Department of Oral and Maxillofacial Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Mol Cancer. 2010 Nov 22;9:296. doi: 10.1186/1476-4598-9-296.
To 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 of MAL silencing and the effects of MAL on the proliferation, invasion, and apoptotic potential in HNSCC.
MAL was 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 the MAL gene were remarkably decreased by five-fold in nine HNSCC cell lines as compared with normal head and neck epithelium cells. MAL gene 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, M1 and M2) located in MAL promoter 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 in MAL transfectants. Matrigel assay demonstrated that the invasiveness of HNSCC cells significantly decreased. A significant increase in the population of apoptotic cells was observed in MAL transfected cells. The exogenous expression of the MAL gene suppressed malignant phenotypes, while the cell death induced by MAL gene 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 expressing MAL as compared with cells not expressing MAL.
Our data suggest that the epigenetic inactivation of MAL, as a candidate tumor suppressor gene, can contribute to human epithelial cell carcinoma and may be served as a biomarker in HNSCC.
为了在头颈部鳞状细胞癌（HNSCC）中鉴定新的有用的候选生物标志物，我们进行了全基因组调查，发现髓鞘和淋巴细胞相关蛋白（MAL）是在 HNSCC 中明显下调的基因。因此，我们研究了 MAL 沉默的机制以及 MAL 对 HNSCC 增殖、侵袭和凋亡潜能的影响。
与相邻正常组织相比，MAL 在 91.7%的 HNSCC 标本中在 mRNA 水平显著下调（P = 0.0004）。此外，与正常头颈部上皮细胞相比，MAL 基因在 9 种 HNSCC 细胞系中的相对转录水平降低了 5 倍。在 TSA、5-Aza-dC 和 TSA 加 5-Aza-dC 处理的 HNSCC 细胞系中，MAL 基因表达分别恢复了 44%、67%和 89%。此外，亚硫酸氢盐处理的 DNA 测序表明，位于 MAL 启动子区域的两个 CpG 岛（即 M1 和 M2）在 HNSCC 细胞系中完全甲基化（CpG 甲基化率超过 90%），而在 HNSCC 组织中仅一个 CpG 岛（即 M1）部分甲基化（CpG 甲基化率在 20%至 90%之间）。MAL 转染也观察到细胞增殖显著减少和细胞周期谱改变。Matrigel 测定表明 HNSCC 细胞的侵袭性显著降低。在 MAL 转染的细胞中观察到凋亡细胞群体显著增加。外源性表达 MAL 基因抑制恶性表型，而 MAL 基因转移诱导的细胞死亡是细胞凋亡的结果，如多聚（即 ADP-核糖）聚合酶的切割诱导所示。此外，与不表达 MAL 的细胞相比，表达 MAL 的细胞的肿瘤生长受到抑制。
我们的数据表明，MAL 的表观遗传失活作为候选肿瘤抑制基因，可能有助于人类上皮细胞癌，并且可以作为 HNSCC 的生物标志物。
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