TOPK promotes metastasis of esophageal squamous cell carcinoma by activating the Src/GSK3β/STAT3 signaling pathway via γ-catenin

Yanan Jiang, Jing Zhang, Jimin Zhao, Zhenzhen Li, Hanyong Chen, Yan Qiao, Xinhuan Chen, Kangdong Liu, Ziming Dong

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Abstract

Background: Esophageal squamous cell carcinoma (ESCC) is a fatal disease with poor prognosis. The predominant reason for ESCC-related death is distal metastasis. A comprehensive understanding of the molecular mechanism underlying metastasis is needed for improving patient prognosis. T-LAK cell-originated protein kinase (TOPK) is a MAPKK-like kinase, which plays a vital role in various physiological and pathophysiological processes. However, the role of TOPK in ESCC metastasis is unclear. Methods: Tissue array was used to evaluate the correlation between TOPK expression and ESCC lymph node metastasis. Wound healing assay, transwell assay, and lung metastasis mice model were used to examine the role of TOPK in the migration of ESCC cells in vitro and in vivo. Protein kinase array, mass spectrometry (MS), and molecular modeling were used to examine the pathways and direct target proteins of TOPK that are involved in ESCC metastasis. Additionally, immunofluorescence and western blotting analyses were performed to verify these findings. Results: The enhanced expression of TOPK was correlated with lymph node metastasis in the ESCC tissues. TOPK knockdown or treatment with the TOPK inhibitor (HI-TOPK-032) decreased the invasion and migration of ESCC cells in vitro. HI-TOPK-032 also inhibited the lung metastasis in ESCC cell xenograft in vivo model. Moreover, TOPK promoted the invasion of ESCC cells by activating the Src/GSK3β/STAT3 and ERK signaling pathways via γ-catenin. Conclusion: The findings of this study reveal that TOPK is involved in ESCC metastasis and promoted the ESCC cell mobility by activating the Src/GSK3β/STAT3 and ERK signaling pathways. This indicated that TOPK may be a potential molecular therapeutic target for ESCC metastasis.

Original languageEnglish (US)
Article number1264
JournalBMC Cancer
Volume19
Issue number1
DOIs
StatePublished - Dec 30 2019

Keywords

  • Esophageal squamous cell carcinoma
  • Src/GSK3β/STAT3
  • TOPK
  • Tumor metastasis
  • γ-Catenin

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