Cadmium Increases HIF-1 and VEGF Expression through ROS, ERK, and AKT Signaling Pathways and Induces Malignant Transformation of Human Bronchial Epithelial Cells
Cadmium Increases HIF-1 and VEGF Expression through ROS, ERK, and AKT Signaling Pathways and Induces Malignant Transformation of Human Bronchial Epithelial Cells
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DOI：
10.1093/toxsci/kfr256
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发表时间：
2012-01-01
影响因子：
3.8
通讯作者：
Jiang, Bing-Hua
中科院分区：
文献类型：
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作者：
Jing, Yi;Liu, Ling-Zhi;Jiang, Bing-Hua
镉被归类为人类致癌物，尤其是肺癌。血管生成被认为是肿瘤发生的基本条件，但镉诱导肿瘤血管生成的机制知之甚少。利用体外和体内模型，我们研究了镉在人支气管上皮细胞和肿瘤形成中的血管生成机制。我们的研究结果表明，镉（CdCl 2）激活细胞外信号调节激酶（ERK）和AKT信号，并提高了一个关键的下游促血管生成分子缺氧诱导因子-1（HIF-1）在永生化人肺上皮BEAS-2B细胞的表达。镉还诱导活性氧（ROS）的产生，这可以抑制ROS清除剂，过氧化氢酶和氯化二苯基碘。ROS生成的抑制也减弱了ERK、AKT、p70 S6 K1活化和HIF-1 α表达。在正常人支气管上皮（NHBE）细胞中获得类似的结果，表明镉通过ROS/ERK/AKT信号通路诱导HIF-1表达。此外，镉通过ROS、ERK和AKT途径诱导血管内皮生长因子表达和转录激活。最后，镉转化培养的人支气管上皮细胞，转化细胞诱导管形成在体外，鸡绒毛尿囊膜上的血管生成，并在裸鼠中形成肿瘤。本研究结果为阐明镉促进肺上皮细胞血管生成和恶性转化的作用及其分子机制提供了理论依据，为镉致肺癌的职业防护、预防和化疗提供了理论依据。
Cadmium is categorized as a human carcinogen especially involved in lung cancers. Angiogenesis is considered a fundamental requirement for tumorigenesis, but the mechanisms underlying the tumor angiogenesis induced by cadmium are poorly understood. Using in vitro and in vivo models, we investigated the angiogenic mechanisms of cadmium in human bronchial epithelial cells and tumor formation. Our results demonstrated that cadmium (CdCl2) activated extracellular signal-regulated kinases (ERK) and AKT signaling and elevated the expression of a key downstream proangiogenic molecule hypoxia-inducible factor-1 (HIF-1) in immortalized human lung epithelial BEAS-2B cells. Cadmium also induced reactive oxygen species (ROS) production, which could be inhibited by ROS scavengers, catalase and diphenyleneiodonium chloride. Inhibition of ROS generation also attenuated ERK, AKT, p70S6K1 activation, and HIF-1 alpha expression. Similar results were obtained in normal human bronchial epithelial (NHBE) cells, showing that cadmium induced HIF-1 expression via ROS/ERK/AKT signaling pathway. Furthermore, cadmium induced vascular endothelial growth factor expression and transcriptional activation through ROS, ERK, and AKT pathways. Finally, cadmium transformed human bronchial epithelial cells in culture; the transformed cells induced tube formation in vitro, angiogenesis on chicken chorioallantoic membrane, and formed tumors in nude mice. Taken together, the results of this study provide explanation for the role and molecular mechanisms of cadmium in promoting angiogenesis in lung epithelial cells and malignant transformation and will be helpful for improved occupational protection, prevention, as well as chemotherapy of human lung cancers caused by heavy metal cadmium.