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

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.

HBx regulates transcription factor PAX8 stabilization to promote the progression of hepatocellular carcinoma

“…More importantly, we found that PAX8 silencing inhibited the proliferation and clonogencity of HCC cells in vitro and the growth of implanted HCC xenografts in vivo. Furthermore, PAX8 silencing induced HCC cell cycle arrest in S phase by downregulating E2F1, RB and P53 expression in HCC cells, consistent with previous reports [16,33]. Therefore, PAX8 may be a new biomarker and therapeutic target for prognosis and intervention of HCC.…”

“…PAX8 is important for embryogenesis, and morphogenesis of the thyroid and kidney [14]. Furthermore, PAX8 expression is upregulated in several types of cancers and is a valuable biomarker for diagnosis of glioma, ovarian carcinoma, gastric cancer and others [15][16][17]. A recent study has reported that single nuclear polymorphism of the PAX8 gene is associated with prognosis of Chinese patients with HCC [18].…”

PAX8 orchestrates an angiogenic program through interaction with SOX17

“…The sustained expression of PAX8 in the adult FTSEC and in nearly all HGSOCs (16), previously led us to use the PAX8 promoter to develop a genetically engineered mouse model of HGSOC (17,18). Knockdown of PAX8 in ovarian cancer cells leads to apoptosis (19)(20)(21) supporting a definitive role for PAX8 in ovarian cancer growth and progression. However, it remains unclear how PAX8 drives the development of the Mullerian reproductive tract or how it supports neoplastic growth.…”

Before and After: Comparison of Legacy and Harmonized TCGA Genomic Data Commons’ Data

“…Some of the new protein coding associations involved alternative promoters of known cancer genes that were not represented in the hg19 version, such as epigenetic regulation of the PAX8 gene in a subset of CHOL tumors ( Figures 3D and 3E). While PAX8 activity has been associated with cancers originating from the thyroid, M€ ullerian, and renal tracts (Ghannam-Shahbari et al, 2018;Laury et al, 2011), neither this new isoform nor upregulation in cholangiocarcinoma have been previously described. In Supplemental Methods, we describe additional resources available at the GDC that can aid users in analyzing TCGA methylation data: (1) improved HM27/HM450 probe annotation (Zhou et al, 2017) and data generation pipelines (Zhou et al, 2018b), which are planned to become the default processing version in a forthcoming GDC data release; and Whole-Genome Bisulfite Sequence data for 47 TCGA samples (Zhou et al, 2018a), which can be used to investigate whole-genome methylation patterns.…”