Chronic cadmium exposure in vitro induces cancer cell characteristics in human lung cells.
Chronic cadmium exposure in vitro induces cancer cell characteristics in human lung cells.
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DOI：
10.1016/j.taap.2013.06.013
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发表时间：
2013-12-01
影响因子：
3.8
通讯作者：
Waalkes MP
中科院分区：
文献类型：
--
作者：
Person RJ;Tokar EJ;Xu Y;Orihuela R;Ngalame NN;Waalkes MP
镉是一种已知的人类肺癌致癌物。在这里，我们试图建立一个体外模型，镉诱导的人肺癌细胞系，HPL-1D，长期暴露于低水平的镉。将细胞长期暴露于5 μM镉（非细胞毒性水平），并监测获得性癌症特征。通过20周的连续镉暴露，这些慢性镉处理的肺（CCT-LC）细胞表现出分泌的MMP-2活性（3.5倍），侵袭（3.4倍），并在软琼脂集落形成（2倍）显着增加。CCT LC细胞过度增殖，在无血清培养基中生长良好，并过表达细胞周期蛋白D1。CCT LC细胞中抑癌基因p16和SLC 38 A3的蛋白水平表达也降低。同样与获得性癌细胞表型一致，CCT-LC细胞显示癌蛋白K-RAS和N-RAS以及上皮-间充质转化标志物蛋白波形蛋白的表达增加。金属硫蛋白（MT）的表达增加镉，通常是在人类肺癌过表达。MT的主要亚型MT-1A和MT-2A在CCT LC细胞中升高。氧化适应性反应基因HO-1和HIF-1A在CCT LC细胞中也被激活。金属转运基因ZNT-1，ZNT-5和ZIP-8的表达增加，最终在减少镉积累的CCT-LC细胞，表明适应金属。总的来说，这些数据表明，暴露于镉的人肺上皮细胞导致收购的癌细胞的特征。此外，尽管细胞有能力适应慢性镉暴露，但仍会发生转化。
Cadmium is a known human lung carcinogen. Here, we attempt to develop an in vitro model of cadmium-induced human lung carcinogenesis by chronically exposing the peripheral lung epithelia cell line, HPL-1D, to a low level of cadmium. Cells were chronically exposed to 5 μM cadmium, a noncytotoxic level, and monitored for acquired cancer characteristics. By 20 weeks of continuous cadmium exposure, these chronic cadmium treated lung (CCT-LC) cells showed marked increases in secreted MMP-2 activity (3.5-fold), invasion (3.4-fold), and colony formation in soft agar (2-fold). CCT-LC cells were hyperproliferative, grew well in serum-free media, and overexpressed cyclin D1. The CCT-LC cells also showed decreased expression of the tumor suppressor genes p16 and SLC38A3 at the protein levels. Also consistent with an acquired cancer cell phenotype, CCT-LC cells showed increased expression of the oncoproteins K-RAS and N-RAS as well as the epithelial-to-mesenchymal transition marker protein Vimentin. Metallothionein (MT) expression is increased by cadmium, and is typically overexpressed in human lung cancers. The major MT isoforms, MT-1A and MT-2A were elevated in CCT-LC cells. Oxidant adaptive response genes HO-1 and HIF-1A were also activated in CCT-LC cells. Expression of the metal transport genes ZNT-1, ZNT-5, and ZIP-8 increased in CCT-LC cells culminating in reduced cadmium accumulation, suggesting adaptation to the metal. Overall, these data suggest that exposure of human lung epithelial cells to cadmium causes acquisition of cancer cell characteristics. Furthermore, transformation occurs despite the cell’s ability to adapt to chronic cadmium exposure.
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影响因子：
10.4
作者：
Benbrahim-Tallaa L;Tokar EJ;Diwan BA;Dill AL;Coppin JF;Waalkes MP
通讯作者：
Waalkes MP
影响因子：
2.6
作者：
Demirhan, Osman;Tastemir, Deniz;Hanta, Ismail
通讯作者：
Hanta, Ismail
影响因子：
4.5
作者：
Hart, BA;Potts, RJ;Watkin, RD
通讯作者：
Watkin, RD
影响因子：
--
作者：
Cucu D;D'Haese PC;De Beuf A;Verhulst A
通讯作者：
Verhulst A
影响因子：
4.1
作者：
He, Xiaoqing;Chen, Michael G.;Ma, Qiang
通讯作者：
Ma, Qiang