GLI1 activation by non-classical pathway integrin αvβ3/ERK1/2 maintains stem cell-like phenotype of multicellular aggregates in gastric cancer peritoneal metastasis
GLI1 activation by non-classical pathway integrin αvβ3/ERK1/2 maintains stem cell-like phenotype of multicellular aggregates in gastric cancer peritoneal metastasis
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DOI：
10.1038/s41419-019-1776-x
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发表时间：
2019-07-31
影响因子：
9
通讯作者：
Yu, Peiwu
中科院分区：
文献类型：
--
作者：
Dong, Hui;Liu, Hongchang;Yu, Peiwu
腹膜转移是胃癌患者术后死亡的最重要原因之一，其具体机制尚不清楚。腹腔内脱落的恶性胃细胞的多细胞聚集体的增殖是当前研究的焦点。然而，胃癌多细胞聚集体的存活机制仍不清楚。在这项研究中，我们证明腹腔中脱落的胃癌细胞的多细胞聚集体表达干细胞样表型。我们发现整合素α(v)β(3)不仅介导胃癌多细胞聚集体粘附形成独立的功能单位，而且还通过非经典途径整合素α(v)β(3)/ERK1/2/GLI1维持其干细胞样表型。此外，ERK1/2直接调节GLI1的转录活性。 GLI1 是整合素 α(v)β(3) 途径的关键效应子，可调节多细胞聚集体中的干细胞样表型。我们的数据表明，尽管非经典整合素α(v)β(3)途径和经典Hedgehog途径之间存在串扰，但在胃癌细胞的多细胞聚集体中，GLI1的激活几乎独立于Hedgehog途径。我们的研究为阻断GLI1活性预防和治疗胃癌腹膜转移提供了依据。
Peritoneal metastasis is one of the most important causes of postoperative death in patients with gastric cancer, and the exact mechanism remains unclear. The proliferation of multicellular aggregates of exfoliated malignant gastric cells in the abdominal cavity is the focus of current research. However, the mechanism how gastric cancer multicellular aggregates survive remains unclear. In this study, we demonstrated that multicellular aggregates of exfoliated gastric cancer cells in the abdominal cavity expressed a stem cell-Like phenotype. We found that Integrin alpha(v)beta(3) not only mediated adhesion of gastric cancer multicellular aggregates to form independent functional units, but also maintained their stem cell-like phenotype by the non-classical pathway Integrin alpha(v)beta(3)/ERK1/2/GLI1. In addition, ERK1/2 directly regulates the transcriptional activity of GLI1. GLI1 is a key effector of the Integrin alpha(v)beta(3) pathway in regulating stem cell-like phenotype in multicellular aggregates. Our data indicates that although there is a crosstalk between the non-classical Integrin alpha(v)beta(3) pathway and the classical Hedgehog pathway, the activation of GLI1 is almost independent of the Hedgehog pathway in multicellular aggregates of gastric cancer cells. Our study provides a basis for blocking GLI1 activity in the prevention and treatment of peritoneal metastases of gastric cancer.