Transcription factor PAX4 facilitates gastric cancer progression through interacting with miR-27b-3p/Grb2 axis.
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ABSTRACT:
SUBMITTER: Zhang Y
PROVIDER: S-EPMC8266315 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background:Recently, many emerging circular RNAs (circRNAs) have been studied in human malignancies, including gastric cancer (GC). Researches concerning cancers have revealed that aberrant expression of circRNAs play a big part in tumorigenesis and development of diverse malignant tumors. Although hsa_circ_0014130 (circPIP5K1A) has been confirmed to be closely related to non-small cell lung cancer (NSCLC) progression, the knowledge of its function on GC progression remains unclear. Therefore, it is of great interest to uncover the underlying role of circPIP5K1A in GC. Methods:The expression and characteristic of circPIP5K1A were separately analyzed by RT-qPCR, nucleic acid electrophoresis, RNase R and Actinomycin D treatment. CCK-8, colony formation, EdU, transwell, TUNEL, flow cytometry, luciferase reporter, RIP and RNA pull-down assays were employed to testify the regulatory role of circPIP5K1A in GC. Results:In current study, circPIP5K1A, featured with closed-loop structure, was proved to be highly expressed in tissues and cells of GC. Loss-of-function assays depicted that silencing circPIP5K1A suppressed GC development. Follow-up mechanism tests unveiled that circPIP5K1A bound with miR-376c-3p and inhibition of miR-376c-3p reversed circPIP5K1A downregulation-mediated effect on GC progression. Additionally, ZNF146 was verified to be the downstream molecule of circPIP5K1A/miR-376c-3p axis in modulating GC progression. Conclusions:circPIP5K1A stimulates GC progression by sponging miR-376c-3p to upregulate ZNF146 expression.
| S-EPMC7071687 | biostudies-literature
Project description:BackgroundThough circular RNAs (circRNAs) are the key regulators in tumor carcinogenesis, they remain largely unexplored in hepatocellular carcinoma (HCC).MethodsThe expression of RanGAP1-derived circRNAs (circ_0063531, circ_0063534, circ_0063513, circ_0063518, circ_0063507, circ_0063723) were evaluated in eight paired HCC and normal tissues, and the correlation between circRanGAP1 (circ_0063531) expression and clinicopathological characteristics in 40 HCC patients was determined. The association between miR-27b-3p and circRanGAP1 or NRAS was predicted using bioinformatics analysis. The expression of circRanGAP1, miR-27b-3p, and NRAS were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The potential oncogenic role of circ-RanGAP1 was assessed using CCK-8, colony formation, transwell assays in vitro, subcutaneous tumor mouse model, vein tail metastatic model, and orthotopically implanted intrahepatic HCC model in vivo. Luciferase reporter and RNA immunoprecipitation (RIP) assays were used to explore the binding site between miR-27b-3p and circ-RanGAP1 or NRAS. Protein expression was detected using western blotting. The localization of miR-27b-3p and circ-RanGAP1 was investigated using fluorescence in situ hybridization (FISH). The level of immune infiltration was assessed by bioinformatics analysis, flow cytometry, and orthotopically implanted intrahepatic HCC models.ResultsHere, we found elevated circRanGAP1 in the cells and clinical tissues of patients with HCC. Increased circRanGAP1 levels are associated with enlarged tumors and the advanced stage of TNM. CircRanGAP1 promotes the growth, migration, and HCC cell invasion, concurrently with the growth and metastasis of tumors in-vivo. Moreover, circRanGAP1 is mainly located inside the cytoplasm. Mechanistically, circRanGAP1 as an oncogene promotes HCC progression by miR-27b-3p/NRAS/ERK axis, furthermore, affects the infiltration level of tumor-associated macrophages probably by sponging miR-27b-3p. Immune infiltration analysis shows that NRAS is positively correlated with the levels of CD68+ tumor-associated macrophages in HCC samples and that NRAS and CD68 are related to the poor outcome of HCC.ConclusionThese results reveal that circRanGAP1 is a HCC oncogene that function by the miR-27b-3p/NRAS/ERK axis and regulates the infiltration levels of tumor-associated macrophages by sponging miR-27b-3p. Therefore, circRANGAP1/ NRAS axis may be an important potential treatment target against HCC.
| S-EPMC9644583 | biostudies-literature
Project description: Not available
| S-EPMC9841122 | biostudies-literature
Project description:Long non-coding RNAs (lncRNAs) play important regulatory roles in the initiation and progression of various cancers. However, the biological roles and the potential mechanisms of lncRNAs in gastric cancers remain unclear. Here, we report that the expression of lncRNA SNHG22 (small nucleolar RNA host gene 22) was significantly increased in GC (Gastric Cancer) tissues and cells, which confers poor prognosis of patients. Knockdown of SNHG22 inhibited the proliferation and invasion ability of GC cells. Moreover, we identified that the transcriptional factor, ELK4 (ETS transcription factor ELK4), could promote SNHG22 expression in GC cells. In addition, using RNA pull-down followed MS assay, we found that SNHG22 directly bound to EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) to suppress the expression of tumor suppressor genes. At the same time, SNHG22 sponged miR-200c-3p to increase Notch1 (notch receptor 1) expression. Taken together, our findings demonstrated the role of SNHG22 on promoting proliferation and invasion of GC cells. And we revealed a new regulatory mechanism of SNHG22 in GC cells. SNHG22 is a promising lncRNA biomarker for diagnosis and prognosis and a potential target for GC treatment.
| S-EPMC8523719 | biostudies-literature
Project description:Background:Abnormally expressed circular RNAs (circRNAs) are implicated in the development and treatment of gastric cancer (GC). Previous study has reported that hsa_circ_0003159 is expressed in GC. However, the role and mechanism of hsa_circ_0003159 in GC progression remain unclear. Methods:GC tissues and normal tissues were harvested from 55 patients in this study. The levels of hsa_circ_0003159, microRNA (miR)-223-3p and N-myc downstream regulated gene 1 (NDRG1) were measured by quantitative real-time polymerase chain reaction or western blot. Cell proliferation, migration, invasion and apoptosis were determined by cell counting kit (CCK)-8, transwell assay, flow cytometry and western blot, respectively. The target association of miR-223-3p-hsa_circ_0003159 and miR-223-3p-NDRG1 was explored by dual-luciferase reporter assay. Xenograft model was established to assess the roles of hsa_circ_0003159 in GC in vivo. Results:Hsa_circ_0003159 was lowly expressed in GC tissues and cells and mainly presented in the cytoplasm. Low expression of hsa_circ_0003159 was associated with lower overall survival and disease-free survival. Hsa_circ_0003159 overexpression inhibited proliferation, migration and invasion but induced apoptosis in GC cells. MiR-223-3p was a target of hsa_circ_0003159 and abated the effect of hsa_circ_0003159 on proliferation, migration, invasion and apoptosis in GC cells. Hsa_circ_0003159 promoted NDRG1 expression by competitively sponging miR-223-3p. Knockdown of NDRG1 reversed the suppressive effect of hsa_circ_0003159 on GC progression. Besides, hsa_circ_0003159 decreased GC cell xenograft tumor growth by regulating miR-223-3p and NDRG1. Conclusion:Hsa_circ_0003159 suppressed proliferation, migration, invasion and xenograft tumor growth but promoted apoptosis by decreasing miR-223-3p and increasing NDRG1 in GC, indicating a novel target for treatment of GC.
| S-EPMC7031989 | biostudies-literature
Project description:BackgroundWith the broadened application of gene expression profiles analysis, the role of miRNA and circRNA are of increasing concern in recent years, especially during the pathogenesis of cancer. However, to date, the reported on this area in cervical cancer are limited.MethodIn this study, Weighted Gene Co-Expression Network Analysis (WGCNA) and differential gene expression analysis were utilized to screen out differentially expressed (DE) circular RNAs in cervical cancer, and then we predicted and screened the combined microRNAs (miRNA) and downstream mRNAs to construct circular (circ)RNA-miRNA-mRNA network.ResultAs a result, a regulatory circular (circ)RNA-miRNA-mRNA with 1 circRNA node, 4 miRNA nodes, 135 mRNA nodes were constructed in an attempt to provide novel biomarkers for the pathogenesis of cervical cancer. In addition, enrichment analysis including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed on mRNAs in the network. After further screening of mRNAs by two online databases of GEPIA2 and RNAyhrid, precise target genes were obtained. Next, we screened out four target genes (CXCL16, IRF4, OAS3 and PTGER3) by constructing the protein-protein interaction (PPI) network, and mapped them to the initial network to reconstruct the circRNA-miRNA-mRNA network. Notably, the low expression of IRF4 was demonstrated to be associated with a significantly poorer overall survival in the GEPIA2 database, which was also verified by the immunofluorescence of the sections in Human Protein Atlas (HPA). The upstream miRNA corresponding to IRF4 is hsa-miR-1228-3p.ConclusionFrom above concern, it can conclude that hsa_circ_0000301/hsa-miR-1228-3p/IRF4 may be involved in the occurrence and development of cervical cancer. However, the specific mechanism should be further studied and confirmed.
| S-EPMC8140416 | biostudies-literature
Project description:Drug resistance remains a major problem in the treatment of conventional chemotherapeutic agents in breast cancers. Owing to heterogeneity and complexity of chemoresistance mechanisms, most efforts that focus on a single pathway were unsuccessful, and exploring novel personalized therapeutics becomes urgent. By a system approach, we identified that microRNA-27b-3p (miR-27b), a miRNA deleted in breast cancer tissues and cell lines, has a master role in sensitizing breast cancer cells to a broad spectrum of anticancer drugs in vitro and in vivo. Mechanistic analysis indicated that miR-27b enhanced responses to PTX by directly targeting CBLB and GRB2 to inactivate both PI3K/Akt and MAPK/Erk signaling pathways. Further, miR-27b was identified as a promising molecular biomarker in chemoresistance, clinicopathological features, and prognosis for breast cancer patients. In conclusion, we propose that combinational use of miR-27b and chemotherapeutic agents might be a promising therapeutic strategy to increase long-term drug responses in breast cancers.
| S-EPMC5833695 | biostudies-literature
Project description:Oxaliplatin (OXA) resistance is the major obstacle to the anticancer effects of chemotherapy in colorectal cancer (CRC) patients. MicroRNAs (miRNAs) play an important role in the chemoresistance of various tumors. Our objective is to clarify the underlying mechanism of miRNAs in chemoresistance and provide a potential strategy to improve the response of CRC patients to chemotherapeutics. Methods: MiRNA microarray and Real-time PCR were performed to compare changes in miRNA expression between oxaliplatin-resistant and the parental cells. CCK8, apoptosis assay, immunofluorescence and xenograft studies were used to elucidate the impact of miR-27b-3p on regulating chemoresistance. Luciferase reporter assay and western blot were carried to assess the regulatory role of miR-27b-3p in ATG10 expression. The effects of miR-27b-3p and ATG10 on autophagy were investigated by GFP-LC3 fluorescence microscopy, transmission electron microscopy, and western blot. ChIP assay and luciferase assay were performed to test the c-Myc's occupancy on the miR-27B promoter. Results: We observed that miR-27b-3p expression was significantly downregulated in oxaliplatin-resistant cell lines (SW480-OxR and HCT116-OxR) compared to the corresponding parental cell lines and that miR-27b-3p expression was positively correlated with disease-free survival (DFS) time in colorectal cancer patients. MiR-27b-3p could sensitize colorectal cancer cells to oxaliplatin in vitro and in vivo. Under oxaliplatin treatment, chemoresistant cells showed a higher autophagy level than parental cells. Moreover, we also identified that miR-27b-3p inhibited the expression of ATG10 at the posttranscriptional level, thus inhibiting autophagy. Further study demonstrated that c-Myc can inhibit the expression of miR-27b-3p via binding to the promoter region of miR-27B gene. Conclusions: Our study identifies a novel c-Myc/miR-27b-3p/ATG10 signaling pathway that regulates colorectal cancer chemoresistance. These results suggest that miR-27b-3p is not only a potential indicator for evaluating efficiency of chemotherapy, but also a valuable therapeutic target for CRC, especially for patients with chemoresistance.
| S-EPMC7019154 | biostudies-literature
Project description:The receptor tyrosine kinase-like orphan receptors (ROR) family contains the atypical member ROR1, which plays an oncogenic role in several malignant tumors. However, the clinical potentials and underlying mechanisms of ROR1 in gastric cancer progression remain largely unknown. In this study, we validated the microRNA-mediated gene repression mechanism involved in the role of ROR1.Bioinformatic prediction, luciferase reporter assay, quantitative real-time PCR (qRT-PCR) and western blotting were used to reveal the regulatory relationship between miR-27b-3p and ROR1. The expression patterns of miR-27b-3p and ROR1 in human gastric cancer (GC) specimens and cell lines were determined by microRNA RT-PCR and western blotting. Cell proliferation, colony formation assay in soft agar in vitro and tumorigenicity in vivo were performed to observe the effects of downregulation and upregulation miR-27b-3p expression on GC cell phenotypes.miR-27b-3p suppressed ROR1 expression by binding to the 3'UTR of ROR1 mRNA in GC cells. miR-27b-3p was significantly downregulated and reversely correlated with ROR1 protein levels in clinical samples. Analysis of the clinicopathological significance showed that miR-27b-3p and ROR1 were closely correlated with GC characteristics. Ectopic miR-27b-3p expression suppressed cell proliferation, colony formation in soft agar, xenograft tumors of GC cells. By contrast, miR-27b-3p knockdown enhanced these malignant behaviors. Our studies further revealed that the c-Src/STAT3 signaling pathway was involved in miR-27b-3p-ROR1-mediated cell proliferation regulation.These results show that miR-27b-3p suppresses ROR1 expression through the binding site in the 3'UTR inhibiting the cell proliferation. These findings indicate that miR-27b-3p exerts tumor-suppressive effects in GC through the suppression of oncogene ROR1 expression and suggest a therapeutic application of miR-27b-3p in GC.
| S-EPMC4650850 | biostudies-other
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