OVEREXPRESSION OF LERK-5 EPLG5 MESSENGER-RNA - A NOVEL MARKER FOR INCREASED TUMORIGENICITY AND METASTATIC POTENTIAL IN HUMAN-MALIGNANT MELANOMAS/

The Lerks, ligands of eph-related receptor tyrosine kinases, are a rap idly expanding family of genes thought to play an important role in th e development and oncogenesis of various tissues, However, very little experimental evidence supports this hypothesis, Using RNA fingerprint ing, we detected increased expression of Lerk-5 mRNA in human melanocy tes as a response to the tumor-promoting drug 12-O-tetradecanoylphorbo l-13-acetate, which suggests a possible role of the Lerks in melanoma tumorigenesis and progression, Therefore, we studied Lerk-5 mRNA expre ssion in various melanoma cell lines and tissues of melanocytic tumors by semiquantitative reverse transcription-PCR, Modest expression of L erk-5 mRNA was found in two melanoma cell lines derived from early pri mary tumors (WM35 and WM1645B); two metastatic cell lines tested showe d a 3.9-fold increased transcript abundance when compared to the prima ry cell lines (RPMI-7951 and SK-MeI5), Progeny of a melanoma cell line with very low Lerk-5 mRNA abundance (WM35) showed a 5-fold increase i n Lerk-5 mRNA expression when it was selected for higher tumorigenicit y and multicytokine resistance by passaging in nude mice or repeated h igh-dose WE irradiation, Consistent with these experimental data, we f ound high levels of Lerk-5 mRNA expression in advanced primary maligna nt melanomas and metastases (n = 22) but significantly lower or undete ctable mRNA expression in benign melanocytic nevi (n = 9; P < 0.001), We conclude that increased Lerk-5 expression possibly reflects or indu ces an increased potential of growth, tumorigenicity, and metastatic a bilities in human melanomas, This makes the yet to be elucidated eph-r elated receptor tyrosine kinase/Lerk signaling system a potential new source for molecular markers as well as a target for new therapies.