SOX9 is a novel cancer stem cell marker surrogated by osteopontin in human hepatocellular carcinoma.
SOX9 is a novel cancer stem cell marker surrogated by osteopontin in human hepatocellular carcinoma.
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DOI：
10.1038/srep30489
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发表时间：
2016-07-26
影响因子：
4.6
通讯作者：
Uemoto S
中科院分区：
文献类型：
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作者：
Kawai T;Yasuchika K;Ishii T;Miyauchi Y;Kojima H;Yamaoka R;Katayama H;Yoshitoshi EY;Ogiso S;Kita S;Yasuda K;Fukumitsu K;Komori J;Hatano E;Kawaguchi Y;Uemoto S
目前缺乏易于通过血液样本评估的癌症干细胞(CSC)标记物，阻碍了肝细胞癌(HCC)新治疗策略的建立。在此，我们研究了性别决定区Y-box 9(SOX9)是否代表了一个新的CSC标志物，以及骨桥蛋白(OPN)是否可以作为SOX9在肝细胞癌中的替代标志物。在转导SOX9启动子驱动的增强型绿色荧光蛋白基因的肝癌细胞系中，流式细胞仪分离的SOX9+细胞具有自我更新和分化为SOX9−细胞的能力，并在体外表现出较高的增殖能力。异种移植实验表明，SOX9+细胞在体内繁殖、分化为SOX9−细胞，并产生高频率的肿瘤。此外，SOX9+细胞还参与了上皮-间充质转化(EMT)和TGFb/Smad信号的激活。功能得失实验表明，SOX9调控Wnt/β-catenin信号转导，包括细胞周期蛋白D1和骨桥蛋白。免疫组织化学和血清骨桥蛋白检测结果显示，与SOX9−患者相比，SOX9+患者的无复发生存率明显降低，静脉侵犯更强，血清骨桥蛋白水平更高。综上所述，SOX9是一个新的肝癌-CSC标记物，调节Wnt/β-catenin通路及其下游靶标OPN。OPN是SOX9在肝细胞癌中的有用替代标记物。
The current lack of cancer stem cell (CSC) markers that are easily evaluated by blood samples prevents the establishment of new therapeutic strategies in hepatocellular carcinoma (HCC). Herein, we examined whether sex determining region Y-box 9 (SOX9) represents a new CSC marker, and whether osteopontin (OPN) can be used as a surrogate marker of SOX9 in HCC. In HCC cell lines transfected with a SOX9 promoter-driven enhanced green fluorescence protein gene, FACS-isolated SOX9+ cells were capable of self-renewal and differentiation into SOX9− cells, and displayed high proliferation capacity in vitro. Xenotransplantation experiments revealed that SOX9+ cells reproduced, differentiated into SOX9− cells, and generated tumors at a high frequency in vivo. Moreover, SOX9+ cells were found to be involved in epithelial-mesenchymal transition (EMT) and activation of TGFb/Smad signaling. Gain/loss of function experiments showed that SOX9 regulates Wnt/beta-catenin signaling, including cyclin D1 and OPN. Immunohistochemistry of 166 HCC surgical specimens and serum OPN measurements showed that compared to SOX9− patients, SOX9+ patients had significantly poorer recurrence-free survival, stronger venous invasion, and higher serum OPN levels. In conclusion, SOX9 is a novel HCC-CSC marker regulating the Wnt/beta-catenin pathway and its downstream target, OPN. OPN is a useful surrogate marker of SOX9 in HCC.