Isoproterenol regulates CD44 expression in gastric cancer cells through STAT3/MicroRNA373 cascade
Isoproterenol regulates CD44 expression in gastric cancer cells through STAT3/MicroRNA373 cascade
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异丙肾上腺素通过STAT3/MicroRNA373级联调节胃癌细胞CD44表达
DOI：
10.1016/j.biomaterials.2016.07.040
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发表时间：
2016-10-01
期刊：
影响因子：
14
通讯作者：
Fu, Xiaobing
中科院分区：
文献类型：
--
作者：
Wei, Bo;Sun, Xiaoyan;Fu, Xiaobing
胃癌是一种异质性疾病，干细胞被认为是导致胃癌的起源细胞。然而，对乳腺癌和肠癌模型的研究表明，非干细胞癌细胞可以改变其表面表型，并在周围肿瘤微环境发出的信号的诱导下转化为肿瘤起始细胞。在此，我们发现，与原发性肿瘤相比，CD 44在胃转移瘤中以不同水平表达，并且与miR-373的表达呈负相关。通过使用一组人胃癌细胞系并分析来自癌症基因组学Altas（TCGA）数据库的存档数据，我们验证了CD 44和miR-373之间的负相关性。此外，应激相关激素异丙肾上腺素可增加“干”相关蛋白如CD 44、Nanog和雷克斯-1的表达水平，并诱导胃癌细胞的化疗耐药性。然而，用miR-373转染不仅逆转了异丙肾上腺素对表型转化的作用，而且逆转了其对药物敏感性的作用。异丙肾上腺素主要通过β 2-肾上腺素能受体（32-AR）触发下游靶点STAT 3。活化的STAT 3通过与其启动子结合而发挥miR-373抑制剂的作用，该启动子形成正反馈回路以维持CD 44活性并指导从CD 44（低）到CD 44（高）表达的表型转化。我们的数据表明β 2-AR/STAT 3/miR-373信号通路在胃癌细胞转化中起重要作用。这项研究还表明，一个潜在的治疗或预防治疗胃癌患者谁是特别容易受到心理社会压力。(C)2016爱思唯尔有限公司版权所有
Gastric cancer is a heterogeneous disease, and stem cells are thought to be the cell of origin contributed to this malignancy. However, studies with breast and intestinal cancer models show non-stem cancer cells can change their surface phenotype and convert into tumor-initiating cells induced by the signals emanating from surrounding tumor microenvironment. Here, we show that CD44 was expressed at different levels in gastric metastases compared with primary tumors, and also negatively correlated with the expression of miR-373. By using a panel of human gastric cancer cell lines and analysis of archived data from The Cancer Genomics Altas (TCGA) database, we verified the inverse correlation between CD44 and miR-373. Furthermore, the stress-associated hormone, isoproterenol, could increase the expression levels of "stem"-related proteins, such as CD44, Nanog, and Rex-1, and induce chemoresistance in gastric cancer cells. Transfection with miR-373, however, reversed not only the effect of isoproterenol on phenotypic conversion but also its effect on drug sensitivity. Isoproterenol triggered downstream target STAT3 mainly through beta(2)-adrenergic receptors ((32-ARs). Activated STAT3 functioned as a miR-373 suppressor by binding to its promoter, which forms a positive feedback circuit to maintain CD44 activity and direct the phenotypic conversion from CD44(low) to CD44(hi) expression. Our data suggest an important role of beta 2-AR/STAT3/miR-373 signaling on the transformation of gastric cancer cells. This study also suggests a potential therapeutic or preventive treatment for gastric cancer patients who are especially prone to psychosocial stress. (C) 2016 Elsevier Ltd. All rights reserved.