Worldwide, cervical cancer is the second most common cancer in women; and is estimated to cause over 470,000 new cases and 233,000 deaths each year. Based on strong epidemiological evidence, supported by basic experimental findings, there is no doubt that persistent infections with high-risk types of human papillomavirus (HPV) represent a necessary cause of cervical cancer (Walboomers et al. 1999
). HPVs infect epithelial cells and cause a variety of lesions ranging from common warts to cervical neoplasia and cancer. Over 100 different HPV types have been identified so far, with a subset of these being classified as high risk. High-risk HPV DNA is found in almost all cervical cancers (>99.7%), with HPV16 being the most prevalent type in both low-grade disease and cervical neoplasia. Productive infection by high-risk HPV types is manifest as cervical flat warts or condyloma that shed infectious virions from their surface. Viral genomes are maintained as episomes in the basal layer, with viral gene expression being tightly controlled as the infected cells move towards the epithelial surface. The pattern of viral gene expression in low-grade cervical lesions resembles that seen in productive warts caused by other HPV types. High-grade neoplasia represents an abortive infection in which viral gene expression becomes deregulated, and the normal life cycle of the virus cannot be completed. Most cervical cancers arise within the cervical transformation zone at the squamous/columnar junction, and it has been suggested that this is a site where productive infection may be inefficiently supported (Doorbar, 2006
Although HPV infection is widespread, few people even know they are infected as the symptoms are seldom noticeable. It is even less well known is that nearly all cervical cancers (99.7%) are directly linked to previous infection with one or more of the oncogenic types of HPV (Walboomers et al. 1999
). It is estimated that for every 1 million women infected, a hundred thousand (about 10%) will develop precancerous changes in their cervical tissue. Of these, about 8% of them will develop early carcinoma limited to cervical epithelium (carcinoma in situ
; CIS) and a few of them will develop invasive cancer unless the precancerous lesions are detected and treated with such cases having been found to carry the oncogenic HPVs (e.g. types 16 and 18) that cause cervical cancer.
The HPV genome consists of 8 kb, and is a double-stranded DNA molecule. The relative arrangement of the 8–10 open reading frames (ORFs) within the genome is the same in all papillomavirus types, and a particular characteristic of papilloma viruses is that the partly overlapping ORFs are arranged on only one DNA strand. The genome can be divided into three regions: the long control region (LCR) without coding potential; the region of early proteins (E1–E8); and the region of late proteins (L1 and L2) (Walter and Philip, 2004). E6 and E7 are the most important oncogenic proteins. These proteins have pleiotropic functions, such as transmembrane signaling, regulation of the cell cycle, transformation of established cell lines, immortalization of primary cell line and regulation of chromosomal stability. Both E6 and E7 proteins can bind to multiple cellular targets. The interactions that are thought to be most relevant for their transforming functions are E6 binding, via the cellular protein E6-AP, to the tumor suppressor gene product p53, and E7 binding to the retinoblastoma tumor suppressor gene product pRb and its related pocket proteins, p107 and p130 (Dyson et al. 1989
; Davies, 1993
). The first interaction results in rapid ubiquitin-dependent proteolytic degradation of p53, which prevents cells from undergoing p53-mediated apoptosis (Thomas, 1999
). A consequence of E7-pRb interaction is interfering with cell cycle control. In combination, the E6-p53 and E7-pRb interactions seem to compromise the accuracy of mitosis. In addition, HPV E6 can activate the telomere lengthening enzyme telomerase independent of p53 binding, and E7 can induce abnormal centrosome duplication through a mechanism independent of inactivation of pRb and its family member. It is likely that these latter properties also contribute to the transforming characteristic of these viral oncoproteins.
HPV infection causes changes in expression of host cervical cell cycle regulatory proteins. Such differentially expressed host proteins and nucleic acids may have a role as ‘biomarker’ of dysplastic cells. Investigation of potential biomarkers may also help to unravel new pathways involved in the HPV-mediated pathogenesis of cervical dyskaryosis.