CMTM5 exhibits tumor suppressor activities and is frequently silenced by methylation in carcinoma cell lines
CMTM5 exhibits tumor suppressor activities and is frequently silenced by methylation in carcinoma cell lines
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DOI：
10.1158/1078-0432.ccr-06-3082
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发表时间：
2007-10-01
影响因子：
11.5
通讯作者：
Ta, Qian
中科院分区：
文献类型：
--
作者：
Shao, Luning;Cui, Yan;Ta, Qian
目的：CMTM 5（CKLF-like MARVEL transmembrane domain containing member 5）位于14q11.2，是一个与多种癌症相关的基因座。它有六个RNA剪接变体，其中CMTM 5-v1为主要变体。我们探讨了它在正常组织和肿瘤细胞系中的表达模式，以及它在癌细胞中的功能。实验设计：我们评估CMTM 5的表达，通过半定量逆转录-PCR（RT-PCR）在正常组织和癌细胞系的宫颈，乳腺，鼻咽，肺，肝细胞，食管，胃，结肠和前列腺。我们进一步检查了这些细胞系中的CMTM 5启动子甲基化。结果：CMTM 5-v1在人正常成人和胎儿组织中广泛表达，但在大多数肿瘤细胞系中表达不明显或下调。在几乎所有沉默或下调的细胞系中检测到其启动子甲基化。CMTM 5的沉默可以通过药物去甲基化或DNMT 1和DNMT 3B的基因双敲除来逆转，表明甲基化介导的机制。CMTM 5-vl的恢复抑制癌细胞增殖、迁移和侵袭。结论：这些结果表明CMTM 5具有肿瘤抑制活性，但在癌细胞系中具有频繁的表观遗传失活。
Purpose: CMTM5 (CKLF-like MARVEL transmembrane domain containing member 5) is located at 14q11.2, a locus associated with multiple cancers. It has six RNA splicing variants with CMTM 5-v1 as the major one. We explored its expression pattern in normal tissues and tumor cell lines, as well as its functions in carcinoma cells.Experimental Design: We evaluated CMTM5 expression by semiquantitative reverse transcription-PCR (RT-PCR) in normal tissues and carcinoma cell lines of cervical, breast, nasopharyngeal, lung, hepatocellular, esophageal, gastric, colon, and prostate. We further examined CMTM5 promoter methylation in these cell lines. We also analyzed CMTM5 expression after 5-aza2'-deoxycytidine treatment and genetic demethylation and the functional consequences of restoring CMTM5 in HeLa and PC-3 cells.Results: CMTM5-v1 is broadly expressed in human normal adult and fetal tissues, but undetectable or down-regulated in most carcinoma cell lines. Its promoter methylation was detected in virtually all the silenced or down-regulated cell lines. The silencing of CMTM5 could be reversed by pharmacologic demethylation or genetic double-knockout of DNMT1 and DNMT3B, indicating methylation- mediated mechanism. Restoration of CMTM5-vl suppressed carcinoma cell proliferation, migration, and invasion.Conclusions: These results indicate that CMTM5 exhibits tumor suppressor activities, but with frequent epigenetic inactivation in carcinoma cell lines.