| Research background:As one of the most common malignant tumors in gynecology,cervical cancer seriously threatens women’s life and health.Although the incidence rate has declined with the popularization of cervical cancer screening,the degree of tumor invasion still has been deep or metastasis has occurred at the time of diagnosis in some cases,which has a great impact on the treatment.What’s more,the mortality rate has been reached3.20/100,000 in a rising trend.Therefore,it is necessary to find new therapeutic targets to improve the treatment.Eph A2(erythropietin-producing human hepatocellular)is a member of the Eph subfamily with tyrosine kinase activity,which mainly acts on cell growth,migration and other processes.Under physiological conditions,Eph A2 can be rapidly reduced and expressed at a low level combined with the ligand;while elevated Eph A2 expression in tumor cells can promote tumor metastasis.In studies on cervical cancer,the expression of Eph A2 is elevated and is closely related to invasion and metastasis,but its specific mechanism is still unclear.Epithelial mesenchymal transition(EMT)is the process by which epithelial-derived cells undergo morphological changes,disappearance of polarity,weakened intercellular connections,and increased gaps,which allow them to acquire the characteristics of mesenchymal cells.It is an important mechanism of malignant tumor’s infiltration and transfer.EMT related proteins include:E-cadherin,Vimentin,Twsit,Snail,etc.Among them,E-cadherin(E-cadherin)plays an inhibitory role in tumor invasion and metastasis,and the lack of E-cadherin expression is a typical feature of the EMT process.Vimentin is a mesoplasmic marker of the EMT process.Its expression increases in many tumors,such as colon cancer,lung cancer,breast cancer,etc.,and is closely related to tumor invasion and metastasis.Twist and Snail enhance the expression of VEGF by up-regulating their own expression and promote angiogenesis,thereby promoting tumor invasion and metastasis.In oncology,angiogenesis is an important marker of tumor progression.Vasculogenic mimicry(VM)is a new tube-like type of tumor blood supply,which is only formed by tumor cells without vascular endothelial cells.Because of its independent formation on vascular endothelial cells,it provides a new idea for anti-tumor vascular therapy.In some tumors such as breast cancer,it is found that the formation of VM is closely related to the positive expression of Eph A2,and affects the development and prognosis of the tumor.At present,the specific molecular mechanism of cervical squamous cell carcinoma invasion and metastasis and the relationship between VM and EMT has not been unified.A large number of studies have shown that Eph A2 is related to the occurrence and development of a variety of tumors,such as human gastric cancer,breast cancer,prostate cancer and melanoma and so on.However,there are few reports on the mechanism of Eph A2 in the invasion and metastasis of cervical squamous cell carcinoma at home and abroad.Therefore,this study detected the expression of Eph A2,Vimentin,E-cadeherin,Twist,Snail,and VM in cervical squamous cell carcinoma to discuss the relationship between Eph A2,EMT and VM in process of invasion and metastasis and its possible mechanism.It provides a theoretical basis for discovering the possible mechanism of cervical squamous cell carcinoma metastasis and the treatment of invasion and metastasis.Objective:This study aims to investigate the expression and correlation analysis of Eph A2and EMT related proteins in normal cervical tissues,cervical squamous intraepithelial lesion tissues and cervical squamous cell carcinoma tissues.Explore the relationship between Eph A2,EMT and VM in the process of invasion and metastasis of cervical squamous cell carcinoma combined clinical data and discuss the possible mechanism of Eph A2 in promoting cervical squamous cell carcinoma metastasis to provide help for the pathological diagnosis and targeted therapy of cervical squamous cell carcinoma invasion and metastasisMethods:In this study,tissue microarrays and immunohistochemistry were used to detect the expression of Eph A2,Vimentin,E-cadeherin,Twist,Snail and VM in normal cervical tissue,cervical squamous intraepithelial lesion tissue,cervical cancer with metastasis and cervical cancer without metastasis.The relationship between the expression level of each protein and clinicopathological characteristics,and the correlation of expression in cervical cancer were analyzed.Results:1.Eph A2 presents a light brown-yellow distribution in the cytoplasm and nucleus of tumor cells.The positive expression rate of Eph A2 in cervical cancer tissue is64.91%,which is higher than that in control group(26.67%)and HSIL group(43.33%).Compared with the control group,the expression of Eph A2 in HSIL group and cervical cancer group increased significantly(P<0.05).There was no significant difference in the expression of Eph A2 in different cervical cancer clinical stages,degree of differentiation,and tissue types.The positive rate of cervical cancer with muscular invasion was significantly higher than that in the non-muscular invasion group,the difference was statistically significant(P<0.01).The positive rate in the cervical cancer with lymph node metastasis group was higher than that in the non-lymph node metastasis group,the difference was statistically significant(P<0.05).2.VM was expressed as a purple-red ring in the tumor stroma,with tumor cells inside without vascular endothelial cells surrounding,which was expressed as CD34-/PAS+.The positive rate of VM in the cervical cancer group was 40.35%.There was no significant difference in the expression of VM in different cervical cancer clinical stages,degree of differentiation,and tissue types.The positive rate of cervical cancer with muscular invasion was significantly higher than that in the non-muscular invasion group,the difference was statistically significant(P<0.05).The positive rate in the cervical cancer with lymph node metastasis group was higher than that in the non-lymph node metastasis group,the difference was statistically significant(P<0.05).3.Vimentin presented light brown in the cytoplasm of tumor cells,and the positive expression rate in cervical cancer tissues was 57.89%.The expression of vimentin in cervical cancer tissues with muscle infiltration was significantly higher than that in tissues without muscle infiltration(χ~2=3.898,P<0.05).The expression of vimentin in the group with lymphatic metastasis was significantly higher than that in the non-metastasis group,and the difference was statistically significant(χ~2=9.286,P<0.01),There was no significant statistical significance with different clinical stages,degree of differentiation,and tissue types.The expression of E-cadherin was brown-yellow in the cell membrane of normal cells,and the positive expression rate in cervical cancer tissue was 29.82%.The expression in the group with lymphatic metastasis was significantly lower than that in the group without metastasis,and the difference was statistically significant(χ~2=5.786,P<0.05).The expression in cervical cancer tissues with muscular invasion was significantly lower than that in non-muscular invasion tissues(χ~2=5.116,P<0.05).There is no significant statistical significance in clinical stage,degree of differentiation,and tissue types.Twist was mainly expressed in the cytoplasm,and was also expressed in a few nuclei;Snail positive expression products were located in the cytoplasm,showing obvious brown-yellow diffuse granular expression.The positive expression rate of Twist in cervical cancer tissue was 88.3%,and that of Snail was 78.3%.The positive expression of both in cervical cancer presented no correlation with clinical stages,degree of differentiation,tissue types,but related to lymphatic metastasis(P<0.05).4.In cervical cancer tissues,the expression of Eph A2,vimentin,Twist,and Snail increased,while the expression of E-cadherin decreased significantly.The expression of Eph A2 was positively correlated with the positive expression of vimentin(r=0.490,P<0.01);and also significantly positively correlated with the positive expression of Twist(r=0.509,P<0.01);as well as positively correlated with the expression of Snail(r=0.301,P<0.05))and the formation of VM(r=0.455,P<0.01);but negatively correlated with the expression of E-cadherin(r=-0.324,P<0.05).Conclusions:1.Eph A2 is highly expressed in cervical squamous cell carcinoma,and is closely related to EMT proteins when it is accompanied by lymphatic metastasis and myometrial invasion,suggesting that Eph A2 may participate in the invasion and metastasis of cervical squamous cell carcinoma through the EMT process.2.The expression of Eph A2 in cervical squamous cell carcinoma is positively correlated with the formation of VM and lymph node metastasis,suggesting that Eph A2may promote the development of cervical squamous cell carcinoma through the formation of VM and play a role in the invasion and metastasis of cervical squamous cell carcinoma. |
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