| Co-Investigator(Kenkyū-buntansha) |
KOTUJI Fumikazu FUKUI MED.UNI. OB/GYN, PROF., 医学部, 教授 (50153573)
KAWAHARA Kazumi FUKUI MED.UNI. OB/ GYN, ASSISTANT, 医学部, 助手 (60234100)
細川 久美子 福井医科大学, 医学部, 講師 (60199495)
佐々木 博正 福井医科大学, 医学部・附属病院, 講師 (20225890)
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| Budget Amount *help |
¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2001: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
Our goal was to define the active sites on laminin important in ovarian tumor growth and spread and determine if these active sites regulated survival genes. Here we investigated the possible mechanism by which laminin-1 exerts its promotion of tumorigenesis and metastasis. Cells were co-injected with laminin-1 and active laminin peptides from feed (A13 : RQWQVAYTIIKA, A12 : WVTVTLDLRQVFQ, AG73 : LQVQLSIR, IKVAV) and 6 (YIGSR) chains. Ovarian tumor growth and metastasis were increased in the presence of laminin-1 plus either AG73 peptide, IKVAV, or A13, and were significantly reduced in the presence of A12 or YIGSR. Expression of Bcl-2 and Mdm2 was higher by 3.5 fold and about 100-fold, respectively, in ovarian tumors grown in the presence of laminin-1 compared to tumors grown in the presence of gelatin. Moreover, peptides A13 and AG73 further elevated Bcl-2 expression by 6-fold and 7-fold respectively, while IKVAV yielded expression similar to laminin-1. YIGSR and A12 reduced the expression of Bcl-2 by 7- and 3-fold, respectively, compared to treatment with laminin-1. A13 and AG73 increased Mdm2 expression by 1.8 and 1.3 fold, respectively, while IKVAV, A12, and YIGSR were without effect. Thus, laminin-1 exerts its proliferative effect on the development of ovarian tumor via upregulation of survival genes such as Bcl-2 and Mdm2, which can block the activity of P53. Peptides A13 and AG73 (which increased tumor growth and spread) enhance the expression of these genes and A12 and YIGSR (which decrease tumor growth and spread) attenuate their expression. IKVAV probably enhances tumor growth and metastasis by another mechanism,
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