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Increased Expression of Nucleoside Diphosphate Kinase/nm23 and c-Ha-ras mRNA Is Associated with Spontaneous Lung Metastasis in Rat-transplantable Osteosarcomas¹

Department of Orthopedic Surgery [K. H., Y. Miy., Y. Mii., T. M., S. M., M. A., S. T.] and Department of Oncological Pathology, Cancer Center [M. T., T. T., E. K., Y. K.], Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634, Japan

The relationship between expression of nucleoside diphosphate kinase (NDP kinase)/nm23, c-Ha-ras, and c-myc genes and metastatic potential was assessed in rat-transplantable osteosarcoma lines, derived from spontaneous and chemical carcinogen (4-hydroxyamino quinoline 1-oxide)-induced osteosarcomas in Fisher 344/NS1c rats. These osteosarcomas possess metastatic potential and highly metastatic lines spontaneous osteosarcoma-selected lung metastatic lesions and 4-hydroxyamino-quinoline 1-oxide-induced osteosarcoma-selected lung metastatic lesions were respectively established by selectively transplanting lung metastatic lesions. Northern blot analysis revealed that the levels of NDP kinase/nm23 and c-Ha-ras gene expression were increased in line with metastatic ability; thus transcript levels were remarkably greater in both spontaneous osteosarcoma-selected lung metastatic lesions and 4-hydroxyamino-quinoline 1-oxide-induced osteosarcoma-selected lung metastatic lesions highly metastatic lines than in their respective low metastatic spontaneous and chemical carcinogen (4-hydroxyamino quinoline 1-oxide)-induced osteosarcoma counterparts. c-myc mRNA expression was observed in all tumor lines, without any correlation with metastatic ability. Southern blot analysis did not show evidence of gross rearrangement or amplification of NDP kinase/nm23, c-Ha-ras, or c-myc genes suggesting regulation of their gene expression at the transcriptional and/or posttranscriptional level. These results indicate that NDP kinase/nm23 and c-Ha-ras might be cooperatively involved in a positive manner in signal transduction processes, especially involving G-protein reactions, responsible for metastasis of rat-transplantable osteosarcomas.

¹ Supported in part by Grants-in-Aid for Cancer Research (02151066 to M. T. and 03670711 to Y. M.) from the Ministry of Education, Science and Culture and by a Grant-in-Aid to Y. K. from the Ministry of Health and Welfare for the Comprehensive 10-Year Strategy for Cancer Control, Japan.

² To whom requests for reprints should be addressed.

Received 5/24/93. Accepted 8/11/93.

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