Dr. G. Paolo Dotto and colleagues have found that the decreased expression of a single gene, called Notch1, is instrumental in the late stages of human papilloma virus-induced cervical cancer. The report is published in the September 1 issue of Genes & Development.
Human papilloma virus (HPV) is the most prevalent sexually transmitted infection in the world, and HPV infection is associated with the majority of the 400,000 new cervical cancer cases reported annually. Previous genetic studies have, to some degree, elucidated the molecular mechanism of HPV-induced cervical carcinogenesis: The HPV genome encodes two viral proteins, E6 and E7, which interfere with two of the infected cell's primary tumor suppressor pathways (p53 and Rb). However, it is thought that while basal levels of E6/7 expression are necessary for HPV-induced cervical tumorigenesis, other genetic changes are needed to fully transform a normal cervical cell into a malignant one.
Dr. Dotto and colleagues have identified one such change.
Dr. Dotto and colleagues have discovered that the down-regulation of a cell signaling molecule, called Notch1, in HPV-infected cervical cells allows for the increased expression of E6 and E7, which, in turn, promote malignant cervical cell transformation. The researchers found that in low-grade HPV-positive cervical lesions, Notch1 is expressed at an adequate level to suppress E6 and E7, and thereby protects the cell against HPV-induced transformation. However, in high-grade HPV-positive cervical lesions, Notch1 expression is markedly decreased, relieving the suppression of E6 and E7 activity, and creating the correct genetic milieu for malignant cell transformation.