Nickel (Ni), which is a carcinogenic workplace hazard, increases the risk of lung cancer. Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional cytokine that is involved in both angiogenesis and metastasis, but its role in lung cancer is still not clear. In this study, we assessed the role of ANGPTL4 in lung carcinogenesis under nickel exposure and investigated the effects of the antidiabetic drug metformin on ANGPTL4 expression and lung cancer chemoprevention. Our results showed that ANGPTL4 is increased in NiCl2-treated lung cells in a dose- and time-course manner. The expression of ANGPTL4 and HIF-1α induced by NiCl2 were significantly repressed after metformin treatment. The downregulation of HIF-1α expression by ROS savenger and HIF-1α inhibitor or knockdown by lentiviral shRNA infection diminished NiCl2-activated ANGPTL4 expression. Chromatin immunoprecipitation and the luciferase assay revealed that NiCl2-induced HIF-1α hypoxia response element interactions activate ANGPTL4 expression, which is then inhibited by metformin. In conclusion, the increased presence of ANGPTL4 due to HIF-1α accumulation that is caused by nickel in lung cells may be one mechanism by which nickel exposure contributes to lung cancer progression. Additionally, metformin has the ability to prevent NiCl2-induced ANGPTL4 through inhibiting HIF-1α expression and its binding activity. These results provide evidence that metformin in oncology therapeutics could be a beneficial chemopreventive agent.

译文

:镍(Ni)是工作场所的致癌物质,会增加患肺癌的风险。血管生成素样蛋白4(ANGPTL4)是一种多功能细胞因子,参与血管生成和转移,但在肺癌中的作用仍不清楚。在这项研究中,我们评估了ANGPTL4在镍暴露下肺癌发生中的作用,并研究了抗糖尿病药物二甲双胍对ANGPTL4表达和肺癌化学预防的影响。我们的研究结果表明,ANGPTL4在经过NiCl2处理的肺细胞中呈剂量和时间过程增加。二甲双胍处理后,NiCl2诱导的ANGPTL4和HIF-1α的表达明显降低。 ROS savenger和HIF-1α抑制剂对HIF-1α表达的下调或慢病毒shRNA感染的抑制可降低NiCl2激活的ANGPTL4的表达。染色质的免疫沉淀和荧光素酶测定表明,NiCl2诱导的HIF-1α缺氧反应元件相互作用激活ANGPTL4表达,然后被二甲双胍抑制。总之,由镍在肺细胞中引起的HIF-1α积累导致ANGPTL4的存在增加,可能是镍暴露导致肺癌进展的一种机制。另外,二甲双胍具有通过抑制HIF-1α表达及其结合活性来预防NiCl2诱导的ANGPTL4的能力。这些结果提供证据表明二甲双胍在肿瘤治疗中可能是有益的化学预防剂。

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