PAX8 activates a p53-p21-dependent pro-proliferative effect in high grade serous ovarian carcinoma

Dima Ghannam-Shahbari, Eyal Jacob, Reli Rachel Kakun, Tanya Wasserman, Lina Korsensky, Ofir Sternfeld, Juliana Kagan, Debora Rosa Bublik, Sarit Aviel-Ronen, Keren Levanon, Edmond Sabo, Sarit Larisch, Moshe Oren, Dov Hershkovitz, Ruth Perets

Research output: Contribution to journalArticlepeer-review

Abstract

High grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer and it is now widely accepted that this disease often originates from the fallopian tube epithelium. PAX8 is a fallopian tube lineage marker with an essential role in embryonal female genital tract development. In the adult fallopian tube, PAX8 is expressed in the fallopian tube secretory epithelial cell (FTSEC) and its expression is maintained through the process of FTSEC transformation to HGSC. We now report that PAX8 has a pro-proliferative and anti-Apoptotic role in HGSC. The tumor suppressor gene TP53 is mutated in close to 100% of HGSC; in the majority of cases, these are missense mutations that endow the mutant p53 protein with potential gain of function (GOF) oncogenic activities. We show that PAX8 positively regulates the expression of TP53 in HGSC and the pro-proliferative role of PAX8 is mediated by the GOF activity of mutant p53. Surprisingly, mutant p53 transcriptionally activates the expression of p21, which localizes to the cytoplasm of HGSC cells where it plays a non-canonical, pro-proliferative role. Together, our findings illustrate how TP53 mutations in HGSC subvert a normal regulatory pathway into a driver of tumor progression.

Original languageEnglish
Pages (from-to)2213-2224
Number of pages12
JournalOncogene
Volume37
Issue number17
DOIs
StatePublished - 1 Apr 2018

Bibliographical note

Funding Information:
Acknowledgements The work presented here was funded by The Israel Science Foundation (1901/13), Israel Cancer Research Fund, The European Commission (PCIG13-GA-2013-618174), Israel Cancer Association (20150894, 20170117), The women’s health grant at Rambam (all to R.P.), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to M.O.), Israel Science Foundation (822/12) (to S.L.), The Hymen Milgrom Trust (to S.L.). We would like to thank Prof. Ronny Drapkin (University of Pennsylvania) for FT237 immortalized FTSEC line and Prof. Reuven Agami (AVL, Nederland Cancer Institute) for retroviral p21 shRNA construct.

Publisher Copyright:
© 2018 Macmillan Publishers Limited, part of Springer Nature.

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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