SOX1 Functions as a Tumor Suppressor by Antagonizing the WNT/β-Catenin Signaling Pathway in Hepatocellular Carcinoma
SOX1 Functions as a Tumor Suppressor by Antagonizing the WNT/β-Catenin Signaling Pathway in Hepatocellular Carcinoma
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DOI：
10.1002/hep.25933
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发表时间：
2012-12-01
期刊：
影响因子：
13.5
通讯作者：
Lin, Ya-Wen
中科院分区：
文献类型：
--
作者：
Tsao, Chun-Ming;Yan, Ming-De;Lin, Ya-Wen
Wnt/β-连环蛋白信号通路的致癌激活在肝细胞癌（HCC）中是常见的。我们最近的研究表明，SRY（sex determining region Y）-box 1（SOX 1）和分泌的卷曲相关蛋白在HCC中伴随着启动子的高甲基化，这可能导致Wnt信号通路的异常激活。SOX 1编码一种参与胚胎发育和细胞命运决定的转录因子。然而，SOX 1在HCC中的表达和功能作用仍不清楚。在这项研究中，我们通过定量甲基化特异性聚合酶链反应证实，SOX 1经常通过启动子高甲基化在肝癌细胞和组织中下调。通过组成性或诱导性方法过表达SOX 1可以抑制HCC细胞系中的细胞增殖、集落形成和侵袭能力，以及非肥胖糖尿病/严重联合免疫缺陷小鼠中的肿瘤生长。相反，通过撤除多西环素敲低SOX 1可以部分恢复HCC细胞的细胞增殖和集落形成。我们使用T细胞因子（TCF）响应的荧光素酶报告分析和蛋白质印迹分析，以证明SOX 1可以调节TCF响应的转录活性和抑制Wnt下游基因的表达。此外，我们使用谷胱甘肽S-转移酶下拉，免疫共沉淀，共聚焦显微镜，以证明SOX 1可以与β-连环蛋白，但不与β-连环蛋白/TCF复合物相互作用。此外，SOX 1表达的恢复诱导Hep 3B细胞中显著的细胞衰老。结论：我们的数据表明，发育基因，SOX 1，可能作为一个肿瘤抑制因子，通过干扰Wnt/β-连环蛋白信号在肝癌的发展。（肝脏学2012;56：2277-2287）
Oncogenic activation of the Wnt/beta-catenin signaling pathway is common in hepatocellular carcinoma (HCC). Our recent studies have demonstrated that SRY (sex determining region Y)-box 1 (SOX1) and secreted frizzled-related proteins are concomitantly promoter-hypermethylated, and this might lead to abnormal activation of the Wnt signaling pathway in HCC. SOX1 encodes a transcription factor involved in the regulation of embryonic development and cell fate determination. However, the expression and functional role of SOX1 in HCC remains unclear. In this study, we confirmed via quantitative methylation-specific polymerase chain reaction that SOX1 was frequently downregulated through promoter hypermethylation in HCC cells and tissues. Overexpression of SOX1 by a constitutive or inducible approach could suppress cell proliferation, colony formation, and invasion ability in HCC cell lines, as well as tumor growth in nonobese diabetic/severe combined immunodeficiency mice. Conversely, knockdown of SOX1 by withdrawal of doxycycline could partially restore cell proliferation and colony formation in HCC cells. We used a T cell factor (TCF)-responsive luciferase reporter assay and western blot analysis to prove that SOX1 could regulate TCF-responsive transcriptional activity and inhibit the expression of Wnt downstream genes. Furthermore, we used glutathione S-transferase pull-down, co-immunoprecipitation, and confocal microscopy to demonstrate that SOX1 could interact with beta-catenin but not with the beta-catenin/TCF complex. Moreover, restoration of the expression of SOX1 induces significant cellular senescence in Hep3B cells. Conclusion: Our data show that a developmental gene, SOX1, may function as a tumor suppressor by interfering with Wnt/beta-catenin signaling in the development of HCC. (HEPATOLOGY 2012;56:2277-2287)