p53 expression in human rectal tissue after radiotherapy: upregulation in normal mucosa versus functional loss in rectal carcinomas.
OBJECTIVE
In vitro, ionizing radiation of epithelial cells leads to upregulation of wild-type p53 and subsequent induction of p21(waf1). The effect of radiotherapy (RT) on the expression of these proteins in patients is unknown. We assessed the influence of RT on the expression of p53 and p21(waf1) in normal mucosa and rectal carcinomas in vivo.


METHODS
Tumor and normal tissue samples were derived from rectal cancer patients randomized in a clinical trial in which the value of preoperative RT was evaluated. p53 and p21(waf1) expression was determined in 51 irradiated and 52 nonirradiated patients using immunohistochemistry.


RESULTS
In normal mucosa, both p53 and p21(waf1) were strongly upregulated after RT compared with the expression in unirradiated normal tissue (p <0.001). In tumor cells, no significant difference in the expression of p53 or p21(waf1) was found in the irradiated vs. nonirradiated group. In the few rectal tumors with wild-type p53, induction of p53 after RT did not necessarily lead to upregulation of p21(waf1).


CONCLUSIONS
These findings demonstrate that in normal mucosa, a functional p53-p21(waf1) pathway is present, whereas in tumor cells it is defective in almost all cases because of either p53 mutation or down- or upstream disruption in tumors with wild-type p53. Therefore, we believe that the role of p53 expression as a single prognostic marker in rectal cancer needs reconsideration.
Marijnen
Corrie A M
CA
Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands. marijnen@lumc.nl
Kapiteijn
Ellen
E
Nagtegaal
Iris D
ID
Mulder-Stapel
Adri A
AA
van de Velde
Cornelis J H
CJ
Schrier
Peter I
PI
Peltenburg
Lucy T C
LT
van Krieken
J Han J M
JH
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism / Q000528:radiation effects*; D005260:Female; D015870:Gene Expression / Q000528:radiation effects; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D008875:Middle Aged; D012004:Rectal Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D012007:Rectum / Q000378:metabolism / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000528:radiation effects*; D015854:Up-Regulation
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53