Expression Of FAPα, Integrinα3β1 And RAC1 In CIN And Cervical Cancer

Background and ObjectiveCervical cancer is the third largest female deaths worldwide in malignant tumor. Although HPV and TCT were applied in screening for cervical cancer early detection and treatment, but so far, cervical cancer did not significantly reduce mortality. Exploring the sensitive indicators of early invasion, metastisis of the cervical cancer and the metastasis of cell signaling pathways, to judge prognosis, guide the clinical targeted therapy and improve the patients survival rate is a hotspot of research on cervical cancer. Fibroblast activation protein alpha(FAPa) also called Seprase, belongs to the family of serine-integral membrance peptidase(SIMP). It is secreted by activated stromal fibroblasts and can promote cancer cell proliferation, migration and invasion. Integrin alpha 3 beta 1 is one member of cell matrix protein receptor family, plays an important role in cell adhesion, migration and signal transduction, et al. It abnormally expresses in a wide variety of tumor. RAC1(i ’the as- related C3 botulinum toxin substrate l) protein is guanosine monophosphate(GTP) made binding protein, has a GTP enzyme activity, it controls cell shape, cell adhesion and the contractions that drive cell migration. RAC1 is closely related to the invasion and metastasis of tumor cells. But three prorein in expression of cervical disease and the correlation of their with the features of cervical cancer are not clear. Recently a study showes[1] that of FAPa can promote HO-8910 PM cell of proliferation, migration and invasion; but inhibiting integrin α3β1 and RAC1 can inhibit HO-8910 PM invasion, migration, proliferation, and the promoting role of FAP was weakened. Probably, three prorein have a connection in tumor invasion and metastasis. But, the expression of FAPα, integrinα3β1 and RAC1 in CIN and cervical cancer and its relationship with the features of cervical cancer is not clear.So, immunohistochemistry was employed to measure the protein expression of FAPa, integrinα3β1 and RAC1 have been detected in 23 patients with chronic cervicitis, 40 patients with cervical intraepithelial neoplasia and 81 patients with cervical cancer. The aim of this study was to analyze the correlation of FAPa, integrinα3β1 and RAC1 with the features of cervical cancer. Help us to further study its role in cervical cancer invasion, metastasis and the related mechanisms, may become new drug for the treatment target of cervical cancer. Possiblly offers a new sensitive index for judging the prognosis of cervical cancer.Materials and Experimental Methods1. 23 patients with chronic cervicitis, 40 patients with cervical intraepithelial neoplasia and 81 patients with cervical cancer were respectively collected in our hospital from January 2012 to April 2014. The inclusion criteria of cervical cancer: primary cervical cancer, pathological types of squamous carcinoma, adenocarcinoma, preoperative without treatment of radiotherapy, chemotherapy and immunotherap, clinical data is complete. Exclusion criteria: with other malignant tumor, special cervical cancer pathological type. 81 cases of cervical cancer tissues, the age range of 40-71 years(median age = 48); clinical stage(FIGO, 2012) : I 58 cases, II 23 cases; without lymph node metastasis of 70 cases, with metastasis 11 cases; the pathological types:68 cases of squamous cell carcinoma, 13 cases of adenocarcinoma; histological differentiation: G1 / G2 60 cases, G3 21 cases; Infiltration depth: 40 cases of infiltration depth > 1/2 cervical thickness, 41 cases of infiltrating depth≤ 1/2cervical thickness.2. Immunohistochemistry was employed to measure the protein expression of FAP α, integrinα3β1 and RAC1 in the 3 groups. Analysis of the differences expressed in three groups and futher explore the relation between the expression of their with the clinical and pathological factors of cervical cancer.3. Statistical analysis: The SPSS statistical package program 17.0 was applied to analyze the results of experiment. The comparison between positive rate between the different groups by chi-square test; Kruskal Wallis Test analyzed cervical cancer tissue protein expression of the strength of the correlation between clinical pathological factors; Spearman rank correlation analysis analyzed the correlation between the three kinds of proteins; Significant level is=0.05, P<0.05 for the difference was statistically significant.Results1. The positive expression of fibroblast activation prorein α in the cervical cancer is 98.77%, significantly higher than that in the group of cervical intraepithelial neoplasia(57.50%) and chronic cervicitis(0.00%). The relative expression of the cervical cancer is higher than in the cervical intraepithelial neoplasia and chronic cervicitis, the difference has statistically significant(both P﹤0.05). Higher FAP expression was significantly correlated with histopathologic type(H=4.198, P=0.040), lymph node metastisis(H=11.526, P=0.001) and depth of invasion(H=5.538, P=0.019). But not associated with ages(H =0.000,P=0.996), high histological grade(H =3.160,P=0. 075) and clinical stages(H =0.494,P=0. 482).2. The positive expression of integrinα3β1 prorein in the cervical cancer is 77.70% and cervical intraepithelial neoplasia is 80.00%, significantly higher than that in the group of chronic cervicitis(21.74%). The relative expression of the cervical cancer and cervical intraepithelial neoplasia are higher than in the chronic cervicitis, the difference has statistically significant(P﹤0.05), between the groups of cervical cancer and cervical intraepithelial neoplasia, the difference has not statistically significant(P>0.05). Higher integrinα3β1 expression was significantly correlated with high histological grade(χ2 =8.100, P=0.004), lymph node metastisis(χ2 =4.025, P=0.045. But not associated with histopathologic type(χ2 =0.654, P=0.419), depth of invasion(χ2=0.226, P=0.635), ages(χ2=0.057, P=0.635) and clinical stages(χ2 =0.278, P=0.598).3.The positive expression of RAC1 prorein in the cervical cancer is 70.37%, significantly higher than that in the group of cervical intraepithelial neoplasia(45.00%) and chronic cervicitis(13.04%). The relative expression of the cervical cancer is higher than in the cervical intraepithelial neoplasia and chronic cervicitis, the difference has statistically significant(both P﹤0.05). Higher RAC1 expression was significantly correlated with depth of invasion(χ2=8.714, P=0.003), high histological grade(χ2=5.496, P=0.019) and lymph node metastisis(χ2=5.931, P=0.015).But not associated with histopathologic type(χ2=1.194, P=0.275), ages(χ2 =0.720, P=0.396)and clinical stages(χ2 =0.193, P=0.660).4. FAPa is a positive correlation with integrin alpha 3 beta 1(r=0.591, P=0.000) and RAC1 protein(r=0.348, P=0.010) in cervical cancer tissue.Conclusions1. FAPα, integrinα3β1 and RAC1 Prorein expression could be detected in CIN lesions and cervical cancer. They may have joined the transformation process with cervical intraepithelial neoplasia to cervical cancer.2. FAPα, integrinα3β1 and RAC1 prorein express in cervical intraepithelial neoplasia and cervical cancer. Their expression was significantly correlated with lymph node metastisis. They may play an important role in nvasion and metastasis in cervical cancer.