TLX3 repressed SNAI1-induced epithelial-mesenchymal transition by directly constraining STAT3 phosphorylation and functionally sensitized 5-FU chemotherapy in hepatocellular carcinoma
TLX3 repressed SNAI1-induced epithelial-mesenchymal transition by directly constraining STAT3 phosphorylation and functionally sensitized 5-FU chemotherapy in hepatocellular carcinoma
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DOI：
10.7150/ijbs.33844
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发表时间：
2019-06
影响因子：
9.2
通讯作者：
Cong-xia Wang;Changwei Dou;Yufeng Wang;Zhikui Liu;L. Roberts;Xin Zheng
中科院分区：
文献类型：
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作者：
Cong-xia Wang;Changwei Dou;Yufeng Wang;Zhikui Liu;L. Roberts;Xin Zheng
TLX 3作为序列特异性转录因子在神经系统中具有重要功能。尽管一些研究表明TLX 3在白血病中异常上调，但其在肝细胞癌（HCC）中的表达和功能仍然未知。我们发现，68/100（68%）的肝癌病例中，TLX 3表达下降，并与p-STAT 3、SNAI 1和Vimentin的表达呈负相关，而与E-cadherin的表达正相关。ITRAQ蛋白质组分析显示，原发性肝癌肿瘤中TLX 3的表达显著低于门静脉癌栓。Kaplan-Meier曲线的比较显示，HCC中TLX 3的下调与术后生存率差相关。TLX 3过表达抑制HCC细胞活力、增殖、迁移、侵袭和增强5-FU处理，而沉默TLX 3产生相反的结果。进一步的实验表明，TLX 3减弱EMT表型。体内实验表明，TLX 3的敲低促进了肝癌异种移植物的生长，并减弱了5-FU治疗的抗肿瘤作用。基因表达芯片分析显示TLX 3抑制IL-6/STAT 3信号转导。在另外的机制研究中，TLX 3通过与STAT 3结合、抑制STAT 3磷酸化和下调SNAI 1表达来逆转HCC细胞的EMT表型。总之，TLX 3表达的缺失通过增强IL-6/STAT 3/SNAI 1信号传导诱导EMT，并加速HCC进展，同时也减弱了5-FU对HCC的作用。
TLX3 has an established role as a sequence-specific transcription factor with vital functions in the nervous system. Although several studies have shown that TLX3 is aberrantly up-regulated in leukemia, its expression and function in hepatocellular carcinoma (HCC) remain unknown. We found that TLX3 expression was decreased in 68/100 (68%) HCC cases and negatively correlated with the expression of p-STAT3, SNAI1, and Vimentin, while it was positively associated with E-cadherin expression. ITRAQ proteomic profiling revealed significantly less TLX3 expression in primary HCC tumors than in portal vein tumor thrombi. Comparison of Kaplan-Meier curves showed that down-regulation of TLX3 in HCC was associated with poor post-surgical survival. TLX3 over-expression inhibited HCC cell viability, proliferation, migration, invasion and enhanced 5-FU treatment, whereas silencing TLX3 produced the opposite results. Further experiments showed that TLX3 attenuated the EMT phenotype. In vivo experiments showed that knockdown of TLX3 promoted the growth of HCC xenografts and attenuated the anti-tumor effects of 5-FU treatment. Gene expression microarray analysis revealed that TLX3 inhibited IL-6/STAT3 signaling. In additional mechanistic studies TLX3 reversed the EMT phenotype of HCC cells by binding to STAT3, inhibiting STAT3 phosphorylation, and down-regulating SNAI1 expression. Taken together, loss of expression of TLX3 induces EMT by enhancing IL-6/STAT3/SNAI1 signaling, and accelerates HCC progression while also attenuated the effect of 5-FU on HCCs.