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Sophoridine inhibits lung cancer cell growth and enhances cisplatin sensitivity through activation of the p53 and Hippo signaling pathways.

槐定碱通过激活p53 和Hippo信号通路抑制肺癌细胞生长并增强顺铂敏感性。

  • 影响因子:2.60
  • DOI:10.1016/j.gene.2020.144556
  • 作者列表:"Zhu L","Huang S","Li J","Chen J","Yao Y","Li L","Guo H","Xiang X","Deng J","Xiong J
  • 发表时间:2020-06-05
Abstract

BACKGROUND:Sophoridine, a quinolizidine alkaloid extracted from the Chinese herb Sophora alopecuroides L., has been reported to exert antitumor effects against multiple human cancers. However, few studies have evaluated its tumor-suppressing effects and associated mechanism with respect to lung cancer, in addition to its potential to be used for clinical lung cancer treatment. METHODS:Different types of lung cancer cells were used to investigate the antitumor effects of sophoridine using cell viability, colony formation, and cell invasion, and migration assays. To determine the signaling pathways involved, western blot analysis, quantitative real-time polymerase chain reaction, an in vivo ubiquitination assay, and immunohistochemistry were used in cellular assays and with a subcutaneous xenograft model in BALB/c mice. RESULTS:Sophoridine significantly suppressed the proliferation of and colony formation by lung cancer cells in vitro. Transwell assays demonstrated that sophoridine also inhibited invasion and migration in lung cancer cells. In addition, sophoridine enhanced the effects of cisplatin on lung cancer cells. A mechanistic study revealed that sophoridine significantly activated the Hippo and p53 signaling pathways, and mouse xenograft experiments further confirmed in vitro findings in lung cancer cells. CONCLUSIONS:Taken together, these results suggest that sophoridine can inhibit lung cancer progression and enhance the effects of the anticancer drug cisplatin against lung cancer cells. The mechanism of action of sophoridine might involve the Hippo and p53 signaling pathways.

摘要

背景: 据报道,槐定碱是一种从中草药苦豆子中提取的喹啉类生物碱,对多种人类癌症具有抗肿瘤作用。然而,除了用于临床肺癌治疗的潜力之外,很少有研究评估其对肺癌的肿瘤抑制作用和相关机制。 方法: 使用不同类型的肺癌细胞,使用细胞活力,集落形成,细胞侵袭和迁移试验来研究槐定碱的抗肿瘤作用。为了确定所涉及的信号通路,蛋白质印迹分析,定量实时聚合酶链反应,体内泛素化测定,在BALB/c小鼠的细胞测定和皮下异种移植模型中使用免疫组织化学。 结果: 槐定碱能明显抑制肺癌细胞的增殖和集落形成。Transwell试验证明槐定碱也抑制肺癌细胞的侵袭和迁移。此外,槐定碱增强顺铂对肺癌细胞的作用。一项机制研究发现槐定碱显著激活Hippo和p53 信号通路,小鼠异种移植实验进一步证实了肺癌细胞的体外发现。 结论: 总之,这些结果表明槐定碱可以抑制肺癌的进展,并增强抗癌药物顺铂对肺癌细胞的作用。槐定碱的作用机制可能涉及Hippo和p53 信号通路。

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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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