Overexpression of p16 and p14ARF is associated with human papillomavirus infection in cervical squamous cell carcinoma and dysplasia

Abstract

The CDKN2 gene encodes two structurally different proteins: a cyclin-dependent kinase inhibitor, p16, which regulates retinoblastoma protein (pRb)-dependent G1 arrest, and a cell cycle inhibitor, p14ARF, which blocks MDM2-induced p53 degradation resulting in an increase in p53 levels that leads to cell cycle arrest. Recent studies have revealed that expression of p16 and p14ARF is influenced markedly by the status of pRb and p53, and p16 overexpression has been demonstrated in cervical neoplasia because of functional inactivation of pRb by the human papillomavirus (HPV) E7 protein. To clarify the p14ARF status and the relationship between p16/p14ARF and other cell cycle molecules in cervical carcinogenesis, immunohistochemical analysis of p16, p14ARF, p53 and MDM2 was performed on 65 samples of cervical and genital condylomatous and neoplastic lesions, including nine HPV-negative tumors. In most cervical cancers and preneoplastic lesions with HPV infection of high and intermediate risk, a marked overexpression of p14ARF as well as the p16 protein (i.e. dotted nuclear immunostaining) was observed. All condyloma acuminata except one and low-grade dysplasia with HPV infection of low risk, such as HPV 6, immunohistochemically showed completely negative staining for p14ARF, also seen in non-neoplastic and mesenchymal cells. Our results clearly show that the mode of p14ARF overexpression in cervical neoplastic cells with HPV association differs from that in cancers of other organs without HPV association, and the p14ARF overexpression may be attributable to a negative feedback result in the functional inactivation of the pRb and p53 proteins by HPV oncoproteins.

Senescence and apoptosis in carcinogenesis of cervical squamous carcinoma

“…INK4a and p14 ARF confirm previous reports that these markers are overexpressed in cervical carcinomas [20][21][22] and are consistent with a compensatory mechanism activated in response to direct interference p53 and pRb by the E6 and E7 HPV oncoproteins.…”

Quercetin elevates p27Kip1 and arrests both primary and HPV16 E6/E7 transformed human keratinocytes in G1

“…Additional confirmation of E7 expression was provided by the increase in p16 INK4a (Figure 1b), which is correlated to E7 expression (Sano et al, 2002).…”

“…INK4a has been correlated to E7 expression in cervical cancer samples (Sano et al, 2002). Quercetin treatment lead to a reduction of p16…”

Expression of p14ARF, p15INK4b, p16INK4a and skp2 increases during esophageal squamous cell cancer progression

“…The inactivation of senescence markers, due to homozygous deletion or hypermethylation of the genes which encode them, may be a significant mechanism in the dysfunction of the Rb and p53 growth regulation pathways during ESCC development (30). However, it has been reported that the senescence pathway remains intact in a large number of prostate cancer and cervical squamous carcinoma cases (31) even if the ki-67 index indicates increased proliferation in these cancers. Zhang et al found that the senescence markers p14 ARF , p15 INK4b , p16…”