| Background and ObjectiveCervical cancer is one of the most common malignant disease and a leading cause of cancer mortality among women worldwide.The number of new cases and death each year in China accounts for a third of the global cases,and the cases occur tend to be younger.It is a important reason that the infiltration and metastasis cause the death in patients who suffered from advanced cervical cancer.Therefore,it is very important to study the mechanism of the invasion and metastasis in cervical cancer,to find the key elements of its development,and to improve the survival of the patients.The development of cancer is closely related to the microenvironment of tumor cells.Combining with literatures and our previous study,it shows that tumor-associated fibroblasts(TAFs)play an important role in malignant transformation and progression of cervical cancer.TAFs exhibit morphological phenotypes of myofibroblasts,and are known to promote tumor progression by interaction with adjacent cancer cells.Fibroblast activation has a sign of the expression of a-SMA in myofibroblasts,the tumor-associated fibroblasts,which is a sign of a reactive cancer matrix.TGF-β is a key cytokine that mediates this interaction,but its mechanism of development is still unclear.It has been shown that TGF-β1 may stimulate CLIC4 levels in normal tissue fibroblasts in breast cancer,ovarian cancer,colorectal cancer and other cancers.Therefore,CLIC4,TGF-β1 and α-SMA play important roles in the development and progression of cervical cancer.There may be a correlation among CLIC4,TGF-β1 and α-SMA in cervical cancer,but there are few reports about CLIC4 on cervical cancer in China.In this study we used immunohistochemical SP method to detect the expression of CLIC4,TGF-β1 and α-SMA in 117 samples of cervical cancer,48 samples of HSIL and 28 samples of chronic cervicitis,to analyze the the correlation of CLIC4,TGF-β1 and α-SMA and clinicopathological features of cervical cancerr.The relationship between cervical cancer cells and interstitial fibroblasts is helpful to the further reveal of the mechanism of invasion and metastasis of cervical cancer,which may provide new sensitive indicators for discovering the prognosis of cervical cancer.Materials and methods1.Study object:117 samples of cervical cancer tissue(Exclusion criteria: all the patients had no radiotherapy or chemotherapy before surgery),48 samples of HSIL(CINⅡ-Ⅱ)and 28 samples of chronic cervicitis tissue were collected from January 2014 to January 2015 from the Pathological specimen library of the first affiliated hospital of Zhengzhou University.All the histopathology were confirmed by diagnosis.117 cases of cervical cancer tissue were divided in groups according to age(median age 46,ranging from 29 to 70),clinical stage(FIGO,2012 : I 67,II 27),lymph node metastasis(without it 96,with it 21),pathological types(squamous cell carcinoma 99,adenocarcinoma18),histological differentiation(G1 64,G2 27,and G3 26),and infiltration depth(> 1/2 35,≤ 1/2 82).2.Immunohistochemistry was employed to measure the expression of CLIC4,TGF-β1 and α-SMA in cervical cancer,CIN and chronic cervicitis.The expression differences between the 3 groups were analyzed to explor the relationship between the expression and clinical pathological factors,and the correlation between the 3 proteins.4.Statistical analysis: SPSS statistical package program 21.0was used to analyse the experimental result.The comparison between positive rate between the different groups by chi-square test.The correlation of expression of CLIC4,TGF-β1 and α-SMA was analyzed by Spearman rank correlation analysis.P <0.05 for the difference was statistically significant Results1.The positive expression of CLIC4 in cervical cancer tissues was 76.92%(90/117),which mainly expressed in the cytoplasm or nucleus of the cancer stroma.The expression of CLIC4 in HSIL was 45.83%(22/48),which was mainly expressed in the cytoplasmic and interstitial cells.The expression of CLIC4 in chronic cervicitis tissue was 10.71%(3/28).The expression rate of CLIC4 in cervical cancer was significantly higher than that in HSIL tissues(P < 0.05)and chronic cervicitis tissue(P < 0.05).Higher CLIC4 expression was significantly correlated withdepth of invasion(χ2=8.48,P=0.009),lymph node metastisis(χ2=4.84,P=0.04)and clinical stages(χ2=8.41,P=0.001).But not associated with ages(χ2=0.33,P=0.66),high histological grade(χ2=2.50,P=0.12)and histopathologic type(χ2=1.08,P=0.37).2.The positive expression rate of TGF-β1 in cervical cancer tissues was 70.08%(82/117),which was mainly expressed on the cytoplasm or nucleus of cancer tissue,which was diffuse brownish yellow.The expression of TGF-β1 in HSIL was 47.91%(23/48),which was mainly expressed in the cytoplasmic and interstitial cells.The expression of TGF-β1 in chronic cervicitis tissue was 17.85%(5/28).The expression rate of TGF-β1 in cervical cancer was significantly higher than that in CIN tissues(P < 0.05)and chronic cervicitis tissue(P < 0.05).Higher TGF-β1 expression was significantly correlated withdepth of invasion(χ2=10.85,P=0.001),lymph node metastisis(χ2=5.08,P=0.03)and clinical stages(χ2=8.41,P=0.01),But not associated with ages(χ2=0.03,P=0.60),high histological grade(χ2=2.45,P=0.15)and histopathologic type(χ2=3.38,P=0.10).3.The positive expression rate of α-SMA in cervical cancer tissues was 97.43%(114/117),which was mainly expressed on the cytoplasm of cancer tissue,which was diffuse brownish yellow.The expression of α-SMA in HSIL was 47.91%(23/48),which was mainly expressed in the cytoplasmic and interstitial cells.The expression of α-SMA in chronic cervicitis tissue was 7.14%(2/28).The expression rate of α-SMA in cervical cancer was significantly higher than that in HSIL(P < 0.05)and chronic cervicitis tissue(P < 0.05).Higher α-SMA expression was significantly correlated withdepth of invasion(χ2=7.21,P=0.03)and lymph node metastisis(χ2=14.08,P=0.001),But not associated with ages(χ2=0.23,P=0.80),high histological grade(χ2=2.30,P=0.26),clinical stages(χ2=3.52,P=0.12),and histopathologic type(χ2=4.67,P=0.89).4.CLIC4 is a positive correlation with TGF-β(r = 0.625,P = 0.000)and α-SMA(r=0.624,P=0.000)in cervical cancer.Conclusion1.The expression of CLIC4,TGF-β1 and α-SMA in cervical cancer was significantly high.The expression of CLIC4,TGF-β1 and α-SMA increased gradually with the progress of cervical lesions,suggesting that CLIC4,TGF-β1 and α-SMA may be related to the development of cervical cancer.2.The expression of CLIC4 and TGF-β1 in cervical cancer was related to the FIGO staging,the lymph node metastasis and the depth of interstitial infiltration.The positive expression of α-SMA was related to the lymph node metastasis and the depth of interstitial infiltration,but not to age,histological type,FIGO staging or differentiation.The expression of CLIC4 and TGF-β1、 α-SMA in cervical cancer was positively correlated,suggesting that there may be synergistic effect in the three groups and participate in the invasion and metastasis of cervical cancer. |
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