Miele M E, Robertson G, Lee J H, Coleman A, McGary C T, Fisher P B, Lugo T G, Welch D R
Department of Experimental Pathology, The Pennsylvania State University College of Medicine, Hershey, PA 17033-0850, USA.
Mol Carcinog. 1996 Apr;15(4):284-99. doi: 10.1002/(SICI)1098-2744(199604)15:4<284::AID-MC6>3.0.CO;2-G.
Progression of human melanoma toward increasing malignant behavior is associated with several nonrandom chromosomal aberrations, most commonly involving chromosomes 1, 6, 7, 9, and 10. We previously showed that introduction of human chromosome 6 into the highly metastatic human malignant melanoma cell line C8161 completely suppressed metastasis without altering tumorigenicity (Welch DR, Chen P, Miele ME, et al., Oncogene 9:255-262, 1994). Alterations of chromosome 1 are the most frequent chromosome abnormality observed in melanomas, and they frequently arise late in tumor progression. The purpose of the study presented here was to compare the effects of chromosomes 1 and 6 on malignant melanoma metastasis. By using microcell-mediated chromosome transfer, single copies of neo-tagged human chromosomes 1 or 6 were introduced into the human melanoma cell line MelJuSo. The presence of the added chromosome was verified by G banding of karyotypes, fluorescence in situ hybridization, and screening for polymorphic markers on each chromosome. The incidence and number of metastases per lung after intravenous or intradermal injection of parental MelJuSo cells was significantly (P<0.01) greater than those of hybrids containing either chromosome 1 or chromosome 6, although chromosome 1 was a less potent inhibitor of metastasis than chromosome 6. Cultures established from primary tumors and metastases remained neomycin resistant, suggesting that portions of the added chromosomes were retained. These results strengthen the evidence for the presence of a melanoma metastasis suppressor gene on chromosome 6. neo6/MelJuSo hybrids expressed 2.4- to 3.4-fold more of the melanoma differentiation-associated gene mda-6 (previously shown to be identical to WAF1/CIP1/Sdi1/CAP20) than parental metastatic cells. mda-6/WAF1 is among the candidate genes on chromosome 6. These results also demonstrate, for the first time, the existence of metastasis suppressor genes on human chromosome 1, although these genes appear to be less potent than the one encoded on chromosome 6.
人类黑色素瘤向恶性程度增加的进展与几种非随机染色体畸变相关，最常见的涉及染色体1、6、7、9和10。我们之前表明，将人类6号染色体导入高转移性人类恶性黑色素瘤细胞系C8161可完全抑制转移，而不改变致瘤性（韦尔奇·DR、陈·P、米耶勒·ME等，《癌基因》9:255 - 262，1994）。1号染色体的改变是黑色素瘤中最常见的染色体异常，且它们常在肿瘤进展后期出现。本文所述研究的目的是比较1号和6号染色体对恶性黑色素瘤转移的影响。通过微细胞介导的染色体转移，将新标记的人类1号或6号染色体的单拷贝导入人类黑色素瘤细胞系MelJuSo。通过核型G显带、荧光原位杂交以及筛选每条染色体上的多态性标记来验证添加染色体的存在。静脉内或皮内注射亲代MelJuSo细胞后，每只肺的转移发生率和转移数量显著（P<0.01）高于含有1号或6号染色体的杂交细胞，尽管1号染色体作为转移抑制剂的效力低于6号染色体。从原发性肿瘤和转移灶建立的培养物仍对新霉素耐药，表明添加染色体的部分得以保留。这些结果进一步证明了6号染色体上存在黑色素瘤转移抑制基因。neo6/MelJuSo杂交细胞比亲代转移性细胞表达的黑色素瘤分化相关基因mda - 6（先前显示与WAF1/CIP1/Sdi1/CAP20相同）多2.4至3.4倍。mda - 6/WAF1是6号染色体上的候选基因之一。这些结果还首次证明了人类1号染色体上存在转移抑制基因，尽管这些基因的效力似乎低于6号染色体上编码基因的效力。
