Axis Inhibition Protein 2 Mutation Facilitates the Progression of Wilms' Tumor

Abstract

Background: Axis inhibition protein 2 (AXIN2), negatively regulates β-catenin expression through forming a degradation complex with CK1, APC, GSK-3β and β-catenin. Here, we investigated the mutated types of AXIN2 in Wilms' tumor and determine its function in the progression of Wilms' tumor. Methods: Whole exome sequencing and Sanger sequencing were done on Wilms' Tumor tissues and RT-PCR was used to detected the expression of mRNAs, we explored the roles of AXIN2 both in vitro and in vivo. Findings: Wilms' tumor patients with AXIN2 mutation showed a shorter overall survival. Inactivity of AXIN2 increased cell proliferation, clone formation capacity, migration and invasion and decreased cell apoptosis, and also increased the protein expression of β-catenin. Meanwhile, the protein expression of GSK-3β and its protein stability was also decreased while its ubiquitination was enhanced. Furthermore, Niclosamide exploration inhibited cell proliferation and enhanced apoptosis of cells in the presence of AXIN2 mutation, as well as increased GSK-3β expression and decreased β-catenin expression. AXIN2 mutation also enhanced the tumor formation ability of tumor cells in vivo. Interpretation: AXIN2 mutation can predicts a poor prognosis of Wilms' tumor patients. Inactivity of AXIN2 significantly facilitates the malignant progression of Wilms' tumor through GSK-3β down-regulation induced β-catenin signaling activation, which would be reversed by Niclosamide administration. Funding Statement: This study received financial support from Shanghai Key Disciplines (no.2017ZZ02022), National Natural Science Foundation of China (no. 81771633 and no. 81572324), The Science Foundation of Shanghai Excellent Youth Scholars (no. 2017YQ042), and The Science Foundation of Shanghai (no. 17411960600). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: This study was obtained the approval of the Ethics Committee of Children’s Hospital of Fudan University. Written consent was obtained from all parents.