Nouri A M, Cannell H, Dagini B, Dabare A A, Habib N, Fowler C G
Department of Medical Oncology, The Royal London Hospital Trust, Whitechapel, E1 1BB, London, UK.
Eur J Cancer. 2000 Sep;36(14):1853-62. doi: 10.1016/s0959-8049(00)00174-x.
In this investigation the profile of p53 and epidermal growth factor receptor (EGFR) expression in tumour tissue biopsies of transitional cell carcinoma of bladder (TCC) and of oral-pharyngeal carcinoma (OP) were compared using an immunocytochemical staining method. In addition, various techniques including sodium dodecyl sulphate-polyacrylamide gel elecrophoresis (SDS-PAGE), colorimetric assay and gene transfection were used to investigate the influence of p53 on the behaviour of human tumour cell lines in vitro. The results showed that: (a) p53 was detectable in more than 45% of cases in both tumour types, although the profile and intensity of expression differed. (b) Concomitant strong expression of EGFR and p53 for TCC and OP was 21% and 38% (P>0.05%), respectively. (c) Treatment of tumour cells by either gamma radiation or by cisplatin resulted in the induction of p53 independent of the origin of the tumour. (d) Susceptibility of two cell lines, one with and one without constitutive expression of p53 showed that the expressing cells were more sensitive to gamma radiation (the percentage inhibition at 250 cGy was 57% versus -15%, P<0.01), and also cisplatin (the percentage inhibition at 1 microgram/ml was 71.0+/-6.0 versus 2.6+/-7.0, P<0.001). (e) Transfection of wild-type TP53 gene into a bladder tumour cell line resulted in a rapid cell apoptosis (by as much as 90%) whereas cells receiving mutated TP53 survived. A similar frequency of TP53 mutation in TCCs and OPs was observed. In addition, the pattern of p53 expression within the squamous type of TCC was similar to that in OPs. If the data from the in vitro studies could be translated into an in vivo setting, one could envisage a situation where the introduction of wild-type TP53 gene by gene transfection into tumour cells (independent of their TP53 gene mutational status), would prove to be beneficial. If the cellular TP53 gene is mutated, then an introduction of the normal TP53 gene would induce cells to undergo apoptosis. Alternatively, if TP53 is wild-type, then the increased levels of p53 expression would enable the cells to become more susceptible to DNA damaging treatments such as cisplatin or gamma radiation.
在本研究中，采用免疫细胞化学染色方法比较了膀胱移行细胞癌（TCC）和口咽癌（OP）肿瘤组织活检中p53和表皮生长因子受体（EGFR）的表达情况。此外，还运用了包括十二烷基硫酸钠-聚丙烯酰胺凝胶电泳（SDS-PAGE）、比色测定法和基因转染等多种技术，来研究p53对体外人肿瘤细胞系行为的影响。结果显示：（a）在两种肿瘤类型中，超过45%的病例可检测到p53，尽管表达情况和强度有所不同。（b）TCC和OP中EGFR与p53同时强表达的比例分别为21%和38%（P>0.05%）。（c）用γ射线或顺铂处理肿瘤细胞会导致p53的诱导，且与肿瘤起源无关。（d）对两种细胞系进行敏感性研究，一种有p53组成型表达，另一种没有，结果表明有表达的细胞对γ射线更敏感（250 cGy时抑制率为57%对-15%，P<0.01），对顺铂也更敏感（1微克/毫升时抑制率为71.0±6.0对2.6±7.0，P<0.001）。（e）将野生型TP53基因转染到膀胱肿瘤细胞系中会导致细胞迅速凋亡（高达90%），而接受突变型TP53的细胞则存活下来。在TCC和OP中观察到相似频率的TP53突变。此外，TCC鳞状细胞类型中p53的表达模式与OP中的相似。如果体外研究的数据能够转化为体内情况，那么可以设想一种情形，即通过基因转染将野生型TP53基因导入肿瘤细胞（无论其TP53基因突变状态如何）将被证明是有益的。如果细胞的TP53基因发生突变，那么导入正常的TP53基因将诱导细胞发生凋亡。或者，如果TP53是野生型，那么p53表达水平的提高将使细胞对顺铂或γ射线等DNA损伤治疗更敏感。
