Twenty-five years of WWOX insight in cancer: a treasure trove of knowledge

More than two decades ago, MD Anderson Cancer group discovered, characterised, and identified the WW domain-containing oxidoreductase (WWOX) as a genes of interest mapping to the chromosomal region 16q23.3-24.2. This was pioneering research since WWOX is a critical tumour suppressor gene implicated in various cancers, involving interactions with numerous signalling pathways and molecular mechanisms. Notably, it inhibits the Wnt/β-catenin pathway, which is often activated in tumours. This inhibition helps prevent tumour formation by regulating cell proliferation and promoting apoptosis. Restoration of WWOX expression in cancer cell lines has been shown to reduce tumour growth and increased sensitivity to treatments. In addition to its role in tumour suppression, WWOX has been found to interact with proteins involved in critical signalling pathways such as TGF-β. Recent advancements allowed to reveal its interactions with key proteins and microRNAs that regulate cellular adhesion, invasion, and motility. Proteomic studies have shown that WWOX directly interacts with signalling molecules like Dishevelled and SMAD3, further underscoring its role in antagonizing metastasis. Challenges remain in translating this knowledge into clinical applications. For instance, the mechanisms underlying WWOX loss in tumours and its role across diverse cancer types require further investigation. Overall, WWOX serves as a vital player in maintaining cellular stability and preventing cancer progression through its multifaceted functions. Here, we include an updated molecular function of WWOX in cancers to possibly contribute to the potential use of WWOX expression as a biomarker regarding prognosis and response to the treatment. CLINICAL TRIAL NUMBER: Not applicable.