Role of laminin in ovarian cancer turner growth and metastasis via regulation of Mdm2 and Bcl-2 expression

Ovarian cancer is among the most lethal cancers in women because of its hig h metastatic potential and lack of response to therapy. An experimental mod el to study this disease was developed using a transformed granulosa cell l ine expressing a mutant p53 and Ha-ras. When injected into the ovary of nud e mice in the presence of laminin-l, tumors develop in the ovary and perito neum and metastasize to various organs, leading to death within 21 days. In contrast, when cells were injected in the presence of gelatin, development of tumors was slower and no metastases were observed by day 21. Here we in vestigated the possible mechanism by which laminin-l exerts its promotion o f tumorigenesis and metastasis. Cells were co-injected with laminin-l and a ctive laminin peptides from the al; (A13: RQVFQVAYIIIKA, A12: WVTVTLDL RQVF Q, AG73: LQVQLSIR, IKVAV) and beta1 (YIGSR) chains. Ovarian tumor growth an d metastasis were increased in the presence of laminin-l plus either AG73 p eptide, IKVAV, or A13, and were significantly reduced in the presence of A1 2 or YIGSR. Expression of Bcl-2 and Mdm2 was higher by 3.5- and about 100-f old, respectively, in ovarian tumors grown in the presence of laminin compa red to tumors grown in the presence of gelatin. Moreover, peptides A13 and AG73 further elevated Bcl-2 expression by 6- and 7-fold respectively, while IKVAV yielded expression similar to laminin-l. YIGSR and A12 reduced the e xpression of Bcl-2 by 7- and 3-fold, respectively, compared to treatment wi th laminin-l. A13 and AG73 increased Mdm2 expression by 1.8- and 1.3-fold, respectively, while IKVAV, A12, and YIGSR were without effect. Thus, lamini n-l exerts its proliferative effect on the development of ovarian tumors vi a upregulation of survival genes such as Bcl-2 and Mdm2. Peptides A13 and A G73 (which increased tumor growth and spread) enhance the expression of the se genes and A12 and YIGSR (which decrease tumor growth and spread) attenua te their expression. IKVAV probably enhances tumor growth and metastasis by another mechanism.