DNA damage triggers the activation of checkpoints that delay cell cycle progression to allow for DNA repair. Loss of G2 checkpoints provides a growth advantage for tumor cells undergoing aberrant mitosis. However, the precise mechanisms of G2 checkpoints acting in gastric cancer are unknown. Here, we analyzed the G2 checkpoint function in two gastric cancer cells, MKN-28 cells containing a mutant p53 gene and MKN-45 cells which have wild-type p53. Two agents damaging DNA, camptothecin (CPT) or ultraviolet light (UV), were utilized to trigger a G2 phase cell cycle checkpoint response in these tumor cells. Both CPT and UV inhibited the growth of MKN-45 cells, whereas they did not affect the growth of MKN-28 cells. CPT induced cell cycle arrest at the G2/M phase and enhanced the expression of human RAD9 (hRAD9) in MKN-45 cells. In addition, hRAD9 showed perinuclear staining and similar localization with Bcl-2 in MKN-45 cells but not in MKN-28 cells after having applied CPT or UV light. These results suggest that besides p53 activity, the induction of hRAD9 is required for G2/M checkpoint signal transduction in gastric cancer cells.
An 81-year-old female consulted us because of an ulcerated tumor in her left breast of several years' duration. Partial biopsy showed that the tumor consisted of anaplastic squamous cells, indicating squamous cell carcinoma from unknown origin. CT images demonstrated tumors in the left breast, liver and bile duct. However, further investigation was not possible due to the patient's refusal. To avoid possible localized complication caused by tumor rupture and/or infection, the breast tumor was totally excised. Histopathology revealed that irregularly shaped tumor nests had invaded the entire dermis resulting in massive necrosis. The tumor cells were of various sizes and shapes, and showed individual keratinization and atypical mitotic figures. In addition, other larger masses consisted of hyperchromatic small squamous cells with basophilic cytoplasms. These cells were poorly differentiated without apparent keratinization. Immunohistochemically, the excised tumor was stained strongly positive for epidermal growth factor receptor, partially positive for epithelial membrane antigen and BerEP4 but negative for cytokeratins 5, 6 and 20, estrogen receptor, progesterone receptor, ErbB2/HER2, gross cystic disease fluid protein-15, carcinoembryonic antigen and S-100. Since these findings were not sufficient to identify the tumor origin, we carefully rechecked the histopathology of the surgical specimens and found irregular elongation at the periphery of the overlying epidermis, which contained atypical keratinocytes with pleomorphic nuclei, suggesting a diagnosis of Bowen's disease. We therefore concluded that tumor cells of Bowen's disease in the epidermis, independently from the tumors of liver and bile duct, had invaded downward, finally reaching the breast tissue.
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