MiR-509-5p Inhibits the Proliferation and Invasion of Osteosarcoma by Targeting TRIB2.
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ABSTRACT:
SUBMITTER: Guo J
PROVIDER: S-EPMC6942763 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveThis study aimed to explore the effect of miR-509-5p on pancreatic cancer progression and clarify the underlying mechanisms.MethodsReal-time quantitative reverse transcription polymerase chain reaction was employed to determine miR-509-5p expression in pancreatic cancer tissues and noncancerous adjacent tissues. CCK-8 and Transwell experiments were employed to examine cellular proliferation, migration, and invasion after miR-509-5p mimic or inhibitor transfection. Bioinformatics tools were used to identify the target gene of miR-509-5p, and cotransfection of the target gene and miR-509-5p mimic was performed to determine the effect on the proliferation and migration of pancreatic cancer cells. A xenograft mouse model and histological analysis were also used to test the effect of miR-509-5p on tumor growth in vivo.ResultsmiR-509-5p expression was dramatically downregulated in pancreatic cancer tissues and in pancreatic cancer cell lines. miR-509-5p mimic markedly inhibited PANC-1 cell proliferation, migration, and invasion. Conversely, miR-509-5p inhibitor promoted PANC-1 cell proliferation, migration, and invasion. Furthermore, the 3'UTR-specific target site luciferase reporter assay also showed that miR-509-5p negatively regulated MDM2 at the post-transcriptional level. miR-509-5p effectively reversed the MDM2 overexpression-induced increase in PANC-1 cell proliferation and invasion. Moreover, miR-509-5p inhibited tumor growth and accelerated cell death in the tumor samples.ConclusionsOur results suggested that miR-509-5p served as a new tumor suppressor via targeting the MDM2 gene, inhibiting pancreatic cancer progression.
| S-EPMC5602284 | biostudies-literature
Project description:Osteosarcoma (OS) has emerged as the most common primary musculoskeletal malignant tumour affecting children and young adults. Cyclin-dependent kinases (CDKs) are closely associated with gene regulation in tumour biology. Accumulating evidence indicates that the aberrant function of CDK14 is involved in a broad spectrum of diseases and is associated with clinical outcomes. MicroRNAs (miRNAs) are crucial epigenetic regulators in the development of OS. However, the essential role of CDK14 and the molecular mechanisms by which miRNAs regulate CDK14 in the oncogenesis and progression of OS have not been fully elucidated. Here we found that CDK14 expression was closely associated with poor prognosis and overall survival of OS patients. Using dual-luciferase reporter assays, we also found that miR-216a inhibits CDK14 expression by binding to the 3'-untranslated region of CDK14. Overexpression of miR-216a significantly suppressed cell proliferation, migration and invasion in vivo and in vitro by inhibiting CDK14 production. Overexpression of CDK14 in the miR-216a-transfected OS cells effectively rescued the suppression of cell proliferation, migration and invasion caused by miR-216a. In addition, Kaplan-Meier analysis indicated that miR-216a expression predicted favourable clinical outcomes for OS patients. Moreover, miR-216a expression was downregulated in OS patients and was negatively associated with CDK14 expression. Overall, these data highlight the role of the miR-216a/CDK14 axis as a novel pleiotropic modulator and demonstrate the associated molecular mechanisms, thus suggesting the intriguing possibility that miR-216a activation and CDK14 inhibition may be novel and attractive therapeutic strategies for treating OS patients.
| S-EPMC5682665 | biostudies-literature
Project description:Osteosarcoma (OS) is the most common primary pediatric malignancy of the bone having poor prognosis and long-term survival rates of less than 30% in patients with metastasis. MicroRNA-509 was reported to be downregulated in OS. We and others previously published that miR-509-3p can strongly attenuate cellular migration/invasion and sensitize ovarian cancer to cisplatin. Here, we show that overexpression of miR-509-3p inhibited migration of primary OS cell lines U2OS, HOS, and SaOS2 as well as metastatic derivatives 143B and LM7. miR-509-3p overexpression also inhibited proliferation and invasion of HOS and 143B cells and sensitized cells to cisplatin. Luciferase reporter assays using 3'-UTRs of predicted miR-509-3p targets associated with metastatic phenotypes revealed ARHGAP1 could be one of the downstream effectors of miR-509-3p in HOS. To find the global impact of miR-509-3p overexpression and cisplatin treatment we performed Reverse Phase Protein Analysis (RPPA). AXL, which has been reported to play a critical role in cisplatin resistance and confirmed as direct target of miR-509-3p was downregulated upon miR-509-3p treatment and further down-regulated upon miR-509-3p + cisplatin treatment. We propose that the miR-509-3p/AXL and miR-509-3p/ARHGAP1 axes have the potential to uncover new druggable targets for the treatment of drug resistant metastatic osteosarcoma.
| S-EPMC6911094 | biostudies-literature
Project description:Osteosarcoma is one of the commonest metastatic tumor in children and teenagers, and has a hopeless, prognosis. Long non-coding RNA (lncRNA) acts momentous roles as a regulator on the proliferation and migration of cancer. Here, we performed GEO database analysis and qPCR to identify differentially expressed lncRNAs in osteosarcoma cells. Knockdown of lncRNA LINC01140 was used to detect the effect of LINC01140 on the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of osteosarcoma cells. Bioinformatics analysis and qPCR identified the LINC01140/miR-139-5p/Homeobox A9 (HOXA9) regulatory axis. RNA immunoprecipitation assay, Dual-luciferase assay, and rescue experiments confirmed the interaction of LINC01140/miR-139-5p/HOXA9 in osteosarcoma. LINC01140 was overexpressed in osteosarcoma and knocking down LINC01140 restrained the proliferation and invasion of osteosarcoma cells and EMT. In Saos2 and MG63 cells, LINC01140 sponged miR-139-5p, and a miR-139-5p inhibitor overturned the suppression of LINC01140 knockdown on the proliferation and migration of osteosarcoma cells. Moreover, miR-139-5p depressed the invasion, proliferation, and EMT of osteosarcoma cells via targeting HOXA9. Our results indicate that LINC01140 downregulation inhibits the invasion, proliferation, and EMT in osteosarcoma cells through targeting the miR-139-5p/HOXA9 axis. Therefore, LINC01140 is a potential therapeutic target for osteosarcoma.
| S-EPMC9253409 | biostudies-literature
Project description:Recently, aberrant expression of miR-876-5p has been reported to participate in the progression of several human cancers. However, the expression and function of miR-876-5p in osteosarcoma (OS) are still unknown. Here, we found that the expression of miR-876-5p was significantly down-regulated in OS tissues compared to para-cancerous tissues. Clinical association analysis indicated that underexpression of miR-876-5p was positively correlated with advanced clinical stage and poor differentiation. More importantly, OS patients with low miR-876-5p level had a significant shorter overall survival compared to miR-876-5p high-expressing patients. In addition, gain- and loss-of-function experiments demonstrated that miR-876-5p restoration suppressed whereas miR-876-5p knockdown promoted cell proliferation, migration and invasion in both U2OS and MG63 cells. In vivo studies revealed that miR-876-5p overexpression inhibited tumour growth of OS in mice. Mechanistically, miR-876-5p reduced c-Met abundance in OS cells and inversely correlated c-Met expression in OS tissues. Herein, c-Met was recognized as a direct target of miR-876-5p using luciferase reporter assay. Notably, c-Met restoration rescued miR-876-5p attenuated the proliferation, migration and invasion of OS cells. In conclusion, these findings indicate that miR-876-5p may be used as a potential therapeutic target and promising biomarker for the diagnosis and prognosis of OS.
| S-EPMC6484334 | biostudies-literature
Project description:Angiosarcoma is a rare malignant mesenchymal tumor with poor prognosis. We aimed to identify malignancy-associated miRNAs and their target genes, and explore biological functions of miRNA and its target in angiosarcoma. By miRNA microarrays and reverse transcription polymerase chain reaction, we identified 1 up-regulated miRNA (miR-222-3p) and 3 down-regulated miRNAs (miR-497-5p, miR-378-3p and miR-483-5p) in human angiosarcomas compared with human capillary hemangiomas. The intermediate-conductance calcium activated potassium channel KCa3.1 was one of the putative target genes of miR-497-5p, and marked up-regulation of KCa3.1 was detected in angiosarcoma biopsy specimens by immunohistochemistry. The inverse correlation of miR-497-5p and KCa3.1 also was observed in the ISO-HAS angiosarcoma cell line at the mRNA and protein levels. The direct targeting of KCa3.1 by miR-497-5p was evidenced by reduced luciferase activity due to complementary binding of miR-497-5p to KCa3.1 mRNA 3' untranslated region. For the functional role of miR-497-5p/KCa3.1 pair, we showed that application of TRAM-34, a specific KCa3.1 channel blocker, or transfection of ISO-HAS cells with KCa3.1 siRNA or miR-497-5p mimics inhibited cell proliferation, cell cycle progression, and invasion by down-regulating cell-cycle related proteins including cyclin D1, surviving and P53 and down-regulating matrix metallopeptidase 9. In an in vivo angiosarcoma xenograft model, TRAM-34 or miR-497-5p mimics both inhibited tumor growth. In conclusion, the tumor suppressor miR-497-5p down-regulates KCa3.1 expression and contributes to the inhibition of angiosarcoma malignancy development. The miR-497-5p or KCa3.1 might be potential new targets for angiosarcoma treatment.
| S-EPMC5295420 | biostudies-literature
Project description:BackgroundStudies of aberrantly expressed circular RNAs (circRNAs) can provide insights into the molecular mechanisms of osteosarcoma (OS). However, the role of circ_0001174 in OS progression remains unknown. This study is aimed to identify differentially expressed circRNAs and messenger RNAs (mRNAs) in patients with OS and to investigate potential regulatory ways of circ_0001174.MethodsHigh-throughput sequencing was performed to screen aberrantly expressed circRNAs and mRNAs between tumor and paracancerous tissues from patients with OS. Several bioinformatics tools were used to analyze the functions and pathways of the differentially expressed genes between the tissues. Cell counting kit-8, cell migration and invasion assays were performed to evaluate the functions of the critical circRNAs. RNA interference experiments, quantitative real-time polymerase chain reaction (RT-qPCR) and western blotting were used to explore the relationship between miR-186-5p and circ_0001174 or metastasis-associated in colon cancer 1 (MACC1).ResultsCompared with the paracancerous tissues, 109 circRNAs and 1264 mRNAs were differentially expressed in the OS tissues, including 88 circRNAs and 707 mRNAs that were upregulated and 21 circRNAs and 557 mRNAs that were downregulated. The expression of four upregulated and four downregulated circRNAs was validated using RT-qPCR; the results were consistent with the sequencing data, and circ_0001174 was found to be significantly upregulated in 16 pairs of OS tissues and OS cell lines (fold change > 2.0, P value < 0.05). Knockdown of circ_0001174 inhibited the proliferation, migration, and invasion of OS cells. Additionally, circ_0001174 directly and negatively modulated the expression of miR-186-5p and positively regulated the expression of MACC1.ConclusionsAbnormally high expression of circ_0001174 may promote the proliferation, migration, and invasion of OS cells through up-regulating MACC1 by sponging miR-186-5p. These results provide insight into therapeutic targets for preventing and treating OS.
| S-EPMC8917736 | biostudies-literature
Project description:Osteosarcoma (OS) accounts for 9 percent of cancer-related deaths in young people. The PI3K/Akt signaling, a well-known carcinogenic signaling pathway in human cancer, cooperates with other signaling pathways such as Wnt signaling to promote cancer progression. Wnt7b, as a transforming member of the Wnt family, could activate mTORC1 through PI3K-AKT signaling and is upregulated in OS. In the present study, we found that miR-342-5p inhibits Wnt7b expression via direct binding to Wnt7b 3'-UTR. miR-342-5p overexpression remarkably suppressed the viability and invasion while enhanced the apoptosis of OS cells; meanwhile, Wnt7b, β-catenin, c-myc, and cyclin D1 proteins were reduced while E-cadherin protein showed to be increased. Consistent with its expression pattern, Wnt7b exerted oncogenic effects on OS cells. Wnt7b could significantly attenuate the impacts of miR-342-5p. In conclusion, we demonstrated a miR-342-5p/Wnt7b axis that regulates the capacity of OS cells to proliferate and to invade through Wnt/β-catenin signaling. The miR-342-5p/Wnt7b axis might be novel targets for OS targeted therapy, which needs further in vivo and clinical investigations.
| S-EPMC6927707 | biostudies-literature
Project description:BackgroundMany studies have shown that microRNAs (miRNAs) play an essential role in gene regulation and tumor development. This study aimed to explore the expression of miR-379-5p and its mechanisms of affecting proliferation, migration, and invasion in breast cancer (BC).MethodsMiRNAs and mRNAs expression data of BC and normal breast tissue samples were downloaded from the TCGA and GEO databases. qRT-PCR was used to detect the expression of miR-379-5p in human normal breast epithelial cell lines and human BC cell lines. The proliferation ability of transfected cells was detected by colony formation and EdU assays. The mobility and invasion ability of transfected cells was measured by wound healing and transwell assays. The relative protein expression of transfected cells was detected by western blot. Dual luciferase reporter assay was performed to identify the targeted binding of miR-379-5p and KIF4A.ResultsMiR-379-5p was lowly expressed in BC tissue samples and BC cell lines. The target genes of miR-379-5p were involved in many cancer-related signaling pathways. PPI analysis and the cytoHubba algorithm of Cytoscape identified 10 genes as the hub genes. Survival analysis showed that only KIF4A expression in 10 hub genes was significantly associated with the prognosis of BC patients and was significantly upregulated in BC. Overexpression of miR-379-5p inhibited proliferation, migration, and invasion in the BC cell line MDA-MB-231, which could be reversed by KIF4A.ConclusionsMiR-379-5p inhibits proliferation, migration, and invasion of BC by targeting KIF4A.
| S-EPMC9250835 | biostudies-literature
Project description:KCNQ1OT1 exerts an important role in various cancers, but its role in osteosarcoma (OS) and the potential mechanism remain to be clarified. In the present research, we aimed to explore the effect of KCNQ1OT1 on osteosarcoma and further explore the special molecular mechanism. The expression of KCNQ1OT1 was analyzed in tumor and adjacent tissues of 30 patients with osteosarcoma by RT-PCR. Cell proliferation and invasion were explored using MTT and transwell assay, respectively. Luciferase reporter analysis and pull-down assay were performed to determine the binding activity of KCNQ1OT1 and miR-129-5p. The result revealed that KCNQ1OT1 was highly expressed in osteosarcoma tissues and cells. KCNQ1OT1-siRNA inhibited the proliferation, invasion, and drug resistance of osteosarcoma cells. The luciferase reporter assay and pull-down assay demonstrated that KCNQ1OT1 directly interact with miR-129-5p. In addition, miR-129-5p binds to LARP1 directly, and LARP1 promoted the proliferation, invasion, and drug resistance of osteosarcoma cells. What is more, KCNQ1OT1 promoted proliferation, invasion, and drug resistance via inhibiting the expression of miR-129-5p and further promoting the expression of miR-129-5p-mediated LARP1. Collectively, it suggests that downregulation of KCNQ1OT1 inhibits proliferation, invasion, and drug resistance by regulating miR-129-5p-mediated LARP1 in osteosarcoma cells.
| S-EPMC7487100 | biostudies-literature