Suppression of C8161 melanoma metastatic ability by chromosome 6 induces differentiation-associated tyrosinase and decreases proliferation on adhesion-restrictive substrates mediated by overexpression of p21WAF1 and down-regulation of bcl-2 and cyclin D3.
Metastatic tumors grow under conditions that restrict proliferation of non-metastatic, more differentiated cells. To investigate this prediction, we developed a simple adhesion-restrictive assay which allows proliferation of human metastatic C8161 melanoma, but prevents growth of neo 6.3/C8161 cells in which metastasis is suppressed by introduction of neo-tagged chromosome 6. We show that tyrosinase, a key enzyme in melanocytic cell differentiation, and expression of chromosome 6-encoded cell cycle modulators like p21WAF1 and cyclin D3 is selectively increased in C8161 tumors in which metastasisis is suppressed by chromosome 6. In the latter cells, growth arrest evidenced only under adhesion-restrictive conditions correlated with down-regulation of cyclin D3 and anti-apoptotic bcl-2. No comparable growth arrest or down-regulation was detected under comparable conditions in metastatic cells, which showed activation of invasion-associated MMP-9 92 kDa gelatinase B. Our data suggests that the metastasis-suppressing effects of chromosome 6 involving increased differentiation-associated tyrosinase and growth arrest on adhesion-restrictive substrates; are partly mediated by modulation of growth regulators, like p21WAF1 and cyclin D3.
Strasberg Rieber
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IVIC, Tumor Cell Biology, Apartado 21827, Caracas, 1020 A, Venezuela.
Welch
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Rieber
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D000818:Animals; D017209:Apoptosis; D002448:Cell Adhesion; D002454:Cell Differentiation; D002455:Cell Division; D002896:Chromosomes, Human, Pair 6; D056743:Cyclin D3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D015536:Down-Regulation; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008545:Melanoma / Q000235:genetics*; D051379:Mice; D016513:Mice, SCID; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000235:genetics*; D009368:Neoplasm Transplantation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013489:Suppression, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
C534696:CCND3 protein, human; C493956:CDKN1A protein, human; C534697:Ccnd3 protein, mouse; C493957:Cdkn1a protein, mouse; D056743:Cyclin D3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019253:Proto-Oncogene Proteins c-bcl-2; D014442:Monophenol Monooxygenase; D018093:Gelatinases; D020780:Matrix Metalloproteinase 9