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BMC Cancer
Published in: BMC Cancer 1/2024

Open Access 01-12-2024 | Research

WNT3 promotes chemoresistance to 5-Fluorouracil in oral squamous cell carcinoma via activating the canonical β-catenin pathway

Authors: Xuyang Zhang, Kairui Sun, Ruihuan Gan, Yuxiang Yan, Chaochao Zhang, Dali Zheng, Youguang Lu

Published in: BMC Cancer | Issue 1/2024

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Abstract

Background

5-Fluorouracil (5FU) is a primary chemotherapeutic agent used to treat oral squamous cell carcinoma (OSCC). However, the development of drug resistance has significantly limited its clinical application. Therefore, there is an urgent need to determine the mechanisms underlying drug resistance and identify effective targets. In recent years, the Wingless and Int-1 (WNT) signaling pathway has been increasingly studied in cancer drug resistance; however, the role of WNT3, a ligand of the canonical WNT signaling pathway, in OSCC 5FU-resistance is not clear. This study delved into this potential connection.

Methods

5FU-resistant cell lines were established by gradually elevating the drug concentration in the culture medium. Differential gene expressions between parental and resistant cells underwent RNA sequencing analysis, which was then substantiated via Real-time quantitative PCR (RT-qPCR) and western blot tests. The influence of the WNT signaling on OSCC chemoresistance was ascertained through WNT3 knockdown or overexpression. The WNT inhibitor methyl 3-benzoate (MSAB) was probed for its capacity to boost 5FU efficacy.

Results

In this study, the WNT/β-catenin signaling pathway was notably activated in 5FU-resistant OSCC cell lines, which was confirmed through transcriptome sequencing analysis, RT-qPCR, and western blot verification. Additionally, the key ligand responsible for pathway activation, WNT3, was identified. By knocking down WNT3 in resistant cells or overexpressing WNT3 in parental cells, we found that WNT3 promoted 5FU-resistance in OSCC. In addition, the WNT inhibitor MSAB reversed 5FU-resistance in OSCC cells.

Conclusions

These data underscored the activation of the WNT/β-catenin signaling pathway in resistant cells and identified the promoting effect of WNT3 upregulation on 5FU-resistance in oral squamous carcinoma. This may provide a new therapeutic strategy for reversing 5FU-resistance in OSCC cells.
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Metadata
Title
WNT3 promotes chemoresistance to 5-Fluorouracil in oral squamous cell carcinoma via activating the canonical β-catenin pathway
Authors
Xuyang Zhang
Kairui Sun
Ruihuan Gan
Yuxiang Yan
Chaochao Zhang
Dali Zheng
Youguang Lu
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-024-12318-2

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