Cross-Talking Between JAK/STAT3 And MAPK/ERK Signaling Transduction Pathways And Its Significance On Invasion And Metastasis Of The Human Breast Cancer Cells

Objective: To explore the effect of Janus kinase inhibitor AG490 on phosphorylation of STAT3 and ERK of the human breast cancer cell MDA-MB-231 and elucidate the cross-talking between JAK/STAT3 and MAPK/ERK signal transduction pathways and roles of two pathways on invasion and metastasis of human breast cancer cells.Methods: MDA-MB-231 cell line was used as the research model, and they were treated with Janus kinase inhibitor AG490. The expression of P-STAT3 and P-ERK proteins were detected by Western-blot.The expression of STAT3, ERK1, ERK2 mRNA were measured by RT-PCR. Proliferation of MDA-MB-231 cell was measured with MTT assay. The expression of MMP-9 protein was detected by Western-blot and the secretion of MMP-2 and MMP-9 were tested by gelatin zymography. Adhesion of MDA-MB-231 cells to matrigel was measured with MTT assay. Invasion and migration of MDA-MB-231 cells was investigated with transwell chamber.Results: In MDA-MB-231 cells the expression level of P-STAT3, P-ERK proteins were reduced obviously to 37.6%, 48.9% respectively and the expression level of STAT3, ERK1 and ERK2 mRNA were decreased to 41.8%, 44.8% and 56.2% respectively after treated with 40μmol/L AG490 for 24 hours compared with untreated group,(P<0.01). The proliferation was inhibited on a time and dose-dependent manner after treated with AG490.The adhesion, invasion and migration of human breast cancer cells were also depressed after treated with 40μmol/L AG490 for 48 hours compared with that of untreated group, (P<0.05).The expression of MMP-9 was reduced to 44.9% and the secretion of MMP-2 , MMP-9 were diminished to 30.6%, 62.2% respectively after treated with 40μmol/L AG490 for 24 hours compared with untreated group, (P<0.01).Conclusion: Our study demonstrates transcription factor STAT3 and kinase ERK could affect gene expression each other likely by phosphorylation interactions.Cross-talking occurs between JAK/STAT3 and MAPK/ERK signal transduction pathways.The inhibitory effects of JAK kinase on MMPs expression and invasion of breast cancer cells was associated with the down-regulation of these two pathways.