| Co-Investigator(Kenkyū-buntansha) |
OHUE Masayuki Osaka University Medical School, Assistant Professor, 医学部, 助手 (40294095)
SEKIMOTO Mitsugu Osaka University Medical School, Assistant Professor, 医学部, 助手 (10273658)
MONDEN Takushi Osaka University Medical School, Lecturer, 医学部, 講師 (20174477)
SHIMANO Takashi Osaka University Medical School, Associate Professor, 医学部, 助教授 (80144476)
大西 直 大阪大学, 医学部・附属病院, 医員
冨田 尚裕 (富田 尚裕) 大阪大学, 医学部, 助手 (00252643)
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| Budget Amount *help |
¥7,400,000 (Direct Cost: ¥7,400,000)
Fiscal Year 1997: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1996: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1995: ¥4,100,000 (Direct Cost: ¥4,100,000)
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| Research Abstract |
The expression of cell cycle regurating genes, eg., positive regulators : G1 cyclins (cyclin D,E), cyclin dependent kinases (CDK2,4), negative regulators : CDK inhibitor (CDK4I/pI6), RB,in normal mucosa, hyperplasia, adenoma, carcinoma in adenoma and advanced carcinoma of colorectum was analyzed by immunohistochemistry and Western blottings. In normal mucosa, each protein was detected only in a few cells of bottom parts of the gland. In hyperplastic mucosa, the expression of cyclin D and E was detected in large number of cells of upper parts from the bottom of the gland. In adenomas, the overexpression of these proteins are frequently detected, eg., cyclin D : 55/66 (83%), cyclin E : 42/50 (84%). In carcinoma in adenoma, the overexpression of CDK2, p16 and RB,as well as cyclin D,E,was noted, eg., cyclin D : 8/8 (100%), cyclin E : 13/13 (100%), CDK2 : 10/12 (83%), p16 : 10/14 (71%), RB : 10/12 (83%). Finally, in advanced carcinomas, all the proteins were overexpressed, eg., cyclin D : 2
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6/45 (58%), cyclin E : 41/45 (91%), CDK2 : 34/45 (76%), CDK4 : 39/45 (87%), p16 : 59/60 (98%), RB : 34/45 (76%). The quantitative analysis by Western blottings further confirmed a few times higher expression of these proteins in colon carcinomas compared to normal mucosa. Also, the rate of hyperphosphorylated (inactivated) form of RB was shown to be 1.46 times higher compared to normal mucosa. The comparative analysis using immunohistochemistry on the adjacent sections revealed that the cancer cells overexpressing RB also overexpressed cyclin E/CDK2 and those overexpressing CDK4 also expressed p16. In summary, during the multistep colon carcinogenesis based on adenoma-carcinoma sequence, cyclin D and E are overexpressed from the stage of hyperplasia or adenoma, CDK2 and CDK4I/p16 are overexpressed from the stage of carcinoma in adenoma, and CDK4 is overexpressed at the stage of advanced carcinoma. Thus, it was suggested that the expression of cell cycle regulators such as G1 cyclins, CDKs and CDK inhibitors are deeply involved in colon carcinogenesis. And, the overexpression of cyclin E/CDK2 was thought to be involved in hyperphosphorylation of RB protein. Less
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