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Pracinostat (SB939), a histone deacetylase inhibitor, suppresses breast cancer metastasis and growth by inactivating the IL-6/STAT3 signalling pathways.

Pracinostat (SB939) 是一种组蛋白去乙酰化酶抑制剂,通过灭活IL-6/STAT3 信号通路抑制乳腺癌转移和生长。

  • 影响因子:0
  • DOI:10.1016/j.lfs.2020.117469
  • 作者列表:"Chen J","Li N","Liu B","Ling J","Yang W","Pang X","Li T
  • 发表时间:2020-05-01
Abstract

AIMS:Histone deacetylases inhibitors have shown favorable antitumor activity in clinical investigations. In the present study, we assessed the effects of a novel hydroxamic acid-based HDAC inhibitor, SB939, on breast cancer metastasis and tumor growth and characterized the underlying molecular mechanisms. MAIN METHODS:MTS, Wound-healing, and Transwell chamber invasion assays were used to detect the inhibition effects of SB939 on proliferation, migration, and invasion of breast cancer cells. Western blot, cellular immunofluorescence, and EMSA were used to explore the molecular mechanism of SB939 in suppressing breast cancer metastasis. MDA-MB-231 subcutaneous tumor-bearing model of nude mice and the spontaneous metastasis model of breast cancer were both applied to verify in vivo anti-tumor growth and anti-metastatic effects. KEY FINDINGS:Our results demonstrated that SB939 at 0.5-1 μmol/L markedly impaired the chemotactic motility of breast cancer cells. SB939 reversed epithelial-mesenchymal transition (EMT) process, as evidenced by upregulation E-cadherin expression and downregulation expressions of N-cadherin and vimentin through increasing the levels of ac-histone H3 and H4 and drecreasing the expressiongs of HDAC 5 and 4. This cascade inhibition mediated by SB939 was well interpreted by inactivating phosphorylation of STAT3, blocking its DNA-binding activity, and decreasing the expressions of STAT3-dependent target genes, including MMP2 and MMP9. Furhtermore, we found that SB939 significantly inhibited breast cancer metastasis and tumor growth in vivo and showed superior anti-tumor properties compared with SAHA in two breast cancer animal models. SIGNIFICANCE:Our findings indicate that SB939 may be an effective therapeutic option for treating advanced breast cancer.

摘要

目的: 组蛋白去乙酰化酶抑制剂在临床研究中显示出良好的抗肿瘤活性。在本研究中,我们评估了基于异羟肟酸的新型HDAC抑制剂SB939 对乳腺癌转移和肿瘤生长的影响,并表征了潜在的分子机制。 主要方法: 采用MTS、伤口愈合和Transwell小室侵袭试验检测SB939 对乳腺癌细胞增殖、迁移和侵袭的抑制作用。采用Western blot、细胞免疫荧光、EMSA等方法探讨SB939 抑制乳腺癌转移的分子机制。MDA-MB-231 裸鼠皮下荷瘤模型和乳腺癌自发转移模型均用于验证体内抗肿瘤生长和抗转移作用。 主要发现: 我们的结果表明,SB939 在 0.5-1 μ mol/L时显著损害乳腺癌细胞的趋化运动。SB939 逆转上皮-间质转化 (EMT) 过程,正如通过增加ac-组蛋白H3 和H4 的水平和降低HDAC 5 和 4 的表达来上调E-cadherin表达和下调N-cadherin和vimentin的表达所证明的那样。这种由SB939 介导的级联抑制作用通过灭活STAT3 的磷酸化,阻断其DNA结合活性得到了很好的解释,降低STAT3-dependent个靶基因的表达,包括MMP2 和mmp9。Furhtermore,我们发现SB939 在体内显著抑制乳腺癌转移和肿瘤生长,并且在两种乳腺癌动物模型中与SAHA相比显示出优越的抗肿瘤特性。 意义: 我们的研究结果表明,SB939 可能是治疗晚期乳腺癌的有效治疗选择。

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DOI:10.1016/j.athoracsur.2019.04.100
作者列表:["Mammana M","Zuin A","Serra E","Bellini A","Rea F"]

METHODS::Pulmonary artery sling is a rare congenital anomaly of the origin and course of the left pulmonary artery. Patients with this condition typically present with respiratory failure in young infancy, and asymptomatic cases are uncommon. We describe the case of an adult patient with a lung adenocarcinoma of the right upper lobe, extending into the hilum and superior mediastinum, and with a previously unknown pulmonary artery sling anomaly. The local invasiveness of the tumor and the peculiar vascular anatomy contributed to a unique surgical scenario, wherein multiple reconstructive procedures were required.

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翻译标题与摘要 下载文献
影响因子:6.93
发表时间:2020-01-15
DOI:10.1002/ijc.32532
作者列表:["Hata A","Nakajima T","Matsusaka K","Fukuyo M","Morimoto J","Yamamoto T","Sakairi Y","Rahmutulla B","Ota S","Wada H","Suzuki H","Matsubara H","Yoshino I","Kaneda A"]

METHODS::Patients with idiopathic pulmonary fibrosis (IPF) have higher risk of developing lung cancer, for example, squamous cell carcinoma (SCC), and show poor prognosis, while the molecular basis has not been fully investigated. Here we conducted DNA methylome analysis of lung SCC using 20 SCC samples with/without IPF, and noncancerous lung tissue samples from smokers/nonsmokers, using Infinium HumanMethylation 450K array. SCC was clustered into low- and high-methylation epigenotypes by hierarchical clustering analysis. Genes hypermethylated in SCC significantly included genes targeted by polycomb repressive complex in embryonic stem cells, and genes associated with Gene Ontology terms, for example, "transcription" and "cell adhesion," while genes hypermethylated specifically in high-methylation subgroup significantly included genes associated with "negative regulation of growth." Low-methylation subgroup significantly correlated with IPF (78%, vs. 17% in high-methylation subgroup, p = 0.04), and the correlation was validated by additional Infinium analysis of SCC samples (n = 44 in total), and data from The Cancer Genome Atlas (n = 390). The correlation between low-methylation subgroup and IPF was further validated by quantitative methylation analysis of marker genes commonly hypermethylated in SCC (HOXA2, HOXA9 and PCDHGB6), and markers specifically hypermethylated in high-methylation subgroup (DLEC1, CFTR, MT1M, CRIP3 and ALDH7A1) in 77 SCC cases using pyrosequencing (p = 0.003). Furthermore, low-methylation epigenotype significantly correlated with poorer prognosis among all SCC patients, or among patients without IPF. Multivariate analysis showed that low-methylation epigenotype is an independent predictor of poor prognosis. These may suggest that lung SCC could be stratified into molecular subtypes with distinct prognosis, and low-methylation lung SCC that significantly correlates with IPF shows unfavorable outcome.

翻译标题与摘要 下载文献
影响因子:6.93
发表时间:2020-01-01
DOI:10.1002/ijc.32530
作者列表:["Zhang L","Yang Y","Chai L","Bu H","Yang Y","Huang H","Ran J","Zhu Y","Li L","Chen F","Li W"]

METHODS::The role of Fyn-related kinase (FRK) in malignant tumors remains controversial. Our study investigated the function of FRK in lung cancer. Immunohistochemistry staining and generating a knockout of FRK by CRISPR/Cas9 in H1299 (FRK-KO-H1299) cells were strategies used to explore the role of FRK. Immunohistochemistry staining indicated that FRK expression was elevated in 223 lung cancer tissues compared to 26 distant normal lung tissues. FRK contributed to poor survival status in lung cancer patients and acted as a predictor for poor prognosis of lung cancer. Knockout of FRK by CRISPR/Cas9 markedly inhibited proliferation, invasion, colony formation and epithelial-mesenchymal transition (EMT) process in the lung cancer cell line H1299. Further exploration indicated that FRK-KO damaged the stemness phenotype of H1299 by inhibiting CD44 and CD133 expression. Seahorse detection and a U-13 C flux assay revealed that FRK-KO induced metabolism reprogramming by inhibiting the Warburg effect and changing the energy type in H1299 cells. Epidermal growth factor stimulation recovered the expression of FRK and biological functions, metabolic reprogramming and stemness phenotype of H1299 cells. FRK plays an oncogenic role in lung cancer cells via a novel regulation mechanism of enhancing the stemness of H1299 cells by inducing metabolism reprogramming, which finally promotes EMT and metastasis. Our study also indicates that FRK could be used as a potential therapeutic target for drug development.

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肺肿瘤方向

肺肿瘤,又叫支气管肺癌,是常见的恶性肿瘤之一。肺肿瘤的治疗为包括手术、中药、放疗、化疗及免疫等多学科的综合治疗。

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