Background/Objectives: S100A4, a small calcium-binding protein, promotes metastasis in a variety of human malignancies, but little is known about its involvement in ovarian clear cell carcinoma (OCCC). Herein, we characterized the functional role of S100A4 in this tumor type. Methods: We analyzed immunohistochemical sections from 120 OCCC patients. OCCC cell lines in which S100A4 was knocked out (KO) or overexpressed were also used to study the protein’s effects. Results: Stable overexpression of S100A4 decreased the proliferation of OCCC cell lines (concomitant with more cells in G1 and fewer in the G2/M phase of the cell cycle). S100A4 overexpression also reduced susceptibility to cisplatin-induced apoptosis (probably due to an increased BCL2: BAX ratio), accelerated epithelial–mesenchymal transition (EMT)-related cell mobility, and enhanced cancer stem cell (CSC) properties (including increases in both spheroid formation and in the aldehyde dehydrogenase 1 (ALDH1)highpopulation). In contrast, S100A4 KO generally induced the opposite phenotypes, although it did not affect migration capability. In clinical OCCC samples, high S100A4 expression was associated with a low frequency of cleaved poly-(ADP-ribose) polymerase 1-positive apoptotic cells, a reduced proliferative rate, and expression of high ALDH1 and vimentin levels. In addition, a high S100A4 score was a significant (but not independent) prognostic factor in OCCC. Conclusions: Our findings suggest that S100A4 may be an unfavorable prognostic factor in OCCC, as it accelerates tumor progression and promotes chemoresistance through the modulation of proliferation, susceptibility to apoptosis, and EMT/CSC properties.
背景/目的：S100A4作为一种小型钙结合蛋白，在多种人类恶性肿瘤中促进转移，但其在卵巢透明细胞癌中的作用尚不明确。本研究旨在阐明S100A4在该肿瘤类型中的功能作用。方法：我们分析了120例卵巢透明细胞癌患者的免疫组织化学切片，并利用S100A4敲除及过表达的卵巢透明细胞癌细胞系探究该蛋白的功能效应。结果：S100A4稳定过表达可降低卵巢透明细胞癌细胞系的增殖能力（伴随G1期细胞比例增加及G2/M期细胞比例减少），同时降低顺铂诱导的细胞凋亡敏感性（可能与BCL2:BAX比值升高有关），加速上皮-间质转化相关细胞运动，并增强癌症干细胞特性（包括提高细胞球形成能力及醛脱氢酶1高表达细胞群比例）。相反，S100A4敲除通常诱导相反表型，但对细胞迁移能力无显著影响。临床样本分析显示，S100A4高表达与裂解多聚腺苷二磷酸核糖聚合酶1阳性凋亡细胞频率降低、增殖速率下降以及醛脱氢酶1和波形蛋白高表达相关。此外，高S100A4评分是卵巢透明细胞癌的重要（非独立）预后因素。结论：本研究提示S100A4可能通过调控细胞增殖、凋亡敏感性及上皮-间质转化/癌症干细胞特性，加速肿瘤进展并促进化疗耐药，成为卵巢透明细胞癌的不良预后因素。
肿瘤(癌症)患者之家