Abstract
BackgroundWe previously demonstrated that ovarian high grade serous carcinomas (OHGSeCa) and ovarian clear cell carcinomas (OCCCa) with an HNF-1β+/p53+/ARID1A+ immunophenotype were associated with the worst unfavorable prognosis. To clarify the molecular mechanisms underlying this finding, we focused on alterations in the p53 signaling pathway in these tumors.MethodsChanges in cell phenotype and function following knockdown of wild-type p53 (p53-KD) were assessed using OCCCa cells expressing endogenous HNF-1β and ARID1A. The prognostic significance of molecules that were deregulated following p53-KD was also examined using 129 OCCCa/OHGSeCa cases.Resultsp53-KD cells had increased expression of Snail, phospho-Akt (pAkt), and pGSK3β, and decreased E-cadherin expression, leading to epithelial-mesenchymal transition (EMT)/cancer stem cell (CSC) features. The cells also exhibited acceleration of cell motility and inhibition of cell proliferation and apoptosis. Next generation sequencing revealed that fibronectin (FN) expression was significantly increased in the p53 KD-cells, in line with our observation that wild-type p53 (but not mutant p53) repressed FN1 promoter activity. In addition, treatment of OCCCa cells with FN significantly increased cell migration capacity and decreased cell proliferation rate, independent of induction of EMT features. In clinical samples, FN/p53 scores were significantly higher in OCCCa/OHGSeCa with the HNF-1β+/p53+/ARID1A+ immunophenotype when compared to others. Moreover, high FN/high p53 expression was associated with the worst overall survival and progression-free survival in OCCCa/OHGSeCa patients.ConclusionThese findings suggest that upregulation of FN following loss of p53 function may impact the biological behavior of OCCCa/OHGSeCa, particularly in tumors with an HNF-1β+/p53+/ARID1A+ immunophenotype, through alterations in cell mobility and cell proliferation. The accompanying induction of EMT/CSC properties and inhibition of apoptosis due to p53 abnormalities also contribute to the establishment and maintenance of tumor phenotypic characteristics.4HYHfp8oPTLQGnKo7co1TGVideo
Highlights
We previously demonstrated that ovarian high grade serous carcinomas (OHGSeCa) and ovarian clear cell carcinomas (OCCCa) with an HNF-1β+/p53+/ARID1A+ immunophenotype were associated with the worst unfavorable prognosis
We demonstrated that tumors with an HNF-1β+/p53+/ARID1A+ immunophenotype including OHGSeCa and ovarian clear cell carcinomas (OCCCa) were associated with the most unfavorable prognosis
Loss of p53 function leads to induction of epithelial-mesenchymal transition (EMT) features To examine the phenotypic characteristics of Ovarian epithelial carcinomas (OECa) cells with the HNF-1β+/p53+/ARID1A+ immunophenotype, we first established two independent cell lines in which p53 expression was blocked by a p53-specific short hairpin RNA (shRNA) (OV-shp53#2 and #8) using OVISE (OV) cells
Summary
We previously demonstrated that ovarian high grade serous carcinomas (OHGSeCa) and ovarian clear cell carcinomas (OCCCa) with an HNF-1β+/p53+/ARID1A+ immunophenotype were associated with the worst unfavorable prognosis. P53 is widely acknowledged as the most frequently mutated gene in human malignancy and its mutational status is a prognostic marker in several tumor types [4]. Mutations in the TP53 gene are found in more than 50% of human malignancies and its inactivation can occur at various stages depending on the tissue that gives rise to the tumor. In OECa, and in ovarian high-grade serous carcinomas (OHGSeCa), mutant p53 (p53mt) missense mutations are frequently found in the hotspot codon R175, R248, and R273 (http://www-p53.iarc.fr/) that are critical contact residues in the p53 DNA-binding domain. The mutations occur early during tumorigenesis, most likely in precursor lesions of OECa, highlighting the importance of p53mt as a driver of the malignancy [8,9,10,11]
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