The relationship between c-FLIP expression and human papillomavirus E2 gene disruption in cervical carcinogenesis.
OBJECTIVE
Human papillomavirus (HPV) is the essential causative factor in cervical carcinogenesis, and apoptosis inhibition is one of the key features of HPV-induced malignant transformation. This study is to investigate the possible cause-effect association between high-risk HPV and cellular FLICE-like inhibitory protein (c-FLIP), an important apoptosis regulator, during cervical carcinogenesis.


METHODS
A series of 80 archival samples, including 20 squamous cervical carcinomas (SCC) 54 cervical intraepithelial neoplasia (CIN) lesions and 6 normal cervical tissues, were subjected for c-FLIP immunohistochemical staining and HPV HC-II analysis. Typing HPV-16 infection was analyzed by the polymerase chain reaction (PCR), and its status was assessed with the integrity and disruption of the HPV-16 E2 gene, which was amplified in three overlapping fragments.


RESULTS
The types of HR-HPV infection and E2 disruption were associated closely with cervical lesion severity. There was a significant relationship between lesion grade and c-FLIP expression level. c-FLIP overexpression was also closely associated with HR-HPV infection and its integration status. Multivariate regression analysis revealed c-FLIP as a strong independent predictor for CIN, with 100% PPV, and showed 90.9% PPV in detecting HR-HPV, and remained a significance factor to rule out which case has no HR-HPV integration, with a 94.7% sensitivity and a 90.0% NPV.


CONCLUSIONS
The present data approved that c-FLIP overexpression is related significantly to the presence of HR-HPV infection and its integration status during progression of cervical squamous cell cancer and confirmed the role of c-FLIP as an early marker of cervical carcinogenesis.
Wang
Wei
W
Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China.
Wang
Shixuan
S
Song
Xingfu
X
Sima
Ni
N
Xu
Xinhua
X
Luo
Aiyue
A
Chen
Gang
G
Deng
Dongrei
D
Xu
Qian
Q
Meng
Li
L
Lu
Yunping
Y
Ma
Ding
D
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis* / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D052162:Human papillomavirus 16 / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D030361:Papillomavirus Infections / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral