Evidence that Expression of a Mutated p53 Gene Attenuates Apoptotic Cell Death in Human Gastric Intestinal-type Carcinomas in vivo

To examine in vivo the validity of the results of experiments in vitro , we analyzed the relationship between p53 gene status and apoptotic cell death of human gastric intestinal-type adenocarcinomas. Surgical specimens were classified into two categories: 18 gastric cancers with nuclear p53 protein (A), and 17 gastric cancers without nuclear p53 protein (B). Polyraerase chain reaction-single strand conformation polymorphism disclosed a shifted band that corresponded to a mutation in the p53 gene in 13 cases (72%) in category A and 3 cases (18%) in category B, the frequency being significantly higher in the former ( P <0.05). Apoptotic cells were identified from routinely stained sections and by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL). The TUNEL index [TI: (the number of TUNEL-positive apoptotic cells/the total number of tumor cells) X100] was 3.8 ±1.4% in category A and 4.9 ±1.2% in category B, the value being significantly lower in the former ( P < 0.05). The proliferating cell nuclear antigen index, defined similarly to the TI, was 56.4±16.3% in category A, and it was significantly higher than that in category B ( P <0.05). The immunohistochemically detected expression of P21^CIP1/WAF1 did not differ between the two categories, while Bax-positive tumor cells were more frequently detected in category A. These results indicate that (1) expression of a mutated p53 gene attenuates apoptotic cell death of gastric cancer, in accordance with the previous in vitro finding that p53 gene mutation provides a possible selective advantage for tumor cell proliferation, and (2) apoptosis is related not only to expression of p53 and the stage of the cell cycle, but also to p53-independent and cell cycle-independent events.