Roles of Wnt/β-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment.
Roles of Wnt/β-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment.
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DOI：
10.1038/cddis.2013.515
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发表时间：
2014-01-30
影响因子：
9
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中科院分区：
文献类型：
--
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Wnt1蛋白是一种激活Wnt信号通路的分泌配体，有助于癌症干细胞（CSCs）的自我更新，因此可能是肿瘤进展和化疗耐药的主要决定因素。在一系列胃癌标本中，我们发现Wnt1表达、CD44表达与胃癌分级有很强的相关性。Wnt1的稳定过表达增加了AGS胃癌细胞的增殖率和球体的形成，这些球体表达CSC表面标记物Oct4和CD44。皮下注射过表达wnt1的AGS细胞的裸鼠肿瘤比注射对照AGS细胞的肿瘤大。Salinomycin是一种抗肿瘤药物，在体内可显著降低过表达wnt1的AGS细胞引起的肿瘤体积。这是通过抑制CD44+Oct4+ CSC亚群的增殖来实现的，至少部分是通过抑制Wnt1和β-catenin的表达。综上所述，Wnt1信号的激活加速了胃CSCs的增殖，而盐碱霉素通过抑制CSCs中的Wnt信号来抑制胃肿瘤的生长。这些结果表明，Wnt信号通路可能在胃CSCs的自我更新中起关键作用，而盐霉素靶向Wnt信号通路可能在胃癌治疗中具有重要的临床应用价值。
The Wnt1 protein, a secreted ligand that activates Wnt signaling pathways, contributes to the self-renewal of cancer stem cells (CSCs) and thus may be a major determinant of tumor progression and chemoresistance. In a series of gastric cancer specimens, we found strong correlations among Wnt1 expression, CD44 expression, and the grade of gastric cancer. Stable overexpression of Wnt1 increased AGS gastric cancer cells' proliferation rate and spheroids formation, which expressed CSC surface markers Oct4 and CD44. Subcutaneous injection of nude mice with Wnt1-overexpressing AGS cells resulted in larger tumors than injection of control AGS cells. Salinomycin, an antitumor agent, significantly reduced the volume of tumor caused by Wnt1-overexpressing AGS cells in vivo. This is achieved by inhibiting the proliferation of CD44+Oct4+ CSC subpopulation, at least partly through the suppression of Wnt1 and β-catenin expression. Taken together, activation of Wnt1 signaling accelerates the proliferation of gastric CSCs, whereas salinomycin acts to inhibit gastric tumor growth by suppressing Wnt signaling in CSCs. These results suggest that Wnt signaling might have a critical role in the self-renewal of gastric CSCs, and salinomycin targeting Wnt signaling may have important clinical applications in gastric cancer therapy.
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