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Hydroxychloroquine suppresses lung tumorigenesis via inducing FoxO3a nuclear translocation through STAT3 inactivation.

羟基氯喹通过STAT3 失活诱导FoxO3a核转位抑制肺肿瘤发生。

  • 影响因子:3.40
  • DOI:10.1016/j.lfs.2020.117366
  • 作者列表:"Lyu X","Zeng L","Zhang H","Ke Y","Liu X","Zhao N","Yuan J","Chen G","Yang S
  • 发表时间:2020-04-01

BACKGROUND:Hydroxychloroquine exhibits synergistic anticancer properties as an adjuvant. However, the role and molecular mechanisms underlying of HCQ as monotherapy for lung adenocarcinoma (LUAD) have yet to be elucidated. METHODS:We assessed the antitumor effects of HCQ in LUAD cells through a series of in vitro and in vivo assays. GEO database and R packages were used to predict molecular mechanisms of HCQ in the treatment of lung adenocarcinoma, followed by verification of gene expression and subcellular localization via immunoblotting, immunofluorescent and immunohistochemistry assays. RESULTS:We showed the phenotypic effects that HCQ inhibited cell growth, induced apoptosis and cell cycle arrest at G1/S transition in A549 and PC-9 cells, which was associated with inhibition of CDK2, CDK4, CyclinD1 and CyclinE, but up-regulation of p21 and p27Kip1. Bioinformatic analysis predicted that 63 targets related to HCQ and LUAD were mainly enriched in JAK-STAT and FoxO pathways. Then, we observed that HCQ decreased the phosphorylation of STAT3, but increased the expression of FoxO3a and its accumulation in the nucleus. The specific STAT3 inhibitor cryptotanshinon augmented the HCQ-induced upregulation and nuclear translocation of FoxO3a. In addition, HCQ increased the expression of p27Kip1, which was impaired by FoxO3a blockade with siRNA. Finally, ablation of p27Kip1 expression abrogated the cytotoxicity of HCQ. More importantly, similar results were further confirmed in vivo. CONCLUSIONS:Taken together, this study suggests that STAT3/FoxO3a/p27Kip1 signaling pathway is involved in the anticancer effects of HCQ, and provides preliminary evidence for therapeutic prospects of HCQ alone in LUAD.


背景: 羟基氯喹作为佐剂具有协同抗癌特性。然而,HCQ作为肺腺癌 (LUAD) 单一疗法的潜在作用和分子机制尚未阐明。 方法: 我们通过一系列体外和体内试验评估了HCQ在LUAD细胞中的抗肿瘤作用。使用GEO数据库和R包预测HCQ治疗肺腺癌的分子机制,然后通过免疫印迹、免疫荧光和免疫组织化学测定验证基因表达和亚细胞定位。 结果: HCQ抑制A549 和PC-9 细胞生长,诱导细胞凋亡和细胞周期阻滞于G1/S期的表型效应,与抑制CDK2,CDK4,cyclinD1 和CyclinE,但p21 和p27Kip1 上调。生物信息学分析预测,与HCQ和LUAD相关的 63 个靶标主要富集在jak-stat和FoxO通路中。然后,我们观察到HCQ降低了STAT3 的磷酸化,但增加了FoxO3a的表达及其在细胞核中的积累。特异性STAT3 抑制剂隐丹参酮增强了HCQ诱导的FoxO3a上调和核转位。此外,HCQ增加p27Kip1 的表达,其通过siRNA的FoxO3a阻断而受损。最后,p27Kip1 表达的消融消除了HCQ的细胞毒性。更重要的是,在体内进一步证实了类似的结果。 结论: 总之,本研究提示STAT3/FoxO3a/p27Kip1 信号通路参与了HCQ的抗癌作用,并为HCQ单独用于LUAD的治疗前景提供了初步证据。



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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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.

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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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