Vogt T, Stolz W, Welsh J, Jung B, Kerbel R S, Kobayashi H, Landthaler M, McClelland M
Sidney Kimmel Cancer Center, San Diego, California 92121, USA.
Clin Cancer Res. 1998 Mar;4(3):791-7.
The Lerks, ligands of eph-related receptor tyrosine kinases, are a rapidly expanding family of genes thought to play an important role in the development and oncogenesis of various tissues. However, very little experimental evidence supports this hypothesis. Using RNA fingerprinting, we detected increased expression of Lerk-5 mRNA in human melanocytes as a response to the tumor-promoting drug 12-O-tetradecanoylphorbol-13-acetate, which suggests a possible role of the Lerks in melanoma tumorigenesis and progression. Therefore, we studied Lerk-5 mRNA expression in various melanoma cell lines and tissues of melanocytic tumors by semiquantitative reverse transcription-PCR. Modest expression of Lerk-5 mRNA was found in two melanoma cell lines derived from early primary tumors (WM35 and WM1645B); two metastatic cell lines tested showed a 3.9-fold increased transcript abundance when compared to the primary cell lines (RPMI-7951 and SK-Mel5). Progeny of a melanoma cell line with very low Lerk-5 mRNA abundance (WM35) showed a 5-fold increase in Lerk-5 mRNA expression when it was selected for higher tumorigenicity and multicytokine resistance by passaging in nude mice or repeated high-dose UVB irradiation. Consistent with these experimental data, we found high levels of Lerk-5 mRNA expression in advanced primary malignant melanomas and metastases (n = 22) but significantly lower or undetectable mRNA expression in benign melanocytic nevi (n = 9; P < 0.001). We conclude that increased Lerk-5 expression possibly reflects or induces an increased potential of growth, tumorigenicity, and metastatic abilities in human melanomas. This makes the yet to be elucidated eph-related receptor tyrosine kinase/Lerk signaling system a potential new source for molecular markers as well as a target for new therapies.
Lerks是Eph相关受体酪氨酸激酶的配体，是一个迅速扩展的基因家族，被认为在各种组织的发育和肿瘤发生中起重要作用。然而，很少有实验证据支持这一假说。利用RNA指纹图谱技术，我们检测到在人黑素细胞中，促肿瘤药物12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯可使Lerk - 5 mRNA表达增加，这提示Lerks在黑色素瘤的肿瘤发生和进展中可能发挥作用。因此，我们通过半定量逆转录 - PCR研究了Lerk - 5 mRNA在各种黑色素瘤细胞系和黑素细胞瘤组织中的表达。在源自早期原发性肿瘤的两个黑色素瘤细胞系（WM35和WM1645B）中发现了适度的Lerk - 5 mRNA表达；与原发性细胞系（RPMI - 7951和SK - Mel5）相比，测试的两个转移细胞系的转录本丰度增加了3.9倍。Lerk - 5 mRNA丰度非常低的黑色素瘤细胞系（WM35）的子代，在通过裸鼠传代或反复高剂量UVB照射选择具有更高致瘤性和多细胞因子抗性时，Lerk - 5 mRNA表达增加了5倍。与这些实验数据一致，我们发现在晚期原发性恶性黑色素瘤和转移灶（n = 22）中Lerk - 5 mRNA表达水平很高，但在良性黑素细胞痣（n = 9；P < 0.001）中mRNA表达显著较低或无法检测到。我们得出结论，Lerk - 5表达增加可能反映或诱导人黑色素瘤生长、致瘤性和转移能力的增加。这使得尚未阐明的Eph相关受体酪氨酸激酶/Lerk信号系统成为分子标志物的潜在新来源以及新疗法的靶点。
