Correlation between p14ARF/p16INK4A expression and HPV infection in uterine cervical cancer

The CDKN2A locus on human chromosome 9p21 encodes two tumor suppressors, p14ARF and p16INK4A, 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 p14ARF/p16INK4A 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 p14ARF mRNA in all 21 HPV-positive cases (100%). p16INK4A mRNA was overexpressed in 17 cases of the HPV-positive cases (81%). In four HPV-negative cancers, reduced expression of p14ARF mRNA was detected in two cases (50%) and reduced p16INK4A mRNA in three cases (75%). Our data indicate that the overexpression of p14ARF and p16INK4A strongly associates with HPV-positive cervical cancers and that reduced expression of p14ARF and p16INK4A correlates with HPV-negative cervical cancers. These findings may indicate that impaired p14ARF and p16INK4A 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.