Oncology: A very early warning
Published online 24 November 2010
The human papillomavirus protein E2 may serve as a diagnostic marker for cervical intraepithelial neoplasia, the precursor stages of cervical cancer
Fig. 1: E2 expression (stained brown) in clinical samples of precancerous HPV16-infected cervical tissue. The tissue is in an intermediate stage between CIN1 (left, higher E2 expression) and CIN2 (right, lower E2 expression).
Cervical cancer is one of the most common cancers affecting women, and high-risk human papillomavirus type 16 (HPV16) and type 18 (HPV18) are responsible for causing 70% of cervical cancer cases worldwide. Cervical cancer does not develop overnight. Cells that form the surface (epithelium) of the cervix must go through a series of changes in order to become cancerous. The precancerous phase, known as cervical intraepithelial neoplasia (CIN), could take years to develop.
There are three grades of CIN: CIN1, CIN2 and CIN3. CIN1 corresponds to the earliest stage of CIN just after viral infection when the majority of epithelial cells are still normally differentiated, whereas CIN3 corresponds to the final stage of CIN prior to cancer formation when the majority of epithelial cells have become abnormally ‘dedifferentiated’.
Intensive research on HPV16 and HPV18 has provided extensive knowledge on the roles of viral genes and proteins in cancer formation, but little information regarding CIN progression. Françoise Thierry at the A*STAR Institute of Medical Biology and co-workers1 have now shown that the viral gene E2 plays a crucial role in CIN progression. They also suggested that E2—the protein encoded by the E2 gene—may serve as a diagnostic marker for CIN, which is useful for the early prevention of cervical cancer.
The researchers analyzed the gene expression of 99 cervical biopsy specimens, including 5 normal tissues, as well as 35 CIN1, 31 CIN2 and 28 CIN3 lesions. They found that viral proteins E2 and E7 were expressed at high levels in a mutually exclusive manner; CIN1 lesions expressed high levels of E2 but not of E7, whereas CIN2 and CIN3 lesions expressed high levels of E7 but not of E2 (Fig. 1). They also showed that E2 was expressed at high levels in cells forming the intermediate and upper layers of CIN1 lesions where viral DNA replication occurs, but not in cells forming the basal layers where genome integration should occur.
HPV16 and HPV18 are known to use viral proteins E6 and E7 to inactivate tumor-suppressor proteins p53 and pRb. Previous studies have suggested that the viral protein E2 is a repressor of viral gene E6 and E7 transcription and an activator of viral replication. The findings from this study are in good agreement with these assumptions.
E7 is widely used as a diagnostic marker for CIN2 and CIN3. There is currently no diagnostic marker for CIN1 or HPV infection and its progression. The researchers believe that the E2 protein, which is highly expressed in CIN1 lesions, may serve this purpose, providing the earliest warning of abnormal cervical cell growth and serving as a predictive marker for progression versus regression.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Medical Biology
- Xue, Y. et al. HPV16 E2 is an immediate early marker of viral infection, preceding E7 expression in precursor structures of cervical carcinoma. Cancer Research 70, 5316–5325 (2010). | article