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Small molecule inhibition of Ewing sarcoma cell growth via targeting the long non coding RNA HULC.

小分子通过靶向长链非编码RNA HULC抑制尤文肉瘤细胞生长。

  • 影响因子:6.50
  • DOI:10.1016/j.canlet.2019.10.026
  • 作者列表:"Mercatelli N","Fortini D","Palombo R","Paronetto MP
  • 发表时间:2020-01-28
Abstract

:Ewing sarcomas (ES) are aggressive pediatric cancers of bone and soft tissues characterized by in frame chromosomal translocations giving rise to chimeric transcription factors, such as EWS-FLI1. An emerging strategy to block EWS-FLI1 activity is represented by the small molecule YK-4-279, which binds to EWS-FLI1 and alters its transcriptional activity. The specific effectors of the anti-oncogenic activity of YK-4-279 are still largely unknown. Herein, by performing a high-throughput screening we identify the lncRNA HULC (Highly Upregulated in Liver Cancer) as a prominent target of YK-4-279 activity in ES cells. High levels of HULC correlate with ES aggressiveness, whereas HULC depletion reduces ES cell growth. Mechanistically, we find that HULC promotes the expression of TWIST1 oncogene by sponging miR-186. Downregulation of HULC upon treatment with YK-4-279 reduces the expression of TWIST1 by unleashing miR-186 and favoring its binding to TWIST1 transcripts. Notably, high levels of miR-186 and low levels of TWIST1 correlate with better prognosis in ES patients. Our results disclose a novel oncogenic regulatory circuit mediated by HULC lncRNA that is disrupted by the small molecule YK-4-279, with promising therapeutic implications for ES treatment.

摘要

: 尤因肉瘤 (Ewing sarcomas,ES) 是侵袭性骨和软组织儿童癌症,其特征是框架染色体易位产生嵌合转录因子,如EWS-FLI1。阻断EWS-FLI1 活性的新策略是小分子YK-4-279,它与EWS-FLI1 结合并改变其转录活性。YK-4-279 的抗癌活性的具体效应器在很大程度上仍然是未知的。在此,通过进行高通量筛选,我们确定lncRNA HULC (在肝癌中高度上调) 是ES细胞中YK-4-279 活性的突出靶点。高水平的HULC与ES侵袭性相关,而HULC耗竭可减少ES细胞生长。从机理上说,我们发现HULC通过海绵miR-186 促进TWIST1 癌基因的表达。YK-4-279 处理后HULC的下调通过释放miR-186 并有利于其与TWIST1 转录本的结合来降低TWIST1 的表达。值得注意的是,高水平的miR-186 和低水平的TWIST1 与ES患者较好的预后相关。我们的研究结果揭示了一种由HULC lncRNA介导的新型致癌调控回路,该回路被小分子YK-4-279 破坏,对ES治疗具有潜在的治疗意义。

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发表时间:2020-03-01
DOI:10.1259/bjr.20180883
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"]

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影响因子:1.41
发表时间:2020-03-01
DOI:10.1177/1078155219842277
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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影响因子:2.83
发表时间:2020-01-01
DOI:10.1007/s00520-019-04843-9
作者列表:["Dohzono S","Sasaoka R","Takamatsu K","Hoshino M","Nakamura H"]

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骨肿瘤方向

骨肿瘤是发生于骨骼或其附属组织的肿瘤。有良性,恶性之分,良性骨肿瘤易根治,预后良好,恶性骨肿瘤发展迅速,预后不佳,死亡率高。

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