Horne Hisani N, Lee Paula S, Murphy Susan K, Alonso Miguel A, Olson John A, Marks Jeffrey R
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
Mol Cancer Res. 2009 Feb;7(2):199-209. doi: 10.1158/1541-7786.MCR-08-0314. Epub 2009 Feb 10.
Dysregulation of MAL (myelin and lymphocyte protein) has been implicated in several malignancies including esophageal, ovarian, and cervical cancers. The MAL protein functions in apical transport in polarized epithelial cells; therefore, its disruption may lead to loss of organized polarity characteristic of most solid malignancies. Bisulfite sequencing of the MAL promoter CpG island revealed hypermethylation in breast cancer cell lines and 69% of primary tumors analyzed compared with normal breast epithelial cells. Differential methylation between normal and cancer DNA was confined to the proximal promoter region. In a subset of breast cancer cell lines including T47D and MCF7 cells, promoter methylation correlated with transcriptional silencing that was reversible with the methylation inhibitor 5-aza-2'-deoxycytidine. In addition, expression of MAL reduced motility and resulted in a redistribution of lipid raft components in MCF10A cells. MAL protein expression measured by immunohistochemistry revealed no significant correlation with clinicopathologic features. However, in patients who did not receive adjuvant chemotherapy, reduced MAL expression was a significant predictive factor for disease-free survival. These data implicate MAL as a commonly altered gene in breast cancer with implications for response to chemotherapy.
MAL（髓鞘和淋巴细胞蛋白）失调与包括食管癌、卵巢癌和宫颈癌在内的多种恶性肿瘤有关。MAL蛋白在极化上皮细胞的顶端运输中发挥作用；因此，其破坏可能导致大多数实体恶性肿瘤所特有的有组织极性丧失。对MAL启动子CpG岛进行亚硫酸氢盐测序发现，与正常乳腺上皮细胞相比，乳腺癌细胞系和69%的分析原发性肿瘤中存在高甲基化。正常DNA和癌症DNA之间的差异甲基化局限于近端启动子区域。在包括T47D和MCF7细胞在内的一部分乳腺癌细胞系中，启动子甲基化与转录沉默相关，而这种沉默可被甲基化抑制剂5-氮杂-2'-脱氧胞苷逆转。此外，MAL的表达降低了MCF10A细胞的运动性，并导致脂筏成分重新分布。通过免疫组织化学测量的MAL蛋白表达与临床病理特征无显著相关性。然而，在未接受辅助化疗的患者中，MAL表达降低是无病生存的一个重要预测因素。这些数据表明MAL是乳腺癌中一种常见的改变基因，对化疗反应有影响。
