WWOX (WW Domain Containing Oxidoreductase)

Moreover, a decline in reactive oxygen species generation by pretreatment of Wwox+/+ MEFs with an antioxidant N-acetyl-L-cysteine leads to decreased WWOX induction upon serum starvation. Taken together, our results suggest that stress stimuli trigger WWOX induction by elevating the production of reactive oxygen species in cells, which promotes the degradation of Bcl-XL and Mcl-1 proteins via a lysosome-mediated pathway, thereby further aggravating oxidative stress and cell death.

WWOX2 serves as a tumor suppressor, whereas FUT1 functions as a promoter of malignancy. The interplay between tumor inducers and suppressors may serve as a survival mechanism for cancer cells, a subject that has received limited research attention.

Using SigProfilerAssignment, similar analyses performed with Fhit ko samples where Wwox is also frequently lost identified SBS40c. These findings implicate fragile-site gene inactivation as a major source of clock-like mutational signatures, contributing to lifelong mutation accumulation and potentially influencing aging, evolution, and speciation.

Cancers with high co-expression of ELF3 and HNF4A were frequently chromosomally instability (CIN), intestinal-type adenocarcinomas, and harbored TP53 mutations and WWOX deletions. Expression of E74 like ETS transcription factor 3 (ELF3), an ETS transcription family member, correlates with expression of other key factors in gastric cancer and confers specific characteristics that may become exploited in targeted therapeutic interventions.

This study identifies WWOX and THBS2 as potential therapeutic targets for mature T/NK-cell lymphoma. Treatment strategies based on epigenetic reprogramming and immune microenvironment regulation targeting WWOX and THBS2 provide new directions for precision therapy of this refractory lymphoma.

We detail its impact on uncontrolled proliferation, invasive potential, metastatic spread, metabolic reprogramming that favors tumor growth, interactions with the immune response, and the maintenance of genetic stability. Following this exploration of WWOX's diverse mechanistic roles in cancer biology, the review further discusses the emerging translational potential of targeting WWOX pathways, including its application as a prognostic biomarker and the development of strategies that exploit WWOX function or restoration for novel cancer therapeutics.

These findings suggest that RUNX2 overexpression is a defining characteristic of ES and may contribute to tumor progression and metastasis. In contrast, WWOX does not appear to play a critical role in ES pathogenesis. The advanced stage at presentation and poor survival outcomes underscore the need for earlier detection and biomarker-driven interventions. Further research is warranted to validate RUNX2 as a prognostic biomarker and potential therapeutic target in ES.

Finally, low WWOX expression is found to be associated with epithelial-mesenchymal transition and aggressive phenotype in thyroid cancer. These findings provide the first genetic and functional evidence that germline WWOX loss-of-function variants drive cancer pathogenesis by perturbing multiple tumor-suppressive mechanisms.

Wwox KO plasmablastic tumors displayed mutations affecting classical cancer genes, DNA damage response (DDR) genes, as well as overexpression of Aid/Apobec family members associated to hypermutation and DDR mutational signatures. These findings illustrate the significant pathobiological effects of B-cell-specific Wwox deletion and support a relevant role for WWOX loss of function in B-cell neoplastic progression toward more aggressive phenotypes.

GBM showed similar patterns: metabolic and cAMP pathways indicated better outcomes, while NFKB, TNF, JAK-STAT, and PI3K/AKT pathways marked poor prognosis. These findings suggest the WWOX/HIF1A ratio is a robust prognostic marker and a possible guide for developing targeted treatments.

We describe: (1) the native, large-sized HA is not proapoptotic but signals with an overexpressed HYAL-2/WWOX/SMAD4 complex to induce apoptosis, which is likely to occur in an inflamed microenvironment; (2) HA-binding proteins are connected via signal pathway networks. The competitive binding of HA and TGF-β to the membrane HYAL-2 and the downstream HYAL-2/WWOX/SMAD4 signaling is addressed; (3) the phase-separated proteins or small molecules in the HA matrices may contribute to the aberrant interactions, leading to inflammation and disease progression; (4) the role of HA and complement C1q in Alzheimer's disease via connection with a risk factor for Alzheimer's disease WWOX is also discussed; (5) a hidden function is the inducible HA conformational changes that confer cancer suppression and, probably, retardation of neurodegeneration.

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.