The review of six early genes encoded by the human papillomavirus (hpv) viral genome in incidence cervical cancer

Zahra Baghersad,1,*

1. Master of midwifery, School of Nursing and Midwifery, Isfahan University of Medical Sciences, Isfahan, Iran



Infection by human papillomavirus (hpv) is a major etiological factor associated with cervical–uterine cancer, though cancer incidence in infected women is low. although, it is predicted that stem cells are the target of hpv oncogenes during cancer initiation, viral replication and expression of major hpv oncogenes (e.g., e6, e7) occur in the suprabasal layers of the growing epithelium to ensure a productive infection. neoplasias of the genital tract include cervical (cin) and a fraction of these neoplasias progresses to invasive cancers. hpv infection is detected in almost all cervical, half of the vulvar and approximately 70% of cervical tumors. the present study aimed to define the review of six early genes encoded by the hpv viral genome in incidence cervical cancer.


This study is a review (review article) analysis was performed of systematically using keywords "human papillomavirus, cervical cancer, cin, hpv oncogenes" in information resources "pubmed, up to date, google scholar, biomed, wiley online library, elsevier" among 1995 to 2018 years and found 74 articles and 3 theses were connected with topics that that have been used of full-text articles.


There are six early genes that are encoded by the hpv viral genome. the e6 and e7 proteins are expressed from the p97 promoter and are viral oncogenic proteins. the e6 protein binds to the p53 tumour suppressor in host cells, causing ubiquitination and degradation of p53 and thereby preventing growth arrest. the e7 protein binds to the retinoblastoma protein (prb) tumour suppressor and disrupts the interaction between prb and the e2f family of transcription factors. this then allows e2f to transactivate its target genes, many of which are necessary for dna replication. together, e6 and e7 control cell proliferation and are primarily responsible for the expansion of infected cells. the e1 and e2 proteins are expressed from the p670 promoter and serve as regulatory proteins and are required for viral replication27. the e2 protein is a dna-binding protein that binds near the viral origin and recruits the e1 helicase to the viral origin. e2 also has the ability to act as a transcription factor by regulating the p97 promoter and thus, e6 and e7 gene expression. lastly, the e4 and e5 proteins are also involved in viral genome amplification although the e1 and e2 proteins play a more important role. the phenotype of the cervical neoplasia was suggested to vary depending on the expression levels of e6 and e7 were suggested to increase from cervical intraepithelial neoplasia grade 1 to 3 (cin1 to cin3). these interactions of hpv proteins with cellular pathways of the host cell will give a chance for potential targets for hpv based cancer treatment strategies. additionally, e2 gene is also believed to take a part in cervical cancer since in about 35% of hpv induced cervical cancers full length viral genomes are expressed regulation of gene expression is changed when the viral dna integrates with the cell chromosomes. this integration leads to a continuous expression of e6 and e7 proteins causing accumulation of mutations of the cellular dna and promoting malignancies.


These accumulations of mutations, mostly monosomies, trisomies, structural changes, chromatid gaps and breaks and double minutes, are often detected in cervical cancers as well as other epithelial tumors. increased expression levels of e6 and e7 in high-risk hpv type infections causes cin2+ phenotypes. this phenotype leads genetic changes that contribute to cancer progression. these suggest that low expression levels of e6 and e7 does not affect the function of the cellular targets in cin1 and therefore does not contribute to cancer progression. in cin2/ cin3+, the viral deregulation assists the viral episome into the host cell chromosome. this may further cause deregulation of e6 and e7 expression. in clinical vaccine trials it was shown that young women can have cin2+ soon after infection. for these cases, it is possible that deregulation of the gene expression is due to cell signaling changes or epigenetic modifications, such as viral dna methylation. an important step has been taken towards prevention of hpv induced cervical cancers with the use of vaccines against hpv. however, due to various reasons, including the unavailability of the vaccines in certain regions of the world or the high costs of the vaccines, the wide application of the vaccines is not available. therefore, in case of cervical cancer development, early detection strategies and treatment play a vital role to prevent any deaths. the treatment for the early cervical cancers is usually performed by conisation or radical hysterectomy. for the more advanced tumors, cisplatin based chemo-radiotherapy is preferred that results in 65-80% survival rates. surgical excisions are usually the standard for the hpv associated anogenital lesions. the treatment strategy for cin is to eliminate the abnormal hpv infected precancerous cells and maintain the cervical integrity. one of the most commonly used treatments for cin involves loop electrosurgical excision procedure, electrofulgaration and cryotherapy.


Hpv, cervical cancer, cin, hpv oncogenes.