YWHAZ amplification/overexpression defines aggressive bladder cancer and contributes to chemo-/radio-resistance by suppressing caspase-mediated apoptosis
Menée à l'aide de lignées cellulaires humaines de cancer de la vessie et à l'aide d'échantillons tumoraux prélevés sur des patients atteints d'un carcinome urothélial de la vessie, cette étude met en évidence une association entre la surexpression et l'amplification du gène YWHAZ et le caractère agressif de la tumeur, puis démontre que le gène YWHAZ contribue à la chimio- et radiorésistance des cellules cancéreuses en supprimant l'apoptose induite par la caspase
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 zeta
/
delta
) 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 (GSEA) 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.
The Journal of Pathology , résumé, 2019