Fas-mediated pathway and apoptosis in normal cervix, cervical intraepithelial neoplasia and cervical squamous cancer

The aim of this study was to examine the expression patterns of apoptosis-related antigens, such as Fas, FasL, and cFLIP, in cervical squamous cells, and investigate the role of Fas-mediated apoptosis in the pathogenesis of cervical neoplasia. Using specific antibodies for Fas, FasL, and cFLIP, we examined protein expression in 19 specimens of normal cervix, 15 mild dysplasia (CIN I), 22 moderate dysplasia (CIN II), 23 severe dysplasia (CIN III), and 34 invasive squamous cell carcinoma (SCC) by immunohistochemistry. We detected the apoptotic indices by TUNEL in the same specimens. Fas expression levels were quite similar in CIN I, CIN II and the normal cervix. Though Fas expression tended to increase in grade 2 cancer compared to grade 1 cancer and CIN III, and a slight decline was present in grade 3 compared with grade 2 cancer, these differences did not reach statistical significance. Almost all CINs did not express FasL, while FasL expression increased with the grade of the tumor. Statistically significant differences could be observed between grade 1 and grade 2 (p<0.01) and between grade 2 plus grade 3 and grade 1 (p<0.001). All cases of normal cervix and CIN, except two cases of CIN III, did not express cFLIP. cFLIP expression tended to increase with the grade of the tumor. Apoptosis was determined in all samples by TUNEL. There was a decreasing tendency of apoptotic cells from normal cervix to cancers. A negative correlation between cFLIP and apoptosis (r=−0.499 and p=0.000) was observed. Deregulated Fas/FasL system and constitutive expression of cFLIP in SCC may be an important mechanism by which SCCs escape apoptosis during the malignant transformation and progression of these tumors.