Retinoblastoma protein function and p16INK4a expression in actinic keratosis, squamous cell carcinoma in situ and invasive squamous cell carcinoma of the skin and links between p16INK4a expression and infiltrative behavior

Abstract

p16 INK4a is involved in many important regulatory events in the cell and the expression and function is closely associated with the retinoblastoma protein (Rb). Earlier, we have in colorectal cancer and in basal cell carcinoma showed that p16 INK4a is upregulated at the invasive front causing cell cycle arrest in infiltrative tumor cells via a functional Rb. This role for p16 INK4a as a regulator of proliferation when tumor cells infiltrate might besides a general cyclin-dependent kinase (cdk) inhibitory effect explain why p16 INK4a is deregulated in many tumor forms. The expression pattern of p16 INK4a in relation to Rb-function in squamous cancer and precancerous forms of the skin has not been fully detailed. We therefore characterized the expression of p16 INK4a , Rb-phosphorylation and proliferation in actinic keratosis, squamous cell carcinoma in situ and invasive squamous cell carcinoma with special reference to infiltrative behavior. The expression of p16 INK4a varied between the lesions, with weak and cytoplasmic p16 INK4a expression and functional Rb in actinic keratosis. Strong nuclear and cytoplasmic p16 INK4a expression was observed in all carcinomas in situ in parallel with lack of Rb-phosphorylation but high proliferation indicating a nonfunctional Rb. Invasive squamous carcinoma showed a mixed p16 INK4a expression pattern where some tumors had strong cytoplasmic p16 INK4a expression, large fraction of Rb-phosphorylated cells and high proliferation. Interestingly, despite this disability of p16 INK4a to inhibit proliferation there was an upregulation of cytoplasmic p16 INK4a in infiltrative cells compared to tumor cells towards the tumor center. A similar scenario but strong and combined nuclear and cytoplasmic p16 INK4a expression in infiltrative cells, was observed in other invasive squamous cancers. This suggests that the p16 INK4a upregulation in infiltrative cells is governed independently of the subcellular localization or of the potential to affect proliferation via Rb, and suggests a potentially proliferation independent function for p16 INK4a in infiltrative behavior.

Correlations Between Prognosis and Regional Biomarker Profiles in Head and Neck Squamous Cell Carcinomas

“…p16 ink4 inhibits cyclin dependent kinase (cdk) 4/6, which prevents the formation of the active cyclin D-cdk4/6 complex and early cell cycle progression. The lack of cyclin D mediated phosphorylation of the retinoblastoma (Rb) protein results in the inactivation of the cell cycle in phase G1 [17]. Several reports suggest that reduced expression or the lack of p16 ink4 protein correlates with poor prognosis of HNSCC [18,19], which we confirmed in our tested patient cohort.…”

p16Ink4a overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors

“…The second pattern is characterized by a very low p16 Ink4a immunostaining in normal mucosa, with a progressively higher expression in aberrant crypt foci, non-serrated adenomas, primary carcinomas and metastatic tumors (Dai et al, 2000;Zhao et al, 2006). A similar pattern has been observed in skin where p16 Ink4a expression increases from relatively low levels in pre-malignant lesions (actinic keratosis) to high levels in in situ and infiltrating carcinomas (Nilsson et al, 2004), and in breast tissues where negative or low expression is seen in normal ductal epithelium, together with a progressive increase in benign lesions and carcinoma (Milde-Langosch et al, 2001;Di Vinci et al, 2005). Furthermore, increased nuclear p16 Ink4a protein expression compared with normal epithelium has been demonstrated in preneoplastic and tumor tissues of the gallbladder (Lynch et al, 2008).…”

Differential Biomarker Expression in Head and Neck Cancer Correlates with Anatomical Localization

“…The initial cyclin D-associated phosphorylation of the retinoblastoma protein (Rb), fundamental for cell cycle progression, is therefore inhibited resulting in a G1-arrest [12]. Many early cancers of head and neck show the loss of the chromosomal region which causes the inactivation of p16 ink4 .…”