Role of laminin in ovarian cancer tumor growth and metastasis via regulation of Mdm2 and Bcl-2 expression.
Ovarian cancer is among the most lethal cancers in women because of its high metastatic potential and lack of response to therapy. An experimental model to study this disease was developed using a transformed granulosa cell line expressing a mutant p53 and Ha-ras. When injected into the ovary of nude mice in the presence of laminin-1, tumors develop in the ovary and peritoneum 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 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 the alpha1; (A13: RQVFQVAYIIIKA, A12: WVTVTLDL RQVFQ, AG73: LQVQLSIR, IKVAV) and beta1 (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- and about 100-fold, respectively, in ovarian tumors grown in the presence of laminin compared 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-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 tumors via upregulation of survival genes such as Bcl-2 and Mdm2. 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.
Yoshida
Y
Y
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Hosokawa
K
K
Dantes
A
A
Kotsuji
F
F
Kleinman
H K
HK
Amsterdam
A
A
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007797:Laminin / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D008855:Microscopy, Electron, Scanning; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D014407:Tumor Cells, Cultured / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein
D007797:Laminin; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2