TY - JOUR
T1 - PAX8 activates a p53-p21-dependent pro-proliferative effect in high grade serous ovarian carcinoma
AU - Ghannam-Shahbari, Dima
AU - Jacob, Eyal
AU - Kakun, Reli Rachel
AU - Wasserman, Tanya
AU - Korsensky, Lina
AU - Sternfeld, Ofir
AU - Kagan, Juliana
AU - Bublik, Debora Rosa
AU - Aviel-Ronen, Sarit
AU - Levanon, Keren
AU - Sabo, Edmond
AU - Larisch, Sarit
AU - Oren, Moshe
AU - Hershkovitz, Dov
AU - Perets, Ruth
N1 - Publisher Copyright:
© 2018 Macmillan Publishers Limited, part of Springer Nature.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85041124570&partnerID=8YFLogxK
U2 - 10.1038/s41388-017-0040-z
DO - 10.1038/s41388-017-0040-z
M3 - Article
C2 - 29379162
AN - SCOPUS:85041124570
SN - 0950-9232
VL - 37
SP - 2213
EP - 2224
JO - Oncogene
JF - Oncogene
IS - 17
ER -
