Interplay between Epidermal Growth Factor Receptor and Janus Kinase 3 Regulates Polychlorinated Biphenyl–Induced Matrix Metalloproteinase-3 Expression and Transendothelial Migration of Tumor Cells

Abstract

We hypothesize that environmental toxicants, such as polychlorinated biphenyl congeners, can activate vascular endothelial cells and thus increase formation of blood-borne metastases. This study indicates that exposure of human microvascular endothelial cells to 2,2 ¶,4,6,6 ¶-pentachlorobiphenyl can stimulate transendothelial migration of tumor cells through up-regulation of matrix metalloproteinase (MMP)-3. In a series of experiments with specific small interfering RNA and pharmacologic inhibitors, we provide evidence that 2,2 ¶,4,6,6 ¶-pentachlorobiphenyl can activate epidermal growth factor receptor (EGFR) and Janus kinase 3 (JAK3) in a closely coordinated and cross-dependent fashion. Activated EGFR and JAK3 stimulate in concert c-Jun NH 2 -terminal kinase and extracellular signal-regulated kinase 1/2 as well as increase DNA-binding activity of transcription factors activator protein-1 and polyomavirus enhancer activator protein 3, leading to transcriptional up-regulation of MMP-3 expression. These results indicate that the interplay among EGFR, JAK3, and mitogen-activated protein kinases, such as c-Jun NH 2 -terminal kinase and extracellular signal-regulated kinase 1/2, is critical for polychlorinated biphenyl -induced MMP-3 expression and accelerated transendothelial migration of tumor cells. (Mol Cancer Res 2006;4(6):361 -70)

Oral administration of PCBs induces proinflammatory and prometastatic responses

“…It appears that a low absorption or high metabolism rate of this PCB may be responsible for its low tissue levels. High biological activity of PCB104 is in the line with our published reports which indicated stimulation of endothelial permeability, tumor cell adhesion to microvascular endothelial cells, and transendothelial migration of tumor cells in response to exposure to this PCB (Eum et al, 2004;Eum et al, 2006a;Eum et al, 2006b).…”

“…Our research has focused on the vascular effects of highly ortho-chlorine-substituted PCBs and PCB104 is an example of this group of compounds (Choi et al, 2003;Eum et al, 2004;Eum et al, 2006a;Eum et al, 2006b). Exposure of human endothelial cells to PCB104 significantly increases oxidative stress in human vascular endothelial cells and activates redoxresponsive transcription factors (Choi et al, 2003;Eum et al, 2004;Eum et al, 2006a;Eum et al, 2006b).…”

“…Finally, MMPs play a critical role in the growth, invasion, and metastasis of malignant tumors (Deryugina and Quigley, 2006;Jodele et al, 2006). We have shown that specific MMP-3 is involved in PCB-induced migration of tumor cells across the vascular endothelium (Eum et al, 2006b). …”

“…Quantitative real-time PCR was performed using the ABI Prism 7000 Sequence Detection system (Applied Biosystems, Foster City, CA) as described earlier (Eum et al, 2006a;Eum et al, 2006b). Briefly, total RNA was extracted from the tissues using the RNeasy kit (Qiagen, Valencia, CA) and 1 or 2 µg RNA were reverse transcribed using Reverse Transcription system (Promega, Madison, WI, USA) in a total volume of 20 µL.…”

“…Our group reported that selected PCBs can activate endothelial cells, disrupt endothelial monolayers, and stimulate both extravasation and transmigration of the cancer cells (Toborek et al, 1995;Choi et al, 2003;Eum et al, 2004;Eum et al, 2006a;Eum et al, 2006b). Several signal transduction pathways, such as the PI3K, epidermal growth factor receptor (EGFR) and Janus kinase 3 (JAK3), and c-Src kinase signaling pathways appear to be involved at different stages of these effects (Eum et al, 2006a;Eum et al, 2006b). Based on these observations, we hypothesize that PCBs can not only induce carcinogenic effects, but also contribute to the development of cancer metastases.…”