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By targeting TRAF6, miR-140-3p inhibits TGF-β1-induced human osteosarcoma epithelial-to-mesenchymal transition, migration, and invasion

通过靶向 TRAF6,miR-140-3p 抑制 tgf-β 1 诱导的人骨肉瘤上皮-间质转化、迁移和侵袭

  • 影响因子:2.22
  • DOI:10.1007/s10529-020-02943-9
  • 作者列表:"Guo, Qianchen","Zhang, Nai","Liu, Shen","Pang, Zixuan","Chen, Zhao
  • 发表时间:2020-06-19
Abstract

Objectives We evaluated the effects of miR-140-3p on EMT, cellular migration, and invasion in TGF-β1 treated human OS cells. Human fresh OS tissue and normal bone tissue specimens were gathered from 42 patients (29 male and 13 female, 11 to 24 years of age with a mean age of 17.5 ± 2.3 years) diagnosed with OS by pathology. By targeting TRAF6, miR-140-3p inhibits TGF-β1-induced human osteosarcoma epithelial-to-mesenchymal transition, migration, and invasion. Results In this study, we found microRNA (miR)-140-3p to be down-regulated and tumor necrosis factor receptor-associated factor 6 (TRAF6) to be up-regulated in patient OS samples. Lower levels of miR-140-3p and higher levels of TRAF6 were found in the advanced Enneking stage of OS. Furthermore, both mRNA and protein levels of TRAF6 were negatively associated with miR-140-3p mRNA expression in human OS tissue. TRAF6 was verified as a direct target of miR-140-3p in TGF-β1-treated human U2OS cells. Further, a miR-140-3p mimic dramatically inhibited while a miR-140-3p inhibitor enhanced TGF-β1-induced epithelial-to-mesenchymal transition, migration, and invasion of U2OS cells. Small interfering RNA was found to silence TRAF6 and to partly reverse the effects of the miR-140-3p inhibitor on TGF-β1-treated U2OS cells in vitro. Conclusion These results demonstrate miR-140-3p to function as a tumor inhibitor of human OS cells by decreasing TRAF6 expression. miR-140-3p and TRAF6 may be valuable and novel biomarkers for diagnosis and treatment of OS.

摘要

目的: 我们在 tgf-β 1 处理的人 OS 细胞中评估了 miR-140-3p 对 EMT 、细胞迁移和侵袭的影响。收集 42 例患者 (男 29 例,女 13 例,11 ~ 24 岁,平均年龄 17.5 ± 2.3 岁) 的人新鲜 OS 组织和正常骨组织标本病理诊断为 OS。通过靶向 TRAF6,miR-140-3p 抑制 tgf-β 1 诱导的人骨肉瘤上皮间质转化、迁移和侵袭。结果在本研究中,我们发现患者 OS 样本中 microRNA (miR)-140-3p 下调,肿瘤坏死因子受体相关因子 6 (TRAF6) 上调。在 OS 的晚期 Enneking 阶段发现较低水平的 miR-140-3p 和较高水平的 TRAF6。此外,人 OS 组织中 TRAF6 的 mRNA 和蛋白水平均与 miR-140-3p mRNA 表达呈负相关。在 tgf-β 1 处理的人 U2OS 细胞中,TRAF6 被证实是 miR-140-3p 的直接靶点。此外,miR-140-3p 模拟物显著抑制了 tgf-β 1 诱导的 U2OS 细胞上皮间质转化、迁移和侵袭,而 miR-140-3p 抑制剂则增强了 tgf-β 1。在体外实验中发现小干扰 RNA 可沉默 TRAF6,并部分逆转 miR-140-3p 抑制剂对 tgf β 1 处理的 U2OS 细胞的作用。结论 miR-140-3p 通过降低 TRAF6 的表达发挥肿瘤抑制作用,miR-140-3p 和 TRAF6 可能成为诊断和治疗 OS 的新型生物标志物。

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影响因子:2.87
发表时间:2020-01-31
来源期刊:Bioscience reports
DOI:10.1042/BSR20191251
作者列表:["Ying T","Dong JL","Yuan C","Li P","Guo Q"]

METHODS:BACKGROUND:Osteosarcoma is the most common primary bone malignancy in children and adolescents. In order to find factors related to its recurrence, and thus improve recovery prospects, a powerful clinical signature is needed. Long noncoding RNAs (lncRNAs) are essential in osteosarcoma processes and development, and here we report significant lncRNAs to aid in earlier diagnosis of osteosarcoma. METHODS:A univariate Cox proportional hazards regression analysis and a multivariate Cox regression analysis were used to analyze osteosarcoma patients' lncRNA expression data from the Therapeutically Applicable Research To Generate Effective Treatments (TARGET), a public database. RESULTS:A lncRNA signature consisting of three lncRNAs (RP1-261G23.7, RP11-69E11.4 and SATB2-AS1) was selected. The signature was used to sort patients into high-risk and low-risk groups with meaningful recurrence rates (median recurrence time 16.80 vs. >128.22 months, log-rank test, P143.80 months, log-rank test, P=0.006). A multivariate Cox regression analysis showed that the significant lncRNA was an independent prognostic factor for osteosarcoma patients. Functional analysis suggests that these lncRNAs were related to the PI3K-Akt signaling pathway, the Wnt signaling pathway, and the G-protein coupled receptor signaling pathway, all of which have various, important roles in osteosarcoma development. The significant 3-lncRNA set could be a novel prediction biomarker that could aid in treatment and also predict the likelihood of recurrence of osteosarcoma in patients.

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影响因子:6.50
发表时间:2020-03-31
来源期刊:Cancer letters
DOI:10.1016/j.canlet.2019.12.041
作者列表:["Yang D","Liu K","Fan L","Liang W","Xu T","Jiang W","Lu H","Jiang J","Wang C","Li G","Zhang X"]

METHODS::Long non-coding RNAs (lncRNAs) regulates the initiation and progression of osteosarcoma (OS), specifically lncRNA RP11-361F15.2 has been shown to play prominent roles in tumorigenesis. Previously, M2-Like polarization of tumor-associated macrophages (TAMs) has been identified to play a key role in cancer migration/invasion. Hence, it is essential to understand the role of RP11-361F15.2 in tumorigenesis and its association with M2-Like polarization of TAMs. The results indicate that RP11-361F15.2 is significantly increased in OS tissues, and its expression is positively correlated with cytoplasmic polyadenylation element binding protein 4 (CPEB4) expression and negatively associated with miR-30c-5p expression. Further, overexpression of RP11-361F15.2 increased OS cell migration/invasion and M2-Like polarization of TAMs in vitro, as well as promoted xenograft tumor growth in vivo. Mechanistically, luciferase reporter assays indicated that RP11-361F15.2 upregulated CPEB4 expression by competitively binding to miR-30c-5p. Further, we have identified that RP11-361F15.2 promotes CPEB4-mediated tumorigenesis and M2-Like polarization of TAMs through miR-30c-5p in OS. We also identified that RP11-361F15.2 acts as competitive endogenous RNA (ceRNA) against miR-30c-5p thereby binding and activating CPEB4. This RP11-361F15.2/miR-30c-5p/CPEB4 loop could be used as a potential therapeutic strategy for the treatment of OS.

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影响因子:11.08
发表时间:2020-01-13
DOI:10.1200/JCO.19.00827
作者列表:["Kelley LM","Schlegel M","Hecker-Nolting S","Kevric M","Haller B","Rössig C","Reichardt P","Kager L","Kühne T","Gosheger G","Windhager R","Specht K","Rechl H","Tunn PU","Baumhoer D","Wirth T","Werner M","von Kalle T","Nathrath M","Burdach S","Bielack S","von Lüttichau I"]

METHODS:PURPOSE:The objective of this study was to investigate potential correlations between pathologic fractures (PFs) and prognosis of patients with primary central high-grade osteosarcoma of the extremities. METHODS:We retrospectively analyzed 2,847 patients registered in the Consecutive Cooperative Osteosarcoma Study Group database with primary central high-grade osteosarcoma of the extremities, treated between 1980 and 2010. Intended treatment included pre- and postoperative chemotherapy and surgery. Univariable and multivariable survival analyses were performed for all patients and then differentiated for adult and pediatric (≤ 18 years at time of diagnosis) patients. RESULTS:A total of 2,193 patients were ≤ 18 years of age; 11.3% of all patients had PFs. In the overall cohort, presence of PF correlated significantly with tumor site, histologic subtype, relative tumor size, and primary metastases, but not with body mass index or local surgical remission. In univariable analysis, 5-year overall survival (OAS) of patients with and without PF was 63% versus 71%, respectively (P = .007), and 5-year event-free survival (EFS) was 51% versus 58% (P = .026). In pediatric patients, OAS and EFS did not differ significantly between patients with and without PF. In adults, 5-year OAS in patients with and without PF was 46% versus 69% (P < .001), and 5-year EFS was 36% versus 56% (P < .001). In multivariable analysis, PF was not a statistically significant factor for OAS or EFS in the total cohort or in pediatric patients. In adult patients, PF remained an independent prognostic factor for OAS (P = .013; hazard ratio [HR], 1.893). It was not a significant prognostic factor for EFS (P = .263; HR, 1.312). CONCLUSION:In this largest study to date with extremity osteosarcomas, we observed the occurrence of PF to correlate with inferior OAS expectancies in adult but not in pediatric patients.

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