Abstract
With the emergence of combined surgical treatments, complemented by radiotherapy and chemotherapy, survival rates for esophageal cancer patients have improved, but the overall 5-year survival rate remains low. Therefore, there is an urgent need for further research into the pathogenesis of esophageal cancer and the development of effective prevention, diagnosis, and treatment methods. We initially utilized the GeneCards and DisGeNET databases to identify the esophageal cancer-associated gene WWOX (WW domain containing oxidoreductase). Subsequently, we employed RT-qPCR (Reverse transcription-quantitative PCR) and WB (western blot) to investigate the differential expression of WWOX in HEEC (human esophageal endotheliocytes) and various ESCC (esophageal squamous cell carcinoma) cell lines. We further evaluated alterations in cell proliferation, migration and apoptosis via CCK8 (cell counting kit-8) and clonal formation, Transwell assays and flow cytometry. Additionally, we investigated changes in protein expressions related to the Hippo signaling pathway (YAP/TEAD) through RT-qPCR and WB. Lastly, to further elucidate the regulatory mechanism of WWOX in ESCC, we performed exogenous YAP rescue experiments in ESCC cells with WWOX overexpression to investigate the alterations in apoptosis and proliferation. Results indicated that the expression of WWOX in ESCC was significantly downregulated. Subsequently, upon overexpression of WWOX, ESCC cell proliferation and migration decreased, while apoptosis increased. Additionally, the expression of YAP and TEAD were reduced. However, the sustained overexpression of YAP attenuated the inhibitory effects of WWOX on ESCC cell malignancy. In conclusion, WWOX exerts inhibitory effects on the proliferation and migration of ESCC and promotes apoptosis by suppressing the Hippo signaling pathway. These findings highlight the potential of WWOX as a novel target for the diagnosis and treatment of esophageal cancer.
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Data Availability
The dataset used and/or analyzed in this study is available from the corresponding author on reasonable request.
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This study was financially supported by the Xuzhou Medical key talent project (No. XWRCHT20220044).
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Qiang Wang, Longzhen Zhang, Zihan Chen and **gyu Sun conceived and designed the study. Zihan Chen and **gyu Sun performed the experiment and drafted the manuscript. Lili Zhang and Yanglin Sun performed the literature searching and data analysis. Qingqing Ni, Hongkun Zhu and Miao Hui contributed to the data analysis. Qiang Wang, Longzhen Zhang, Zihan Chen and **gyu Sun discussed the results. Qiang Wang, Longzhen Zhang, Zihan Chen and **gyu Sun revised the manuscript. All authors reviewed the manuscript.
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Chen, Z., Sun, J., Zhang, L. et al. Molecular Mechanism of WWOX Inhibiting the Development of Esophageal Cancer by Inhibiting Hippo Signaling Pathway. Biochem Genet (2024). https://doi.org/10.1007/s10528-024-10856-9
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DOI: https://doi.org/10.1007/s10528-024-10856-9