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ECRG4 acts as a tumor suppressor in nasopharyngeal carcinoma by suppressing the AKT/GSK3β/β-catenin signaling pathway

Abstract

Nasopharyngeal carcinoma (NPC) is a malignant tumor with a poor prognosis. Studies have shown that esophageal carcinoma related gene 4 (ECRG4) is hypermethylated and significantly downregulated in NPC tissues. However, the role of ECRG4 in NPC, and in particular the underlying molecular mechanism, is largely unclear. In this study, using immunohistochemical staining of ECRG4 in NPC and normal specimens, we confirmed that ECRG4 was downregulated in human NPC tissues. In addition, various biological and molecular studies were carried out and the results showed that ECRG4 exerted anticancer effect in NPC, including inhibiting cell growth, migration, and invasion of NPC cells in vitro. Moreover, restoring ECRG4 expression suppressed the in vivo tumorigenesis of CNE2 cells. ECRG4 inhibited AKT/GSK3β/β-catenin signaling, as well as the downstream targets of β-catenin. LiCl treatment, which reduced GSK3β phosphorylation and upregulated β-catenin expression, restored the invasive ability of ECRG4-overexpressing NPC cells. Furthermore, we showed that the DNA methylation inhibitor 5-aza-dC reduced ECRG4 methylation and the invasive ability of negative control cells, but not that of ECRG4-overexpressing cells, suggesting that the inhibitory effect of 5-aza-dC depends on low expression of ECRG4. Collectively, our results demonstrated that ECRG4 downregulation contributed to NPC growth and invasion by activating AKT/GSK3β/β-catenin signaling pathway. ECRG4 could be a promising therapeutic target for the treatment of NPC.

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Funding

This study was funded by Scientific Research Project of the Guangdong Bureau of Traditional Chinese Medicine (Grant No. 20191182), the Fund for Youth Scientific Research from the Tumor Hospital of Shantou University Medical College (Grant No. 2018A008), Medical scientific Research Foundation of Guangdong Province (Grant No. A2020460), and the Innovation Strong School Project of Department of Education of Guangdong Province (Grant No. 2019KTSCX037)

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Correspondence to Yunzhu Zeng or Jiongyu Chen.

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Fig. S1. Treatment with 5-aza-dC suppresses cell invasion in NPC cells with low ECRG4 expression

. C666-1 and CNE1 cells were treated with or without 5-aza-dC (5 μM). The invasive ability of C666-1 and CNE1 cells was assessed by transwell assay. Left, images of invading cells. Right, quantitative result of cell invasion. Scale bars: 200 μm. *p<0.05. **p<0.01. (TIF 1013 KB)

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Yang, Z., Ye, X., Zhang, Y. et al. ECRG4 acts as a tumor suppressor in nasopharyngeal carcinoma by suppressing the AKT/GSK3β/β-catenin signaling pathway. Cytotechnology 74, 231–243 (2022). https://doi.org/10.1007/s10616-022-00520-8

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  • DOI: https://doi.org/10.1007/s10616-022-00520-8

Keywords

  • Nasopharyngeal carcinoma
  • ECRG4
  • Tumorigenesis
  • AKT
  • GSK3β
  • β-catenin
  • Methylation