Correlation between p14(ARF)/p16(INK4A) expression and HPV infection in uterine cervical cancer.
The CDKN2A locus on human chromosome 9p21 encodes two tumor suppressors, p14(ARF) and p16(INK4A), which enhance the growth-suppressive functions of the retinoblastoma (Rb) and the p53 proteins, respectively. Conversely, the E6 and E7 oncoproteins of the high-risk human papillomaviruses (HPVs) causally associated with carcinogenesis of the uterine cervix contributes to tumor development by inactivating p53 and Rb. Nevertheless, a correlation between expression of p14(ARF)/p16(INK4A) and HPV infection in uterine cervix is less clear. To clarify this, we examined 25 cervical cancers and 11 normal uterine cervixes. HPV was detected in 21 of 25 cervical cancers (84%) and their subtype was determined by PCR-RFLP. Quantitative real-time RT-PCR assays showed overexpression of p14(ARF) mRNA in all 21 HPV-positive cases (100%). p16(INK4A) mRNA was overexpressed in 17 cases of the HPV-positive cases (81%). In four HPV-negative cancers, reduced expression of p14(ARF) mRNA was detected in two cases (50%) and reduced p16(INK4A) mRNA in three cases (75%). Our data indicate that the overexpression of p14(ARF) and p16(INK4A) strongly associates with HPV-positive cervical cancers and that reduced expression of p14(ARF) and p16(INK4A) correlates with HPV-negative cervical cancers. These findings may indicate that impaired p14(ARF) and p16(INK4A) mRNA expression contribute to tumor development in HPV-negative cervical cancers by failure to support p53 and Rb instead of their inactivation by HPV E6 and E7.
Department of Obstetrics and Gynecology, Osaka University Faculty of Medicine, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan.
Hiroyuki
H
Kanao
Takayuki
T
Enomoto
Yutaka
Y
Ueda
Masami
M
Fujita
Ryuichi
R
Nakashima
Yuko
Y
Ueno
Takashi
T
Miyatake
Tatsuo
T
Yoshizaki
Gregory S
GS
Buzard
Toshihiro
T
Kimura
Kiyoshi
K
Yoshino
Yuji
Y
Murata
D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000821:virology*; D002471:Cell Transformation, Neoplastic; D002899:Chromosomes, Human, Pair 9; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis*; D017931:DNA Primers; D005260:Female; D006801:Humans; D027383:Papillomaviridae / Q000472:pathogenicity*; D030361:Papillomavirus Infections / Q000150:complications*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012333:RNA, Messenger / Q000096:biosynthesis; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000378:metabolism; D012307:Risk Factors; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53