Onken Michael D, Worley Lori A, Harbour J William
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA.
Clin Cancer Res. 2008 Jun 15;14(12):3737-45. doi: 10.1158/1078-0432.CCR-07-5144.
To identify genes that modify metastatic risk in uveal melanoma, a type of cancer that is valuable for studying metastasis because of its remarkably consistent metastatic pattern and well-characterized gene expression signature associated with metastasis.
We analyzed 53 primary uveal melanomas by gene expression profiling, array-based comparative genomic hybridization, array-based global DNA methylation profiling, and single nucleotide polymorphism-based detection of loss of heterozygosity to identify modifiers of metastatic risk. A candidate gene, leucine zipper tumor suppressor-1 (LZTS1), was examined for its effect on proliferation, migration, and motility in cultured uveal melanoma cells.
In metastasizing primary uveal melanomas, deletion of chromosome 8p12-22 and DNA hypermethylation of the corresponding region of the retained hemizygous 8p allele were associated with more rapid metastasis. Among the 11 genes located within the deleted region, LZTS1 was most strongly linked to rapid metastasis. LZTS1 was silenced in rapidly metastasizing and metastatic uveal melanomas but not in slowly metastasizing and nonmetastasizing uveal melanomas. Forced expression of LZTS1 in metastasizing uveal melanoma cells inhibited their motility and invasion, whereas depletion of LZTS1 increased their motility.
We have described a metastatic modifier locus on chromosome 8p and identified LZTS1 as a potential metastasis suppressor within this region. This study shows the utility of integrative genomic methods for identifying modifiers of metastatic risk in human cancers and may suggest new therapeutic targets in metastasizing tumor cells.
鉴定可改变葡萄膜黑色素瘤转移风险的基因。葡萄膜黑色素瘤是一种癌症，因其显著一致的转移模式以及与转移相关的特征明确的基因表达特征，对于研究转移具有重要价值。
我们通过基因表达谱分析、基于芯片的比较基因组杂交、基于芯片的全基因组DNA甲基化分析以及基于单核苷酸多态性的杂合性缺失检测，对53例原发性葡萄膜黑色素瘤进行分析，以鉴定转移风险的调节因子。对一个候选基因亮氨酸拉链肿瘤抑制因子1（LZTS1）在培养的葡萄膜黑色素瘤细胞中对增殖、迁移和运动能力的影响进行了研究。
在发生转移的原发性葡萄膜黑色素瘤中，8号染色体p12 - 22区域的缺失以及保留的半合子8p等位基因相应区域的DNA高甲基化与更快的转移相关。在缺失区域内的11个基因中，LZTS1与快速转移的联系最为紧密。LZTS1在快速转移和已转移的葡萄膜黑色素瘤中沉默，但在缓慢转移和未转移的葡萄膜黑色素瘤中未沉默。在发生转移的葡萄膜黑色素瘤细胞中强制表达LZTS1可抑制其运动和侵袭能力，而敲低LZTS1则增加其运动能力。
我们描述了8号染色体p上的一个转移调节位点，并鉴定出LZTS1是该区域内潜在的转移抑制因子。本研究显示了整合基因组方法在鉴定人类癌症转移风险调节因子方面的实用性，并可能为转移肿瘤细胞提示新的治疗靶点。
