Hypoxia‐induced PGK1 expression promotes esophageal squamous cell carcinoma progression via stimulating MYH9‐mediated GSK3β/β‐catenin signalling
Abstract Background Phosphoglycerate kinase 1 (PGK1) serves as a critical metabolic enzyme in the process of glycolysis and has many nonmetabolic functions in tumour progression. One of the most prevalent malignant tumours is still esophageal squamous cell carcinoma (ESCC), with high recurrence rate...
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Wiley
2025-06-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.70376 |
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| author | Jia‐cheng Xu Lin‐feng Wu Tian‐yin Chen Yan‐bo Liu Yi‐fei Zhang Ping‐hong Zhou Yi‐qun Zhang |
| author_facet | Jia‐cheng Xu Lin‐feng Wu Tian‐yin Chen Yan‐bo Liu Yi‐fei Zhang Ping‐hong Zhou Yi‐qun Zhang |
| author_sort | Jia‐cheng Xu |
| collection | DOAJ |
| description | Abstract Background Phosphoglycerate kinase 1 (PGK1) serves as a critical metabolic enzyme in the process of glycolysis and has many nonmetabolic functions in tumour progression. One of the most prevalent malignant tumours is still esophageal squamous cell carcinoma (ESCC), with high recurrence rates, high probabilities of metastasis, and poor prognoses. However, the molecular mechanisms and physiological contribution of PGK1 to ESCC carcinogenesis remain largely elusive. Methods Esophageal cancer bioinformatics analysis and tissue microarray analysis were employed to elucidate the aberrant expression of PGK1 during ESCC progression. The carcinogenic effect of PGK1 was examined using cell proliferation, migration and sphere formation assays. Mass spectrometry analysis, immunoprecipitation, ChIP and luciferase assays, hypoxia assays and in vitro and in vivo experiments were used to clarify the mechanism of the PGK1‒MYH9 interaction in the β‐catenin/c‐Myc signalling pathway. Results We clarified that in patients with ESCC, elevated PGK1 levels were linked to poor survival, tumour size, lymph node metastatic status, and TNM stage. In vivo and in vitro experimental analyses revealed that PGK1 promoted ESCC cell tumour stemness and EMT both in vivo and in vitro. Mechanistically, we discovered that PGK1 interacts with myosin‐9 (MYH9), leading to MYH9‐mediated ubiquitination‐mediated degradation of GSK‐3β, thereby triggering the β‐catenin signalling pathway and transcriptionally increasing c‐Myc expression. In addition, we found that hypoxic conditions upregulated PGK1, with HIF‐1α transactivating PGK1 expression, further promoting the PGK1‐MYH9 interaction and PGK1/MYH9/β‐catenin/c‐Myc axis activation. Conclusions PGK1 promotes ESCC tumourigenicity and migratory capacity by facilitating β‐catenin‐dependent c‐Myc transcription. Under hypoxic conditions, the PGK1‒MYH9 interaction is strengthened, and HIF‐1α‐mediated transcription increases PGK1 expression, thereby activating the β‐catenin/c‐Myc signalling pathway. Taken together, PGK1 holds promise as a potential biomarker for predicting postoperative prognosis and recurrence in patients with ESCC. |
| format | Article |
| id | doaj-art-bffadc47d4af41a8b71df1bd4450099c |
| institution | DOAJ |
| issn | 2001-1326 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
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| series | Clinical and Translational Medicine |
| spelling | doaj-art-bffadc47d4af41a8b71df1bd4450099c2025-08-20T03:23:56ZengWileyClinical and Translational Medicine2001-13262025-06-01156n/an/a10.1002/ctm2.70376Hypoxia‐induced PGK1 expression promotes esophageal squamous cell carcinoma progression via stimulating MYH9‐mediated GSK3β/β‐catenin signallingJia‐cheng Xu0Lin‐feng Wu1Tian‐yin Chen2Yan‐bo Liu3Yi‐fei Zhang4Ping‐hong Zhou5Yi‐qun Zhang6Department of Endoscopy Center and Endoscopy Research Institute Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Endoscopy Center and Endoscopy Research Institute Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Endoscopy Center and Endoscopy Research Institute Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Endoscopy Center and Endoscopy Research Institute Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Endoscopy Center and Endoscopy Research Institute Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Endoscopy Center and Endoscopy Research Institute Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Endoscopy Center and Endoscopy Research Institute Zhongshan Hospital Fudan University Shanghai ChinaAbstract Background Phosphoglycerate kinase 1 (PGK1) serves as a critical metabolic enzyme in the process of glycolysis and has many nonmetabolic functions in tumour progression. One of the most prevalent malignant tumours is still esophageal squamous cell carcinoma (ESCC), with high recurrence rates, high probabilities of metastasis, and poor prognoses. However, the molecular mechanisms and physiological contribution of PGK1 to ESCC carcinogenesis remain largely elusive. Methods Esophageal cancer bioinformatics analysis and tissue microarray analysis were employed to elucidate the aberrant expression of PGK1 during ESCC progression. The carcinogenic effect of PGK1 was examined using cell proliferation, migration and sphere formation assays. Mass spectrometry analysis, immunoprecipitation, ChIP and luciferase assays, hypoxia assays and in vitro and in vivo experiments were used to clarify the mechanism of the PGK1‒MYH9 interaction in the β‐catenin/c‐Myc signalling pathway. Results We clarified that in patients with ESCC, elevated PGK1 levels were linked to poor survival, tumour size, lymph node metastatic status, and TNM stage. In vivo and in vitro experimental analyses revealed that PGK1 promoted ESCC cell tumour stemness and EMT both in vivo and in vitro. Mechanistically, we discovered that PGK1 interacts with myosin‐9 (MYH9), leading to MYH9‐mediated ubiquitination‐mediated degradation of GSK‐3β, thereby triggering the β‐catenin signalling pathway and transcriptionally increasing c‐Myc expression. In addition, we found that hypoxic conditions upregulated PGK1, with HIF‐1α transactivating PGK1 expression, further promoting the PGK1‐MYH9 interaction and PGK1/MYH9/β‐catenin/c‐Myc axis activation. Conclusions PGK1 promotes ESCC tumourigenicity and migratory capacity by facilitating β‐catenin‐dependent c‐Myc transcription. Under hypoxic conditions, the PGK1‒MYH9 interaction is strengthened, and HIF‐1α‐mediated transcription increases PGK1 expression, thereby activating the β‐catenin/c‐Myc signalling pathway. Taken together, PGK1 holds promise as a potential biomarker for predicting postoperative prognosis and recurrence in patients with ESCC.https://doi.org/10.1002/ctm2.70376β‐catenin signalling pathwayesophageal squamous cell carcinomahypoxiaMYH9PGK1 |
| spellingShingle | Jia‐cheng Xu Lin‐feng Wu Tian‐yin Chen Yan‐bo Liu Yi‐fei Zhang Ping‐hong Zhou Yi‐qun Zhang Hypoxia‐induced PGK1 expression promotes esophageal squamous cell carcinoma progression via stimulating MYH9‐mediated GSK3β/β‐catenin signalling Clinical and Translational Medicine β‐catenin signalling pathway esophageal squamous cell carcinoma hypoxia MYH9 PGK1 |
| title | Hypoxia‐induced PGK1 expression promotes esophageal squamous cell carcinoma progression via stimulating MYH9‐mediated GSK3β/β‐catenin signalling |
| title_full | Hypoxia‐induced PGK1 expression promotes esophageal squamous cell carcinoma progression via stimulating MYH9‐mediated GSK3β/β‐catenin signalling |
| title_fullStr | Hypoxia‐induced PGK1 expression promotes esophageal squamous cell carcinoma progression via stimulating MYH9‐mediated GSK3β/β‐catenin signalling |
| title_full_unstemmed | Hypoxia‐induced PGK1 expression promotes esophageal squamous cell carcinoma progression via stimulating MYH9‐mediated GSK3β/β‐catenin signalling |
| title_short | Hypoxia‐induced PGK1 expression promotes esophageal squamous cell carcinoma progression via stimulating MYH9‐mediated GSK3β/β‐catenin signalling |
| title_sort | hypoxia induced pgk1 expression promotes esophageal squamous cell carcinoma progression via stimulating myh9 mediated gsk3β β catenin signalling |
| topic | β‐catenin signalling pathway esophageal squamous cell carcinoma hypoxia MYH9 PGK1 |
| url | https://doi.org/10.1002/ctm2.70376 |
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