T-lymphocyte maturation-associated protein gene as a candidate metastasis suppressor for head and neck squamous cell carcinomas
T-lymphocyte maturation-associated protein gene as a candidate metastasis suppressor for head and neck squamous cell carcinomas
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DOI：
10.1111/j.1349-7006.2009.01132.x
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发表时间：
2009-05-01
期刊：
影响因子：
5.7
通讯作者：
Yamanaka, Noboru
中科院分区：
文献类型：
--
作者：
Beder, Levent Bekir;Gunduz, Mehmet;Yamanaka, Noboru
先前的基因表达谱显示，T 淋巴细胞成熟相关蛋白 (MAL) 基因在头颈癌中经常下调。为了明确 MAL 基因与转移过程之间的关系，我们通过半定量逆转录聚合酶链反应评估了头颈癌匹配的原发性和转移性肿瘤中该基因的表达状态。此外，我们的目的是确定与 MAL 下调相关的潜在遗传和表观遗传机制，包括杂合性丢失 (LOH)、突变和高甲基化。对来自头颈癌的图尔科大学鳞状细胞癌（UT-SCC）系列的 35 个细胞系进行了分析，其中包括 9 对来自匹配的原发性和转移性肿瘤，以及 30 对匹配的原发性和转移性肿瘤样本。 35 个细胞系中的 20 个 (57%) 显示 MAL 表达下调，而 10 个细胞系 (29%) 中未发现表达。考虑匹配的原发性和转移性肿瘤衍生细胞系对，与原发性细胞系相比，四对仅在转移性衍生细胞中表现出表达降低。对 21 个组织样本的表达分析表明，与匹配的原发肿瘤相比，43% 的转移性肿瘤中 MAL mRNA 表达减少或不表达。关于下调机制，通过 MAL 特异性微卫星标记在 30% 的原发性肿瘤和 38% 的转移性肿瘤中观察到 LOH。此外，我们发现用去甲基化剂（5-氮杂-2'-脱氧胞苷）处理后，20 个细胞系中的 9 个（45%）细胞系中 MAL mRNA 恢复。 UT-SCC细胞系中未发现突变。总之，我们的研究结果表明转移细胞中 MAL 表达选择性下调，表明 MAL 基因是头颈癌新的转移抑制候选基因。 LOH 和高甲基化似乎是 MAL 功能失活的重要机制。 （《癌症科学》2009 年；100：873-880）。
Previous gene expression profiles revealed the T-lymphocyte maturation-associated protein (MAL) gene as being frequently downregulated in head and neck cancer. To define the relationship between the MAL gene and the metastatic process, we evaluated the expression status of the gene in matched primary and metastatic tumors of head and neck cancer by semiquantitative reverse transcription-polymerase chain reaction. Furthermore, we aimed to identify potential genetic and epigenetic mechanisms associated with downregulation of MAL, including loss of heterozygosity (LOH), mutation, and hypermethylation. Thirty-five cell lines of University of Turko squamous cell carcinoma (UT-SCC) series derived from head and neck cancer, including nine pairs from matched primary and metastatic tumors, and 30 pairs of matched primary and metastatic tumor samples were analyzed. Twenty out of 35 (57%) cell lines showed downregulation of MAL expression, whereas no expression was found in 10 cell lines (29%). Considering matched primary and metastatic tumor-derived cell-line pairs, four pairs showed decreased expression only in metastasis-derived cells compared with their primary counterparts. Expression analysis of 21 tissue samples demonstrated decreased or no expression of MAL mRNA in 43% of metastatic tumors compared with matched primary tumors. Relating to mechanisms of downregulation, LOH was observed in 30% of primary tumors and 38% of their metastatic counterparts by a MAL-specific microsatellite marker. Furthermore, we found restoration of MAL mRNA after treatment with demethylating agent (5-aza-2'-deoxycytidine) in 9 (45%) out of 20 cell lines. No mutation was found in UT-SCC cell lines. In conclusion, our findings indicate selective downregulation of MAL expression in metastatic cells, suggesting the MAL gene as a new metastasis-suppressor candidate for head and neck cancer. LOH and hypermethylation appeared to be important mechanisms for inactivation of MAL function. (Cancer Sci 2009; 100: 873-880).