CircPVT1 promotes progression in clear cell renal cell carcinoma by sponging miR-145-5p and regulating TBX15 expression.
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ABSTRACT:
SUBMITTER: Zheng Z
PROVIDER: S-EPMC8019224 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAccumulating evidence has revealed that circular RNAs (circRNAs), as novel noncoding RNAs, play critical roles in carcinogenesis and tumor progression. However, the functions and molecular mechanisms of circRNAs in clear cell renal cell carcinoma (ccRCC) are largely unknown.MethodsThe expression and functions of circAGAP1 were identified in clinical samples, ccRCC cells and in vivo animal models. The molecular mechanism of circAGAP1 was investigated by fluorescence in situ hybridization, RNA immunoprecipitation and luciferase assays.ResultscircAGAP1 (circ0058792) expression was significantly upregulated in ccRCC tissues compared to adjacent nontumor tissues. Moreover, the expression of circAGAP1 was closely related to the tumor size, nuclear grade and clinical stage of ccRCC in patients. Mechanistic studies demonstrated that cytoplasmic circAGAP1 targeted miR-15-5p in an RNA-induced silencing complex. Additionally, miR-15-5p expression was downregulated in ccRCC. Luciferase reporter assays showed that E2F transcription factor 3 (E2F3) was a target of miR-15-5p, and upregulated E2F3 expression was positively correlated with circAGAP1 in ccRCC. Furthermore, the tumor-promoting functions of circAGAP1 could be alleviated by miR-15-5p mimics in vitro and in vivo.ConclusionOur results clarify that circAGAP1 exerts its oncogenic functions as a competitive endogenous RNA (ceRNA) by sponging miR-15-5p, which promotes E2F3 expression. Targeting circAGAP1 might be a new attractive therapeutic strategy in ccRCC.
| S-EPMC7901094 | biostudies-literature
Project description:Osteosarcoma is the most common primary malignant bone tumor in adolescents. While chemotherapy combined with surgery can improve the prognosis of some patients, chemo-resistance is still a huge obstacle in osteosarcoma treatment. Accumulating evidence demonstrates that circular RNAs (circRNAs) are involved in cancer progression and metastasis, but their specific role in osteosarcoma remains mostly undescribed. In this study, we performed circRNA deep sequencing and identified 88 distinct circRNAs from a human osteosarcoma cell lines group (143B, HOS, SJSA, and U2OS) and the human osteoblast hFOB 1.19 (control). We found that circCAMSAP1, also named hsa_circ_0004338, is significantly upregulated in human osteosarcoma tissues and cell lines, and it is positively correlated with osteosarcoma development. Silencing of circCAMSAP1 effectively suppresses osteosarcoma cell growth, apoptosis, migration, and invasion. Furthermore, we validated that circCAMSAP1 functions in osteosarcoma tumorigenesis through a circCAMSAP1/miR-145-5p/friend leukemia virus integration 1 (FLI1) pathway. FLI1 promotes osteosarcoma tumorigenesis and miR-145-5p suppresses FLI translation. circCAMSAP1 directly sequesters miR-145-5p in the cytoplasm and inhibits its activity to suppress osteosarcoma tumorigenesis. Moreover, the regulatory role of circCAMSAP1 upregulation was examined and validated in rats. In summary, our findings provide evidence that circCAMSAP1 act as a "microRNA sponge" and suggest a new therapeutic target of human osteosarcoma.
| S-EPMC7901030 | biostudies-literature
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.
| S-EPMC8024300 | biostudies-literature
Project description:BackgroundDue to the poor prognosis for advanced renal cell carcinoma (RCC), there is an urgent need for new therapeutic targets and for prognostic markers to identify high risk tumors. MicroRNAs (miRNAs) are frequently dysregulated in tumors, play a crucial role during carcinogenesis and therefore might be promising new biomarkers. In previous studies, we identified miR-141-3p and miR-145-5p to be downregulated in clear cell RCC (ccRCC). Our objective was to investigate the functional association of these miRNAs, focusing on the cooperative regulation of new specific targets and their role in ccRCC progression.MethodsThe effect of miR-141-3p and miR-145-5p on cell migration was examined by overexpression in 786-O cells. New targets of both miRNAs were identified by miRWalk, validated in 786-O and ACHN cells and additionally characterized in ccRCC tissue on mRNA and protein level.ResultsIn functional analysis, a tumor suppressive effect of miR-141-3p and miR-145-5p by decreasing migration and invasion of RCC cells could be shown. Furthermore, co-overexpression of the miRNAs seemed to result in an increased inhibition of cell migration. Both miRNAs were recognized as post-transcriptional regulators of the targets EAPP, HS6ST2, LOX, TGFB2 and VRK2. Additionally, they showed a cooperative effect again as demonstrated by a significantly increased inhibition of HS6ST2 and LOX expression after simultaneous overexpression of both miRNAs. In ccRCC tissue, LOX mRNA expression was strongly increased compared to normal tissue, allowing also to distinguish between non-metastatic and already metastasized primary tumors. Finally, in subsequent tissue microarray analysis LOX protein expression showed a prognostic relevance for the overall survival of ccRCC patients.ConclusionThese results illustrate a jointly strengthening effect of the dysregulated miR-141-3p and miR-145-5p in various tumor associated processes. Focusing on the cooperative effect of miRNAs provides new opportunities for the development of therapeutic strategies and offers novel prognostic and diagnostic capabilities.
| S-EPMC4919070 | biostudies-literature
Project description:BackgroundCircular RNAs (circRNAs) have displayed important roles in the development and progression of various cancers. However, the functions of the majority of circRNAs in osteosarcoma (OS) remain unknown.MethodsCircular RNA microarray analysis was performed in three OS cell lines (Saos-2, U2OS and MG63) and normal vascular endothelial cells. The co-differentially expressed circRNAs (CDECs) were identified in OS cell lines with the criterion of FDR (false discovery rate) < 0.05 and |fold change (FC)|> 2. Quantitative real-time PCR was used to validate the expression levels of selected CDECs. A series of functional assays, including MTT assay, flow cytometry and transwell assay were conducted in OS cells. The interaction between circRNA and miRNAs was confirmed by luciferase reporter assay and RNA immunoprecipitation assay.ResultsA total of 241 CDECs, including 75 upregulated and 166 downregulated CDECs, were identified in three OS cell lines compared with normal vascular endothelial cells. PCR validation showed that hsa_circ_0000704, hsa_circ_0001017 and hsa_circ_0005035 were all highly expression in the three OS cell lines, compared with osteoblast cell lines (HECC, hFOB1.19 and HFF-1). Functionally, overexpression of circ_0001017 significantly promoted the cell proliferation, migration and invasion and decreased apoptosis in U2OS cells. Knockdown of circ_0001017 obtained the opposite results. Circ_0001017 may downregulate miR-145-5p through direct binding. Furthermore, the expression of miR-145-5p was negatively regulated by circ_0001017 in OS cells. In addition, further functional studies indicated that miR-145-5p inhibitor eliminated the effects caused by si-circ_0001017 in OS cells.ConclusionsIn conclusion, our study suggested that circ_0001017 may be a novel oncogenic factor during the progression and development of OS by targeting miR-145-5p.
| S-EPMC8962139 | biostudies-literature
Project description:BackgroundLong-non-coding RNA PVT1 (lncRNA PVT1) can be used as an oncogenic regulatory non-coding RNA (ncRNA) for many cancers. However, its function and mechanism in breast cancer (BRCA) are still not clearly elucidated.ObjectiveWe attempt to explain the mechanism of PVT1's role in breast cancer from different perspectives.MethodsWe analyzed the expression of PVT1 and its correlation with the breast cancer related clinical data in the The Cancer Genome Atlas (TCGA) database. We used PVT1 overexpression and knockdown lentivirus to infect breast cancer MDA-MB-231 cell line for cell function verification, in vitro using CCK-8 to measure proliferation, flow cytometry to measure apoptosis, transwell test to measure invasion and migration ability, detecting cell extracellular acidification rate (ECAR) to assess glycolysis metabolism and explore the biological functions of PVT1 in breast cancer cells. Transcriptome sequencing was used to analyze the changes of related genes in cells after overexpression of PVT1. In vivo we used a xenograft model to study the effect of PVT1 on breast cancer.ResultsPVT1 was up-regulated in breast cancer tissues and was positively correlated with the clinical stage of breast cancer patients. Overexpression of PVT1 in vitro promoted cell proliferation, migration and invasion, and promoted tumor growth in vivo. Knockdown of PVT1 led to the opposite biological consequence. Further bioinformatics analysis showed that PVT1 changes the glycolysis metabolism of tumors through regulation of glycolysis-related genes. In addition, the expression of miR-145-5p is negatively correlated with PVT1. We consider the possibility of PVT1 promoting cell proliferation and metastasis by regulating the aerobic glucose metabolism in breast cancer cells through sponging the miR-145-5p.ConclusionOur results reveal a potential pathway for competing endogenous RNA to regulate breast cancer glucose metabolism. PVT1 regulates glycolysis related genes expression by competitively binding to endogenous miR-145-5p in breast cancer cells to change the metabolic phenotype. This may Provide new ideas for precise molecular therapy targets for breast cancer.
| S-EPMC10113361 | biostudies-literature
Project description:BackgroundCircular RNAs (circRNAs) as a novel subgroup of non-coding RNAs act a critical role in the pathogenesis of gastric cancer (GC). However, the underlying mechanisms by which hsa_circ_0003855 (circDUSP16) contributes to GC are still undocumented.MaterialsThe differentially expressed circRNAs were identified by GEO database. The association of circDUSP16 or miR-145-5p expression with clinicopathological features and prognosis in GC patients was analyzed by FISH and TCGA-seq data set. Loss- and gain-of-function experiments as well as a xenograft tumor model were performed to assess the role of circDUSP16 in GC cells. circDUSP16-specific binding with miR-145-5p was confirmed by bioinformatic analysis, luciferase reporter, and RNA immunoprecipitation assays.ResultsThe expression levels of circDUSP16 were markedly increased in GC tissue samples and acted as an independent prognostic factor of poor survival in patients with GC. Knockdown of circDUSP16 repressed the cell viability, colony formation, and invasive potential in vitro and in vivo, but ectopic expression of circDUSP16 reversed these effects. Moreover, circDUSP16 possessed a co-localization with miR-145-5p in the cytoplasm, and acted as a sponge of miR-145-5p, which attenuated circDUSP16-induced tumor-promoting effects and IVNS1ABP expression in GC cells. MiR-145-5p had a negative correlation with circDUSP16 expression and its low expression was associated with poor survival in GC patients.ConclusionsCircDUSP16 facilitates the tumorigenesis and invasion of GC cells by sponging miR-145-5p, and may provide a novel therapeutic target for GC.
| S-EPMC7165161 | biostudies-literature
Project description:Spermatogenesis associated serine rich 2 (SPATS2) has been reported to contribute to the tumorigenesis of multiple malignancies. The molecular function of SPATS2 in hepatocellular carcinoma (HCC) is still not fully understood. In this study, we aimed to investigate the expression pattern and function roles of SPATS2 in HCC. The regulation of SPATS2 expression was also explored. We found that SPATS2 was highly expressed in HCC tissues in comparison with that in adjacent normal tissues. High expression of SPATS2 was associated with vascular invasion, advanced TNM stages, tumor multiplicity, and poor survival. Functionally, SPATS2 was found to promote the proliferation and metastasis of HCC cells both in vitro and in vivo, while knockdown of SPATS2 enhanced apoptosis and G1 arrest of HCC cells in vitro. Mechanistically, bioinformatics analysis revealed that MiR-145-5p directly targeted SPATS2 and functional rescue experiments verified that MiR-145-5p overexpression could abolish the effect of SPATS2 on the regulation of HCC malignant phenotype. Taken together, our findings suggest that SPATS2 functions as an oncogene in HCC. The MiR-145-5p/SPATS2 axis provides a novel mechanism underlying HCC progression and may serve as a potential therapeutic target for HCC.
| S-EPMC7547105 | biostudies-literature
Project description:Analysis of microRNA (miRNA) regulatory networks is useful for exploring novel biomarkers and therapeutic targets in cancer cells. The Cancer Genome Atlas dataset shows that low expression of both strands of pre-miR-101 (miR-101-5p and miR-101-3p) significantly predicted poor prognosis in clear cell renal cell carcinoma (ccRCC). The functional significance of miR-101-5p in cancer cells is poorly understood. Here, we focused on miR-101-5p to investigate the antitumor function and its regulatory networks in ccRCC cells. Ectopic expression of mature miRNAs or siRNAs was investigated in cancer cell lines to characterize cell function, ie, proliferation, apoptosis, migration, and invasion. Genome-wide gene expression and in silico database analyses were undertaken to predict miRNA regulatory networks. Expression of miR-101-5p caused cell cycle arrest and apoptosis in ccRCC cells. Downstream neighbor of son (DONSON) was directly regulated by miR-101-5p, and its aberrant expression was significantly associated with shorter survival in propensity score-matched analysis (P = .0001). Knockdown of DONSON attenuated ccRCC cell aggressiveness. Several replisome genes controlled by DONSON and their expression were closely associated with ccRCC pathogenesis. The antitumor miR-101-5p/DONSON axis and its modulated replisome genes might be a novel diagnostic and therapeutic target for ccRCC.
| S-EPMC7156888 | biostudies-literature
Project description:BackgroundCircular RNAs are key regulators in human cancers, however, there is a lack of studies on circRNAs' specific functions in ovarian cancer.MethodsOur study used qRT-PCR to detect the differentially expressed circRNAs between normal ovaries and ovarian cancer tissues. Cell function experiments were performed to verify the role of overexpression and silence of circWHSC1, including MTT assay, cell apoptosis assay, wound healing and Matrigel-coated Transwell assay. In vivo tumorigenesis model was constructed by subcutaneous injection in nude mice. Bioinformatics analysis predicted the possible binding sites of circWHSC1 with miRNAs, and confirmed with dual-luciferase reporter assay and RNA pull-down assay. The exosomes were extracted with ultracentrifugation. HE staining was also used to detect morphology of nude mice peritoneum.ResultsWe found that circWHSC1 was up-regulated in ovarian cancer tissues, and circWHSC1 expression was higher in moderate & poor differentiation ovarian cancer tissues than in well differentiation ovarian cancer tissues. Overexpression of circWHSC1 increased cell proliferation, migration and invasion, and inhibited cell apoptosis. Silence of circWHSC1 exerted the opposite effects. Additionally, circWHSC1 could sponge miR-145 and miR-1182 and up-regulate the expression of downstream targets MUC1 and hTERT. Exosomal circWHSC1 can be transferred to peritoneal mesothelial cells and promotes peritoneal dissemination.ConclusionsOur study demonstrates the highly expressed circWHSC1 in ovarian cancer promotes tumorigenesis by sponging miR-145 and miR-1182, and its exosome forms induce tumor metastasis through acting on peritoneal mesothelium.
| S-EPMC6822369 | biostudies-literature