Skp2, p27kip1 and EGFR assessment in head and neck squamous cell carcinoma: Prognostic implications

Abstract

Abstract. EGFR, p27kip1 and Skp2, have been implicated in human cancer development. We have studied these molecules in a search for molecular markers that may have prognostic value in head and neck squamous cell carcinomas (HNSCC). Tissue samples of 62 patients were collected and immunohistochemical analysis was carried out for p27 kip1 , Skp2 and EGFR protein evaluation. Western blot analysis of p27 kip1 was performed. The p27 kip1 expression is frequently down-regulated in HNSCC (44.4%, 20/45 cases). The immunohistochemical analysis showed p27 kip1 cytoplasmic retention in 7/38 tumors. Strong Skp2 signals were detected at the invasive edge of the tumor in cells lacking p27 kip1 staining. We found a high EGFR staining in 49% (23/47) of the cases. The staining tended to be more frequent in lymph node-positive cases. The dysplastic tissue exhibited no Skp2 immunoreactivity, whereas 51.06% (24/47) of invasive tumors expressed high levels. Of note is that Skp2 overexpression was the only factor that significantly correlated with a shorter overall survival in multivariate analysis (p=0.048). Our results suggest that Skp2 is a useful prognostic marker for HNSCC management. IntroductionHead and neck squamous cell carcinoma (HNSCC) remains a significant cause of morbidity and mortality, afflicting 500,000 new cases worldwide each year (1). The clinical course of these tumors cannot be completely predicted by clinicopathological features. Therefore, new molecular markers that can be used for a more accurate clinical management of these tumors are needed (2).Cell cycle progression is governed by cyclin-dependent kinases (cdks) that are regulated by phosphorylation, cyclin binding and cdk inhibitors. The coordinated expression of cyclins, cdks and cdk inhibitors is often deregulated in cancer. The cdk inhibitor p27 kip1 regulates cellular progression from G 1 to S phase (3). The inactivation of p27 kip1 has been implicated in the development of a broad range of human malignancies suggesting that it plays an important role in human cancer pathogenesis (4-11).The regulation of p27 kip1 expression occurs predominately at the post-translational level by a ubiquitin-proteasomedependent degradation mechanism. Skp2 is a rate-limiting component of this machinery (12) and it plays a critical role in the regulation of p27 kip1 , a key mediator of PTEN-induced G 1 arrest, through the PI 3-K/Akt/PTEN pathway (13). Skp2 overexpression has been observed in various types of human tumors (14). The p27 kip1 and Skp2 levels are inversely correlated in colorectal cancer (15). These findings suggest that the enhanced p27 kip1 degradation observed in many aggressive human tumors is attributable to increased levels of Skp2. However, not all aggressive cancers exhibit low p27 kip1 expression levels. The inactivation of p27 kip1 may also occur at cytoplasmic retention as a consequence of p27 kip1 phosphorylation by Akt and its binding to 14-3-3 (16). This mechanism has been associated with a poor patient outcome in breast cancer (17). Additional...

Prognostic significance of cytoplasmic p27 in oral squamous cell carcinoma

“…colon cancer, ovarian cancer, Barrett‐associated adenocarcinoma and malignant peripheral nerve sheath tumour . Two studies on OSCC have reported a diffuse cytoplasmic staining in occasional tumour cells, although nuclear staining was predominant . However, scoring of this cytoplasmic p27 staining and correlation with survival were not performed by them.…”

Correlation between Skp2 expression and nodal metastasis in Stage I and II oral squamous cell carcinomas

“…However, an important element emerges from the present data: patients who presented Skp2 values greater than 20% deceased within 3 years from surgery. The previous studies demonstrated a strong correlation between Skp2 overexpression, metastatic capability of the tumour and a decrease in overall survival (Harada et al , 2005a,b; Carracedo et al , 2008).…”

“…The cyclin/CDK complexes are activated by means of phosphorylation which is carried out by CDK activating kinases (CAK) and that, in turn, are negatively regulated by diverse CDK inhibitors (CDIs) (Toyoshima and Hunter, 1994; Sherr, 1996). The expression of cyclins, CDKs and CDIs, which is finely coordinated in non‐pathological conditions, is often deregulated in tumours (Carracedo et al , 2008). The role played by p27 is that of a negative regulator of G0/G1 phase and a low expression of this protein is associated with disease progression (Hunter and Pines, 1994; Toyoshima and Hunter, 1994).…”

Secretion of inflammatory and regulatory cytokines and the association with depth and type of tumour invasion in patients with cancer of the larynx

“…W dostępnym piśmiennictwie można znaleźć prace, w których autorzy wskazują na rolę wielu biomarkerów związanych m.in. z regulacją cyklu komórkowego, p27kip1, Skp2, Ki67, jako potencjalnych wskaźników inwazyjności zmian, determinujących rokowanie oraz wybór właściwego postępowania terapeutycznego [1][2][3][4][5][6]. Wśród publikacji dotyczących tego tematu można jednak wskazać prace, które nie potwierdzają roli wspomnianych wykładników jako niezależnych wskaźników agresywności wzrostu nowotworu i czynników o znaczeniu prognostycznym [7][8][9].…”