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. To clarify the molecular mechanisms underlying this finding, we focused on alterations in the p53 signaling pathway in these tumors. Changes 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. p53-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. These 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.

中文翻译：

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p53 功能丧失后纤连蛋白的上调是具有独特免疫表型的卵巢癌的不良预后因素。

我们之前已经证明，具有 HNF-1β+/p53+/ARID1A+ 免疫表型的卵巢高级别浆液性癌 (OHGSeCa) 和卵巢透明细胞癌 (OCCCa) 与最差的不良预后相关。为了阐明这一发现背后的分子机制，我们专注于这些肿瘤中 p53 信号通路的改变。使用表达内源性 HNF-1β 和 ARID1A 的 OCCCa 细胞评估敲除野生型 p53 (p53-KD) 后细胞表型和功能的变化。还使用 129 个 OCCCa/OHGSeCa 病例检查了在 p53-KD 后失调的分子的预后意义。p53-KD 细胞的 Snail、磷酸化 Akt (pAkt) 和 pGSK3β 表达增加，E-钙粘蛋白表达降低，导致上皮间充质转化 (EMT)/癌症干细胞 (CSC) 特征。细胞还表现出细胞运动的加速和细胞增殖和凋亡的抑制。下一代测序显示，p53 KD 细胞中的纤连蛋白 (FN) 表达显着增加，这与我们观察到的野生型 p53（但不是突变型 p53）抑制 FN1 启动子活性一致。此外，用 FN 处理 OCCCa 细胞显着增加了细胞迁移能力并降低了细胞增殖率，与 EMT 特征的诱导无关。在临床样本中，与其他类型相比，具有 HNF-1β+/p53+/ARID1A+ 免疫表型的 OCCCa/OHGSeCa 的 FN/p53 评分显着更高。此外，高 FN/高 p53 表达与 OCCCa/OHGSeCa 患者最差的总生存期和无进展生存期相关。这些发现表明，p53 功能丧失后 FN 的上调可能会影响 OCCCa/OHGSeCa 的生物学行为，尤其是在具有 HNF-1β+/p53+/ARID1A+ 免疫表型的肿瘤中，通过改变细胞迁移率和细胞增殖。由于 p53 异常引起的 EMT/CSC 特性的诱导和细胞凋亡的抑制也有助于肿瘤表型特征的建立和维持。