Helicobacter pylori upregulates Nanog and Oct4 via Wnt/β-catenin signaling pathway to promote cancer stem cell-like properties in human gastric cancer
Helicobacter pylori upregulates Nanog and Oct4 via Wnt/β-catenin signaling pathway to promote cancer stem cell-like properties in human gastric cancer
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幽门螺杆菌通过 Wnt/β-catenin 信号通路上调 Nanog 和 Oct4，促进人胃癌中的癌症干细胞样特性
DOI：
10.1016/j.canlet.2016.02.032
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发表时间：
2016-05-01
期刊：
影响因子：
9.7
通讯作者：
Yang, Shi-Ming
中科院分区：
文献类型：
--
作者：
Yong, Xin;Tang, Bo;Yang, Shi-Ming
幽门螺杆菌感染被认为是胃癌的主要危险因素。CagA是一种主要的细菌癌蛋白，在幽门螺杆菌诱导的肿瘤发生中起关键作用。癌症干细胞（CSCs）被认为具有启动肿瘤发生和促进肿瘤进展的能力。虽然研究表明癌细胞在肿瘤微环境中可以表现出csc样特性，但幽门螺杆菌感染是否可以诱导胃癌细胞出现csc样特性及其潜在机制尚不清楚。在这里，胃癌细胞与CagA阳性幽门螺杆菌菌株或CagA等基因突变菌株共培养。我们发现幽门螺杆菌感染的胃癌细胞表现出CSC样特性，包括CSC特异性表面标记CD44和Lgr5的表达增加，以及Nanog、Oct4和c-myc（已知的多能基因）的表达增加，自我更新能力增强，而这些特性在CagA等基因突变株感染的细胞中没有观察到。进一步的研究表明，幽门螺杆菌以caga依赖的方式激活Wnt/ β -catenin信号通路，并且该通路的激活依赖于caga阳性的幽门螺杆菌介导的β -catenin在c端Ser675和Ser552残基上以c-met和/或akt依赖的方式磷酸化。我们进一步证明了这种激活是幽门螺杆菌诱导的csc样特性的原因。此外，我们发现Nanog和Oct4启动子活性上调，并且在幽门螺杆菌感染期间观察到β -catenin与这些启动子结合，而Wnt/ β -catenin抑制剂抑制启动子活性和结合。综上所述，这些结果表明幽门螺杆菌通过Wnt/ β -catenin信号通路上调Nanog和Oct4，促进胃癌细胞csc样特性。(C) 2016年作者。爱思唯尔爱尔兰有限公司出版。
Helicobacter pylori (H. pylori) infection is considered a major risk factor for gastric cancer. CagA behaves as a major bacterial oncoprotein playing a key role in H. pylori-induced tumorigenesis. Cancer stem cells (CSCs) are believed to possess the ability to initiate tumorigenesis and promote progression. Although studies have suggested that cancer cells can exhibit CSC-like properties in the tumor microenvironment, it remains unclear whether H. pylori infection could induce the emergence of CSC-like properties in gastric cancer cells and, the underlying mechanism. Here, gastric cancer cells were co-cultured with a CagA-positive H. pylori strain or a CagA isogenic mutant strain. We found that H. pylori-infected gastric cancer cells exhibited CSC-like properties, including an increased expression of CSC specific surface markers CD44 and Lgr5, as well as that of Nanog, Oct4 and c-myc, which are known pluripotency genes, and an increased capacity for self-renewal, whereas these properties were not observed in the CagA isogenic mutant strain-infected cells. Further studies revealed that H. pylori activated Wnt/beta-catenin signaling pathway in a CagA-dependent manner and that the activation of this pathway was dependent upon CagA-positive H. pylori-mediated phosphorylation of beta-catenin at the C-terminal Ser675 and Ser552 residues in a c-met- and/or Akt-dependent manner. We further demonstrated that this activation was responsible for H. pylori-induced CSC-like properties. Moreover, we found the promoter activity of Nanog and Oct4 were upregulated, and beta-catenin was observed to bind to these promoters during H. pylori infection, while a Wnt/beta-catenin inhibitor suppressed promoter activity and binding. Taken together, these results suggest that H. pylori upregulates Nanog and Oct4 via Wnt/beta-catenin signaling pathway to promote CSC-like properties in gastric cancer cells. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.