MiR-135a Reduces Osteosarcoma Pulmonary Metastasis by Targeting Both BMI1 and KLF4.
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ABSTRACT:
SUBMITTER: Chen C
PROVIDER: S-EPMC8019936 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:MiR-429 functions as a tumor suppressor and has been observed in multiple types of cancer, but the effects and mechanisms of miR-429 in osteosarcoma are poorly understood. This study is performed to evaluate the functions of miR-429 in the progression of osteosarcoma. Firstly, the miR-429 expression in osteosarcoma tissues and osteosarcoma cells was detected using real time PCR, and the relationship between miR-429 expression and overall survival of osteosarcoma was analyzed. Secondly, the effects of miR-429 on the migration, invasion, proliferation and apoptosis of osteosarcoma cells were evaluated using transwell assay, wound-healing assay, CCK-8 assay and flow cytometry, respectively. Proteins related to epithelial-mesenchymal transition (EMT), E-cadherin, Vimentin, N-cadherin and Snail, were also detected using Western blot. Finally, the target gene of miR-429 in osteosarcoma was predicted and verified using dual luciferase assay and the expression correlation between them was analyzed using Pearson's correlation. MiR-429 was down-regulated in osteosarcoma tissues and osteosarcoma cells; the expression level of miR-429 was associated with the prognosis of osteosarcoma. High level of miR-429 in osteosarcoma cells significantly suppressed the migration, invasion and proliferation of cells but induced cells apoptosis. Furthermore, high level of miR-429 in osteosarcoma cells obviously increased the expression of E-cadherin protein but decreased the expression of Vimentin, N-Cadherin and Snail proteins. EMT inducer ZEB1 was the target gene of miR-429 and the expression of ZEB1 was negatively related to the miR-429 expression in osteosarcoma. In conclusion, miR-429 may functions as a tumor suppressor and be down-regulated in osteosarcoma. MiR-429 may suppress the progression and metastasis of osteosarcoma by down-regulating the ZEB1 expression.
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Project description:Objectives: This research aimed to explore the role of miR-135a-5p in head and neck squamous cell carcinoma (HNSCC) cells and its influence on cell viability. Moreover, we aimed to compare effects of miR-135a-5p and miR-494 in HNSCC, which was found to repress HOXA10 expression in oral cancer. Methods: The association between miR-135a-5p and HOXA10 was confirmed by green fluorescence protein reporter assay and qRT-PCR. The expression levels of HOXA10 in HNSCC cell lines (CAL-27, FaDu and NEC) were examined using western blot. The expression levels of HOXA10 in FaDu cells and CAL-27 cells were examined by western blot after transfection with miR-135a-5p mimics and miR-494 mimics. Colony formation assay and flow cytometry assay were respectively utilized to detect the proliferation and apoptosis of HNSCC cells after transfection with HOXA10 plasmids and HOXA10-KO plasmids. In vitro tumor xenograft experiments were performed to analyze the inhibitive effect of miR-135a-5p on HOXA10 in BALA/c mice. Results: HOXA10 was overexpressed in HNSCC cells, while miR-135a-5p was under-expressed. Therefore, low expression of HOXA10 lengthened disease-free survival time and overall survival time. MiR-135a-5p overexpression could inhibit HOXA10 expression by directly targeting HOXA10 3'UTR, and the inhibition was more effective than miR-494. HOXA10 suppression inhibited proliferation and enhanced apoptosis of HNSCC cells. In vivo experiments showed that miR-135a-5p could decelerate the growth of tumor cells in mice by downregulating HOXA10 expression. Conclusion: MiR-135a-5p could repress HNSCC cells proliferation and enhance apoptosis by directly targeting HOXA10, implying miR-135a-5p's significance on HNSCC treatment.
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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.
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Project description:Metastasis is a leading cause of mortality for osteosarcoma patients. The molecular pathological mechanism remains to be elucidated. In the previously study, we established two osteosarcoma cell lines with different metastatic potentials. Differential expressed genes and proteins regarding metastatic ability have been identified. MicroRNAs are important regulators in tumorigenesis and tumor progression. In this study, microRNA microarray was used to assess the differential expressed miRNAs level between these two cell lines. One of the top ranked miRNAs-miR-195 was identified highly expressing in lowly metastatic cells. It was showed that over-expression of miR-195 substantially inhibits migration and invasion of osteosarcoma cells in vitro and pulmonary metastasis formation in vivo. Meanwhile, CCND1 was identified as the target gene of miR-195 and further studied. More importantly, using real-time PCR, we evaluated the expression of miR-195 and CCND1 in osteosarcoma samples from 107 frozen biopsy tissues and 99 formalin- or paraformalin-fixed, paraffin-embedded (FFPE) tissues. Results indicated lowly expressed miR-195 or highly CCND1 correlated with positive overall survival and their expression inversely related to each other. In summary, our study suggests miR-195 functions as a tumor metastasis suppressor gene by down-regulating CCND1 and can be used as a potential target in the treatment of osteosarcoma.
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Project description:Dysregulated microRNAs (miRNAs) play an important role in osteosarcoma (OS) progression. In the present study, we investigate the clinical significance of serum miR-491 level and the potential role of miR-491 in OS lung metastasis and chemoresistance. Clinical data show that the level of miR-491 was decreased in serum from OS patients compared with healthy control subjects, and that a decreased serum miR-491 level is correlated with increased metastasis, poor chemoresponse, and lower survival rate in OS patients. In vitro and in vivo experiments show that overexpression of miR-491 suppresses OS cell lung metastasis, whereas it enhances cisplatin (CDDP)-induced tumor growth inhibition and apoptosis. In contrast, inhibition of miR-491 stimulates OS cell lung metastasis and suppresses CDDP-induced tumor growth inhibition and apoptosis. Furthermore, we demonstrate that miR-491 exerts its role by directly targeting αB-crystallin (CRYAB) in OS. Our findings suggest that serum level of miR-491 has potential as a biomarker for predicting OS progression and prognosis of OS patients. Additionally, restoration of miR-491 may be a novel strategy for inhibiting OS lung metastasis and overcoming OS cell resistance to chemotherapy.
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Project description:Lung metastasis and relapse in osteosarcoma (OS) patients indicate poor prognosis. Here, we identified significantly decreased expression of miR-382 in highly metastatic OS cell lines and relapsed OS samples compared to their parental cell lines and primary OS samples, respectively. In addition, our clinical data showed that the miR-382 expression level was inversely associated with relapse and positively associated with metastasis-free survival in OS patients. The overexpression of miR-382 suppressed epithelial-mesenchymal transition (EMT) and metastasis. This overexpression also decreased the cancer stem cell (CSC) population and function in OS cells. In contrast, inhibition of miR-382 stimulated EMT and metastasis and increased CSC population in OS cells. In addition, our in vivo experiments showed that the overexpression of miR-382 inhibited CSC-induced tumor formation, and the combination of miR-382 with doxorubicin prevented disease relapse in OS patients. Furthermore, we demonstrated that miR-382 exerted its tumor-suppressing potential by directly targeting Y box-binding protein 1 (YB-1) in OS. Taken together, our findings suggest that miR-382 functions as a tumor suppressor function and that the overexpression of miR-382 is a novel strategy to inhibit tumor metastasis and prevent CSC-induced relapse in OS.
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Project description:Cadherin-6 (CDH6) is aberrantly expressed in cancer and closely associated with tumor progression. However, the functions of CDH6 in human osteosarcoma and the molecular mechanisms underlying CDH6 in osteosarcoma oncogenesis remain poorly understood. In this work, we assessed the role of CDH6 in human osteosarcoma and identified that the expression of CDH6 was closely related with the overall survival and poor prognosis of osteosarcoma patients. MicroRNAs (miRNAs) have been implicated as important epigenetic regulators during the progression of osteosarcoma. Using dual-luciferase reporter assays, we showed that miR-223-3p suppresses CDH6 expression by directly binding to the 3' UTR of CDH6. miR-223-3p overexpression significantly inhibited cell invasion, migration, growth, and proliferation by suppressing the CDH6 expression in vivo and in vitro. Besides, CDH6 overexpression in the miR-223-3p-transfected osteosarcoma cells effectively rescued the inhibition of cell invasion, migration, growth, and proliferation mediated by miR-223-3p. Additionally, Kaplan-Meier analysis suggests that the expression of miR-223-3p predicts favorable clinical outcomes for osteosarcoma patients. Moreover, the expression of miR-223-3p was downregulated in osteosarcoma patients and was negatively associated with the expression of CDH6. Collectively, these data highlight that miR-223-3p/CDH6 axis is an important novel pleiotropic regulator and could early predict the metastatic potential in human osteosarcoma treatments.
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Project description:Background:Glioma is the most common and aggressive primary brain tumor with high mortality rate around the world. LncRNAs have been identified to play key roles in tumorigenesis in various cancers, including glioma. However, the precise mechanism of DANCR in progression of glioma remains poorly defined. Methods:The expression levels of DANCR, miR-135a-5p and BMI1 were measured by qRT-PCR in glioma tissues and cells. Cell proliferation, migration and invasion were detected by CCK-8 assay and transwell assay, respectively. The possible binding sites of miR-135a-5p and DANCR or BMI1 were predicted by online software and verified using luciferase report assay and RNA immunoprecipitation (RIP) assay. Western blot analysis was carried out to detect the protein of BMI1 expression. A xenograft tumor model was established to investigate the functions of DANCR in glioma progression in vivo. Results:DANCR was upregulated and miR-135a-5p was downregulated in glioma tissues and cells. Knockdown of DANCR inhibited cell proliferation, migration and invasion in glioma cells. In addition, miR-135a-5p was a direct target of DANCR, and its elevated expression could reverse miR-135a-5p inhibition-mediated progression of glioma. Moreover, miR-135a-5p could specially bind to BMI1, and the expression of BMI1 was obviously elevated in glioma tissues and cells. Furthermore, DANCR acted as a ceRNA to regulate BMI1 expression and BMI1-mediated effects on progression of glioma by sponging miR-135a-5p. Besides, inhibition of DANCR limited tumor growth by regulating miR-135a-5p and BMI1 expression in vivo. Conclusion:DANCR knockdown inhibited cell proliferation, migration and invasion in glioma cells through regulating miR-135a-5p/BMI1 axis, providing viable therapeutic avenues for treatment of glioma.
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Project description:Osteosarcoma is an aggressive bone cancer that has a high propensity for metastasis to the lungs. Patients with metastatic disease face a very poor prognosis. Therefore, novel therapeutics, efficiently suppressing the metastatic process, are urgently needed. Integrins play a pivotal role in tumor cell adhesion, motility and metastasis. Here, we evaluated αvβ3 and αvβ5 integrin inhibition with cilengitide as a novel metastasis-suppressive therapeutic approach in osteosarcoma. Immunohistochemical analysis of αvβ3 and αvβ5 integrins expression in a tissue microarray of tumor specimens collected from osteosarcoma patients revealed that αvβ5 integrin is mainly found on tumor cells, whereas αvβ3 is predominantly expressed by stromal cells. In vitro functional assays demonstrated that cilengitide dose-dependently inhibited de novo adhesion, provoked detachment and inhibited migration of osteosarcoma cell lines. Cilengitide induced a decline in cell viability, blocked the cell cycle in the G1 phase and caused anoikis by activation of the Hippo pathway. In a xenograft orthotopic mouse model cilengitide minimally affected intratibial primary tumor growth but, importantly, suppressed pulmonary metastasis. The data demonstrate that targeting αvβ3 and αvβ5 integrins in osteosarcoma should be considered as a novel therapeutic option for patients with metastatic disease.
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