Rodgers Laura H, Ó hAinmhire Eoghainín, Young Alexandria N, Burdette Joanna E
Department of Medicinal Chemistry and Pharmacognosy, Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
Oncotarget. 2016 May 31;7(22):32785-95. doi: 10.18632/oncotarget.9051.
High-grade serous carcinoma (HGSC) is the most common and lethal form of ovarian cancer. PAX8 is a transcription factor expressed in fallopian tube epithelial cells and in 80-96% of HGSC tumors. The ovarian surface epithelium (OSE) only acquires PAX8 expression after malignant transformation. In this study, forced PAX8 expression in OSE cells increased proliferation and migration through upregulation of EMT factors such as N-cadherin and Fibronectin. OSE cells expressing PAX8 also had an increase in the FOXM1 pathway, but PAX8 alone was not sufficient to drive tumorigenesis. PAX8 knockdown in the oviductal epithelium cells did not decrease expression of the FOXM1 pathway and induced only a slight decrease in cell proliferation. No changes in migration, cell cycle, or apoptosis were detected after PAX8 knockdown in oviductal cells. Finally, PAX8 knockdown in HGSC cell lines resulted in increased apoptosis and decreased FOXM1 levels. The results presented here suggest that PAX8 has a cell specific role in governing proliferation and migration in nontransformed ovarian surface epithelium cells compared to the oviductal cells, but its reduction in serous cancer cell lines provides a common mechanism for reducing cell survival.
高级别浆液性癌（HGSC）是卵巢癌最常见且致死率最高的形式。PAX8是一种在输卵管上皮细胞以及80%-96%的HGSC肿瘤中表达的转录因子。卵巢表面上皮（OSE）只有在恶性转化后才获得PAX8表达。在本研究中，OSE细胞中PAX8的强制表达通过上调N-钙黏蛋白和纤连蛋白等EMT因子增加了细胞增殖和迁移。表达PAX8的OSE细胞中FOXM1通路也有所增加，但单独的PAX8不足以驱动肿瘤发生。输卵管上皮细胞中PAX8的敲低并未降低FOXM1通路的表达，仅导致细胞增殖略有下降。在输卵管细胞中敲低PAX8后，未检测到迁移、细胞周期或细胞凋亡的变化。最后，HGSC细胞系中PAX8的敲低导致细胞凋亡增加和FOXM1水平降低。此处呈现的结果表明，与输卵管细胞相比，PAX8在调控未转化的卵巢表面上皮细胞的增殖和迁移中具有细胞特异性作用，但其在浆液性癌细胞系中的减少为降低细胞存活率提供了一种共同机制。
