TY - JOUR
T1 - PAX8 plays an essential antiapoptotic role in uterine serous papillary cancer
AU - Fares, Basem
AU - Berger, Liron
AU - Bangiev-Girsh, Einav
AU - Kakun, Reli Rachel
AU - Ghannam-Shahbari, Dima
AU - Tabach, Yuval
AU - Zohar, Yaniv
AU - Gottlieb, Eyal
AU - Perets, Ruth
N1 - 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.
PY - 2021/8/26
Y1 - 2021/8/26
N2 - 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.
AB - 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.
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U2 - 10.1038/s41388-021-01925-z
DO - 10.1038/s41388-021-01925-z
M3 - Article
C2 - 34244607
AN - SCOPUS:85109881882
SN - 0950-9232
VL - 40
SP - 5275
EP - 5285
JO - Oncogene
JF - Oncogene
IS - 34
ER -