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.

中文翻译：

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PAX8在高度浆液性卵巢癌中激活p53-p21依赖性的促增殖作用。

高度浆液性癌（HGSC）是最常见的卵巢癌亚型，目前已广泛接受，该疾病通常起源于输卵管上皮。PAX8是输卵管谱系标记，在胚胎女性生殖道发育中起重要作用。在成年的输卵管中，PAX8在输卵管分泌上皮细胞（FTSEC）中表达，并通过FTSEC转化为HGSC的过程维持其表达。现在，我们报告PAX8在HGSC中具有促增殖和抗凋亡的作用。肿瘤抑制基因TP53在接近100％的HGSC中发生了突变；在大多数情况下，这些是错义突变，使突变型p53蛋白具有潜在的功能增强（GOF）致癌活性。我们表明，PAX8积极调节HGSC中TP53的表达，并且PAX8的增生作用是由突变体p53的GOF活性介导的。出人意料的是，突变体p53转录激活p21的表达，而p21则位于HGSC细胞的细胞质中，在该细胞质中起着非典型的促增殖作用。总之，我们的发现说明了HGSC中的TP53突变如何将正常的调节途径转化为肿瘤进展的驱动力。