PAX2 function, regulation and targeting in fallopian tube-derived high-grade serous ovarian cancer

• Published in: Oncogene 2017-05, Vol.36 (21), p.3015-3024
• Main Authors: Modi, D A, Tagare, R D, Karthikeyan, S, Russo, A, Dean, M, Davis, D A, Lantvit, D D, Burdette, J E
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/2; 13/31; 13/51; 38/22; 38/77; 631/67; 631/67/1517/1709; 64/60; 96/98; Aging; Animals; Apoptosis; Cancer; Carcinogenesis; Carcinoma, Ovarian Epithelial; Care and treatment; Cell Biology; Cell death; Cell Line, Tumor; Cell proliferation; Cell survival; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Cystadenocarcinoma, Serous - drug therapy; Cystadenocarcinoma, Serous - genetics; Cystadenocarcinoma, Serous - pathology; Development and progression; Epithelium; Fallopian tube; Fallopian Tube Neoplasms - genetics; Fallopian Tube Neoplasms - pathology; Fallopian tubes; Female; Gastric cancer; Gene expression; Genetic aspects; Health aspects; Human Genetics; Humans; Internal Medicine; Latency; Medicine; Medicine & Public Health; Mice; Mice, Nude; Molecular Targeted Therapy; Mutants; Mutation; Neoplasms, Glandular and Epithelial - genetics; Neoplasms, Glandular and Epithelial - secondary; Oncology; original-article; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - secondary; p53 Protein; Pax2 protein; PAX2 Transcription Factor - antagonists & inhibitors; PAX2 Transcription Factor - genetics; PAX2 Transcription Factor - physiology; PTEN Phosphohydrolase - genetics; PTEN protein; RNA, Small Interfering - pharmacology; RNA, Small Interfering - therapeutic use; Stathmin; Tensin; Transcription; Transcription factors; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumorigenesis; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.455

The fallopian tube epithelium (FTE) is one of the progenitor populations for high-grade serous ovarian cancer (HGSC). Loss of PAX2 is the earliest known molecular aberration in the FTE occurring in serous carcinogenesis followed by a mutation in p53. Pathological studies report consistent loss of PAX2 in benign lesions as well as serous tumors. In the current study, the combined loss of PAX2 and expression of the R273H p53 mutant protein in murine oviductal epithelial (MOE) cells enhanced proliferation and growth in soft agar in vitro but was insufficient to drive tumorigenesis in vivo . A serially passaged model was generated to investigate the role of aging, but was also insufficient to drive tumorigenesis. These models recapitulate early benign lesions and suggest that a latency period exists between loss of PAX2, p53 mutation and tumor formation. Stathmin and fut8 were identified as downstream targets regulated by loss of PAX2 and mutation of p53 in MOE cells. Re-expression of PAX2 in PAX2-null human HGSC cells reduced cell survival via apoptosis. Phosphatase and tensin homolog (PTEN) shRNA negatively regulated PAX2 expression and stable re-expression of PAX2 in MOE:PTEN shRNA cells significantly reduced proliferation and peritoneal tumor formation in athymic nude mice. PAX2 was determined to be a direct transcriptional target that was activated by wild-type p53, whereas mutant p53 inhibited PAX2 transcription in MOE cells. A small molecule screen using the proximal PAX2 promoter driving luciferase identified four small molecules that were able to enhance PAX2 mRNA expression in MOE cells. PAX2 re-expression in HGSC cells and PTEN-deficient oviductal tumors may have the potential to induce apoptosis. In summary, mutant p53 and PTEN loss negatively regulated PAX2 and PAX2 re-expression in HGSC cells induced cell death.