miR-181c associates with tumor relapse of high grade osteosarcoma

Mori, Federica; Sacconi, Andrea; Canu, Valeria; Ganci, Federica; Novello, Mariangela; Anelli, Vincenzo; Covello, Renato; Ferraresi, Virginia; Muti, Paola; Biagini, R.; Blandino, Giovanni; Strano, Sabrina

doi:10.18632/oncotarget.3539

Cited by 18 publications

(8 citation statements)

References 52 publications

(42 reference statements)

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“…We previously demonstrated that HCV transcriptionally down‐regulates miR‐181c expression . Suppression of miR‐181c may be a prognostic indicator in rapidly proliferating cells, like glioblastoma, osteosarcoma, and ovarian carcinoma . Multiple molecules act as targets for miR‐181c, including Six2 in metanephric mesenchymal cells, FoxO1 in diabetic endothelial cells, transforming growth factor β in glioblastoma cells, PRKCD in ovarian cells, and Erk in prostate cancer cells .…”

Section: Discussionmentioning

confidence: 99%

“…(16) Suppression of miR-181c may be a prognostic indicator in rapidly proliferating cells, like glioblastoma, osteosarcoma, and ovarian carcinoma. (33)(34)(35) Multiple molecules act as targets for miR-181c, including Six2 in metanephric mesenchymal cells, FoxO1 in diabetic endothelial cells, transforming growth factor β in glioblastoma cells, PRKCD in ovarian cells, and Erk in prostate cancer cells. (35)(36)(37)(38)(39) Here, we focused on the functional importance of miR-181c down-regulation in HCV-infected hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

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Hepatitis C Virus Mediated Inhibition of miR‐181c Activates ATM Signaling and Promotes Hepatocyte Growth

Patra¹,

Meyer²,

Ray³

et al. 2019

Hepatology

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Background and Aims Hepatitis C virus (HCV) infection promotes hepatocyte growth and progress to hepatocellular carcinoma. We previously observed that HCV infection of hepatocytes transcriptionally down‐regulates miR‐181c expression through CCAAT/enhancer binding protein β (C/EBP‐β). Here, we examined the role of miR‐181c in the regulation of cell cycle progression in relation to HCV infection. In silico analysis suggested that ataxia‐telangiectasia mutated (ATM) protein, a protein kinase, is a direct target of miR‐181c. ATM is a central mediator of response for cellular DNA double‐strand break. Approach and Results Our results demonstrated that ATM expression is higher in HCV‐infected hepatocytes and chronic HCV‐infected liver biopsy specimens. We have shown a direct interaction of miR‐181c with the 3′ untranslated region of ATM, and the presence of ATM in miR‐181c‐associated RNA‐induced silencing complex. Exogenous expression of miR‐181c inhibited ATM expression and activation of its downstream molecules, Chk2 and Akt. On the other hand, introduction of anti‐miR‐181c restored ATM and phosphorylated Akt. Furthermore, introduction of miR‐181c significantly inhibited phospho–cyclin‐dependent kinase 2 (CDK2) and cyclin‐A expression, arresting cell cycle progression, whereas overexpression of miR‐181c promoted apoptosis of HCV‐infected hepatocytes and can be inhibited by overexpression of ATM from a clone lacking miR‐181c binding sites. In addition, miR‐181c significantly regressed tumor growth in the xenograft human hepatocellular carcinoma mouse model. Conclusions Together, our results suggest that HCV infection suppresses miR‐181c in hepatocytes, resulting in ATM activation and apoptosis inhibition for promotion of cell cycle progression. The results provide mechanistic insight into understanding the role of miR‐181c in HCV‐associated hepatocyte growth promotion, and may have the potential for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Mediated Inhibition of miR‐181c Activates ATM Signaling and Promotes Hepatocyte Growth

Patra¹,

Meyer²,

Ray³

et al. 2019

Hepatology

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“…There is another report that the loss of miR-181a-1/b-1 dampens the induction of experimental autoimmune encephalomyelitis and reduces basal TCR signaling in peripheral T cells and their migration from lymph nodes to pathogenic sites [ 23 ]. miR - 181c inhibits glioblastoma cell invasion, migration and mesenchymal transition by targeting the TGF-beta pathway and is associated with metastatic brain cancer and high-grade osteosarcoma [ 24 – 26 ]. miR - 181d acts as a glioma suppressor by targeting K-ras and Bcl-2 [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

The miR-181 family promotes cell cycle by targeting CTDSPL, a phosphatase-like tumor suppressor in uveal melanoma

Zhang

et al. 2018

J Exp Clin Cancer Res

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BackgroundMicroRNAs (miRNAs) have been shown to function in many different cellular processes, including proliferation, apoptosis, differentiation and development. miR-181a, -181b, -181c and -181d are miR-181 members of the family, which has been rarely studied, especially uveal melanoma.MethodsThe expression level of miR-181 family in human uveal melanoma cell lines was measured via real-time PCR (RT-PCR). The function of miR-181 on cell cycle was detected through Flow Cytometry assay. Microarray assay and Bioinformatics analysis were used to find the potential target of miR-181b, and dual-luciferase reporter assays further identified the target gene.ResultsMiR-181 family members were found to be highly homologous across different species and their upregulation significantly induces UM cell cycle progression. Of the family members, miR-181b was significantly overexpressed in UM tissues and most UM cells. Bioinformatics and dual luciferase reporter assay confirmed CTDSPL as a target of miR-181b. miR-181b over-expression inhibited CTDSPL expression, which in turn led to the phosphorylation of RB and an accumulation of the downstream cell cycle effector E2F1, promoting cell cycle progression in UM cells. Knockdown CTDSPL using siRNAs showing the same effect, including increase of E2F1 and the progression of cell cycle.ConclusionsMiR-181 family members are key negative regulators of CTDSPL-mediated cell cycle progression. These results highlight that miR-181 family members, especially miR-181b, may be useful in the development of miRNA-based therapies and may serve as novel diagnostic and therapeutic candidate for UM.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0679-5) contains supplementary material, which is available to authorized users.

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“…These findings provide strong evidence that manipulating the functions of specific miRNAs might be a promising approach in tumor therapy. Evidence from previous studies showed that miR-181c correlated with high grade OS recurrence, enhancing chemotherapeutic-induced cell death and reducing cell viability [11]. Therefore, in this study, we aimed to elucidate the molecular mechanism in the regulations of OS with a focus on miR-181c.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-181c Suppresses the Biological Progression of Osteosarcoma via Targeting SMAD7 and Regulating Transforming Growth Factor-β (TGF-β) Signaling Pathway

Tang

Wang

et al. 2019

Med Sci Monit

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Background Osteosarcoma is a primary bone aggressive cancer, affecting adolescents worldwide. Increasing evidence suggests that dysfunction of microRNAs (miRNAs) plays a pivotal role in malignancies. The aim of this study was to evaluate the potential functions of miR-181c and verifying its regulatory effects on SMAD7 in osteosarcoma. Material/Methods The expressions of miR-181c and SMAD7 in osteosarcoma were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation, invasion and migration abilities were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) and Transwell assay. Bioinformatics analysis and luciferase reporter assay were used to explore the interaction between miR-181c and SMAD7. Western blot was performed to determine the functions of miR-181c on osteosarcoma cell epithelial-to-mesenchymal transition (EMT) and transforming growth factor-β (TGF-β) signaling pathway. Results Decreased expression levels of miR-181c and SMAD7 were identified in osteosarcoma using qRT-PCR. The downregulated miR-181c and SMAD7 expressions indicated poor prognosis of osteosarcoma patients. Moreover, miR-181c overexpression prominently repressed osteosarcoma cell proliferation, invasion, and migration abilities via modulating EMT and TGF-β signaling pathway. SMAD7 functioned as an important target for miR-181c in osteosarcoma cells. Furthermore, upregulation of miR-181c dramatically suppressed osteosarcoma tumorigenesis in vivo. Conclusions These findings indicated that miR-181c suppressed osteosarcoma progression, providing new insight into the pathogenesis and representing a potential therapeutic target for osteosarcoma.

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miR-181c associates with tumor relapse of high grade osteosarcoma

Cited by 18 publications

References 52 publications

Hepatitis C Virus Mediated Inhibition of miR‐181c Activates ATM Signaling and Promotes Hepatocyte Growth

Hepatitis C Virus Mediated Inhibition of miR‐181c Activates ATM Signaling and Promotes Hepatocyte Growth

The miR-181 family promotes cell cycle by targeting CTDSPL, a phosphatase-like tumor suppressor in uveal melanoma

MicroRNA-181c Suppresses the Biological Progression of Osteosarcoma via Targeting SMAD7 and Regulating Transforming Growth Factor-β (TGF-β) Signaling Pathway

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