KiSS-1, a novel human malignant melanoma metastasis-suppressor gene
KiSS-1, a novel human malignant melanoma metastasis-suppressor gene
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DOI：
10.1093/jnci/88.23.1731
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发表时间：
1996-12-04
影响因子：
10.3
通讯作者：
Welch, DR
中科院分区：
文献类型：
--
作者：
Lee, JH;Miele, ME;Welch, DR
背景：微细胞介导的6号染色体转移到人C8161和MelJuSo黑色素瘤细胞中，在不影响其致瘤性的情况下，可抑制其转移能力至少95%。这一观察表明，转移能力是一种不同于肿瘤形成的表型，并表明致瘤细胞只有在积累了额外的遗传缺陷后才获得转移能力。这些结果还表明，6号染色体上的基因突变是导致转移潜力的晚期基因变化之一。他们进一步推测，一个黑色素瘤转移抑制基因(S)编码在6号染色体上或受6号染色体上的基因调控。目的：我们的目的是确定在6号染色体/黑色素瘤细胞杂交中抑制转移的基因(S)。方法：采用改进的消减杂交技术，通过互补DNA(CDNAs)分析比较转移细胞(C8161或MeljuSo)和非转移杂交克隆(ne6/C8161或ne6/MeljuSo)中信使RNA(MRNAs)的表达。结果：从恶性黑色素瘤细胞中分离到一个新的基因，命名为KiSS-1。Northern杂交分析表明，KiSS-1mRNA仅在非转移性黑色素瘤细胞中表达。Northern印迹分析未检测到该基因在正常心脏、脑、肝、肺和骨骼肌中的表达。肾脏和胰腺中表达较弱，胎盘中表达最强。KiSS-1基因编码一个主要由164个氨基酸组成的亲水性蛋白质，其富含多脯氨酸的结构域指示SH3配体(与癌蛋白Src的同源3结构域结合)和一个可能的蛋白激酶C-α磷酸化位点。将全长KiSS-1基因导入C8161黑色素瘤细胞，以一种表达依赖的方式抑制转移。结论：KiSS-1表达可能抑制恶性黑色素瘤细胞的转移潜能，提示KiSS-1可能是区分转移性黑色素瘤和非转移性黑色素瘤的有用标记物。
Background: Microcell-mediated transfer of chromosome 6 into human C8161 and MelJuSo melanoma cells suppresses their ability to metastasize by at least 95% without affecting their tumorigenicity. This observation demonstrates that the ability to metastasize is a phenotype distinct from tumor formation and suggests that tumorigenic cells acquire metastatic capability only after accumulating additional genetic defects. These results also imply that mutations of genes on chromosome 6 are among those late genetic changes responsible for metastatic potential. They further suggest that a melanoma metastasis-suppressor gene(s) is encoded on chromosome 6 or is regulated by genes on chromosome 6. Purpose: Our objective was to identify the gene(s) responsible for the suppression of metastasis in chromosome 6/melanoma cell hybrids. Methods: A modified subtractive hybridization technique was used to compare the expression of messenger RNAs (mRNAs), via an analysis of complementary DNAs (cDNAs), in metastatic cells (C8161 or MelJuSo) and nonmetastatic hybrid clones (neo6/C8161 or neo6/MelJuSo). Results: A novel cDNA, designated KiSS-1, was isolated from malignant melanoma cells that had been suppressed for metastatic potential by the introduction of human chromosome 6. Northern blot analyses comparing mRNAs from a panel of human melanoma cells revealed that KiSS-1 mRNA expression occurred only in nonmetastatic melanoma cells. Expression of this mRNA in normal heart, brain, liver, lung, and skeletal muscle was undetectable by northern blot analysis. Weak expression was found in the kidney and pancreas, but the highest expression was observed in the placenta. The KiSS-1 cDNA encodes a predominantly hydrophilic, 164 amino acid protein with a polyproline-rich domain indicative of an SH3 ligand (binds to the homology 3 domain of the oncoprotein Src) and a putative protein-kinase C-alpha phosphorylation site. Transfection of a full-length KiSS-1 cDNA into C8161 melanoma cells suppressed metastasis in an expression-dependent manner. Conclusions: These data strongly suggest that KiSS-1 expression may suppress the metastatic potential of malignant melanoma cells, implications: KiSS-1 may be a useful marker for distinguishing metastatic melanomas from nonmetastatic melanomas.