The Role Of B7-H3 In The Progression Of Cervical Cancer

BackgroundCervical cancer,as one of the most common gynecological malignancies among worldwide,threatens the health of women.It is reported that 80%of cervical cancer occurs in developing countries.It's well known that persistent high-risk HPV infection is closely related to the occurrence of cervical cancer.However,not all the women infected by high-risk HPV finally progress to cervical cancer,but only few of these people progress to CIN(cervical intraepithelial neoplasia,CIN)or cervical cancer.Moreover the women who get infected by HIV(human immunodeficiency virus,HIV)and take immunosuppressive agents are more likely to develop into CIN or cervical cancer.These phenomena indicate that immune factors may be related to the pathogenesis of cervical cancer.The B7 family includes immunostimulatory molecules that provides a stimulatory signal that enhances and maintains a T cell immune response,and can also inhibit and attenuate the T cell immune response.The B7 family play an important role in tumor disease,organ transplantation and autoimmune disease.B7-H3 is a member of the B7 family firstly cloned in 2001 and has two forms:2Ig-B7-H3 and 4Ig-B7-H3.The 2Ig-B7-H3 is expressed in murine and human cells with extracellular of IgV-IgC structure;the 4Ig-B7-H3 is expressed only in human cells and consists of tandem repeating IgV-IgC-IgV-IgC structure.B7-H3 is widely expressed in various organs and cells,such as lung,breast,liver,placenta,prostate and dendritic cells.Previous studies shown that B7-H3 is aberrantly highly expressed in a variety of tumors including prostate cancer,pancreatic cancer,breast cancer,endometrial cancer,liver cancer,colon cancer,osteosarcoma,and hematological malignancies.B7-H3 has similar molecular structure to B7-H1(PD-L1).It has been confirmed that the B7-H1(PD-L1)expressed in tumor cells can bind to PD-1 on T cell surface and down-regulates T cell function,which promote the immune escape of tumor cells.The immunotherapy drugs targeting PD-1/PD-L1(B7-H1)have been applied to the clinical treatment of some tumors including melanoma.The function of B7-H3 in tumor immunity has not been fully clarified.It has been reported that B7-H3 can down-regulate Th-1 mediated immune response,inhibit CD4 + T cell activation,and inhibit the production of cytokines,and thus may promote the immune escape of cancer.Besides the immunological function,B7-H3 may also affect the biological characteristics such as tumor proliferation,invasion and metastasis,and may be associated with poor prognosis of some tumors.Previous studies showed that B7-H3 molecules were highly expressed in lung cancer,colorectal cancer,pancreatic cancer and other cancerous tissues,and their high expression is associated with poor prognosis.Cytological studies have shown that the high expression of B7-H3 in pancreatic cancer,prostate cancer,melanoma and other tumor cell can promote the invasion and metastasis of tumor cells.The reason why B7-H3 affects the biological characteristics of tumor cells is not clear.The role of B7-H3 and its expression in cervical cancer has not been extensively investigated.This study was aimed to investigate the expression of B7-H3 in cervical cancer and its relationship with the prognosis of cervical cancer patients,and to explore the role of B7-H3 in the proliferation,invasion and migration of cervical cancer cells.Materials and Methods1.Clinical pathology studyThe expression of B7-H3 in cervical cancer tissues and cervical tissues in controls was detected by immunohistochemical method.The expression of B7-H3 was detected by immunohistochemistry.And the relationship between disease prognosis;2.B7-H3 expression in the blood of the study:the use of ELISA to compare B7-H3 in cervical cancer and normal control group blood expression;3.Cytology test(1)Construction of cell lines:Construction of plasmids,transfection of cervical cancer cell lines,up-regulation or down-regulation of B7-H3 molecules in Caski,Siha and Hela cervical cancer cell lines;validation of cell lines using Western Blot;(2)To investigate the effect of B7-H3 expression on the proliferation and invasion of cervical cancer cells:Cell proliferation was detected by MTT assay.Cell invasion and migration were detected by Transwell system.Results1.The expression of B7-H3 in cervical cancer is significantly higher than that in cervical tissues of control group(p<0.05).The expression of B7-H3 is correlated with TNM staging(r?0.509,p<0.001).2.The 5-year survival rate of cervical cancer patients with strong B7-H3 expression was significantly lower than that of patients with weak positive or negative B7-H3 expression.Cox analysis showed that B7-H3 overexpression was a risk factor for the death of cervical cancer(HR = 4.463,p = 0.035).3.B7-H3 is significantly higher in the blood of cervical cancer patients than in control group.4.Western Blot and PCR show that B7-H3 interference and overexpression of cell lines were successfully constructed.5.Through MTT assay,we found that high expression level of B7-H3 promoted cervical cancer cells proliferation(p<0.05).6.Through transwell assay,we found that high expression level of B7-H3 enhanced cervical cancer cells migration and invasion(p<0.05).Conclusions1.The expression of B7-H3 was significantly higher in cervical cancer tissues and blood compared to normal cervical tissues,and this high expression was associated with TNM staging and worse prognosis for cervical cancer patients.2.B7-H3 can promote the proliferation and migration of cervical cancer cells,and may be a potential target for the treatment of cervical cancer.