Sox12, a direct target of FoxQ1, promotes hepatocellular carcinoma metastasis through up-regulating Twist1 and FGFBP1
Sox12, a direct target of FoxQ1, promotes hepatocellular carcinoma metastasis through up-regulating Twist1 and FGFBP1
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DOI：
10.1002/hep.27756
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发表时间：
2015-06-01
期刊：
影响因子：
13.5
通讯作者：
Xia, Limin
中科院分区：
文献类型：
--
作者：
Huang, Wenjie;Chen, Zhangqian;Xia, Limin
转移是肝细胞癌根治性切除后复发率高、生存率低的主要原因。然而，HCC转移的分子机制尚不清楚。在这里，我们报道了SRY（性别决定区Y）-box 12 （Sox12）的一种新功能，它是SRY相关高迁移率组box家族蛋白的一员，在促进HCC转移中。Sox12过表达与人类HCC患者肿瘤包被丧失、微血管侵袭和更高的肿瘤结节转移（TNM）分期显著相关，预示预后不良。Sox12表达是治愈性切除后复发和生存率降低的独立且重要的危险因素。Sox12过表达通过反激活Twist1表达诱导上皮-间质转化。Twist1的下调降低了Sox12增强的HCC迁移、侵袭和转移，而Twist1的上调则恢复了Sox12下调引起的迁移、侵袭和转移的减少。此外，序列缺失、定点突变和染色质免疫沉淀实验表明，成纤维细胞生长因子结合蛋白1 （FGFBP1）是Sox12的直接转录靶点。敲低FGFBP1可降低Sox12介导的HCC侵袭和转移，而过表达FGFBP1可挽救Sox12敲低诱导的侵袭和转移。叉头盒Q1 （FoxQ1）直接结合Sox12启动子并反激活其表达，导致Sox12在人类HCC中过表达。Sox12基因敲低可显著降低foxq1介导的HCC转移。在两个独立的人类HCC组织队列中，Sox12表达与Twist1、FGFBP1和FoxQ1表达呈正相关，Sox12/Twist1、Sox12/FGFBP1或FoxQ1/Sox12共表达阳性的患者预后较差。结论：FoxQ1诱导Sox12上调通过反激活Twist1和FGFBP1表达促进HCC侵袭转移。因此，我们的研究表明Sox12是一种潜在的预后生物标志物和HCC的新治疗靶点。(肝脏病学61:1920 2015;1933)
Metastasis is the main reason for high recurrence and poor survival of hepatocellular carcinoma (HCC) after curative resection. However, the molecular mechanism underlying HCC metastasis remains unclear. Here, we report on a novel function of SRY (sex determining region Y)-box 12 (Sox12), a member of the SYR-related high mobility group box family proteins, in promoting HCC metastasis. Overexpression of Sox12 was significantly correlated with loss of tumor encapsulation, microvascular invasion, and a higher tumor-nodule-metastasis (TNM) stage and indicated poor prognosis in human HCC patients. Sox12 expression was an independent and significant risk factor for recurrence and reduced survival after curative resection. Overexpression of Sox12 induced epithelial-mesenchymal transition by transactivating Twist1 expression. Down-regulation of Twist1 decreased Sox12-enhanced HCC migration, invasion, and metastasis, whereas up-regulation of Twist1 rescued the decreased migration, invasion, and metastasis induced by Sox12 knockdown. Additionally, serial deletion, site-directed mutagenesis, and chromatin immunoprecipitation assays showed that fibroblast growth factor binding protein 1 (FGFBP1) was a direct transcriptional target of Sox12. Knockdown of FGFBP1 decreased Sox12-mediated HCC invasion and metastasis, whereas overexpression of FGFBP1 rescued the decreased invasion and metastasis induced by Sox12 knockdown. Furthermore, forkhead box Q1 (FoxQ1) directly bound to the Sox12 promoter and transactivated its expression, which contributed to Sox12 overexpression in human HCC. Knockdown of Sox12 dramatically decreased FoxQ1-mediated HCC metastasis. In two independent cohorts of human HCC tissues, Sox12 expression was positively correlated with Twist1, FGFBP1, and FoxQ1 expression, and patients with positive coexpression of Sox12/Twist1, Sox12/FGFBP1, or FoxQ1/Sox12 were associated with poorer prognosis. Conclusion: Up-regulated Sox12 induced by FoxQ1 promotes HCC invasion and metastasis by transactivating Twist1 and FGFBP1 expression. Thus, our study implicates Sox12 as a potential prognostic biomarker and a novel therapeutic target for HCC. (Hepatology 2015;61:1920-1933)