Epigenetic silencing of MAL, a putative tumor suppressor gene, can contribute to human epithelium cell carcinoma.-猫眼课题宝

MAL（一种假定的肿瘤抑制基因）的表观遗传沉默可能导致人类上皮细胞癌

DOI：

10.1186/1476-4598-9-296

发表时间：

2010-11-22

期刊：

Molecular cancer

影响因子：

37.3

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

Cao W;Zhang ZY;Xu Q;Sun Q;Yan M;Zhang J;Zhang P;Han ZG;Chen WT

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002926/?report=classic

背景为了在头颈部鳞状细胞癌（HNSCC）中鉴定新的和有用的候选生物标志物，我们进行了全基因组调查，发现髓磷脂和淋巴细胞相关蛋白（MAL）是在HNSCC中显著下调的基因。因此，我们研究的机制ofMALsilencing和影响ofMALon的增殖，侵袭，和凋亡的潜力在HNSCC.ResultsMAL91.7%的HNSCC标本在mRNA水平上显着下调相比，与邻近的正常组织（P= 0.0004）。此外，与正常头颈部上皮细胞相比，9个HNSCC细胞株中MAL基因的相对转录水平显著降低了5倍，TSA、5-Aza-dC和TSA +5-Aza-dC处理后的HNSCC细胞株中MAL基因表达恢复率分别为44%、67%和89%。硫酸氢盐处理的DNA测序结果显示，HNSCC细胞系中位于MAL启动子区的两个CpG岛（M1和M2）完全甲基化（CpG甲基化率> 90%），而HNSCC组织中只有一个CpG岛（M1）部分甲基化（CpG甲基化率在20%~ 90%之间）。在MAL转染子中也观察到细胞增殖的显著减少和细胞周期谱的改变。Matrigel法显示HNSCC细胞的侵袭力明显降低。在MAL转染的细胞中观察到凋亡细胞的数量显著增加。MAL基因的外源性表达抑制恶性表型，而MAL基因转移诱导的细胞死亡是细胞凋亡的结果，如通过诱导聚（即ADP-核糖）聚合酶的裂解所证明的。此外，肿瘤的生长被抑制在细胞expressingMALas相比，细胞not expressingMAL.ConclusionOur的数据表明，表观遗传失活的MAL，作为一个候选的肿瘤抑制基因，可以有助于人类上皮细胞癌，并可能作为一个生物标志物在HNSCC。

BackgroundTo identify new and useful candidate biomarkers in head and neck squamous cell carcinoma (HNSCC), we performed a genome-wide survey and found that Myelin and lymphocyte-associated protein (MAL) was a gene that was markedly down-regulated in HNSCC. Hence, we investigated the mechanism ofMALsilencing and the effects ofMALon the proliferation, invasion, and apoptotic potential in HNSCC.ResultsMALwas significantly down-regulated in 91.7% of HNSCC specimens at the mRNA level as compared with adjacent normal tissues (P= 0.0004). Moreover, the relative transcript levels of theMALgene were remarkably decreased by five-fold in nine HNSCC cell lines as compared with normal head and neck epithelium cells.MALgene expression was restored in 44%, 67%, and 89% in HNSCC cell lines treated with TSA, 5-Aza-dC, and TSA plus 5-Aza-dC, respectively. Furthermore, bisulfate-treated DNA sequencing demonstrated that the two CpG islands (that is, M1and M2) located inMALpromoter region were completely methylated in the HNSCC cell lines (CpG methylated ratio was more than 90%), and only one CpG island (that is, M1) was partially methylated in HNSCC tissues (CpG methylated ratio between 20% and 90%). A significant reduction in cell proliferation and a change in the cell cycle profile were also observed inMALtransfectants. Matrigel assay demonstrated that the invasiveness of HNSCC cells significantly decreased. A significant increase in the population of apoptotic cells was observed inMALtransfected cells. The exogenous expression of theMALgene suppressed malignant phenotypes, while the cell death induced byMALgene transfer was a result of apoptosis as demonstrated by the induction of cleavage of the poly (that is, ADP-ribose) polymerase. Additionally, tumor growth was suppressed in cells expressingMALas compared with cells not expressingMAL.ConclusionOur data suggest that the epigenetic inactivation ofMAL, as a candidate tumor suppressor gene, can contribute to human epithelial cell carcinoma and may be served as a biomarker in HNSCC.