p21WAF1/Cip1 expression is associated with cell differentiation but not with p53 mutations in squamous cell carcinomas of the larynx

p21WAF1/Cip1 is a recently identified gene involved in cell cycle regulation through cyclin‐CDK‐complex inhibition. The expression of this gene in several cell lines seems to be induced by wild‐type, but not mutant, p53. p21WAF1/Cip1 expression has been studied at both mRNA and protein levels in a series of 49 normal mucosae and squamous cell carcinomas of the larynx. A significant association was found between mRNA and protein expression in tumours (P<0·0001). p21WAF1/Cip1 expression was strongly associated with squamous cell differentiation of carcinomas, because six of seven (86 per cent) undifferentiated carcinomas (grade 4) showed very low levels of p21WAF1/Cip1 expression, whereas 41 out of 42 (98 per cent) carcinomas with squamous cell differentiation (grades 1–3) had normal or high levels of p21WAF1/Cip1 expression (P<0·0001). In addition, p21WAF1/Cip1 expression was topologically related to the squamous differentiation of tumour cells with a distribution similar to that seen in normal squamous epithelium. No correlation was found between p21WAF1/Cip1 expression and the global S‐phase of the carcinomas. p53 mutations (exons 5–9) were found in ten carcinomas with p21WAF1/Cip1 expression, but no p53 mutations were detected in three p21WAF1/Cip1‐negative tumours. In conclusion, p21WAF1/Cip1 expression is frequently upregulated in squamous cell carcinomas of the larynx and is associated with tumour cell differentiation. p21WAF1/Cip1 expression in these tumours is independent of p53 gene mutations. © 1997 John Wiley & Sons, Ltd.

[1]  V. Tron,et al.  Differentiation-associated overexpression of the cyclin-dependent kinase inhibitor p21waf-1 in human cutaneous squamous cell carcinoma. , 1996, The American journal of pathology.

[2]  M. Barbareschi,et al.  p21/WAF1/CIP1 EXPRESSION IN NORMAL MUCOSA AND IN ADENOMAS AND ADENOCARCINOMAS OF THE COLON: ITS RELATIONSHIP WITH DIFFERENTIATION , 1996, The Journal of pathology.

[3]  F. Bosch,et al.  p53 gene mutations and protein overexpression are associated with aggressive variants of mantle cell lymphomas. , 1996, Blood.

[4]  A. Marchetti,et al.  p21 RNA and protein expression in non-small cell lung carcinomas: evidence of p53-independent expression and association with tumoral differentiation. , 1996, Oncogene.

[5]  F. Miller,et al.  Tumor suppression by p21WAF1. , 1995, Cancer research.

[6]  R. Hruban,et al.  p53-independent expression of the cyclin-dependent kinase inhibitor p21 in pancreatic carcinoma. , 1995, The American journal of pathology.

[7]  K. Kinzler,et al.  Topological control of p21WAF1/CIP1 expression in normal and neoplastic tissues. , 1995, Cancer research.

[8]  L. Tsai,et al.  Involvement of the cell-cycle inhibitor Cip1/WAF1 and the E1A-associated p300 protein in terminal differentiation. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[9]  K. Kinzler,et al.  p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage. , 1995, Genes & development.

[10]  S. Elledge,et al.  p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells , 1995, Science.

[11]  J. Cunningham,et al.  p53 gene mutations inside and outside of exons 5-8: the patterns differ in breast and other cancers. , 1995, Oncogene.

[12]  E. Campo,et al.  p53 expression in normal, dysplastic, and neoplastic laryngeal epithelium. Absence of a correlation with prognostic factors , 1995, The Journal of pathology.

[13]  W. Mercer,et al.  p53-independent induction of WAF1/CIP1 in human leukemia cells is correlated with growth arrest accompanying monocyte/macrophage differentiation. , 1995, Cancer research.

[14]  A. Harris,et al.  Mutations in the p53 gene are not limited to classic 'hot spots' and are not predictive of p53 protein expression in high‐grade non‐Hodgkin's lymphoma , 1995, British journal of haematology.

[15]  K. Hemminki,et al.  p53 mutations in larynx cancer. , 1994, Carcinogenesis.

[16]  B. Vogelstein,et al.  Absence of WAF1 mutations in a variety of human malignancies. , 1994, Blood.

[17]  T. Hunter,et al.  Cyclins and cancer II: Cyclin D and CDK inhibitors come of age , 1994, Cell.

[18]  G. Dardanoni,et al.  P53 expression in stage iii-iv squamous-cell carcinoma of the larynx - an immunohistochemical study related to clinicopathological, flow-cytometric DNA analysis and prognosis. , 1994, International journal of oncology.

[19]  F. Bosch,et al.  PRAD-1/cyclin D1 gene amplification correlates with messenger RNA overexpression and tumor progression in human laryngeal carcinomas. , 1994, Cancer research.

[20]  D. Givol,et al.  Induction of WAF1/CIP1 by a p53-independent pathway. , 1994, Cancer research.

[21]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[22]  S. Elledge,et al.  The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases , 1993, Cell.

[23]  Jing Yin,et al.  Loss of heterozygosity of p53 in oral cancers demonstrated by the polymerase chain reaction , 1993, Cancer.

[24]  Hui Zhang,et al.  D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA , 1992, Cell.

[25]  R. Maestro,et al.  p53 over‐expression is an early event in the development of human squamous‐cell carcinoma of the larynx: Genetic and prognostic implications , 1992, International journal of cancer.

[26]  R. Maestro,et al.  High frequency of p53 gene alterations associated with protein overexpression in human squamous cell carcinoma of the larynx. , 1992, Oncogene.

[27]  Y. Nakamura,et al.  Isolation and mapping of a polymorphic DNA sequence (pYNZ22) on chromosome 17p [D17S30]. , 1988, Nucleic acids research.

[28]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .