Characterization of a Candidate Tumor Suppressor Gene Uroplakin 1A in Esophageal Squamous Cell Carcinoma
Characterization of a Candidate Tumor Suppressor Gene Uroplakin 1A in Esophageal Squamous Cell Carcinoma
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DOI：
10.1158/0008-5472.can-10-0779
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发表时间：
2010-11-01
期刊：
影响因子：
11.2
通讯作者：
Guan, Xin-Yuan
中科院分区：
文献类型：
--
作者：
Kong, Kar Lok;Kwong, Dora L.;Guan, Xin-Yuan
食管鳞状细胞癌（ESCC）的发病率正在增加，但这种疾病的遗传基础的知识仍然有限。在本研究中，我们鉴定了四跨膜蛋白细胞表面受体uroplakin 1A（UPK 1A）作为候选抑癌基因（TSG），并研究了其在食管鳞癌细胞中的功能和机制。UPK 1A在68%的原发性食管鳞癌中表达下调，且与启动子区甲基化程度显著相关（P < 0.05）。UPK 1A在ESCC细胞中的异位表达抑制细胞增殖、克隆形成、细胞运动和裸鼠肿瘤形成。机制研究表明，这些作用可能是通过抑制β-连环蛋白的核转位及其下游靶点（包括细胞周期蛋白-D1、c-jun、c-myc和基质金属蛋白酶7（MMP 7））的失活来介导的。UPK 1A在G（1）-S检查点引起的细胞周期阻滞与细胞周期蛋白D1和细胞周期蛋白依赖性激酶4的下调有关，而转移抑制与MMP 7的减少有关。这些发现与来自临床样本的证据一致，其中UPK 1A下调与淋巴结转移（P = 0.009）、分期（P = 0.015）和总生存期（P < 0.0001）相关。事实上，多变量环氧合酶回归分析显示UPK 1A是总生存率的独立预后因素。总之，我们的研究结果定义了UPK 1A作为ESCC发展中重要的TSG的功能。Cancer Res; 70（21）; 8832-41. (C)2010年AACR。
Esophageal squamous cell carcinoma (ESCC) is increasing in incidence, but the knowledge of the genetic underpinnings of this disease remains limited. In this study, we identified the tetraspanin cell surface receptor uroplakin 1A (UPK1A) as a candidate tumor suppressor gene (TSG), and we investigated its function and mechanism in ESCC cells. UPK1A downregulation occurred in 68% of primary ESCCs examined, where it was correlated significantly with promoter hypermethylation (P < 0.05). Ectopic expression of UPK1A in ESCC cells inhibited cell proliferation, clonogenicity, cell motility, and tumor formation in nude mice. Mechanistic investigations suggested that these effects may be mediated by inhibiting nuclear translocation of beta-catenin and inactivation of its downstream targets, including cyclin-D1, c-jun, c-myc, and matrix metalloproteinase 7 (MMP7). Cell cycle arrest elicited by UPK1A at the G(1)-S checkpoint was associated with downregulation of cyclin D1 and cyclin-dependent kinase 4, whereas metastasis suppression was associated with reduction of MMP7. These findings were consistent with evidence derived from clinical samples, where UPK1A downregulation was correlated with lymph node metastasis (P = 0.009), stage (P = 0.015), and overall survival (P < 0.0001). Indeed, multivariate cyclooxygenase regression analysis showed that UPK1A was an independent prognostic factor for overall survival. Taken together, our findings define a function for UPK1A as an important TSG in ESCC development. Cancer Res; 70(21); 8832-41. (C) 2010 AACR.