Aberrant p21CIP1/WAF1 protein accumulation in head-and-neck cancer

Abstract

p21 CIP1/WAF1 is an inhibitor of cyclin-dependent kinases and, in normal tissues including squamous epithelia, has been associated with cell-cycle exit and differentiation. As shown in this pilot study, however, the majority of head-and-neck squamous-cell carcinomas (HNSCC) display aberrant p21 CIP1/WAF1 expression: of 42 tumors analyzed by immunohistochemical staining, 28 (67%) over-expressed the p21 CIP1/WAF1 protein. Accumulation of p21 CIP1/WAF1 was independent of the histological grade of the tumors as well as the genetic status of the p53 gene. In many cases, most notably in poorly differentiated or undifferentiated HNSCC, p21 CIP1/WAF1 -positive cells were actively proliferating tumor cells, since they also expressed proliferating-cell nuclear antigen (PCNA) and Ki-67. Accumulation of p21 CIP1/WAF1 occurred through a posttranscriptional mechanism since, in contrast to immunohistochemical analysis of the p21 CIP1/WAF1 protein, in situ hybridization showed no increase of mRNA levels as compared with cells in normal mucosa (n 5 25). Clinically, among the patients with p21 CIP1/WAF1 -over-expressing tumors, there was increased recurring disease (p 5 0.03; x 2 -test), shortened disease-free survival (p 5 0.0019; log-rank test) and shortened overall survival (p 5 0.0071; log-rank test). These in vivo data indicate that in many HNSCC, accumulated p21 CIP1/WAF1 is compatible with increased tumor-cell proliferation, and they provide preliminary evidence that p21 CIP1/WAF1 may be of prognostic and predictive significance. Int. J. Cancer 74:383-389, 1997.r 1997 Wiley-Liss, Inc. p21 CIP1/WAF1 has been shown to inhibit the activity of several cyclin/cyclin-dependent kinase complexes and to block cell-cycle progression (Harper et al., 1993;Xiong et al., 1993;Gu et al., 1993). It was identified as a gene whose product was transcriptionally activated by wild-type but not mutant p53 protein, serving as a mediator of the cell-cycle-arrest function of p53 (El-Deiry et al., 1993). Simultaneously, it was found to be associated with senescence (Noda et al., 1994) and terminal differentiation (Jiang et al., 1994;Steinman et al., 1994; Halevy et al., 1995). These properties made the p21 CIP1/WAF1 gene a prominent candidate tumorsuppressor gene. However, extensive searches failed to reveal genetic alterations of the gene in human tumors, except for the rare occurrence of polymorphisms (Shiohara et al., 1994).The precise role of p21 CIP1/WAF1 in the control of proliferation and differentiation is not clear. During mouse embryonic development, p21 CIP1/WAF1 mRNA expression was found in the post-mitotic cells of many tissues, and this expression occurred independently of p53. This suggested that p21 CIP1/WAF1 provides a tight link between cell-cycle arrest and exit and differentiation (Parker et al., 1995). However, knockout mice lacking a functional p21 CIP1/WAF1 developed fairly normally, indicating that the presumed function of p21 CIP1/WAF1 in differentiation was redundant (Deng et al., 1995). In addition, in contrast to p53 kno...

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

“…Expression of p21 Cip1/WAF1 has also been associated with a favorable survival in patients with tongue squamous cell carcinomas, and in patients with ovarian, superficial bladder, gastric, colorectal, and esophageal cancers. 29,43,57,58 In one other study on tonsillar squamous cell carcinomas and two studies on laryngeal squamous carcinomas, no correlation was reported, 36,54,59 and in one study on head-and-neck squamous cell carcinomas derived from multiple head-and-neck localizations even a negative correlation with survival was described, 19 which may be explained by the heterogeneous tumor population. Other strong indicators for a favorable prognosis in our study include tumor diameter o4 cm, low/no expression of cyclin D1, and low/no tobacco consumption.…”

“…5,7,[14][15][16] HPV-negative tumors, in contrast, often show inactivation of p16 INK4A , p53 overexpression as a result of gene mutations, cyclin D1 gene amplification and overexpression, as well as EGFR accumulation. 3,[17][18][19] The literature, however, shows conflicting data with respect to HPV-associated characteristics and clinical outcome of head-and-neck squamous cell carcinomas. First, although many studies describe a significant association between HPV presence and favorable prognosis, some studies did not find such a correlation.…”

Effect of Duration of Fixation on Quantitative Reverse Transcription Polymerase Chain Reaction Analyses

“…EGFR, MMP-1, and VEGF were selected because they have been shown to be overexpressed at the mRNA and protein level in a large proportion of oral squamous cell carcinoma (10 -13). p21 protein is also elevated in large proportion of oral dysplasias and squamous cell carcinomas but shows no mRNA overexpression (14,15).…”

Deregulated Expression of Cell Cycle–Associated Proteins in Solid Pseudopapillary Tumor of the Pancreas

“…Accumulation of p21 has been found to correlate with increased rate of proliferation and aggressive clinical course-for example, in head and neck squamous carcinoma (46) or in multiple myeloma (47)-indicating that the antiproliferative effect of p21 on the cell cycle progression may be overridden by other mechanisms. However, in low-malignancy solid pseudopapillary tumor of the pancreas, p21 and p27 cyclin-dependent kinase inhibitor upregulation appears to continue to function, as judged from the extremely low pool of Ki67-positive cells in both the primary tumor and the liver metastases.…”