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The Low Molecular Weight Cyclin E Isoforms Augment Angiogenesis and Metastasis of Human Melanoma Cells In vivo

¹ Huffington Center on Aging; Departments of ² Molecular and Cellular Biology, ³ Dermatology, and ⁴ Pathology, Baylor College of Medicine; Departments of ⁵ Cancer Biology and ⁶ Experimental Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; and ⁷ Laboratory of Morphology and Molecular Pathology, University Hospitals, Katholieke Universiteit Leuven, Leuven, Belgium

Requests for reprints: Estela E. Medrano, Baylor College of Medicine, One Baylor Plaza M-320, Houston, TX 77030. Phone: 713-798-1569; Fax: 713-798-4161. E-mail: medrano{at}bcm.tmc.edu.

Immunohistochemical analysis has consistently shown that cyclin E is up-regulated in human malignant melanomas in vivo. Here we analyzed such expression in more detail and show that cyclin E is overexpressed and present in low molecular weight (LMW) isoforms in metastatic melanoma and in a subset of primary invasive melanoma tumor tissues, but not in benign nevi. Human metastatic melanoma cell lines, but not normal melanocytes, also expressed the LMW cyclin E forms. The biological significance of these findings was established by showing that overexpression of two LMW cyclin E forms named cyclin E truncated 1 [cyclinE(T1)] and cyclin E truncated 2 [cyclinE(T2)] in a low tumorigenic and non-metastatic primary cutaneous melanoma cell line generated angiogenic tumors with prominent perineural invasion compared with full-length cyclin E. In addition, cyclin E(T1)– and cyclin E(T2)–expressing melanoma cells displayed a dramatic increase in the incidence and number of metastases in an experimental lung metastasis assay. Together, these results indicate that the LMW cyclin E forms are functional and likely act as regulators of human melanoma tumor progression and invasion.

Key Words: human melanoma • cell cycle regulators • cyclin E

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