetic substances for tumor progression and metastasis by increasing lactate production. Lactate dehydrogenase A (LDHA) promotes glycolysis process by catalyzing the conversion of pyruvate to lactate. Despite LDHA exhibiting carcinogenesis in various cancers, its role in oral squamous cell carcinoma (OSCC) remains unclear. This study demonstrated that LDHA was over-expressed in both OSCC tissues and cell lines, and was significantly associated with lower overall survival rates in patients with OSCC. Using weighted gene correlation network analysis and gene set enrichment analysis for the gene expression data of patients with OSCC (obtained from The Cancer Genome Atlas database), a close association was identified between epithelial-mesenchymal transition (EMT) and LDHA in promoting OSCC progression. The knockdown of LDHA suppressed EMT, cell proliferation, and migration and invasion of OSCC cells in vitro. Moreover, the silencing of LDHA inhibited tumor growth in vivo. Oxamate, as a competitive LDHA inhibitor, was also suppressed diverse malignant biocharacteristics of OSCC cells. Our findings reveal that LDHA acts as an oncogene to promote malignant progression of OSCC by facilitating glycolysis and EMT, and LDHA may be a potential anticancer therapeutic target.
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