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

Nadal, Alfons; Jares, Pedro; Cazorla, Maite; Fernández, Pedro; Sanjuán, Xavier; Hernández, Lluís; Pinyol, Magda; Aldea, Martí; Mallofré, Carme; Muntané, Jaume; Traserra, J; Campo, Elı́as; Cardesa, Antonio

doi:10.1002/(sici)1096-9896(199710)183:2<156::aid-path908>3.0.co;2-o

Cited by 48 publications

(50 citation statements)

References 18 publications

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“…The high proliferation (PCNAtot) rate was related to the increased p21 expression, which parallels the results in cutaneous melanoma (Trotter et al, 1997) and in cutaneous squamous cell carcinoma (Tron et al, 1996), but is in contrast to findings in other neoplasms (Nadal et al, 1997) or in normal tissues (El-Deiry et al, 1995;Doglioni et al, 1996). The possible explanations of our result may be either an abnormal function of p21 (Trotter et al, 1997) or that part of the tumour cells may have become refractory to inhibitory signals from p21 (Yasui et al, 1996).…”

Section: Discussionsupporting

confidence: 86%

“…In the previous studies with clinical material, p21 expression has correlated with tumour proliferation and differentiation either in a p53-dependent (Doglioni et al, 1996;Harada et al, 1997;Wakasugi et al, 1997) or in a p53-independent pathway (DiGiuseppe et al, 1995;Tron et al, 1996;Yasui et al, 1996;Nadal et al, 1997). So far, PCNAtot, PCNA expression in ten consecutive high power fields; p53 index, (% of p53-positive tumour cells) × (staining intensity of p53); *log-rank analysis.…”

Section: Discussionmentioning

confidence: 97%

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p21WAF1/CIP1 expression in stage I cutaneous malignant melanoma: its relationship with p53, cell proliferation and survival

et al. 1999

Br J Cancer

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Tumour suppressor p21 WAF1/CIP1 is the main downstream effector gene mediating p53-induced cell cycle arrest, up-regulated by normal wild-type p53 (El-Deiry et al, 1993). In addition to direct transcriptional induction by the tumour suppressor p53, various other signals can induce p21 expression in the absence of wildtype p53 (Michieli et al, 1994;Zeng and El-Deiry, 1996). Harper et al (1993) showed that the ability of the p21 gene product to arrest the cell cycle is based on its virtue to bind and inhibit active cyclin/CDK complexes needed in DNA replication and cell cycle progression. p21 can also inhibit DNA replication by directly binding to the proliferating cell nuclear antigen (PCNA) molecule, thus inhibiting the ability of DNA polymerase δ to extend new DNA chains but still allowing the DNA repair function to continue (Flores-Rozas et al, 1994;Waga et al, 1994;Podust et al, 1995).In human melanoma cell lines, induction of p21 is independent of wild-type p53 expression (Jiang et al, 1995;Vidal et al, 1995), and elevated expression of p21 is associated with melanoma differentiation, growth arrest and metastatic suppression (Jiang et al, 1995). However, the knowledge of p21 expression in clinical materials of cutaneous malignant melanoma is rather limited. Maelandsmo et al (1996) revealed a significant correlation between elevated p21 expression and increasing tumour thickness in superficially spreading melanoma, but no correlation between p21 and survival was found. Elsewhere, a significant overexpression of p21 has been demonstrated in primary and metastatic melanomas (Trotter et al, 1997).As far as the authors are aware, no previous study has compared the relationships between p21, p53 and PCNA expression in primary stage I cutaneous melanoma. In the present study, we used immunohistochemistry to analyse the above-mentioned relationships in a cohort of 369 patients with long-term follow-up data. In addition, our aim was to analyse whether p21 protein levels are related to clinical data, histological parameters (Clark and Breslow levels) and prognosis. MATERIALS AND METHODS PatientsThe retrospective study consists of a consecutive series of 369 clinical stage I cutaneous malignant melanoma patients with complete clinical and histopathological data available, who were diagnosed and treated in the district of Kuopio University Hospital, Finland, between 1974 and 1989. The clinical staging of all tumours was carried out according to UICC (UICC, 1987). Because of insufficient tumour material, pigment or technical artefacts, there were 267 valid immunostainings for p21, 284 for p53 and 219 for PCNA respectively. Patient records were reviewed and the pertinent clinical and histopathological data of the patients are shown in Table 1. The mean follow-up time of all 369 patients was 6.4 years (range 0.2-18 years). When the analysis was restricted to patients with p21, p53 or PCNA data, the mean follow-up times were 6.3 years (range 0.5-18 years), 6.3 years (range 0.5-18 years) or 7.2 years (range 0.5-18 years) re...

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 97%

p21WAF1/CIP1 expression in stage I cutaneous malignant melanoma: its relationship with p53, cell proliferation and survival

et al. 1999

Br J Cancer

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“…For example, p21 WAF1/Cip1 expression is frequently observed in SCCs of the larynx, in association with tumour cell differentiation (Nadal et al, 1997). In gastric carcinomas, p21 WAF1/Cip1 expression is positively correlated with tumour stage, depth of invasion and lymph node metastasis, in line with a positive rather than an inverse association with Ki-67 positivity (Yasui et al, 1996).…”

Section: Discussionmentioning

confidence: 96%

“…For amplification of p21 WAF1/Cip1 mRNA, primers were 5′-GCGC-CATGTCAGAACCGGCTG-3′ and 5′-GCAGGCTTCCT-GTGGGCGGAT-3′, the products including the whole translated region of this gene (Nadal et al, 1997). The PCR procedure was performed with 35 cycles of denaturation at 94°C for 0.5 min.…”

Section: Rt-pcrmentioning

confidence: 99%

“…Reactivity was visualized using the Western Blot Chemiluminescence Reagent (NEN TM Life Science Products, Boston, MA, USA). As positive controls, normal squamous epithelium or squamous cell carcinomas (SCC) of uterine cervix were used since a high frequency of p21 WAF1/Cip1 expression has been demonstrated for the latter (Nadal et al, 1997) and p27 Kip1 immunopositivity is present in the former (Jordan et al, 1998).…”

Section: Western Blot Assaymentioning

confidence: 99%

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DCC expression is related to mucinous differentiation but not changes in expression of p21WAF1/Cip1 and p27Kip1, apoptosis, cell proliferation and human papillomavirus infection in uterine cervical adenocarcinomas

Saegusa

Okayasu

1999

Br J Cancer

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To clarify possible roles of DCC expression in tumour differentiation and cell kinetics, we immunohistochemically investigated 80 uterine cervical adenocarcinomas (C-ACs), including 31 mucinous (M) and 31 endometrioid (E) lesions, and 18 adenocarcinomas in situ (AIS), along with 39 normal cervical samples. The results were compared with findings for p21 WAF1/Cip1 and p27 Kip1 expression, apoptosis, cell proliferation and human papillomavirus (HPV) infection. Nine C-AC cases were also examined using a combination of the reverse transcription-polymerase chain reaction and Southern blot hybridization, as well as Western blot assays. Significantly decreased DCC scores were observed in E-ACs but not M-ACs, as compared to normal cervical glandular epithelia and AIS. Average p21 WAF1/Cip1 and p27 Kip1 scores were significantly higher in E-ACs than M-ACs, in line with high apoptotic, mitotic and Ki-67 labelling indices. A concordance of the results for DCC and p21 WAF1/Cip1 expression between mRNA- and protein-based assays was also noted. Change of DCC expression, however, was not related to any of the cell kinetic markers or clinicopathological features in ACs of either type. There was also no association with the HPV status, although infection was significantly linked with high values for cell kinetics. These results suggest that DCC expression in C-ACs is closely associated with mucinous differentiation. © 1999 Cancer Research Campaign

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Multiple pathways control cell growth and transformation: overlapping and independent activities of p53 and p21Cip1/WAF1/Sdi1

Cox

1997

J. Pathol.

111

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

Cited by 48 publications

References 18 publications

p21WAF1/CIP1 expression in stage I cutaneous malignant melanoma: its relationship with p53, cell proliferation and survival

p21WAF1/CIP1 expression in stage I cutaneous malignant melanoma: its relationship with p53, cell proliferation and survival

DCC expression is related to mucinous differentiation but not changes in expression of p21WAF1/Cip1 and p27Kip1, apoptosis, cell proliferation and human papillomavirus infection in uterine cervical adenocarcinomas

Multiple pathways control cell growth and transformation: overlapping and independent activities of p53 and p21Cip1/WAF1/Sdi1

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