PAX8 plays an essential antiapoptotic role in uterine serous papillary cancer

Basem Fares, Liron Berger, Einav Bangiev-Girsh, Reli Rachel Kakun, Dima Ghannam-Shahbari, Yuval Tabach, Yaniv Zohar, Eyal Gottlieb, Ruth Perets*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)5275-5285
Number of pages11
JournalOncogene
Volume40
Issue number34
DOIs
StatePublished - 26 Aug 2021

Bibliographical note

Funding Information:
RP is supported by grants from the Israel Science Foundation (1990/18), the Israel Cancer Research Fund’s Len and Susan Mark Initiative for Ovarian and Uterine/MMMT Cancers, the Israel Cancer Association’s ICA USA Board of Directors, the EU’s Marie Curie Actions (FP7 People) program, and the Women’s Health Fund at the Rambam Health Care Campus.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.

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