| Background:Lung cancer in China and the world remains a major health problem because of its high morbidity and mortality.Early symptoms of lung cancer onset conceal and not obvious generally,so it’s easy to be neglected in the early stage.In addition,the early diagnosis and treatment of lung cancer are still in a slow development,the 5-year survival rate is only 18% for lung cancer.As one of the six major biological characteristics of tumor,metastasis has always been the main cause of death in patients with tumor recurrence.So,the mechanism of tumor metastatic and the signaling pathways which were involved in are becoming very important for controlling the tumor recurrence and metastasis.Cyclophilin A is a member of Cyclophilins,and it was recognized as intracellular binding protein for the potent immunosuppressive drug cyclosporine A.Studies has shown that Cyp A is widely over-expressed in various cancers,such as hepatocellular carcinoma,breast cancer,non-small cell lung cancer,pancreatic cancer,and so on.The function of Cyp A in cancers has been also studied by many groups,and increasing evidences are found gradually.It has been suggested that Cyp A plays an important role in the whole pathological procession of cancer development.Howard et al.discovered that over-expression of Cyp A stimulates cancer cell growth in non-small cell lung cancer,and that cancer cell growth slowed after Cyp A knock-down.And accumulated evidences have been found that Cyp A is correlated with metastasis in divers cancers,however,the mechanism involved in it is still poorly understood.Our previous studies have found that,cell migration and invasion ability are decreased after Cyp A were down-regulated by RNA interference and the use of inhibitors in non-small cell lung cancer cell,this suggests that Cyp A might promote migration and invasion of non-small cell lung cancer cells.Then we found that the inhibition of the Cyp A non-small cell lung cancer cells affects P38 phosphorylation levels significantly.This suggests that Cyp A promotes non-small cell lung cancer cell migration and invasion ability through P38 MAPK signaling pathway.Method:Lentivirus infection in non-small cell lung cancer cells A549 and H1299 to construct Cyp A down-regulated and the over-expressed cell lines,and control cells were constructed.Then,wound healing assay and Transwell assay were used to observe effect of Cyp A on non-small cell lung cancer cells migration.Western blot was used to observe the effect of Cyp A on the expression of EMT related protein.Animal models were performed to affirm the role of Cyp A in the metastasis of non-small cell lung cancer.Results:1.In our studies,Lentivirus infection was used to construct Cyp A down-regulated and over-expressed cell lines with two human lung adenocarcinoma cancer cell lines,A549 and H1299.2.Next,results of wound healing assay and Transwell assay showed that the expression level of Cyp A correlated with the migration of NSCLC cells significantly.And results of western blot showed that the expression level of β-catenin,Vimentin and Snail were positively regulated by Cyp A.These results suggest that Cyp A plays an important role in the metastasis of NSCLC.4.To confirm the effect of Cyp A on metastasis of NSCLC,mouse models were used to verify the previous results.And we demonstrated that Cyp A promotes metastasis of NSCLC in vivo for the first time.5.SB203580 inhibited the migration of NSCLC cells significantly in Cyp A over-expressed group,while the different in Cyp A down-regulated group was not significant.Conclusion:We demonstrate that Cyclophilin A promotes NSCLC cells migration and the metastasis of NSCLC positively via P38 MAPK signaling pathway in vitro and in vivo. |
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