Simonova Olga A, Kuznetsova Ekaterina B, Tanas Alexander S, Rudenko Viktoria V, Poddubskaya Elena V, Kekeeva Tatiana V, Trotsenko Ivan D, Larin Sergey S, Kutsev Sergei I, Zaletaev Dmitry V, Nemtsova Marina V, Strelnikov Vladimir V
Molecular Genetic Diagnostics Laboratory 2, Research Centre for Medical Genetics, Moskvorechie St 1, 115522 Moscow, Russia.
Epigenetics Laboratory, Research Centre for Medical Genetics, Moskvorechie St 1, 115522 Moscow, Russia.
Biomedicines. 2020 May 10;8(5):116. doi: 10.3390/biomedicines8050116.
Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) substantially contribute to the regulation of intercellular interactions and thereby play a role in maintaining the tissue structure and function. We examined methylation of a subset of 5'-cytosine-phosphate-guanine-3' (CpG) dinucleotides in promoter regions of the , , and genes by methylation-sensitive restriction enzyme digestion PCR. In our collection of 183 breast cancer samples, abnormal hypermethylation was observed for CpGs in , and promoter regions. The non-methylated status of the examined CpGs in promoter regions of , and in tumors was associated with low HER2 expression, while the group of samples with abnormal hypermethylation of at least two of these MMP genes was significantly enriched with HER2-positive tumors. Abnormal methylation of and was significantly associated with a CpG island hypermethylated breast cancer subtype discovered by genome-wide DNA bisulfite sequencing. Our results indicate that abnormal hypermethylation of at least several MMP genes promoters is a secondary event not directly functional in breast cancer (BC) pathogenesis. We suggest that it is elevated and/or ectopic expression, rather than methylation-driven silencing, that might link MMPs to tumorigenesis.
基质金属蛋白酶（MMPs）及其组织抑制剂（TIMPs）在很大程度上有助于调节细胞间相互作用，从而在维持组织结构和功能方面发挥作用。我们通过甲基化敏感限制性内切酶消化PCR检测了基质金属蛋白酶1（MMP1）、基质金属蛋白酶2（MMP2）和基质金属蛋白酶9（MMP9）基因启动子区域中一部分5'-胞嘧啶-磷酸-鸟嘌呤-3'（CpG）二核苷酸的甲基化情况。在我们收集的183份乳腺癌样本中，观察到MMP1、MMP2和MMP9启动子区域的CpG存在异常高甲基化。肿瘤中MMP1、MMP2和MMP9启动子区域检测的CpG的非甲基化状态与低HER2表达相关，而这些MMP基因中至少有两个存在异常高甲基化的样本组中HER2阳性肿瘤显著富集。MMP1和MMP9的异常甲基化与通过全基因组DNA亚硫酸氢盐测序发现的一种CpG岛高甲基化乳腺癌亚型显著相关。我们的结果表明，至少几个MMP基因启动子的异常高甲基化是乳腺癌（BC）发病机制中并非直接起作用的次要事件。我们认为，可能是MMPs的表达升高和/或异位表达，而非甲基化驱动的沉默，将MMPs与肿瘤发生联系起来。
