SOX2 和 SOX9 是转移性高级别浆液性癌中临床侵袭性疾病的标志物。
SOX2 and SOX9 are markers of clinically aggressive disease in metastatic high-grade serous carcinoma.
机构信息
Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway.
出版信息
Gynecol Oncol. 2019 Jun;153(3):651-660. doi: 10.1016/j.ygyno.2019.03.099. Epub 2019 Mar 21.
OBJECTIVE
The aim of this study was to analyze the expression, biological role and clinical relevance of cancer stem cell markers in high-grade serous carcinoma (HGSC).
METHODS
mRNA expression by qRT-PCR of NANOG, OCT4, SOX2, SOX4, SOX9, LIN28A and LIN28B was analyzed in 134 HGSC specimens (84 effusions, 50 surgical specimens). Nanog, OCT3/4, SOX2 and SOX9 protein expression by immunohistochemistry was analyzed in 52 HGSC effusions. Nanog protein expression in exosomes from 80 HGSC effusions was studied by Western Blotting. OVCAR3 cells underwent CRISPR/Cas9 Nanog knockout (KO), and the effect of Nanog KO on migration, invasion, proliferation and proteolytic activity was analyzed in OVCAR3 and OVCAR8 cells.
RESULTS
OCT4 mRNA was overexpressed in effusions compared to solid specimens (p = 0.046), whereas SOX9 was overexpressed in the ovarian tumors compared to effusions and solid metastases (p = 0.003). Higher SOX2 and SOX9 expression was associated with primary (intrinsic) chemoresistance (p = 0.009 and p = 0.02, respectively). Higher SOX9 levels were associated with shorter overall survival in univariate (p = 0.04) and multivariate (p = 0.049) analysis. OCT3/4, SOX2 and SOX9 proteins were found in HGSC cells, whereas Nanog was detected only in exosomes. Higher SOX2 protein expression was associated with shorter overall survival in univariate analysis (p = 0.049). OVCAR cells exposed to OVCAR3 NANOG KO exosomes had reduced migration, invasion and MMP9 activity.
CONCLUSIONS
SOX2 and SOX9 mRNA levels in HGSC effusions may be markers of clinically aggressive disease. Nanog is secreted in HGSC exosomes in effusions and modulates tumor-promoting cellular processes in vitro.
目的
本研究旨在分析癌症干细胞标志物在高级别浆液性卵巢癌（HGSC）中的表达、生物学功能和临床相关性。
方法
采用 qRT-PCR 分析了 134 例 HGSC 标本（84 例腹水，50 例手术标本）中 NANOG、OCT4、SOX2、SOX4、SOX9、LIN28A 和 LIN28B 的 mRNA 表达。采用免疫组织化学法分析了 52 例 HGSC 腹水中 Nanog、OCT3/4、SOX2 和 SOX9 蛋白的表达。采用 Western Blotting 法研究了 80 例 HGSC 腹水中 Nanog 蛋白在 exosomes 中的表达。通过 CRISPR/Cas9 对 OVCAR3 细胞进行 Nanog 敲除（KO），并分析 Nanog KO 对 OVCAR3 和 OVCAR8 细胞迁移、侵袭、增殖和蛋白水解活性的影响。
结果
与实体标本相比，OCT4 mRNA 在腹水中过表达（p=0.046），而 SOX9 在卵巢肿瘤中过表达，与腹水和实体转移相比（p=0.003）。较高的 SOX2 和 SOX9 表达与原发性（内在）化疗耐药性相关（p=0.009 和 p=0.02）。单因素（p=0.04）和多因素（p=0.049）分析中，较高的 SOX9 水平与总生存期较短相关。在 HGSC 细胞中发现了 OCT3/4、SOX2 和 SOX9 蛋白，而 Nanog 仅在 exosomes 中检测到。较高的 SOX2 蛋白表达与单因素分析中的总生存期较短相关（p=0.049）。暴露于 OVCAR3 NANOG KO exosomes 的 OVCAR 细胞的迁移、侵袭和 MMP9 活性降低。
结论
HGSC 腹水中的 SOX2 和 SOX9 mRNA 水平可能是临床侵袭性疾病的标志物。Nanog 在 HGSC 腹水中的 exosomes 中分泌，并在体外调节肿瘤促进细胞过程。
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