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PAX8 activates a p53-p21-dependent pro-proliferative effect in high grade serous ovarian carcinoma.
Ghannam-Shahbari, Dima; Jacob, Eyal; Kakun, Reli Rachel; Wasserman, Tanya; Korsensky, Lina; Sternfeld, Ofir; Kagan, Juliana; Bublik, Debora Rosa; Aviel-Ronen, Sarit; Levanon, Keren; Sabo, Edmond; Larisch, Sarit; Oren, Moshe; Hershkovitz, Dov; Perets, Ruth.
Afiliación
  • Ghannam-Shahbari D; Clinical Research Institute at Rambam, Division of Oncology, Rambam Health Care Campus, Technion-Israel Institute of Technology, Haifa, Israel.
  • Jacob E; Clinical Research Institute at Rambam, Division of Oncology, Rambam Health Care Campus, Technion-Israel Institute of Technology, Haifa, Israel.
  • Kakun RR; Clinical Research Institute at Rambam, Division of Oncology, Rambam Health Care Campus, Technion-Israel Institute of Technology, Haifa, Israel.
  • Wasserman T; Clinical Research Institute at Rambam, Division of Oncology, Rambam Health Care Campus, Technion-Israel Institute of Technology, Haifa, Israel.
  • Korsensky L; Clinical Research Institute at Rambam, Division of Oncology, Rambam Health Care Campus, Technion-Israel Institute of Technology, Haifa, Israel.
  • Sternfeld O; Clinical Research Institute at Rambam, Division of Oncology, Rambam Health Care Campus, Technion-Israel Institute of Technology, Haifa, Israel.
  • Kagan J; Cell Death Research Laboratory, Department of Biology, Faculty of Sciences, University of Haifa, Mount Carmel, Haifa, Israel.
  • Bublik DR; Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
  • Aviel-Ronen S; Department of Pathology, The Talpiot Medical Leadership Program, Sheba Medical Center, Ramat Gan, Israel.
  • Levanon K; Sheba Cancer Research Center, The Talpiot Medical Leadership Program, Sheba Medical Center, Ramat Gan, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.
  • Sabo E; Department of Pathology, Rambam Health Care Campus, Technion-Israel Institute of Technology, Haifa, Israel.
  • Larisch S; Cell Death Research Laboratory, Department of Biology, Faculty of Sciences, University of Haifa, Mount Carmel, Haifa, Israel.
  • Oren M; Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
  • Hershkovitz D; Department of Pathology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.
  • Perets R; Clinical Research Institute at Rambam, Division of Oncology, Rambam Health Care Campus, Technion-Israel Institute of Technology, Haifa, Israel. Ru_Perets@rambam.health.gov.il.
Oncogene ; 37(17): 2213-2224, 2018 04.
Article en En | MEDLINE | ID: mdl-29379162
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.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Proteína p53 Supresora de Tumor / Cistadenocarcinoma Seroso / Proliferación Celular / Inhibidor p21 de las Quinasas Dependientes de la Ciclina / Factor de Transcripción PAX8 Límite: Animals / Female / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2018 Tipo del documento: Article País de afiliación: Israel

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Proteína p53 Supresora de Tumor / Cistadenocarcinoma Seroso / Proliferación Celular / Inhibidor p21 de las Quinasas Dependientes de la Ciclina / Factor de Transcripción PAX8 Límite: Animals / Female / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2018 Tipo del documento: Article País de afiliación: Israel