S100A4/Nonmuscle Myosin IIA/p53 Axis Contributes to Aggressive Features in Ovarian High-Grade Serous Carcinoma
S100A4/Nonmuscle Myosin IIA/p53 Axis Contributes to Aggressive Features in Ovarian High-Grade Serous Carcinoma
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DOI：
10.1016/j.ajpath.2020.07.014
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发表时间：
2020-11-01
影响因子：
6
通讯作者：
Saegusa, Makoto
中科院分区：
文献类型：
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作者：
Hiruta, Ai;Oguri, Yasuko;Saegusa, Makoto
S100A4 是一种小型钙结合蛋白，通过与非肌肉肌球蛋白 IIA (NMIIA) 和 p53 相互作用发挥其生物学功能。尽管 S100A4 促进多种肿瘤的转移，但人们对其在卵巢高级别浆液性癌 (HGSC) 进展中的参与知之甚少。在此，我们重点关注 S100A4/NMIIA/p53 轴在这些肿瘤中的功能作用。在含有突变体 p53 的 HGSC 细胞系中，S100A4 的敲除 (KD) 降低了几种上皮间质转化/癌症干细胞标记物和 ALDH1 高群体的表达，这与干性特征的抑制一致。 S100A4-KD 还增加细胞凋亡、减少细胞增殖并加速细胞迁移。这伴随着 Snail 表达的增加，而这可能是由于 p53 功能的丧失所致。相反，肌球蛋白抑制剂对 NMIIA 的特异性抑制诱导的表型（细胞增殖和迁移除外）与在 S100A4-KD 细胞中观察到的相反。在临床样本中，观察到 S100A4、NMIIA 和突变体 p53 之间的细胞质和/或核相互作用。此外，S100A4的高表达，而不是NMIIA或p53，是HGSC患者显着且独立的不利预后因素。这些发现表明，通过与 NMIIA 和 p53 的相互作用，过度表达的 S100A4 可能会诱导 HGSC 中的上皮-间质转化/癌症干细胞特性，并引发其他几种与肿瘤相关的表型。
S100A4 is a small calcium-binding protein that exerts its biological functions by interacting with nonmuscle myosin IIA (NMIIA) and p53. Although S100A4 promotes metastasis in several tumors, little is known about its involvement in the progression of ovarian high-grade serous carcinomas (HGSCs). Herein, we focused on functional roles of the S100A4/NMIIA/p53 axis in these tumors. In HGSC cell lines harboring mutant p53, knockdown (KD) of S100A4 reduced the expression of several epithelialmesenchymal transition/cancer stem cell markers and the ALDH1high population, consistent with an inhibition of stemness features. S100A4-KD also increased apoptosis, decreased cell proliferation, and accelerated cell mobility. This was accompanied by increased Snail expression, which, in turn, was likely due to loss of p53 function. In contrast, specific inhibition of NMIIA by blebbistatin induced phenotypes thatd-with the exception of cell proliferation and mobilityd-were opposite to those observed in S100A4-KD cells. In clinical samples, cytoplasmic and/or nuclear interactions between S100A4, NMIIA, and mutant p53 were observed. In addition, high expression of S100A4, but not NMIIA or p53, was a significant and independent unfavorable prognostic factor in HGSC patients. These findings suggest that, via its interaction with NMIIA and p53, overexpressed S100A4 may induce epithelial-mesenchymal transition/cancer stem cell properties in HGSC and elicit several other tumor-associated phenotypes.