Hong Chibo, Maunakea Alika, Jun Peter, Bollen Andrew W, Hodgson J Graeme, Goldenberg David D, Weiss William A, Costello Joseph F
Department of Neurological Surgery, Brain Tumor Research Center, University of California-San Francisco, San Francisco, California 94143-0875, USA.
Cancer Res. 2005 May 1;65(9):3617-23. doi: 10.1158/0008-5472.CAN-05-0048.
Tumors arise in part from the deleterious effects of genetic and epigenetic mechanisms on gene expression. In several mouse models of human tumors, the tumorigenic phenotype is reversible, suggesting that epigenetic mechanisms also contribute significantly to tumorigenesis in mice. It is not known whether these are the same epigenetic mechanisms in human and mouse tumors or whether they affect homologous genes. Using an integrated approach for genome-wide methylation and copy number analyses, we identified SLC5A8 on chromosome 12q23.1 that was affected frequently by aberrant methylation in human astrocytomas and oligodendrogliomas. SLC5A8 encodes a sodium monocarboxylate cotransporter that was highly expressed in normal brain but was significant down-regulated in primary gliomas. Bisulfite sequencing analysis showed that the CpG island was unmethylated in normal brain but frequently localized methylated in brain tumors, consistent with the tumor-specific loss of gene expression. In glioma cell lines, SLC5A8 expression was also suppressed but could be reactivated with a methylation inhibitor. Expression of exogenous SLC5A8 in LN229 and LN443 glioma cells inhibited colony formation, suggesting that it may function as a growth suppressor in normal brain cells. Remarkably, 9 of 10 murine oligodendroglial tumors (from p53+/- or ink4a/arf+/- animals transgenic for S100beta-v-erbB) showed a similar tumor-specific down-regulation of mSLC5A8, the highly conserved mouse homologue. Taken together, these data suggest that SLC5A8 functions as a growth suppressor gene in vitro and that it is silenced frequently by epigenetic mechanisms in primary gliomas. The shared epigenetic inactivation of mSLC5A8 in mouse gliomas indicates an additional degree of commonality in the origin and/or pathway to tumorigenesis between primary human tumors and these mouse models of gliomas.
肿瘤部分源于遗传和表观遗传机制对基因表达的有害影响。在几种人类肿瘤的小鼠模型中，致瘤表型是可逆的，这表明表观遗传机制在小鼠肿瘤发生中也起重要作用。目前尚不清楚人类和小鼠肿瘤中的这些表观遗传机制是否相同，或者它们是否影响同源基因。我们采用全基因组甲基化和拷贝数分析的综合方法，在12q23.1染色体上鉴定出SLC5A8，它在人类星形细胞瘤和少突胶质细胞瘤中经常受到异常甲基化的影响。SLC5A8编码一种单羧酸钠共转运体，在正常脑组织中高度表达，但在原发性胶质瘤中显著下调。亚硫酸氢盐测序分析表明，CpG岛在正常脑组织中未甲基化，但在脑肿瘤中经常出现局部甲基化，这与基因表达的肿瘤特异性缺失一致。在胶质瘤细胞系中，SLC5A8的表达也受到抑制，但可被甲基化抑制剂重新激活。在LN229和LN443胶质瘤细胞中外源表达SLC5A8可抑制集落形成，这表明它在正常脑细胞中可能作为生长抑制因子发挥作用。值得注意的是，10个鼠少突胶质细胞瘤中的9个（来自p53+/-或ink4a/arf+/-且转基因表达S100β-v-erbB的动物）显示出mSLC5A8（高度保守的小鼠同源物）有类似的肿瘤特异性下调。综合这些数据表明，SLC5A8在体外作为生长抑制基因发挥作用，并且在原发性胶质瘤中它经常通过表观遗传机制沉默。小鼠胶质瘤中mSLC5A8的共同表观遗传失活表明，原发性人类肿瘤与这些小鼠胶质瘤模型在肿瘤发生的起源和/或途径上存在额外程度的共性。
