He Guoyang, Hu Shuiwang, Zhang Dan, Wu Pingxiang, Zhu Xiaohui, Xin Sainan, Lu Guifeng, Ding Yanqing, Liang Li
Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou City, 510515 Guangdong Province, People's Republic of China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515 Guangdong Province, People's Republic of China; Department of Pathology, Xinxiang Medical University, Xinxiang City, 453003 Henan Province, People's Republic of china.
Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou City, 510515 Guangdong Province, People's Republic of China.
Exp Mol Pathol. 2015 Oct;99(2):374-82. doi: 10.1016/j.yexmp.2015.06.017. Epub 2015 Jun 22.
As a transcriptional repressor, forkhead box D3 (FOXD3) plays an important role in tumorigenesis and progression of several tumors. However, the function and methylation status of FOXD3 remain unknown in the progression of hepatocellular carcinoma (HCC). In this study, we found that FOXD3 was decreased in HCC tissues and correlated with differentiation, AFP and poor survival of HCC patients (p<0.05). Down-regulation of FOXD3 in HCC tissues was mainly due to promoter hypermethylation. In vitro and in vivo functional results showed that ectopic FOXD3 inhibited the proliferation, migration, epithelial-mesenchymal transition (EMT) and invasion in HepG2 and SMMC-7721 cells, and FOXD3 depletion in HepG2 and QGY-7701 cells showed the adverse effects (p<0.05). Moreover, FOXD3 was sufficient to suppress tumor growth and pulmonary metastatic potential in mice. Our findings suggest that down-regulation of FOXD3, due to promoter hypermethylation plays an important role in the progression of HCC and may be a promising prognostic biomarker for HCC patients.
作为一种转录抑制因子，叉头框D3（FOXD3）在多种肿瘤的发生和发展中发挥重要作用。然而，FOXD3在肝细胞癌（HCC）进展中的功能和甲基化状态尚不清楚。在本研究中，我们发现FOXD3在HCC组织中表达降低，且与HCC患者的分化程度、甲胎蛋白水平及不良预后相关（p<0.05）。HCC组织中FOXD3的下调主要归因于启动子高甲基化。体外和体内功能研究结果表明，异位表达的FOXD3可抑制HepG2和SMMC-7721细胞的增殖、迁移、上皮-间质转化（EMT）及侵袭，而敲低HepG2和QGY-7701细胞中的FOXD3则显示出相反的作用（p<0.05）。此外，FOXD3足以抑制小鼠肿瘤生长和肺转移潜能。我们的研究结果表明，由于启动子高甲基化导致的FOXD3下调在HCC进展中起重要作用，可能是HCC患者一个有前景的预后生物标志物。
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