The Role And Molecular Mechanism Of MiR-218-mediated Epithelial-mesenchymal Transition In The Development Of Lung Cancer And Chemotherapy Resistance

Cancer has become the first killer that threatening human health in modern society,lung cancer is a malignant tumor whose mortality rates are the highest in the world,which cause serious damage to human survival and health.At present in our country,the incidence and mortality of lung cancer are the first one among the malignant tumor.Lung cancer is divided into small cell lung cancer and non-small cell lung cancer(NSCLC)based on histopathology.Non-small cell lung cancer(NSCLC)accounts for 85%of the total number of lung cancer,including Squamous carcinoma,adenocarcinoma and large cell carcinoma,and most part of the patient is in middle-late stage.Epithelial-mesenchymal transition(EMT)has been recognized as a key element of cell migration and invasion in lung cancer;however,the underlying mechanisms are not fully elucidated.MicroRNAs(miRNAs)is a class of endogenous non-coding RNA,about 18-24 nucleotides in length,widely present in plants and animals,is highly conserved evolutionarily,mainly regulating the genes expression through post-transcription levels.Humans discovered target genes of miRNAs can be nearly 60%of mammals,most of the genes involved in these physiological and pathological processes of cells,such as cell proliferation,apoptosis and cell cycle and so on.In tumor cells,miRNAs abnormal expression also involves in many biological processes and plays a role in tumor promoters or tumor suppressor in tumor progression.A amount of data showed that miRNAs involved in the regulation of many important functions in cells,such as cell migration,invasion,and resistance to chemotherapy.Recently,emerging evidence suggests that miRNAs play a crucial role in controlling EMT and EMT-associated traits such as migration,invasion and chemo-resistance.MiR-218 were found differentially expressed and acted as suppressor gene in glioma,gallbladder,non-small cell lung cancer,oral cancer,breast cancer,kidney cancer and other tumors.Here,we found that miR-218 was significantly down-regulated in lung cancer compared to adjacent lung tissues,and the down-regulation of miR-218 was significantly associated with histological grade and lymph-node metastasis.Overexpression of miR-218 inhibited cell migration and invasion ability,as well as the EMT process.Of particular importance,miR-218 is involved in the metastatic process of lung cancer cells in vivo by suppressing local invasion and distant colonization.Further studies have identified Slug and ZEB2 as direct target genes of miR-218;overexpression of Slug and ZEB2 partly abrogated the reduction induced by miR-218.Inverse correlations were also observed between miR-218 and Slug and ZEB2 levels in clinical samples.Cisplatin(cisplatin,CDDP)is a first-line drug of lung cancer chemotherapy,acquired drug resistance restricted the effect of CDDP.Recent studies have shown that miRNAs plays an important role in drug resistance of cancer,which miRNAs were differentially expressed in the drug resistant cells and drug sensitive cells.More intriguingly,H1299 cells with overexpressed miR-218 increased chemo-sensitivity to cisplatin compared to the parental cells through suppression of Slug and ZEB2.These findings highlight an important role for miR-218 in the regulation of EMT relative traits and metastasis of lung cancer in part by modulation of Slug/ZEB2signaling.This study illustrated the important role of miRNAs a in regulation of cell proliferation,invasion and metastasis,which involved in tumor migration,angiogenesis,EMT and drug resistance of chemotherapy.The characteristic of miRNAs in cancer have important value in diagnosis and treatment,the molecular mechanism of miRNAs for the occurrence and development of lung cancer may be use as a new therapeutic target in NSCLC.