Department of Internal Medicine-Oncology, The First Affiliated Hospital, Zhengzhou University, People's Republic of China.
Biochem Biophys Res Commun. 2010 Jan 1;391(1):1070-4. doi: 10.1016/j.bbrc.2009.12.022. Epub 2009 Dec 10.
Cystatin M is a secreted inhibitor of lysosomal cysteine proteases and increasing evidences indicate that it is a novel target for epigenetic silencing during mammary tumorigenesis. Aberrant promoter methylation is a well-known mechanism that participates in cystatin M silencing in breast cancer. However, the role of cystatin M in the gastric cancer remains to be elucidated. Immunohistochemistry was used to investigate the expression of cystatin M in 60 gastric carcinomas. Hypermethylation of cystatin M promoter was evaluated by the methylation-specific PCR (MSP) method in gastric carcinomas (tumor and paired adjacent non-tumor tissues). Reverse-transcriptase PCR and BSP were also performed on gastric cancer cell lines before and after treatment with 5-aza-2'-deoxycytidine (5-Aza-dC). Lost expression of cystatin M was observed in 42 of 60 (70%) gastric carcinomas. 55% (33 of 60) of primary tumors analyzed displayed cystatin M promoter hypermethylation, indicating that this aberrant characteristic is common in gastric malignancies. Moreover, a statistically significant inverse association was found between cystatin M methylation status and expression of the cystatin M protein in tumor tissues (p=0.027). We also found that patients with cystatin M promoter methylation had a significantly shorter survival time than those without this methylation (p=0.020). These results suggest that cystatin M promoter hypermethylation is one of the molecular mechanisms that accounts for reduced cystatin M gene expression in gastric carcinomas.
半胱氨酸蛋白酶抑制剂 M 是一种分泌型溶酶体半胱氨酸蛋白酶抑制剂，越来越多的证据表明它是乳腺癌发生过程中表观遗传沉默的新靶点。启动子异常甲基化是导致乳腺癌中胱抑素 M 沉默的一种已知机制。然而，胱抑素 M 在胃癌中的作用仍有待阐明。免疫组织化学法检测 60 例胃癌中胱抑素 M 的表达。采用甲基化特异性 PCR（MSP）法检测胃癌（肿瘤及配对的癌旁非肿瘤组织）中胱抑素 M 启动子的甲基化。胃癌细胞系经 5-氮杂-2'-脱氧胞苷（5-Aza-dC）处理前后进行逆转录 PCR 和 BSP。在 60 例胃癌中有 42 例（70%）观察到胱抑素 M 的表达缺失。在 60 例原发性肿瘤中，有 33 例（55%）显示胱抑素 M 启动子异常甲基化，表明这种异常特征在胃恶性肿瘤中较为常见。此外，在肿瘤组织中，胱抑素 M 甲基化状态与胱抑素 M 蛋白表达之间存在显著的负相关关系（p=0.027）。我们还发现，胱抑素 M 启动子甲基化患者的生存时间明显短于非甲基化患者（p=0.020）。这些结果表明，胱抑素 M 启动子异常甲基化是导致胃癌中胱抑素 M 基因表达降低的分子机制之一。
