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YWHAZ amplification/overexpression defines aggressive bladder cancer and contributes to chemo-/radio-resistance by suppressing caspase-mediated apoptosis |
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| Authors: | Chia-Cheng Yu Chien-Feng Li I-Hsuan Chen Ming-Tsung Lai Zi-Jun Lin Praveen K Korla Chee-Yin Chai Grace Ko Chih-Mei Chen Tritium Hwang Shan-Chih Lee Jim J-C Sheu |
| Affiliation: | 1. Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan School of Medicine, National Yang-Ming University, Taipei, Taiwan;2. Department of Pathology, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan;3. Human Genetic Center, China Medical University Hospital, Taichung, Taiwan Department of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung, Taiwan;4. Institute of Biomedical Sciences, National Sun Yatsen University, Kaohsiung, Taiwan;5. Department of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;6. Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan Institute of Biomedical Sciences, National Sun Yatsen University, Kaohsiung, Taiwan;7. Human Genetic Center, China Medical University Hospital, Taichung, Taiwan;8. Department of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung, Taiwan |
| Abstract: | The objective of this study was to characterize the oncogenic actions of a recently identified cancer-associated gene YWHAZ (also named as 14-3-3 ζ/δ) in urothelial carcinomas of the urinary bladder (UCUB). A genome-wide study revealed YWHAZ to be involved in the amplicon at 8q22.3, and its genetic amplification was detected predominantly in muscle-invasive bladder cancer (MIBC). Immunohistochemical staining confirmed the association of YWHAZ overexpression with higher tumor stages, lymph node/vascular invasion, and mitotic activity. Univariate and multivariate analyses further indicated the prognostic potential of YWHAZ for more aggressive cancer types. Both gene set enrichment analysis and STRING network studies suggested involvement of YWHAZ in regulating caspase-mediated apoptosis. Ectopic expression of YWHAZ in bladder cells with low endogenous YWHAZ levels boosted cell resistance to doxorubicin and cisplatin, as well as to ionizing radiation. Conversely, YWHAZ-knockdown using specific shRNA in cells with high endogenous YWHAZ levels diminished survival activity, suppressing cell growth and increasing cell death. Our findings confirm the essential role played by YWHAZ in sustaining cell proliferation during chemo/radiotherapy. Treatments based on anti-YWHAZ strategies may thus be beneficial for UCUB patients overexpressing YWHAZ. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. |
| Keywords: | urothelial carcinomas of the urinary bladder (UCUB) YWHAZ (14-3-3 ζ/δ) caspase apoptosis chemo-resistance radio-resistance |