HPV infection and the alterations of the pRB pathway in oral carcinogenesis

Abstract

Abstract. Inactivation of the retinoblastoma (pRB) pathway is a common event in oral squamous cell carcinoma particularly through the aberrant expression of the components within this pathway. This study examines the alterations of molecules within the pRB pathway by looking at the presence of homozygous deletions in p16INK4A and the expression patterns of pRB, cyclin D1 and CDK4, as well as the presence of human papillomavirus (HPV) in our samples. In our study, 5/20 samples demonstrated deletions of p16 INK4A exon 1α. pRB overexpression was found in 20/20 samples, the expression was mainly observed in all layers of the epithelia, particularly in the basal layer where cells are actively dividing and aberrant pRB expression was found in 12/20 samples. Cyclin D1 and CDK4 overexpression was detected in 6/20 and 2/20 samples respectively in comparison to hyperplasias where both proteins were either not expressed or expressed at minimal levels (<10%). Strikingly, HPV was found to be present in all of our samples, suggesting that HPV plays a significant role in driving oral carcinogenesis. Notably, 17/20 of our samples showed more than one alteration in the pRB pathway, however, we did not find any significant relationship between the presence of HPV, homozygous deletion of p16 INK4A and overexpression of pRB, cyclin D1 and CDK4. Collectively, this data demonstrates that alterations in the pRB pathway are a common event and involve the aberration of more than one molecule within the pathway. Furthermore, the involvement of HPV in all our samples suggests that HPV infection may play an important role in oral carcinogenesis.

High-Risk HPV, Biomarkers, and Outcome in Matched Cohorts of Head and Neck Cancer Patients Positive and Negative for HIV

“…RB expression was also low in most of the HPV-positive tumors, which is consistent with HPV viral oncogene expression (31, 32). Only one control HPV-positive tumor expressed moderate RB (UM1349, RB score= 11).…”

High-risk human papillomavirus (HPV) is not associated with p53 and bcl-2 expression in oral squamous cell carcinomas

“…This suggests a role of HPV in the etiology of at least some cases of squamous cell carcinomas affecting the oral cavity in our sample, or even attribute to the virus a synergistic action with other important carcinogens such as smoking and alcohol; thus potentiating the effects of these agents and significantly contributing to etiology of some malignant tumors of the mouth. Some studies using other oncogenic markers as those involved in the pRb pathway support this evidence [4,26,31,32].…”

“…In contrast, Grace et al [17] believe that the inactivation of p53 by oncoprotein E6 of high-risk HPVs reverses the repression of bcl-2, causing overexpression of both proteins in uterine cervix carcinomas. It is also possible that other genes, such as cyclin D1 and p16 which are frequently altered in head and neck tumors, and HPV oncoproteins cooperate in the dysregulation of the cell cycle in some tumors and act independently on others [4,7,32]. Thus, these findings suggest that p53 inactivation by mutation and by HPV infection and the altered expression of oncoprotein bcl-2 are important genetic events in the development of oral carcinomas, but are not mutually exclusive events, which can coexist in these tumors.…”

High‐risk human papillomavirus in oral squamous cell carcinoma of young patients

“…However, in younger patients, the role of these factors is uncertain due to the short time of exposure 4, 5. Some studies have reported that high‐risk human papillomavirus (HR‐HPV) infection might exert an important role in carcinogenesis in this group 6–11. HR‐HPVs, especially HPV16 and HPV18 are considered a major cause of certain human cancers; they are responsible for all cervical cancers and about 50% of other anogenital cancers 12.…”