Lin-7C/VELI3/MALS-3: An essential component in metastasis of human squamous cell carcinoma
Lin-7C/VELI3/MALS-3: An essential component in metastasis of human squamous cell carcinoma
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DOI：
10.1158/0008-5472.can-07-1911
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
Tanzawa, Hideki
中科院分区：
文献类型：
--
作者：
Onda, Takeshi;Uzawa, Katsuhiro;Tanzawa, Hideki
使用蛋白质组学选择、功能验证和临床验证，我们鉴定了标志口腔鳞状细胞癌（OSCC）转移的Lin-7 C/VEL 13/MALS-3（Lin-7 C）的特异性下调。尽管Lin-7 C基因在原发性OSCC和OSCC衍生细胞中的序列变异很少，但在CpG岛区域检测到高甲基化的高发生率，这与其下调密切相关。实验性去甲基化可诱导Lin-7 C mRNA在所有检测的OSCC细胞中表达。Lin-7 C基因在OSCC细胞克隆中的过表达不会导致增殖不足，但会导致3-连环蛋白表达升高的非侵袭性表型。在表达Lin-7 C的细胞中，免疫缺陷小鼠的多个器官中的实验性转移被抑制。Lin-7 C在原发肿瘤中的表达状态对预测淋巴结转移具有显著的高准确性（P < 0.001）。这些结果确立了Lin-7 C作为早期检测、预防和治疗OSCC转移的新靶点。
Using proteomic selection, functional verification, and clinical validation, we identified specific down-regulation of Lin-7C/ VEL13/MALS-3 (Lin-7C), which marks oral squamous cell carcinoma (OSCC) metastasis. Despite a rarity of sequence variations in the Lin-7C gene in both primary OSCC and OSCCderived cells, a high prevalence of hypermethylation was detected in the CpG island region that strongly correlated with its down-regulation. Inducible Lin-7C mRNA by experimental demethylation was found in all OSCC cells tested. Overexpression of the Lin-7C gene in an OSCC cell clone does not contribute to underproliferation but results in a noninvasive phenotype with elevated)3-catenin expression. Experimental metastases in multiple organs of immunodeficient mice were inhibited in cells expressing Lin-7C. Finally, the Lin-7C expression status in primary tumors afforded significantly (P < 0.001) high accuracy for predicting lymph node metastasis. These results establish Lin-7C as a novel target of early detection, prevention, and therapy for OSCC metastasis.