Epigenetic silencing of the adhesion molecule ADAM23 is highly frequent in breast tumors
Epigenetic silencing of the adhesion molecule ADAM23 is highly frequent in breast tumors
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DOI：
10.1038/sj.onc.1207263
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发表时间：
2004-02-19
期刊：
影响因子：
8
通讯作者：
Camargo, AA
中科院分区：
文献类型：
--
作者：
Costa, FF;Verbisck, NV;Camargo, AA
细胞黏附的改变与肿瘤的发展密切相关，识别肿瘤中发生改变的黏附分子对于我们理解肿瘤生物学以及发展新的预后和治疗策略至关重要。在这里，我们提供了A去整合素和金属蛋白酶结构域23基因(ADAM 23)在乳腺肿瘤中表观遗传下调的证据，ADAM 23是一个新的表面分子家族的成员，在细胞-细胞黏附和/或细胞基质相互作用中发挥作用。我们检测了不同乳腺肿瘤细胞系和原发乳腺肿瘤中ADAM23基因上游50区的mRNA表达和甲基化状态。我们发现ADAM2350高甲基化存在于12个肿瘤细胞系中的8个(66.7%)和13个原发肿瘤中的9个(69.2%)。启动子高甲基化与mRNA和蛋白质表达的降低密切相关，需要40-60%的修饰CpG二核苷酸才能完全沉默ADAM23的mRNA表达。5‘-氮杂-2’-脱氧胞苷处理MCF-7和SKBR-3细胞后，ADAM23基因表达重新激活，甲基化水平显著降低。值得注意的是，恶性程度越高的原发乳腺肿瘤甲基化程度越高，提示黏附分子ADAM23在乳腺癌进展过程中可能下调。
Altered cell adhesion is causally involved in tumor progression, and the identification of novel adhesion molecules altered in tumors is crucial for our understanding of tumor biology and for the development of new prognostic and therapeutic strategies. Here, we provide evidence for the epigenetic downregulation in breast tumors of the A Desintegrin And Metalloprotease domain 23 gene ( ADAM 23), a member of a new family of surface molecules with roles in cell - cell adhesion and/or cell matrix interactions. W e examined the mRNA expression and methylation status of the 50 upstream region of the ADAM23 gene in different breast tumor cell lines as well as in primary breast tumors. We found ADAM23 50 hypermethylation in eight out of 12 (66.7%) tumor cell lines and in nine out of 13 (69.2%) primary tumors. Promoter hypermethylation was strongly associated with reductions in both mRNA and protein expression, with a threshold of 40 - 60% of modified CpG dinucleotides being required for the complete silencing of ADAM23 mRNA expression. Treatment of MCF-7 and SKBR-3 cell lines with 5'-Aza-2'-deoxycytidine led to a reactivation of ADAM23 mRNA expression and a marked decrease in the methylation level. It is worth noting that primary breast tumors with a more advanced grade showed a higher degree of methylation, suggesting that the adhesion molecule ADAM23 may be downregulated during the progression of breast cancer.