PAX8 plays an essential antiapoptotic role in uterine serous papillary cancer.
Basem FaresLiron BergerEinav Bangiev-GirshReli Rachel KakunDima Ghannam-ShahbariYuval TabachYaniv ZoharEyal GottliebRuth PeretsPublished in: Oncogene (2021)
Endometrial carcinoma (EC) is the fourth-most common cancer in women in the United States, and generally carries a favorable prognosis. However, about 10% of EC patients have a rare and aggressive form, uterine serous papillary carcinoma (USPC), which carries a much higher mortality rate. The developmental transcription factor PAX8 is expressed in nearly 100% of USPCs. We show that PAX8 plays a critical antiapoptotic role in USPC and this role is established via transcriptional activation of two aberrant signaling pathways. First, PAX8 positively regulates mutated p53, and missense p53 mutations have an oncogenic gain of function effect. Second, PAX8 directly transcriptionally regulates p21, in a p53-independent manner, and p21 acquires a growth promoting role that is mediated via cytoplasmic localization of the protein. We propose that mutated p53 and cytoplasmic p21 can independently mediate the pro-proliferative role of PAX8 in USPC. In addition, we performed a genome-wide transcriptome analysis to detect pathways that are regulated by PAX8, and propose that metabolism and HIF-1alpha -related pathways are potential candidates for mediating the role of PAX8 in USPC. Taken together our findings demonstrate for the first time that PAX8 is an essential lineage marker in USPC, and suggest its mechanism of action.
Keyphrases
- transcription factor
- genome wide
- high grade
- end stage renal disease
- chronic kidney disease
- papillary thyroid
- signaling pathway
- gene expression
- dna methylation
- newly diagnosed
- prognostic factors
- peritoneal dialysis
- cardiovascular disease
- risk factors
- risk assessment
- oxidative stress
- type diabetes
- autism spectrum disorder
- young adults
- intellectual disability
- endothelial cells
- coronary artery disease
- childhood cancer
- human health
- heat shock protein
- patient reported
- protein protein