Int J Biol Sci 2019; 15(8):1696-1711. doi:10.7150/ijbs.33844

Research Paper

TLX3 repressed SNAI1-induced epithelial-mesenchymal transition by directly constraining STAT3 phosphorylation and functionally sensitized 5-FU chemotherapy in hepatocellular carcinoma

Cong Wang, Changwei Dou, Yufeng Wang, Zhikui Liu, Lewis Roberts, Xin Zheng

Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China

Abstract

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.

Keywords: TLX3, HCC, EMT, STAT3, SNAI1

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How to cite this article:
Wang C, Dou C, Wang Y, Liu Z, Roberts L, Zheng X. TLX3 repressed SNAI1-induced epithelial-mesenchymal transition by directly constraining STAT3 phosphorylation and functionally sensitized 5-FU chemotherapy in hepatocellular carcinoma. Int J Biol Sci 2019; 15(8):1696-1711. doi:10.7150/ijbs.33844. Available from http://www.ijbs.com/v15p1696.htm