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Circ_0084043 promotes cell proliferation and glycolysis but blocks cell apoptosis in melanoma via circ_0084043-miR-31-KLF3 axis.

ABSTRACT: Melanoma is an aggressive malignant tumor. The crucial role of circular RNAs has been documented in many types of cancer, including melanoma. The objective of this study was to uncover the function of circ_0084043 in the biological process of melanoma and associated mechanism of action. The expression of circ_0084043, miR-31, and Krüppel-like factor 3 (KLF3) was determined by qRT-PCR. Cell proliferation and apoptosis were monitored by the MTT assay and flow cytometry assay, respectively. The progression of glycolysis was evaluated according to the levels of glucose consumption, lactate production, and ATP concentration using appropriate detection kits. The relationship between miR-31 and circ_0084043 or KLF3 was predicted by the bioinformatics tool and ascertained by the dual-luciferase reporter assay. The protein levels of KLF3 and glucose transporter 1 (Glut1) were quantified by western blot. A xenograft model was established to ascertain the role of circ_0084043 in vivo. As a result, circ_0084043 expression was reinforced in melanoma tissues and cells. Circ_0084043 knockdown inhibited cell proliferation, induced cell apoptosis, and restrained glycolysis. MiR-31 was a target of circ_0084043, and miR-31 deficiency reversed the role of circ_0084043 knockdown. KLF3 was targeted by miR-31, and KLF3 upregulation abolished the effects of miR-31 enrichment. Moreover, circ_0084043 knockdown impeded tumor growth in vivo and suppressed the level of Glut1 by modulating miR-31 and KLF3. Circ_0084043 promoted cell proliferation and glycolysis, and blocked apoptosis through the circ_0084043-miR-31-KLF3 regulatory axis in melanoma.

SUBMITTER: Wu S

PROVIDER: S-EPMC7747509 | biostudies-literature |

REPOSITORIES: biostudies-literature

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MSC-derived exosomes promote proliferation and inhibit apoptosis of chondrocytes via lncRNA-KLF3-AS1/miR-206/GIT1 axis in osteoarthritis.

Project description:BACKGROUND:Exosomes secreted by human mesenchymal stem cells (hMSCs) have been shown to promote cartilage regeneration. This study aimed to explore whether exosomal lncRNA-KLF3-AS1 derived from hMSCs can promote chondrocyte proliferation via miR-206/GIT1 axis in osteoarthritis (OA). METHODS:hMSCs and MSC-derived exosomes (MSC-exo) were prepared for morphological observation and identification by transmission electron microscopy (TEM) and flow cytometry. IL-1?-induced OA chondrocytes and collagenase-induced mouse OA model were established for the further experiments. Luciferase activity assay was performed to test whether miR-206 could bind to KLF3-AS1 or GIT1. Cell proliferation and apoptosis were evaluated by CCK-8 assay and flow cytometry, respectively. RESULTS:MSC-Exos increased chondrogenic genes Col2a1 (type II collagen alpha 1) and aggrecan, decreased hondrocyte hypertrophy markers MMP-13 (matrix metalloproteinase-13) and Runx2 (runt-related transcription factor 2) in chondrocytes isolated from OA model mice. Furthermore, MSC-Exos attenuated IL-1?-induced chondrocyte proliferation inhibition and apoptosis induction. Moreover, MSCKLF3-AS1-Exos (exosomes derived from KLF3-AS1-overexpressing-MSCs) ameliorated IL-1?-induced chondrocyte injury. Results also demonstrated that KLF3-AS1 acted as a competitive endogenous RNA (ceRNA) by sponging miR-206 to facilitate GIT1 expression. In addition, miR-206 overexpression and GIT1 knockdown reversed MSCKLF3-AS1-Exos-mediated attenuation of chondrocyte injury. CONCLUSION:Exosomal KLF3-AS1 derived from MSCs involved in MSC-Exos-mediated chondrocyte proliferation induction and chondrocyte apoptosis inhibition via miR-206/GIT1 axis. Abbreviation: G-protein-coupled receptor kinase interacting protein-1 (GIT1).

| S-EPMC6342066 | biostudies-literature

Long Non-Coding RNA TUG1 Promotes Cell Proliferation and Inhibits Cell Apoptosis, Autophagy in Clear Cell Renal Cell Carcinoma via MiR-31-5p/FLOT1 Axis.

Project description:Purpose:Clear cell renal cell carcinoma (ccRCC) is a common urological carcinoma in adults. Long non-coding RNA (lncRNA) taurine-upregulated gene 1 (TUG1) has been reported to be involved in the progression of diverse human cancers, including renal cell carcinoma (RCC). However, the biological mechanism of TUG1 was rarely reported in ccRCC. Methods:The levels of TUG1, microRNA miR-31-5p and flotillin 1 (FLOT1) in ccRCC tissues and cells were detected by qRT-PCR. The interactions between miR-31-5p and TUG1 or FLOT1 were predicted by starBase v2.0 and TargetScan, respectively, which were further validated by RIP assay and RNA pull-down assay. Cell counting kit-8 (CCK-8), flow cytometry and Western blot were used to assess the effects of TUG1 on cell viability, apoptosis rate and the relative protein expression levels in ccRCC cells. In addition, the xenograft tumor assay was conducted to further verify the functions of TUG1 in ccRCC in vivo. Results:TUG1 was dramatically up-regulated in ccRCC tissues and cells. TUG1 silencing inhibited cell proliferation and promoted cell apoptosis, autophagy in 786-0 and A498 cells. In addition, TUG1 depletion repressed tumor growth in vivo. Moreover, miR-31-5p was validated as a direct target of TUG1, and microRNA miR-31-5p inhibitor mitigated the effects of TUG1 knockdown on ccRCC progression. Furthermore, FLOT1 was verified to be negatively interacted with miR-31-5p. FLOT1 overexpression attenuated miR-31-5p-mediated inhibitory effect on cell proliferation and promotion effects on cell apoptosis, autophagy. The restoration experiment implicated that TUG1 positively modulated FLOT1 expression by sponging miR-31-5p. Conclusion:All data demonstrated that TUG1 promotes cell proliferation and inhibits cell apoptosis and autophagy in ccRCC by miR-31-5p/FLOT1 axis, which may provide a therapeutic target for ccRCC patients.

| S-EPMC7311099 | biostudies-literature

CircPOSTN/miR-361-5p/TPX2 axis regulates cell growth, apoptosis and aerobic glycolysis in glioma cells.

Project description:Background:Glioma is the most primary central nervous system tumor in adults. The 5 year survival rate for glioma patients remains poor, although treatment strategies had improved in the past few decades. The cumulative studies have shown that circular RNA (circRNA) is associated with glioma process, so the purpose of this study is to clarify the function of circPOSTN in glioma. Methods:The expression levels of circPOSTN, miR-361-5p, and targeting protein for Xenopus kinesin-like protein 2 (TPX2) were assessed with real-time quantitative polymerase chain reaction (RT-qPCR). The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazol-3-ium bromide (MTT) and flow cytometry assays were executed to examine proliferation and apoptosis of glioma cells, respectively. Western blot was applied to assess protein expression. The glucose metabolism of glioma cells was analyzed by testing the glucose consumption, lactate production, ATP level, reactive oxygen species (ROS) accumulation and performing Seahorse XF assay. The interaction relationship between miR-361-5p and circPOSTN or TPX2 was analyzed by bioinformatics database and dual-luciferase reporter assay. The influences of circPOSTN silencing in vivo were observed by a xenograft experiment. Results:CircPOSTN was overexpressed in glioma tissues and cells. Absence of circPOSTN in glioma cells promoted apoptosis while impeded proliferation and aerobic glycolysis, which were mitigated by silencing miR-361-5p. What's more, loss-of-functional experiment suggested that knockdown of TPX2 repressed proliferation and aerobic glycolysis, while induced apoptosis in glioma cells. In addition, circPOSTN targetedly regulated TPX2 expression in glioma cells via sponging miR-361-5p. In vivo study revealed that deficiency of circPOSTN restrained tumor growth. Conclusion:Mechanistically, circPOSTN regulated cell growth, apoptosis, and aerobic glycolysis in glioma through miR-361-5p/TPX2 axis.

| S-EPMC7409503 | biostudies-literature

Circ_0032821 Facilitates Gastric Cancer Cell Proliferation, Migration, Invasion and Glycolysis by Regulating MiR-1236-3p/HMGB1 Axis.

Project description:Background:Circular RNAs (circRNAs) play an essential role in the pathogenesis of malignant tumors, including gastric cancer (GC). However, the effect of circ_0032821 on GC remains largely unknown. Methods:QRT-PCR assay was employed to examine the levels of circ_0032821, CEP128 mRNA and miR-1236-3p. RNase R digestion assay was utilized to verify the feature of circ_0032821. Cell Counting Kit-8 (CCK-8) assay and transwell assay were adopted to evaluate cell proliferation and metastasis. The level of glycolysis was evaluated through detecting ECAR, OCR, lactate production, glucose uptake and ATP synthesis. Dual-luciferase reporter assay and RIP assay were conducted to analyze the relationship between miR-1236-3p and circ_0032821 or HMGB1. Western blot assay was adopted for high mobility group box 1 (HMGB1) level. Murine xenograft model assay was utilized for the effect of circ_0032821 in vivo. Results:High level of circ_0032821 was observed in GC tissues and cells. Silencing of circ_0032821 markedly repressed cell proliferation, metastasis and glycolysis in GC cells in vitro and blocked tumorigenesis of GC in vivo. For mechanism analysis, circ_0032821 was identified as the sponge of miR-1236-3p and HMGB1 was the target gene of miR-1236-3p. Moreover, miR-1236-3p suppression restored the influences of circ_0032821 deficiency on GC cell proliferation, metastasis and glycolysis. Overexpression of miR-1236-3p relieved the malignant behaviors of GC cells by targeting HMGB1. Conclusion:Circ_0032821 accelerated GC development through elevating HMGB1 expression via sponging miR-1236-3p.

| S-EPMC7567569 | biostudies-literature

hsa_circ_0084811 Regulates Cell Proliferation and Apoptosis in Retinoblastoma through miR-18a-5p/miR-18b-5p/E2F5 Axis.

Project description:BackgroundRetinoblastoma (RB) is the commonest primary intraocular malignancy during childhood. Circular RNAs (circRNAs) act as regulators in RB development, and hsa_circ_E2F5 (circ_0084811 in this study) was found to be highly expressed in RB cells, so we wanted to identify its detailed molecular mechanism.MethodsThe expression level of circ_0084811 in RB cells was tested by RT-qPCR and its effects on RB cells were evaluated through functional assays. The regulatory mechanism that circ_0084811 may exert in RB progression was testified through mechanism experiments.ResultsHigh circ_0084811 expression in RB cells facilitated cell proliferation but inhibited cell apoptosis. The enrichment of acetylation of histone 3 lysine 27 (H3K27ac) in circ_0084811 promoter induced circ_0084811 upregulation. Moreover, circ_0084811 regulated E2F transcription factor 5 (E2F5) expression via sponging microRNA-18a-5p (miR-18a-5p) and microRNA-18b-5p (miR-18b-5p).Conclusioncirc_0084811 modulated RB progression via the miR-18a-5p/miR-18b-5p/E2F5 axis.

| S-EPMC9325647 | biostudies-literature

Lidocaine Suppresses Cell Proliferation and Aerobic Glycolysis by Regulating circHOMER1/miR-138-5p/HEY1 Axis in Colorectal Cancer.

Project description:Background:Increasing evidence has uncovered the anticancer activity of lidocaine in many cancers. However, the role and the underlying molecular mechanism of lidocaine in colorectal cancer (CRC) remain poorly understood. Materials and Methods:Cell viability and apoptosis were measured by cell counting kit-8 assay and flow cytometry. Western blot was used to detect the protein of p53, CyclinD1, Pro-caspase-3, Cleaved-caspase-3, Pro-caspase-9, Cleaved-caspase-9, and hes-related family bHLH transcription factor with YRPW motif 1 (HEY1). Glycolytic metabolism was calculated by measuring the glucose consumption, lactate production and adenosine triphosphate (ATP) contents. The expression of circRNA homer scaffold protein 1 (circHOMER1), microRNA (miR)-138-5p and HEY1 mRNA was detected by quantitative real-time polymerase chain reaction. The interaction between miR-138-5p and circHOMER1 or HEY1 was analyzed using the dual-luciferase reporter assay. In vivo experiments were performed using the murine xenograft model. Results:Lidocaine suppressed CRC cell viability and aerobic glycolysis but promoted cell apoptosis in vitro as well as hindered tumor growth in vivo. CircHOMER1 was elevated in CRC tissues and cells, while lidocaine decreased circHOMER1 expression in CRC cells. Additionally, circHOMER1 overexpression reversed the anti-tumor activity of lidocaine in CRC cells. miR-138-5p was confirmed to interact with circHOMER1 and HEY1 in CRC cells directly, and circHOMER1 regulated HEY1 expression through repressing miR-138-5p expression. Besides, rescue assay indicated the anti-tumor activity mediated by lidocaine could be regulated by circHOMER1/miR-138-5p/HEY1 axis. Conclusion:Lidocaine mediated CRC cell viability loss, apoptosis induction and aerobic glycolysis inhibition by regulating circHOMER1/miR-138-5p/HEY1 axis, providing a novel treatment option for lidocaine to prevent the progression of CRC.

| S-EPMC7323806 | biostudies-literature

Circ_0008039 supports breast cancer cell proliferation, migration, invasion, and glycolysis by regulating the miR-140-3p/SKA2 axis.

Project description:Circular RNAs (circRNAs) have been shown to modulate gene expression and participate in the development of multiple malignancies. The purpose of this study was to investigate the role of circ_0008039 in breast cancer (BC). The expression of circ_0008039, miR-140-3p and spindle and kinetochore-associated protein 2 (SKA2) was detected by qRT-PCR. Cell viability, colony formation, migration and invasion were evaluated using methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay, colony formation assay, and transwell assay, respectively. Glucose consumption and lactate production were measured using commercial kits. Protein levels of hexokinase II (HK2) and SKA2 were determined by western blot. The interaction between miR-140-3p and circ_0008039 or SKA2 was verified by dual-luciferase reporter assay. Finally, a mouse xenograft model was established to investigate the roles of circ_0008039 in BC in vivo. We found that circ_0008039 and SKA2 were upregulated in BC tissues and cells, while miR-140-3p was downregulated. Knockdown of circ_0008039 suppressed BC cell proliferation, migration, invasion, and glycolysis. Moreover, miR-140-3p could bind to circ_0008039 and its inhibition reversed the inhibitory effect of circ_0008039 interference on proliferation, migration, invasion, and glycolysis in BC cells. SKA2 was verified as a direct target of miR-140-3p and its overexpression partially inhibited the suppressive effect of miR-140-3p restoration in BC cells. Additionally, circ_0008039 positively regulated SKA2 expression by sponging miR-140-3p. Consistently, silencing circ_0008039 restrained tumor growth via increasing miR-140-3p and decreasing SKA2. In conclusion, circ_0008039 downregulation suppressed BC cell proliferation, migration, invasion, and glycolysis partially through regulating the miR-140-3p/SKA2 axis, providing an important theoretical basis for treatment of BC.

| S-EPMC7858101 | biostudies-literature

miR-489-3p/SIX1 Axis Regulates Melanoma Proliferation and Glycolytic Potential.

Project description:Sine oculis homeobox 1 (SIX1), a key transcription factor for regulating aerobic glycolysis, participates in the occurrence of various cancer types. However, the role of SIX1 in melanoma and the upstream regulating mechanisms of SIX1 remain to be further investigated. MicroRNAs (miRNAs) have emerged as key regulators in tumorigenesis and progression. Here, we show that miR-489-3p suppresses SIX1 expression by directly targeting its 3' untranslated region (3' UTR) in melanoma cells. miR-489-3p suppressed melanoma cell proliferation, migration, and invasion through inhibition of SIX1. Mechanistically, by targeting SIX1, miR-489-3p dampens glycolysis, with decreased glucose uptake, lactate production, ATP generation, and extracellular acidification rate (ECAR), as well as an increased oxygen consumption rate (OCR). Importantly, glycolysis regulated by the miR-489-3p/SIX1 axis is critical for its regulation of melanoma growth and metastasis both in vitro and in vivo. In melanoma patients, miR-489-3p expression is negatively correlated with SIX1 expression. In addition, patients who had increased glucose uptake in tumors and with metastasis assessed by positron emission tomography (PET) scans showed decreased miR-489-3p expression and increased expression of SIX1. Collectively, our study demonstrates the importance of the miR-489-3p/SIX1 axis in melanoma, which can be a potential and a promising therapeutic target in melanoma.

| S-EPMC7109510 | biostudies-literature

MiR-326/Sp1/KLF3: A novel regulatory axis in lung cancer progression.

Project description:ObjectivesTo investigate the function and regulatory mechanism of Krüppel-like factor 3 (KLF3) in lung cancer.Materials and methodsKLF3 expression was analysed by qRT-PCR and Western blot assays. The proliferation, migration, invasion, cycle and apoptosis were measured by CCK-8 and EdU, wound-healing and Transwell, and flow cytometry assays. The tumour growth was detected by nude mouse tumorigenesis assay. In addition, the interaction between KLF3 and Sp1 was accessed by luciferase reporter, EMSA and ChIP assay. JAK2, STAT3, PI3K and p-AKT levels were evaluated by Western blot and IHC assays.ResultsThe results indicated that KLF3 expression was elevated in lung cancer tissues. Knockdown of KLF3 inhibited lung cancer cell proliferation, migration and invasion, and induced cell cycle arrest and apoptosis. In addition, the downregulation of KLF3 suppressed tumour growth in vivo. KLF3 was transcriptionally activated by Sp1. miR-326 could bind to 3'UTR of Sp1 but not KLF3 and decreased the accumulation of Sp1, which further indirectly reduced KLF3 expression and inactivated JAK2/STAT3 and PI3K/AKT signaling pathways in vitro and in vivo.ConclusionsOur data demonstrate that miR-326/Sp1/KLF3 regulatory axis is involved in the development of lung cancer, which hints the potential target for the further therapeutic strategy against lung cancer.

| S-EPMC6495967 | biostudies-literature

NNT-AS1 modulates prostate cancer cell proliferation, apoptosis and migration through miR-496/DDIT4 axis.

Project description:BackgroundEmerging studies have disclosed long non-coding RNAs (lncRNAs) as pivotal modulators in the progression of prostate cancer (PCa). Current research planned to figure out the involvement of lncRNA nicotinamide nucleotide transhydrogenase antisense RNA 1 (NNT-AS1) in PCa.MethodsRNA expression was examined using RT-qPCR in PCa cells. Functional assays assessed the viability, proliferation, apoptosis and migration of PCa cells. RNA pull down and luciferase reporter experiments detected the interplay between miRNA and lncRNA or mRNA.ResultsNNT-AS1 was apparently upregulated in PCa cells. NNT-AS1 deficiency abrogated PCa cell viability, proliferation and migration but promoted apoptosis. Besides, miR-496 could be sequestered by NNT-AS1 to elevate the expression of DNA damage inducible transcript 4 (DDIT4) in PCa. Rescue assays indicated that overexpressed DDIT4 or restrained miR-496 could reverse the influence of NNT-AS1 depletion on malignant processes in PCa cells.ConclusionNNT-AS1 contributes to the malignant phenotypes of PCa cells through targeting miR-496 to boost DDIT4 expression.

| S-EPMC7513494 | biostudies-literature

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