Expression of cyclin-dependent kinase inhibitors p16MTS1, p21WAF1, and p27KIP1 in HPV-positive and HPV-negative cervical adenocarcinomas

Abstract

Inactivation or down-regulation of the cell-cycle inhibitors p16MTS1, p21WAF1, and p27KIP1 is involved in the carcinogenesis of various human tumors. In cervical squamous cell carcinomas that are associated with human papillomavirus (HPV) infection, the expression or function of these proteins is impaired by the action of viral oncoproteins E6 and E7. Comparably less is known about the role of these cyclin-dependent kinase inhibitors in cervical adenocarcinomas, 15-40% of which are HPV negative. Therefore, we studied the expression of p16MTS1, p21WAF1, and p27KIP1 by immunohistochemistry in 60 cervical adenocarcinomas. HPV infection was determined by PCR, and HPV 16 and 18 E6/E7 oncogene expression was analyzed by RNA-RNA in situ hybridization. We found significant correlations of strong p16 expression with HPV 16/18 infection and HPV 16/18 E6/E7 oncogene expression (P=0.001). Moderate or strong p16 expression was also observed in 41% of HPV-negative carcinomas, indicating that HPV-independent mechanisms might also lead to p16 overexpression. In addition, stronger p21 and p27 expression was significantly associated with the detection of HPV 16 or 18 E6/E7 transcripts (P=0.015 and 0.030, respectively). Obviously, the tumor suppressor action of these proteins can be overcome in HPV-positive lesions. In contrast, absent or low p16, p21, and p27 immunostaining was observed in most HPV-negative cervical adenocarcinomas and might contribute to carcinogenesis in these tumors.

Relationship among human papillomavirus infection, p16INK4a, p53 and NF-κB activation in penile cancer from northern Thailand

“…Therefore, overexpression of p16 INK4a is suggested to be a useful marker for evaluating HPV activity in cancer lesions and its precursors (6,9). The overexpression frequency of p16 INK4a was reported to be 55-97% in cervical squamous cell carcinoma (6-8) and 48-80% in cervical adenocarcinoma (28,29). The overexpression frequency of p16 INK4a was previously reported to be 29-50% in penile squamous cell carcinoma (9,10).…”

Correlation of p16INK4A expression and HPV copy number with cellular FTIR spectroscopic signatures of cervical cancer cells

“…There were, however, differences in the band intensities. A distinctive reduction of 50 lipids was noticed in the IR signal of the cytoplasm compared to the signal of the nucleus, manifest in the CH 2 and CH 3 groups stretching bands in the range of 2850cm -1 -2970cm -1 , due to the double lipid bilayer nuclear envelope, compared to the phospholipid bilayer membrane of the cytoplasm. 55 Furthermore, the peak at 1120cm -1 is present only in the cytoplasm.…”

“…All cell lines were grown in RPMI 1640 medium (Sigma-Aldrich, Ireland) supplemented with 10% Foetal 50 Bovine Serum (FBS, BioWhittaker®, Lonza, Ireland), 1% Penicillin-Streptomycin (BioWhittaker®, Lonza, Ireland), 1% L-glutamine (Sigma-Aldrich, Ireland), and 0.2% Hydrocortisone (Sigma-Aldrich, Ireland). Cells were incubated at 37°C in 5% CO2 and maintained up to 70-80% 55 confluency.…”

“…Putative biomarkers of cervical cancer that are currently under study include proteins such as CDC 6 (DNA licensing protein), minichromosome maintenance proteins (MCM 2, MCM 5), p53 or p16 INK4A 5 . These biomarkers have 50 been used to detect the presence of abnormal cells, based upon immunocytochemical methods. p16 INK4A regulates the levels of active cyclin D/CDK in the cell, providing a feedback mechanism that regulates the levels of MCM (minichromosome maintenance proteins), PCNA 55 (proliferating-cell nuclear antigen) and cyclin E. Overexpression of p16 INK4A , which is considered a marker of elevated E7 expression, can be detected in some CIN1 (Cervical Intraepithelial Neoplasia grade 1) lesions, as well as in CIN2 and CIN3 lesions that show evidence of integration 6-60 7 .…”

Role of HPV in Urothelial Carcinogenesis: Current State of the Problem

“…This phenomenon formed experimental grounds for the immunohistochemical test which is currently widely applied in early CC diagnostics (Klaes et al, 2001(Klaes et al, , 2002Milde-Langosch et al, 2001;Volgareva et al, 2002Volgareva et al, , 2004Volgareva et al, , 2006. This test is becoming popular in diagnostics of HR-HPV-associated carcinomas of other localizations (Begum et al, 2007;Kim et al, 2007).…”