Prognostic significance of p21WAF1/CIP1, p16INK4a and CD44s in tongue cancer

Abstract

Abstract. The role of lost or reduced expression of p21, p16 and CD44s in the survival of tongue cancer patients was investigated. Tumours and adjacent non-tumour epithelia (ANTE) from 36 patients with tongue cancer were retrospectively studied by immunohistochemistry using monoclonal antibodies against p21, p16 and CD44s proteins. Expression of p21, p16 and CD44s and their relationship with clinical and pathological parameters were analyzed. Of 36 patients, 12 (33.33%) developed recurrence and 12 died of the disease (mean survival, 25.5 months). In four cases (11.1%), concomitant low expression (<50% of tumour cells) of p21, p16 and CD44s was detected but had no effect on survival or recurrence in the univariate analysis. In the multivariate analysis, low expression of CD44s was the sole prognostic factor related to survival (p=0.01, hazards ratio: 0.749). There was no expression of p21, p16 or CD44s in ANTE from 3 out of 24 cases studied, and this finding was related to recurrence in the univariate analysis. In the multivariate analysis, low expression of CD44s in ANTE was again the sole factor related to recurrence (p=0.002, hazards ratio: 0.028). In conclusion, low expression of CD44s is related to tumour cell invasiveness and may be of clinical relevance as a prognostic factor. IntroductionCellular programs of proliferation, differentiation, senescence and apoptosis are closely linked to cell cycle regulation, and alterations of the cell cycle machinery have been described as a hallmark of cancer development (1). Molecular mechanisms controlling progression through the restriction point (R), such as the retinoblastoma protein (pRB), are of paramount importance in this context (2). Hypophosphorylated pRB inhibits S phase entry (cell arrest near R point) by forming complexes with E2F transcription factors that actively repress transcription of DNA synthesis-regulating genes (3). Upon pRB phosphorylation, pRB/E2F complexes are disrupted and E2F can activate these promoters, allowing the advance of cells to late G1 and DNA synthesis. Therefore, pRB or members of this regulatory pathway are critical molecular targets for malignant transformation, and there is growing evidence that the pRB pathway is rendered dysfunctional in oral cancer (2). Down-regulation of p16INK4a , a member of the INK family of CDK inhibitors (CDKis), has been described in oral cancer, and p16INK4a inactivation is believed to be an early event in oral carcinogenesis (4-8). Some authors reported that loss of p16INK4a is correlated with a poor prognosis in oral cancer patients (9-11), whereas others found no relationship with survival (12). In addition, some studies found loss of p21 WAF1/CIP1 , a member of CIP/KIP family of CDKis, to be a very early event in oral carcinogenesis (13)(14)(15)(16)(17). However, the prognostic significance of p21 WAF1/CIP1 expression is controversial, with several studies identifying it as a prognostic factor (18-20) and others finding no association (17,(21)(22)(23)(24).Besides alterations in their cell-cycle ...

Combined cytoplasmic and membranous EGFR and p53 overexpression is a poor prognostic marker in early stage oral squamous cell carcinoma

“…(16) had already shown independent prognostic value for p16 expression in carcinomas of the tongue: its absence was correlated with lower OS and DFS. Other authors failed, however, to demonstrate the influence of this protein on the prognosis (46, 47). When we evaluated survival by tumour extension score, the differences obtained were not statistically significant.…”

Prognostic significance of immunohistochemical biomarkers in oral squamous cell carcinoma

“…CD44 has been shown to be a major factor in cell-cell and cell-ECM interactions, including cell migration, adhesion, and some lymphocyte functions 33 . The low expression of CD44s on tumour cells has been significantly correlated with poor prognosis in tongue carcinomas 24 , and the absence of CD44v expression has been associated with a shorter survival time in lip OSSC 22 . Similarly, KOSUNEN et al 33 has shown that the irregular expression of CD44 in OSCC was correlated with poor DFS and OS.…”

The Loss of p16 Expression Worsens the Prognosis of OSCC

“…Other studies, however, did not find any relationship between expression of p16 INK4a and clinical-pathologic stages, 34,35 survival, 36,37 or relapse. 38 This suggests a possible relationship between the lack of protein expression and reduction in the degree of keratinization and differentiation. 36 For Bova et al, 39 the loss of p16 INK4a expression is associated with a reduction in 5-year disease-free survival and, especially, 5-year overall survival.…”