WNT3 promotes chemoresistance to oxaliplatin in oral squamous cell carcinoma via regulating ABCG2 expression.

Oxaliplatin (OXA) is a frontline therapeutic agent used in the treatment of oral squamous cell carcinoma (OSCC). However, the development of chemoresistance has emerged as a significant challenge, compromising the effectiveness of treatment strategies. Therefore, there is a critical need to unravel the mechanisms underpinning drug resistance and to identify potential therapeutic targets. In recent years, there has been a growing interest in understanding the role of drug efflux in cancer chemoresistance mechanisms. Despite this, the contribution of ABCG2, a member of the ATP-binding cassette (ABC) transporter family, to oxaliplatin resistance in OSCC remains unclear. In the current study, we aimed to investigate the involvement of ABCG2 in oxaliplatin resistance in OSCC and to elucidate the molecular mechanisms through which the Wingless and Int-1 (WNT) canonical signaling pathway upregulates ABCG2 to promote chemoresistance. To achieve this, we established oxaliplatin-resistant (OXA-R) OSCC cells as a model system. Our investigations revealed that the efflux ability of resistant cells was enhanced and the ABCG2 expression was up-regulated. Genetic silencing of ABCG2 significantly attenuated both efflux activity and chemoresistance in these resistant cells. Notably, we observed aberrant activation of the WNT canonical signaling pathway in resistant cells, accompanied by heightened expression of the WNT3 ligand. Additionally, overexpression of WNT3 in parental cells recapitulated the activation of the WNT canonical signaling cascade, resulting in increased chemoresistance, enhanced efflux function, and elevated ABCG2 expression levels. Conversely, inhibition of WNT3 in resistant cells resulted in reduced chemoresistance, suppression of efflux activity, and decreased ABCG2 expression. Finally, treatment with the WNT/β-catenin pathway inhibitor methyl 3-benzoate (MSAB) effectively reversed chemoresistance in resistant cells. Mechanistically, our studies revealed that the abnormal activation of the WNT canonical pathway promotes the recruitment of the transcription factor lymphoid enhancer-binding factor 1 (LEF1) to the ABCG2 promoter, thereby enhancing its transcriptional activity. In summary, our findings underscore the critical role of WNT3-mediated activation of the WNT canonical signaling pathway in upregulating ABCG2 expression, which enhances oxaliplatin efflux and contributes to the development of oxaliplatin resistance in OSCC.