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Glucose dysregulation promotes oncogenesis in human bladder cancer by regulating autophagy and YAP1/TAZ expression |
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| Authors: | Shi Li Banzhan Ruan Zhi Wang Jianling Xia Qi Lin Ruoting Xu Hua Zhu Zhixian Yu |
| Affiliation: | 1. Department of Urology, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China;2. Department of Oncology of The First Affiliated Hospital and Tumor Institute, Hainan Medical University, Haikou, Hainan, China Contribution: Investigation (lead), Methodology (lead);3. Department of Urology and Chest Surgery, The People Hospital of Tongjiang, Bazhong, Sichuan, China Contribution: Data curation (lead);4. Department of Oncology and Hematology, The People Hospital of Tongjiang, Bazhong, Sichuan, China Cancer Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Hospital of the University of Electronic Science and Technology of China, Chengdu, China Contribution: Investigation (equal);5. Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China Contribution: Software (equal);6. Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China Contribution: Investigation (equal);7. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China;8. Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China |
| Abstract: | Glucose dysregulation is strongly correlated with cancer development, and cancer is prevalent in patients with Type 2 diabetes (T2D). We aimed to elucidate the mechanism underlying autophagy in response to glucose dysregulation in human bladder cancer (BC). 220 BC patients were included in this retrospective study. The expression of YAP1, TAZ and AMPK, EMT-associated markers, and autophagy marker proteins was analysed by immunohistochemistry, western blotting, and quantitative real-time PCR (qPCR). Further, T24 and UMUC-3 BC cells were cultured in media with different glucose concentrations, and the expression of YAP1, TAZ, AMPK and EMT-associated markers, and autophagy marker proteins was analysed by western blotting and qPCR. Autophagy was observed by immunofluorescence and electron microscopy. BC cell viability was tested using MTT assays. A xenograft nude mouse model of diabetes was used to evaluate tumour growth, metastasis and survival. A poorer pathologic grade and tumour-node-metastasis stage were observed in patients with BC with comorbid T2D than in others with BC. YAP1 and TAZ were upregulated in BC samples from patients with T2D. Mechanistically, high glucose (HG) promoted BC progression both in vitro and in vivo and inhibited autophagy. Specifically, various autophagy marker proteins and AMPK were negatively regulated under HG conditions and correlated with YAP1 and TAZ expression. These results demonstrate that HG inhibits autophagy and promotes cancer development in BC. YAP1/TAZ/AMPK signalling plays a crucial role in regulating glucose dysregulation during autophagy. Targeting these effectors exhibits therapeutic significance and can serve as prognostic markers in BC patients with T2D. |
| Keywords: | AMPK autophagy bladder cancer high glucose YAP1/TAZ |