A circular intronic RNA ciPVT1 delays endothelial cell senescence by regulating the miR-24-3p/CDK4/pRb axis.
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ABSTRACT:
SUBMITTER: Min X
PROVIDER: S-EPMC8761008 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Recently, circular RNAs (circRNAs) have been frequently reported to be involved in hepatocellular carcinoma (HCC) development and progression. However, the role of circRNAs in hepatic fibrosis (HF) is still unclear. Our previous high-throughput screen revealed changes in many circRNAs in mice with carbon tetrachloride (CCl4)-induced HF. For instance, the expression of circPSD3, a circRNA derived from the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene, was considerably downregulated in primary hepatic stellate cells (HSCs) and liver tissues of mice with CCl4-induced HF compared to those in the vehicle group. In vivo overexpression of circPSD3 using AAV8-circPSD3 arrested the deterioration of CCl4-induced HF as indicated by reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) content, liver hydroxyproline level, collagen deposition, and pro-fibrogenic gene and pro-inflammatory cytokine levels. Moreover, in vitro loss-of-function and gain-of-function analyses suggested that circPSD3 inhibited the activation and proliferation of HSCs. Mechanistically, circPSD3 served as a sponge for miR-92b-3p, subsequently promoting the expression of Smad7. In conclusion, our present findings reveal a novel mechanism by which circPSD3 alleviates hepatic fibrogenesis by targeting the miR-92b-3p/Smad7 axis, and they also indicate that circPSD3 may serve as a potential biomarker for HF.
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Project description:MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression by suppressing translation or facilitating mRNA decay. Differential expression of miRNAs is involved in the pathogenesis of several diseases including cancer. Here, we investigated the role of-miR-24-3p as a downregulated miRNA in metastatic cancer. miR-24-3p was decreased in metastatic cancer and lower expression of miR-24-3p was related to poor survival of cancer patients. Consistently, ectopic expression of miR-24-3p suppressed the cell migration, invasion, and proliferation of MCF7, Hep3B, B16F10, SK-Hep1, and PC-3 cells by directly targeting p130Cas. Stable expression of p130Cas restored miR-24-3p-mediated inhibition of cell migration and invasion. These results suggest that miR-24-3p functions as a tumor suppressor and the miR-24-3p/p130Cas axis is a novel factor of cancer progression by regulating cell migration and invasion.
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Project description:Mesenchymal stem cells (MSCs) hold great therapeutic potential. However, MSCs undergo replication senescence during the in vitro expansion process. Wharton's jelly from the human umbilical cord harbors a large number of MSCs. In this study, we hypothesized that Wharton's jelly would be beneficial for in vitro expansion of MSCs. Wharton's jelly extract (WJEs), which is mainly composed of extracellular matrix and cytokines, was prepared as coating substrate. Human MSCs were isolated and cultured on WJE-coated plates. Although the proliferation capacity of cells was not augmented by WJE in early phase culture, adynamic growth in late-phase culture was clearly reduced, suggesting that the replicative senescence of MSCs was efficiently slowed by WJE. This was confirmed by ?-galactosidase staining and telomere length measurements of MSCs in late-phase culture. In addition, the decreased differentiation ability of MSCs after long-term culture was largely ameliorated by WJE. Reactive oxygen species (ROS), p53, and p16INK4a/pRb expression increased with passaging. Analysis at the molecular level revealed that WJE-based culture efficiently suppressed the enhancement of intracellular ROS, p53, and p16INK4a/pRb in MSCs. These data demonstrated that WJE provided an ideal microenvironment for MSCs culture expansion in vitro preserved MSC properties by delaying MSCs senescence, and allowed large numbers of MSCs to be obtained for basic research and clinical therapies.
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Project description:Dysregulation of circular RNAs (circRNAs) has recently been found to play an important role in the progression and development of cancers such as non-small cell lung cancer (NSCLC). Yet the functions of many circRNAs in NSCLC remain unclear. In this study, the circRNA expression profiles in NSCLC tumor tissues and adjacent non-tumorous tissues were detected by high-throughput sequencing. Bioinformatics analyses, the dual-luciferase reporter system, fluorescence in situ hybridization (FISH) and miRNA/mRNA high-throughput sequencing were used to identify circ-EPB41 and its downstream target. The subcutaneous tumor/caudal vein transfer mouse model was used for tumor growth and invasion analysis. The results show that the circ-EPB41 was upregulated in NSCLC tissues and cell lines. Increased circ-EPB41 expression in NSCLC was significantly correlated with malignant characteristics, and positive to post-surgical overall survival of NSCLC patients. Reduced circ-EPB41 expression in NSCLC decreased cell proliferation and invasion in both in vitro and in vivo experiments. The miRNA/mRNA high-throughput sequencing suggested that downregulation of circ-EPB41 promoted microRNA (miR)-486-3p and suppressed eukaryotic translation initiation factor 5A (eIF5A) expression. Luciferase reporter experiments confirmed that miR-486-3p/eIF5A were downstream targets of circ-EPB41. In addition, we also found that downregulation of circ-EPB41 suppressed self-renewal and decreased expression of stemness markers SOX2, OCT-4, Nanog and CD133 by sponging miR-486-3p to enhance eIF5A expression. Taken togeter, these data revealed the important role of circ-EPB41 in regulating NSCLC cell invasion and proliferation by modifying miR-486-3p/eIF5A axis-mediated stemness. We believe our study provides a novel perspective regarding the role of circRNAs in NSCLC progression. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02618-7.
| S-EPMC9210757 | biostudies-literature
Project description:Multiple myeloma (MM) is a hematologic malignancy that results from uncontrolled plasma cell proliferation. Circular RNAs are versatile regulators that influence cancer aggression. The pathogenic mechanism of circXPO1 in MM is still unknown. In this study, the expression of circXPO1, miR-495-3p, and DNA damage-induced transcription 4 (DDIT4) was detected. Knockdown and overexpression assays were used to evaluate the effect of circXPO1 on MM. Specifically, 5-ethynyl-2'-deoxyuridine and cell counting kit-8 assay were used to investigate cell proliferation. Meanwhile, flow cytometry was adopted to detect cell apoptosis and cell cycle. Apoptosis-associated and cell cycle-related proteins were detected by Western blot. Mechanistically, biotin RNA pull-down assay and dual-luciferase assay were implemented to verify the combination among miR495-3p and circXPO1 or DDIT4. The function of circXPO1 in vivo was explored in xenograft experiments. The results showed that circXPO1 was up-regulated in both MM samples and MM cell lines and miR-495-3p was down-regulated in MM patients. Silencing circXPO1 inhibited cell proliferation, increased apoptosis rates, and caused the G1 phase arrest. Overexpression of circXPO1 yielded opposite results. In addition, RNA pull-down experiment demonstrated the interaction between circXPO1 and miR-495-3p. Silencing miR-495-3p rescued the inhibitory function caused by the knockdown of circXPO1. DDIT4 was the target of miR-495-3p. Finally, silencing circXPO1 inhibited the growth of subcutaneous tumors in vivo. In conclusion, our findings showed that circXPO1 could promote MM progression via the miR-495-3p/DDIT4 axis.
| S-EPMC10825292 | biostudies-literature
Project description:CDK4-pRB-E2F1 cell-cycle regulators are robustly expressed in non-proliferating beta cells, suggesting that besides the control of beta-cell number the CDK4-pRB-E2F1 pathway has a role in beta-cell function. We show here that E2F1 directly regulates expression of Kir6.2, which is a key component of the K(ATP) channel involved in the regulation of glucose-induced insulin secretion. We demonstrate, through chromatin immunoprecipitation analysis from tissues, that Kir6.2 expression is regulated at the promoter level by the CDK4-pRB-E2F1 pathway. Consistently, inhibition of CDK4, or genetic inactivation of E2F1, results in decreased expression of Kir6.2, impaired insulin secretion and glucose intolerance in mice. Furthermore we show that rescue of Kir6.2 expression restores insulin secretion in E2f1(-/-) beta cells. Finally, we demonstrate that CDK4 is activated by glucose through the insulin pathway, ultimately resulting in E2F1 activation and, consequently, increased expression of Kir6.2. In summary we provide evidence that the CDK4-pRB-E2F1 regulatory pathway is involved in glucose homeostasis, defining a new link between cell proliferation and metabolism.
| S-EPMC2824657 | biostudies-literature
Project description:BACKGROUND:Circular RNAs (circRNAs) have been reported to have critical regulatory roles in tumor biology. However, their contribution to melanoma remains largely unknown. METHODS:CircRNAs derived from oncogene CD151 were detected and verified by analyzing a large number of melanoma samples through quantitative real-time polymerase chain reaction (qRT-PCR). Melanoma cells were stably transfected with lentiviruses using circ_0020710 interference or overexpression plasmid, and then CCK-8, colony formation, wound healing, transwell invasion assays, and mouse xenograft models were employed to assess the potential role of circ_0020710. RNA immunoprecipitation, luciferase reporter assay and fluorescence in situ hybridization were used to evaluate the underlying mechanism of circ_0020710. RESULTS:Our findings indicated that circ_0020710 was generally overexpressed in melanoma tissues, and high level of circ_0020710 was positively correlated with malignant phenotype and poor prognosis of melanoma patients. Elevated circ_0020710 promoted melanoma cell proliferation, migration and invasion in vitro as well as tumor growth in vivo. Mechanistically, we found that high level of circ_0020710 could upregulate the CXCL12 expression via sponging miR-370-3p. CXCL12 downregulation could reverse the malignant behavior of melanoma cells conferred by circ_0020710 over expression. Moreover, we also found that elevated circ_0020710 was correlated with cytotoxic lymphocyte exhaustion, and a combination of AMD3100 (the CXCL12/CXCR4 axis inhibitor) and anti-PD-1 significantly attenuated tumor growth. CONCLUSIONS:Elevated circ_0020710 drives tumor progression via the miR-370-3p/CXCL12 axis, and circ_0020710 is a potential target for melanoma treatment.
| S-EPMC7204052 | biostudies-literature
Project description:Immune-checkpoint (IC) modulators like the poliovirus receptor (PVR) and programmed death ligand 1 (PD-L1) attenuate innate and adaptive immune responses and are potential therapeutic targets for diverse malignancies, including triple-negative breast cancer (TNBC). The retinoblastoma tumor suppressor, pRB, controls cell growth through E2F1-3 transcription factors, and its inactivation drives metastatic cancer, yet its effect on IC modulators is contentious. Here, we show that RB-loss and high E2F1/E2F2 signatures correlate with expression of PVR, CD274 (PD-L1 gene) and other IC modulators and that pRB represses whereas RB depletion and E2F1 induce PVR and CD274 in TNBC cells. Accordingly, the CDK4/6 inhibitor, palbociclib, suppresses both PVR and PD-L1 expression. Palbociclib also counteracts the effect of CDK4 on SPOP, leading to its depletion, but the overall effect of palbociclib is a net reduction in PD-L1 level. Hydrochloric acid, commonly used to solubilize palbociclib, counteracts its effect and induces PD-L1 expression. Remarkably, lactic acid, a by-product of glycolysis, also induces PD-L1 as well as PVR. Our results suggest a model in which CDK4/6 regulates PD-L1 turnover by promoting its transcription via pRB-E2F1 and degradation via SPOP and that the CDK4/6-pRB-E2F pathway couples cell proliferation with the induction of multiple innate and adaptive immunomodulators, with direct implications for cancer progression, anti-CDK4/6- and IC-therapies.
| S-EPMC10213015 | biostudies-literature
Project description:BackgroundDrug-resistance is a major obstacle to the treatment of breast cancer. Circular RNA (circRNA) circ-MMP11 has been reported to be promoting the progression of breast cancer. This study is designed to explore the role and mechanism of circ-MMP11 in lapatinib resistance in breast cancer.MethodsCirc-MMP11, microRNA-153-3p (miR-153-3p), and Anillin (ANLN) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability, number of colonies, apoptosis, migration, and invasion were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), colony formation, flow cytometry, and transwell assays, respectively. Exosomes were exerted and detected by differential centrifugation and a transmission electron microscope. The protein levels of CD63, CD9, and ANLN were assessed by western blot assay. The binding relationship between miR-153-3p and circ-MMP11 or ANLN was predicted by circinteractome or starbase, and then verified by a dual-luciferase reporter assay and RNA pull-down assay. The biological role of circ-MMP11 on breast cancer tumor growth and drug resistance was detected by the xenograft tumor model in vivo.ResultsCirc-MMP11 and ANLN were highly expressed, and miR-153-3p was decreased in LR breast cancer tissues and cells. Circ-MMP11 could be transported by exosomes. Furthermore, circ-MMP11 knockdown promoted lapatinib sensitivity by repressing cell viability, colony number, migration, invasion, and boosting apoptosis in LR breast cancer cells. Circ-MMP11 deficiency improved the drug sensitivity of breast cancer in vivo. Mechanically, circ-MMP11 could regulate ANLN expression through sponging miR-153-3p.ConclusionCirc-MMP11 could be transferred by exosomes in breast cancer cells. And circ-MMP11 functioned as a sponge of miR-153-3p to regulate ANLN expression, thereby promoting lapatinib resistance in breast cancer cells, providing therapeutic targets for the treatment of breast cancer.
| S-EPMC8290203 | biostudies-literature
Project description:Background:Medulloblastoma is the most common malignant brain tumor in children. Although the 5-year survival rate is high, patients with relapsed medulloblastoma have a guarded prognosis. HOX transcript antisense RNA (HOTAIR) has been proved to be related to the metastasis of various tumors. Therefore, the molecular mechanism of HOTAIR in medulloblastoma cells was investigated in this study. Methods:HOTAIR was stably silenced in medulloblastoma cells (Daoy and D341). Cell proliferation and apoptosis were detected by 5'-Bromo-2'-deoxyuridine (BrdU) staining, Hoechst 33342 staining, immunohistochemical (IHC), Terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) and flow cytometry, respectively. The targeted relationship between HOTAIR/Cyclin-dependent kinase 4 (CDK4) and miR-483-3p were predicted by bioinformatics and confirmed by luciferase reporter assay. Balb/C nude mice were inoculated with shRNA-HOTAIR transfected Daoy cells. Results:We found that the down-regulation of HOTAIR inhibited proliferation and induced apoptosis. Sh-RNA-HOTAIR also inhibited the expression of CKD4. The CDK4 dependent increase of cell proliferation and decrease of cell apoptosis were reversed by shRNA-HOTAIR. Finally, a xenograft model of medulloblastoma in nude mice was built, and the effect of shRNA-HOTAIR on the growth of tumors was analyzed by RT-PCR, immunofluorescence staining, and TUNEL staining. The data suggested interference of HOTAIR inhibited the growth, tumor weight, cell proliferation, and promoted cell apoptosis. Conclusions:Our study altogether demonstrated HOTAIR influence cell proliferation and apoptosis by regulation of miR-483-3p and CDK4 in medulloblastoma cells. HOTAIR can be used as a candidate for potential applications in the treatment of medulloblastoma.
| S-EPMC7396793 | biostudies-literature