miR-139-mediated NOTCH1 regulation is crucial for the inhibition of osteosarcoma progression caused by resveratrol.

MiR-139-mediated NOTCH1 的调控对于抑制白藜芦醇引起的骨肉瘤进展至关重要。

  • 影响因子:3.40
  • DOI:10.1016/j.lfs.2019.117215
  • 作者列表:"Xiao X","Zhang Y","Pan W","Chen F
  • 发表时间:2020-02-01

AIMS:Osteosarcoma (OS) has the highest incidence among primary malignancies. It is characterized by high tumor heterogeneity, poor prognosis and high lung metastases. Here, we aimed to investigate the role of resveratrol on an OS cell line and its mechanism. MATERIALS AND METHODS:Cell apoptosis and proliferation were analyzed by MTT and flow cytometry analysis respectively. In U2OS cells miR-139-5p overexpression or knock-down and NOTCH1 knock-down cell models were constructed. Quantitative real-time PCR were used to determine the expression of miR-139-5p. Western bot was used to detect levels of NOTCH1, caspase3 and cleaved-caspase-3. Dual luciferase activity assay was used to assess the target of miR-139-5p. KEY FINDINGS:The apoptosis of U20S and MG63 cell were induced by resveratrol, and lower levels of miR-139-5p in both U2OS and MG63 cells than in osteoblast cells. Alteration of miR-139-5p had an outstanding effect on apoptosis of U2OS cell. The expression of miR-139-5p in U2OS and MG63 cells can be induced by resveratrol. Bioinformatic analysis indicated that the 3'UTR of NOTCH1 contained the motif for microRNA-139-5p binding. Co-transfection with the luciferase reporter contained the wild-type, but not the mutant, of 3'UTR of NOTCH1, together with miR-139-5p decreased the luciferase activity in U2OS cells. NOTCH1 gene knockout altered the apoptosis of U2OS cell. SIGNIFICANCE:Collectively, these findings indicate that resveratrol induces the apoptosis of OS cells via the miR-139-5p/NOTCH1 signaling pathway, and provides an experimental and theoretical basis for the development of natural plant-derived compounds that can effectively prevent and treat OS.


目的: 骨肉瘤 (OS) 是原发性恶性肿瘤中发病率最高的。其特点是肿瘤异质性高,预后差,肺转移率高。在此,我们旨在研究白藜芦醇对OS细胞系的作用及其机制。 材料与方法: 细胞凋亡和增殖分别用MTT和流式细胞仪分析。在U2OS细胞miR-139-5p过表达或敲低,构建NOTCH1 敲低细胞模子。定量real-time PCR测定miR-139-5p的表达。Western bot检测NOTCH1 、caspase3 和cleaved-caspase-3 水平。双荧光素酶活性测定用于miR-139-5p目标的考核。 关键发现: 白藜芦醇诱导U20S和MG63 细胞凋亡,U2OS和MG63 细胞的miR-139-5p水平均低于成骨细胞。MiR-139-5p的改变对U2OS细胞的凋亡有显著影响。白藜芦醇可引诱U2OS和MG63 细胞miR-139-5p的表达。生物信息学分析表明,NOTCH1 的 3 'utr包含microRNA-139-5p结合的基序。与荧光素酶报告基因共转染含有NOTCH1 的 3 'utr的野生型,而不是突变体,与miR-139-5p一起降低了U2OS细胞中的荧光素酶活性。NOTCH1 基因敲除改变了U2OS细胞的凋亡。 意义: 总的来说,这些发现表明白藜芦醇通过miR-139-5p/NOTCH1 信号通路诱导OS细胞凋亡,并为开发能有效防治OS的天然植物源化合物提供了实验和理论依据。



作者列表:["Tran S","Puric E","Walser M","Poel R","Datta NR","Heuberger J","Pica A","Marder D","Lomax N","Bolsi A","Morach P","Bachtiary B","Seddon BM","Schneider R","Bodis S","Weber DC"]

METHODS:OBJECTIVE:Large inoperable sacral chordomas show unsatisfactory local control rates even when treated with high dose proton therapy (PT). The aim of this study is assessing feasibility and reporting early results of patients treated with PT and concomitant hyperthermia (HT). METHODS: :Patients had histologically proven unresectable sacral chordomas and received 70 Gy (relative biological effectiveness) in 2.5 Gy fractions with concomitant weekly HT. Toxicity was assessed according to CTCAE_v4. A volumetric tumor response analysis was performed. RESULTS: :Five patients were treated with the combined approach. Median baseline tumor volume was 735 cc (range, 369-1142). All patients completed PT and received a median of 5 HT sessions (range, 2-6). Median follow-up was 18 months (range, 9-26). The volumetric analysis showed an objective response of all tumors (median shrinkage 46%; range, 9-72). All patients experienced acute Grade 2-3 local pain. One patient presented with a late Grade 3 iliac fracture. CONCLUSION:Combining PT and HT in large inoperable sacral chordomas is feasible and causes acceptable toxicity. Volumetric analysis shows promising early results, warranting confirmation in the framework of a prospective trial. ADVANCES IN KNOWLEDGE: :This is an encouraging first report of the feasibility and early results of concomitant HT and PT in treating inoperable sacral chordoma.

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作者列表:["Gyori DJ","Bullington SM","Crawford BS","Vernon VP"]

METHODS:BACKGROUND:National guidelines recommend screening and treatment for cancer-related bone disease and continued monitoring of bone-modifying agents. It is unclear whether a standardized screening tool is utilized to identify eligible patients and ensure appropriate supportive care is implemented. The purpose of this study was to evaluate current prescribing practices and optimize management of bone-modifying agents. METHODS:A retrospective chart review was performed to identify patients who received hormone deprivation therapy or had bone metastases through Hematology/Oncology or Urology clinics from 1 November 2016 to 31 October 2017. The primary endpoints of this study were the incidence of completed baseline dual-energy X-ray absorptiometry (DEXA) scan for patients on hormone deprivation therapy and percent of patients started on a bone-modifying agent for the prevention of skeletal-related events secondary to bone metastasis. Secondary endpoints included percent of patients with dental examinations prior to initiation, adequate calcium and vitamin D supplementation, incidence of osteonecrosis of the jaw or flu-like symptoms and education, and percent of bisphosphonate doses appropriately adjusted based on renal function. RESULTS:A total of 375 patients were assessed for baseline DEXA scans and bone-modifying therapy. Of the 226 patients on hormone deprivation therapy, 111 (49%) patients were appropriately screened with a DEXA scan prior to initiation of hormone deprivation therapy. Among the 149 patients with bone metastases, only 94 (63.1%) patients were started on a bone-modifying agent. CONCLUSIONS:Opportunities have been identified to optimize management of patients with cancer-related bone disease. Implementation of standardized tools may increase the rate of appropriate screening and initiation of bone-modifying therapy when warranted.

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作者列表:["Dohzono S","Sasaoka R","Takamatsu K","Hoshino M","Nakamura H"]

METHODS:PURPOSE:Low skeletal muscle mass has been associated with poor prognosis in patients with advanced lung cancer. However, little is known about the relationship between skeletal muscle mass and overall survival in patients with bone metastases from lung cancer. The objective of the present study was to evaluate the prognostic value of low trunk muscle mass in predicting overall survival in these patients. METHODS:The data from 198 patients who were diagnosed with bone metastases from lung cancer from April 2009 to May 2017 were retrospectively reviewed. The areas of the psoas and paravertebral muscles were measured at the level of the third lumbar vertebra on computed tomography scans taken at the time nearest to the diagnosis of bone metastasis. Muscle area was evaluated for male and female cohorts separately using different cutoff points. Cox proportional hazards analysis was performed to evaluate the factors independently associated with overall survival. RESULTS:The overall survival of patients in the lowest quartile for psoas muscle area or paravertebral muscle area was significantly shorter than that of patients above the 25th percentile for muscle area (p < 0.001). Multivariate analyses showed that paravertebral muscle mass (hazard ratio, 1.73; 95% confidence interval, 1.17-2.56; p = 0.006), epidermal growth factor receptor-targeted therapy, and performance status were independent prognostic factors. CONCLUSIONS:Low paravertebral muscle mass was associated with shorter survival, independently of known prognostic factors.

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