High SOX8 expression promotes tumor growth and predicts poor prognosis through GOLPH3 signaling in tongue squamous cell carcinoma
High SOX8 expression promotes tumor growth and predicts poor prognosis through GOLPH3 signaling in tongue squamous cell carcinoma
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SOX8 高表达通过 GOLPH3 信号传导促进舌鳞状细胞癌肿瘤生长并预测不良预后
DOI：
10.1002/cam4.3041
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发表时间：
2020-04-19
期刊：
影响因子：
4
通讯作者：
Song, Ming
中科院分区：
文献类型：
--
作者：
Chen, Shuwei;Li, Huan;Song, Ming
根据我们先前的研究，GOLPH3在舌鳞状细胞癌(TSCC)中显著上调，这也与预后不良有关。然而，目前仍不清楚GOLPH3的关键上游和下游机制。本研究旨在从分子水平阐明调控GOLPH3上调、促进TSCC发生发展的新机制。通过琼脂糖链霉亲和素下拉分析，进一步证实SOX8(SRY-Box 8)是在TSCC细胞内与GOLPH3启动子结合的新蛋白，进一步证实它是GOLPH3上调的调节因子。SOX8基因的敲除抑制了GOLPH3的启动子活性，并在体内和体外抑制了TSCC细胞的增殖。有趣的是，GOLPH3的过表达挽救了SOX8基因下调介导的对TSCC增殖的抑制。此外，外源过表达SOX8还激活了启动子的活性和GOLPH3的表达，同时促进了TSCC的发展。此外，还发现SOX8通过与TFAP2A相互作用来调控GOLPH3的表达。肿瘤组织中SOX8水平明显高于癌旁正常组织，且与GOLPH3水平呈正相关。根据Kaplan-Meier分析，SOX8和GOLPH3高表达的TSCC患者预后较差。综上所述，本研究表明SOX8通过直接转录激活GOLPH3促进TSCC细胞的生长，这也表明SOX8/GOLPH3通路有可能成为TSCC患者的治疗靶点。
According to our previous study, GOLPH3 is markedly up-expressed in tongue squamous cell carcinoma (TSCC), which is also associated with poor survival. However, it remains unclear about key upstream and downstream mechanisms of GOLPH3. This study aimed to illuminate new mechanisms modulating GOLPH3 upregulation and promoting TSCC development at the molecular level. Using mass spectrometry and agarose-streptavidin-biotin pull-down analyses, SOX8 (SRY-Box 8) was identified to be the new protein to bind the GOLPH3 promoter within TSCC cells, which was further verified to be the regulator of GOLPH3 upregulation. The knockdown of SOX8 suppressed the promoter activity of GOLPH3, while secondarily inhibiting TSCC cell proliferation both in vivo and in vitro. Interestingly, GOLPH3 overexpression rescued the SOX8 knockdown-mediated suppression on TSCC proliferation. Additionally, exogenous over-expression of SOX8 also activated the activity of promoter as well as GOLPH3 expression, in the meantime of promoting TSCC development. Moreover it was discovered that SOX8 regulated GOLPH3 expression through interacting with TFAP2A. Moreover our results suggested that the SOX8 level was increased within tumor tissue compared with that in para-cancer normal counterpart, which showed positive correlation with the GOLPH3 level. According to Kaplan-Meier analyses, TSCC cases having higher SOX8 and GOLPH3 expression were associated with poorer prognostic outcomes. Taken together, this study reveals that SOX8 enhances the TSCC cell growth via the direct transcriptional activation of GOLPH3, which also indicates the potential to use SOX8/GOLPH3 pathway as the treatment target among TSCC patients.