YWHAZ amplification/overexpression defines aggressive bladder cancer and contributes to chemo-/radio-resistance by suppressing caspase-mediated apoptosis.

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.

• 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
• Journal: The Journal of pathology (J Pathol) Vol. 248 Issue 4 Pg. 476-487 (08 2019) ISSN: 1096-9896 [Electronic] England
• PMID: 30945298 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Chemical References

• 14-3-3 Proteins
• Antineoplastic Agents
• Biomarkers, Tumor
• YWHAZ protein, human
• Caspases

Topics

• 14-3-3 Proteins (metabolism)
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, physiology, radiation effects)
• Biomarkers, Tumor (metabolism)
• Carcinoma, Transitional Cell (metabolism, pathology)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects, physiology, radiation effects)
• Drug Resistance, Neoplasm (physiology)
• Female
• Genome-Wide Association Study
• Humans
• Male
• Middle Aged
• Neoplasm Invasiveness
• Radiation Tolerance (physiology)
• Retrospective Studies
• Tissue Array Analysis
• Urinary Bladder Neoplasms (metabolism, pathology)