RBM24 exacerbates bladder cancer progression by forming a Runx1t1/TCF4/miR-625-5p feedback loop.
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ABSTRACT:
SUBMITTER: Yin YW
PROVIDER: S-EPMC8178337 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe chemoresistance of breast cancer (BC) has become the main cause of treatment failure. MicroRNAs (miRNAs) play a critical role in tumorigenesis, development, and chemoresistance, but the underlying mechanism of miR-519d in BC development and chemotherapy sensitivity remains to be elucidated.MethodsThe levels of miR-519d-5p in BC samples and cell lines were measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Cell viability was monitored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The in vivo effect of miR-519d-5p on tumor formation and doxorubicin response were investigated in a xenograft study. Bioinformatic analysis, luciferase reporter assay, RT-qPCR, and western blotting were conducted to validate RELA as a target gene of miR-519d-5p. We performed RT-qPCR, western blotting, chromatin immunoprecipitation (ChIP), and DNA pull down to verify miR-519d-5p as a transcriptional target of RELA.ResultsThis study found that miR-519d-5p was expressed at lower levels in BC cells and tissues, and overexpression of miR-519d-5p sensitized BC to chemotherapy both in vitro and in vivo. Meanwhile, the expression of RELA was negatively correlated with miR-519d-5p. We then showed that RELA is one of the targets of miR-519d-5p: miR-519d-5p inhibited RELA expression by directly binding to its 3'-unstranslated region (3'-UTR). Conversely, it was verified that miR-519d-5p is one of the targets of transcription factor RELA, and RELA repressed miR-519d-5p by binding to the promoter region of miR-519d-5p, which forms a feedback loop.ConclusionsOverall, the results provide a novel therapeutic strategy for the combinational use of miR-519d-5p and chemotherapeutic agents to overcome chemo-resistance by forming a negative feedback loop with RELA.
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Project description:How to distinguish indolent from aggressive disease remains a great challenge in prostate cancer (PCa) management. Cullin 4B (CUL4B) is a scaffold protein and exhibits oncogenic activity in a variety of human malignancies. In this study, we utilized PCa tissue specimens, cell lines and xenograft models to determine whether CUL4B contributes to PCa progression and metastasis. Here, we show that CUL4B expression highly correlates with the aggressiveness of PCa. CUL4B expression promotes proliferation, epithelial-mesenchymal transition, and metastatic potential of PCa cells, whereas CUL4B knockdown inhibits. Mechanically, CUL4B positively regulates SOX4, a key regulator in PCa, through epigenetic silencing of miR-204. In turn, SOX4 upregulates CUL4B expression through transcriptional activation, thereby fulfilling a positive feedback loop. Clinically, CUL4B+/SOX4+ defines a subset of PCa patients with poor prognosis. Bioinformatics analysis further reveals that Wnt/ß-catenin activation signature is enriched in CUL4B+/SOX4+ patient subgroup. Intriguingly, Wnt inhibitors significantly attenuates oncogenic capacities of CUL4B in vitro and in vivo. Together, our study identifies CUL4B as a key modulator of aggressive PCa by a positive feedback loop that interacts with SOX4. This regulatory circuit may have a crucial role in PCa progression.
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Project description:miR-17 family microRNAs (miRNAs) are crucial for embryo development, however, their role in muscle development is still unclear. miR-20a-5p and miR-20b-5p belong to the miR-17 family and are transcribed from the miR-17~92 and miR-106a~363 clusters respectively. In this study, we found that miR-20a-5p and miR-20b-5p promoted myoblast differentiation and repressed myoblast proliferation by directly binding the 3' UTR of E2F transcription factor 1 (E2F1) mRNA. E2F1 is an important transcriptional factor for organism's normal development. Overexpression of E2F1 in myoblasts promoted myoblast proliferation and inhibited myoblast differentiation. Conversely, E2F1 inhibition induced myoblast differentiation and repressed myoblast proliferation. Moreover, E2F1 can bind directly to promoters of the miR-17~92 and miR-106a~363 clusters and activate their transcription, and E2F1 protein expression is correlated with the expression of pri-miR-17~92 and pri-miR-106a~363 during myoblast differentiation. These results suggested an auto-regulatory feedback loop between E2F1 and miR-20a-5p/20b-5p, and indicated that miR-20a-5p, miR-20b-5p and E2F1 are involved in myoblast proliferation and differentiation through the auto-regulation between E2F1 and miR-20a-5p/20b-5p. These findings provide new insight into the mechanism of muscle differentiation, and further shed light on the understanding of muscle development and muscle diseases.
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Project description:Short-period (ultradian) oscillations of Hes1, a Notch signaling effector, are essential for maintaining neural progenitors in a proliferative state, while constitutive downregulation of Hes1 leads to neuronal differentiation. Hes1 oscillations are driven by autorepression, coupled with high instability of the protein and mRNA. It is unknown how Hes1 mRNA stability is controlled and furthermore, how cells exit oscillations in order to differentiate. Here, we identify a microRNA, miR-9, as a component of ultradian oscillations. We show that miR-9 controls the stability of Hes1 mRNA and that both miR-9 overexpression and lack of miR-9 dampens Hes1 oscillations. Reciprocally, Hes1 represses the transcription of miR-9, resulting in out-of-phase oscillations. However, unlike the primary transcript, mature miR-9 is very stable and thus accumulates over time. Given that raising miR-9 levels leads to dampening of oscillations, these findings provide support for a self-limiting mechanism whereby cells might terminate Hes1 oscillations and differentiate.
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Project description:BackgroundAngiogenesis plays a critical role in the progression of glioma. Previous studies have indicated that RNA-binding proteins (RBPs) interact with RNAs and participate in the regulation of the malignant behaviors of tumors. As a type of endogenous non-coding RNAs, circular RNAs (circRNAs) are abnormally expressed in various cancers and are involved in diverse tumorigeneses including angiogenesis.MethodsThe expression levels of FUS, circ_002136, miR-138-5p, SOX13, and SPON2 were determined using quantitative real-time PCR (qRT-PCR) and western blot. Transient cell transfection was performed using the Lipofectamine 3000 reagent. The RNA-binding protein immunoprecipitation (RNA-IP) and the RNA pull-down assays were used to detect the interaction between FUS and circ_002136. The dual-luciferase reporter assay system was performed to detect the binding sites of circ_002136 and miR-138-5p, miR-138-5p and SOX13. The chromatin immunoprecipitation (ChIP) assays were used to examine the interactions between transcription factor SOX13 and its target proteins .ResultsWe demonstrated that down-regulation of FUS or circ_002136 dramatically inhibited the viability, migration and tube formation of U87 glioma-exposed endothelial cells (GECs). MiR-138-5p was down-regulated in GECs and circ_002136 functionally targeted miR-138-5p in an RNA-induced silencing complex (RISC). Inhibition of circ_002136, combined with the restoration of miR-138-5p, robustly reduced the angiogenesis of GECs. As a target gene of miR-138-5p, SOX13 was overexpressed in GECs and was proved to be involved in circ_002136 and miR-138-5p-mediated angiogenesis in gliomas. In addition, we found that SOX13 was directly associated with and activated the SPON2 promoter, thereby up-regulating the expression of SPON2 at the transcriptional level. Knockdown of SPON2 suppressed the angiogenesis in GECs. More important, SOX13 activated the FUS promoter and increased its expression, forming a feedback loop.ConclusionOur data suggests that the feedback loop of FUS/circ_002136/miR-138-5p/SOX13 played a crucial role in the regulation of angiogenesis in glioma. This also provides a potential target and an alternative strategy for combined glioma therapy.
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Project description:As a common cause of liver injury, hepatic ischemia/reperfusion injury (HIRI) happens in various clinical conditions including trauma, hepatectomy and liver transplantation. Since transcription factor Yin Yang 1 (YY1) was reported to be downregulated after ischemia/reperfusion (I/R) injury, we focused on YY1 to explore its function in HIRI by functional assays like Cell Counting Kit-8 (CCK-8) assays and flow cytometry assays. The RT-qPCR assay revealed that YY1 was downregulated in hepatocytes after I/R injury. The function assays disclosed that YY1 facilitated cell viability and proliferation, but hindered cell apoptosis in hepatocytes after I/R injury. Through mechanism assays including luciferase reporter assay, RIP and RNA pulldown assay, miR-186-5p was found to bind with YY1 and promote hepatocyte apoptosis by targeting YY1. Subsequently, we verified that small nucleolar RNA host gene 1 (SNHG1) could sponge miR-186-5p to upregulate YY1. Importantly, we figured out that YY1 had a positive regulation on SNHG1. Along the way, YY1 was identified as the upstream transcription factor for SNHG1. In conclusion, our study unveiled a novel competing endogenous RNA (ceRNA) pattern of SNHG1/miR-186-5p/YY1 positive feedback loop in hepatic I/R injury, which might provide new insight into prevention of HIRI during liver transplantation or hepatic surgery.
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Project description:Oxaliplatin resistance is a major challenge in the clinical treatment for advanced colorectal cancer (CRC). Long non-coding RNAs (lncRNAs) are involved in tumorigenesis and progression as critical regulators, while their potential roles in chemoresistance are poorly understood. In this study, we report that the LINC00460-miR-149-5p/miR-150-5p-mutant p53 feedback loop is responsible for oxaliplatin resistance in CRC. First, LINC00460 was found to exhibit higher expression in oxaliplatin-resistant CRC (CRC/OxR) cells compared with parental oxaliplatin-sensitive ones, and this expression pattern depends on mutant p53 (SW480/OxR), not wild-type p53 (HCT116/OxR). Oxaliplatin-induced LINC00460 in SW480/OxR cells was mainly located in the cytoplasm and was associated with AGO2 protein. LINC00460 functions as a competing endogenous RNA (ceRNA) to promote oxaliplatin resistance through sequestering miR-149-5p/miR-150-5p and upregulating the expression of the microRNA (miRNA) target p53. Knockdown of LINC00460 sensitized SW480/OxR cells to oxaliplatin by modulating p53 in vitro and in vivo. In turn, mutant p53 positively regulated the expression of LINC00460, thus forming a feedback loop. Clinical data showed that LINC00460 was upregulated in CRC tissues compared with paired normal tissues and was significantly correlated with clinical stage and node (N) status. Our findings uncover a mechanism for the LINC00460-miR-149-5p/miR-150-5p-mutant p53 feedback loop in oxaliplatin resistance of CRC, and they provide potential therapeutic targets for tumor chemoresistance.
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Project description:BackgroundAs a newfound type of non-coding RNA, circular RNAs (circRNAs) are involved in various physiological and pathological processes via regulation of gene expression. Increasing evidence shows that aberrantly expressed circRNAs play a crucial role in the initiation and progression of many tumors. However, the functions of different circRNAs in gliomas remain elusive.MethodsThe levels of circRNAs, miRNAs, and mRNAs were quantified by qPCR. The interaction between circDENND2A and miR-625-5p was determined by luciferase reporter and pull-down assays. The migratory and invasive capabilities of glioma cells were examined by wound healing and Transwell assays. Immunohistochemistry was performed to analyze the HIF1α level in glioma tissues.ResultsWe predicted circDENND2A (has_circ_0002142) to be a hypoxia-responsive circRNA in glioma via a bioinformatic analysis. We found that hypoxia induced the expression of circDENND2A, which promoted migration and invasion of glioma cells. To understand the behaviors of circDENND2A in glioma, we studied the putative miRNAs targeted by circDENND2A and identified circDENND2A as an efficient sponge of miR-625-5p in glioma cells. Phenotype experiments verified that circDENND2A was required for the hypoxia-induced migration and invasion of glioma cells and that this occurred by sponging of miR-625-5p. Notably, glioma tissues overexpressing HIF1α exhibited a high expression of circDENND2A as well as a low expression of miR-625-5p. circDENND2A was negatively correlated with miR-625-5p.ConclusioncircDENND2A is required for the hypoxia-induced malignancy of glioma cells and functions by sponging miR-625-5p.
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Project description:Osteoporosis is a frequently occurring bone disease in middle-aged and aged men and women. However, current therapies on this disease are still not ideal. MicroRNAs (miRNAs) are a class of endogenous non-protein-coding RNA with a length of 18-25 nucleotides. miRNAs have been identified as important regulators for development, metabolism, carcinogenesis, and bone formation. miR-129-5p has been reported as a regulator of cancer and neuroscience, whereas studies about its function on bone formation is still limited. In this study, we investigated the function and mechanism of miR-129-5p on osteoblast differentiation and bone formation. We have assessed the expression of miRNAs in bone mesenchymal stem cells from aging and menopause osteoporosis C57BL6 mice. The expression of miR-129-5p was altered in all osteoporosis models. Besides, the expression of miR-129-5p was negatively correlated with osteoblastic differentiation markers in the femur tissues of C57BL/6 mice of different ages. We further demonstrated that overexpression of miR-129-5p inhibited osteoblast differentiation in MC3T3-E1 cell line, as well as bone formation of C57BL/6 mice. On the other hand, down-regulation of miR-129-5p enhanced osteoblast differentiation and bone formation. We also found that miR-129-5p inhibited Wnt/β-catenin pathway in osteoblast. The target gene of miR-129-5p has been forecasted and proved as Tcf4. We further found that plasmid containing Tcf4-3' UTR sequence enhanced osteoblast differentiation, as well as Wnt/β-catenin pathway in MC3T3-E1 cells. To further investigate the rescue effect of miR-129-5p inhibitor, we manufactured bioengineered novel recombinant miR-129-5p inhibitor through Escherichia coli system and then tested its function. The results showed that the novel recombinant miR-129-5p inhibitor promoted osteoblast differentiation and greatly ameliorated menopause osteoporosis in C57BL6 mice. In conclusion, we have discovered miR-129-5p as an inhibitor of bone formation. miR-129-5p inhibited downstream transcription factors of Wnt/β-catenin pathway through targeting Tcf4. Moreover, novel recombinant miR-129-5p inhibitor showed rescue effect on osteoporosis. This study has revealed a new mechanism of osteogenic differentiation and provided novel therapeutic strategies for treatment of skeletal disorders.
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Project description:The blood-tumor barrier (BTB) limits the transport of chemotherapeutic drugs to brain tumor tissues and impacts the treatment of glioma. Long non-coding RNAs play critical roles in various biological processes of tumors; however, the function of these in BTB permeability is still unclear. In this study, we have identified that long intergenic non-protein coding RNA 174 (linc00174) was upregulated in glioma endothelial cells (GECs) from glioma tissues. Additionally, linc00174 was also upregulated in GECs from the BTB model in vitro. Knock down of linc00174 increased BTB permeability and reduced the expression of the tight junction-related proteins ZO-1, occludin, and claudin-5. Both bioinformatics data and results of luciferase reporter assays demonstrated that linc00174 regulated BTB permeability by binding to miR-138-5p and miR-150-5p. Furthermore, knock down of linc00174 inhibited FOSL2 expression via upregulating miR-138-5p and miR-150-5p. FOSL2 interacted with the promoter regions and upregulated the promoter activity of ZO-1, occludin, claudin-5, and linc00174 in GECs. In conclusion, the present study demonstrated that the linc00174/miR-138-5p (miR-150-5p)/FOSL2 feedback loop played an essential role in regulating BTB permeability.
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