Lian Sen, Xia Yong, Khoi Pham Ngoc, Ung Trong Thuan, Yoon Hyun Joong, Kim Nam Ho, Kim Kyung Keun, Jung Young Do
Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.
Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.
Toxicology. 2015 Dec 2;338:104-16. doi: 10.1016/j.tox.2015.10.008. Epub 2015 Nov 11.
Cadmium (Cd), a widespread cumulative pollutant, is a known human carcinogen, associated with inflammation and tumors. Matrix metalloproteinase-9 (MMP-9) plays a pivotal role in tumor metastasis; however, the mechanisms underlying the MMP-9 expression induced by Cd remain obscure in human endothelial cells. Here, Cd elevated MMP-9 expression in dose- and time-dependent manners in human endothelial cells. Cd increased ROS production and the ROS-producing NADPH oxidase. Cd translocates p47(phox), a key subunit of NADPH oxidase, to the cell membrane. Cd also activated the phosphorylation of EGFR, Akt, Erk1/2, and JNK1/2 in addition to promoting NF-кB and AP-1 binding activities. Specific inhibitor and mutagenesis studies showed that EGFR, Akt, Erk1/2, JNK1/2 and transcription factors NF-κB and AP-1 were related to Cd-induced MMP-9 expression in endothelial cells. Akt, Erk1/2, and JNK1/2 functioned as upstream signals in the activation of NF-κB and AP-1, respectively. In addition, N-acetyl-l-cystein (NAC), diphenyleneiodonium chloride (DPI) and apocynin (APO) inhibited the Cd-induced activation of EGFR, Akt, Erk1/2, JNK1/2, and p38 MAPK, indicating that ROS production by NADPH oxidase is the furthest upstream signal in MMP-9 expression. At present, it states that Cd displayed marked invasiveness in ECV304 cells, which was partially abrogated by MMP-9 neutralizing antibodies. These results demonstrated that Cd induces MMP-9 expression via ROS-dependent EGFR->Erk1/2, JNK1/2->AP-1 and EGFR->Akt->NF-κB signaling pathways and, in turn, stimulates invasiveness in human endothelial cells.
镉（Cd）是一种广泛存在的累积性污染物，是已知的人类致癌物，与炎症和肿瘤有关。基质金属蛋白酶-9（MMP-9）在肿瘤转移中起关键作用；然而，在人内皮细胞中，Cd诱导MMP-9表达的潜在机制仍不清楚。在此，Cd在人内皮细胞中以剂量和时间依赖性方式提高MMP-9表达。Cd增加活性氧（ROS）生成以及产生活性氧的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶。Cd使NADPH氧化酶的关键亚基p47（phox）转位至细胞膜。除了促进核因子κB（NF-κB）和活化蛋白-1（AP-1）的结合活性外，Cd还激活表皮生长因子受体（EGFR）、蛋白激酶B（Akt）、细胞外信号调节激酶1/2（Erk1/2）和应激活化蛋白激酶1/2（JNK1/2）的磷酸化。特异性抑制剂和诱变研究表明，EGFR、Akt、Erk1/2、JNK1/2以及转录因子NF-κB和AP-1与人内皮细胞中Cd诱导的MMP-9表达有关。Akt、Erk1/2和JNK1/2分别作为NF-κB和AP-1激活中的上游信号。此外，N-乙酰-L-半胱氨酸（NAC）、二苯基碘鎓氯化物（DPI）和夹竹桃麻素（APO）抑制Cd诱导的EGFR、Akt、Erk1/2、JNK1/2和p38丝裂原活化蛋白激酶（p38 MAPK）的激活，表明NADPH氧化酶产生的ROS是MMP-9表达中最上游的信号。目前，研究表明Cd在ECV304细胞中表现出显著的侵袭性，而MMP-9中和抗体可部分消除这种侵袭性。这些结果表明，Cd通过ROS依赖的EGFR->Erk1/2、JNK1/2->AP-1和EGFR->Akt->NF-κB信号通路诱导MMP-9表达，进而刺激人内皮细胞的侵袭性。
