High level HPV-16 E7 oncoprotein expression correlates with reduced pRb-levels in cervical biopsies (original) (raw)

High-risk human papillomaviruses (HPVs) are major etiological agents of cervical cancer. Despite excellent epidemiological evidence for a direct role of HPV-16 in cervical carcinogenesis, molecular pathways underlying carcinogenesis in vivo remain obscure. The E7 gene is required for immortalization and maintenance of the transformed phenotype in vitro; however, little is known about its role for tumorigenesis in vivo. The E7 gene codes for an unstable protein the abundance of which in cervical biopsies is unknown. We show here that E7 protein levels strongly increase during cervical carcinogenesis, underlining its fundamental role in cervical cancer. The E7 protein was found predominantly in the nucleus and to a minor extent in the cytoplasm in the cervical cancer cell line Ca Ski in vitro and in invasive cervical carcinoma in situ, suggesting that nuclear resident E7 plays a major role in cervical carcinogenesis in humans. The retinoblastoma protein (pRb) is a major E7-target in vitro. We show here that pRb expression is initially upregulated in LSIL and disappears in later stages concomitant with increased E7 levels, suggesting that E7-driven degradation of pRb is involved in cervical tumorigenesis in humans. Key words: cervical cancer • retinoblastoma protein • SIL • anti-HPV-16 E7 antibodies uman papillomaviruses (HPVs) are the main etiological factor for cervical cancer (1). HPVs are small DNA viruses that infect basal proliferating epithelial cells of either the skin or mucosa of which >100 different HPV genotypes have been described to date. On the basis of epidemiological and biochemical data, the mucosal genotypes are subdivided into two groups. HPVs of the high-risk group are associated with squamous intraepithelial lesions with a high potential for progression to invasive squamous cell carcinoma, whereas papillomaviruses of the low-risk group cause benign hyperplasias (2). PCR-based studies have shown that >99% of invasive cervical cancers contain high-risk HPV-DNA and HPV-16 is the most prevalent type with an incidence of ~53% (3). H