Study Of The Role And Relative Mechanism Of Chitinase 3-like 1 In Non-small Cell Lung Cancer Angiogenesis

Background Lung cancer is a malignant tumor that seriously threatens human health and life,which is also the leading cause of cancer-related death worldwide.Angiogenesis plays an important role in the progression and metastasis of tumor.Chitinase 3-like 1(CHI3L1),a member of 18-glycosyl hydrolase family,is a secreted glycoprotein.Growing clinical evidence had indicated that aberrant overexpression of CHI3L1 were found in a variety of chronic inflammatory diseases and human carcinomas,such as colorectal cancer,ovarian cancer,breast cancer,lymphoma,glioblastoma and lung cancer.Interestingly,CHI3L1 plays a role in promoting angiogenesis in breast and colon cancer,but its role in non-small cell lung cancer(NSCLC)angiogenesis and the possible molecular mechanism involved is still unclear.Objective Our study is aimed to investigate the role of CHI3L1 in NSCLC angiogenesis and the possible molecular mechanism involved.Methods To test the expression of CHI3L1,VEGF and intratumoral microvessel density(MVD)in the tumor tissues of NSCLC patients,immunohistochemistry(IHC)staining analysis was performed on surgically resected specimens.The relationship between CHI3L1 expression and VEGF expression or MVD in NSCLC tissues was analyzed.At the same time,a comprehensive analysis of the relationship between CHI3L1 expression,VEGF expression or MVD and clinicopathological variables in NSCLC patients was made.Then,five NSCLC cell lines were screened and the relatively high expression of CHI3L1 and the low expression of CHI3L1 cell lines were found.To detect the effect of CHI3L1 protein change on the migration and tube formation of human endothelial cells(HUVECs),CHI3L1 gene knockdown and overexpression were performed on NSCLC cell lines.In order to study the possible mechanism,we examined the effect of CHI3L1 protein changes on the VEGF and IL-8 secretion from tumor cells,and detected the MAPK pathway in tumor cells.Results We demonstrated that the expression of CHI3L1 was high in NSCLC tissues and human NSCLC cell lines.The expression of CHI3L1 was statistically correlation with lymph node metastasis and pleural metastasis.And there was a positive correlation between CHI3L1 expression and VEGF expression or MVD in NSCLC tissues.Moreover,we showed that overexpression of CHI3L1 in NSCLC cells enhanced the migration and tube formation of HUVECs,whereas knockdown of CHI3L1 inhibited the migration and tube formation of HUVECs.ELISA analysis showed that overexpression of CHI3L1 in NSCLC cells could increase the secretion of IL-8 and VEGF from tumor cells via activating extracellular signal-regulated kinase(ERK)pathway.Inhibition of ERK in NSCLC cells significantly reduced the secretion of IL-8 and VEGF and tube formation of HUVECs induced by CHI3L1 overexpression.Conclusion Our findings indicated that CHI3L1 could promote tumor angiogenesis in NSCLC.Furthermore,we found that the mechanism of CHI3L1 in promoting NSCLC angiogenesis was to increase the secretion of IL-8 and VEGF from tumor cells by activating ERK pathway.Thus CHI3L1 might be a novel therapeutic target in NSCLC angiogenesis.