Chibby suppresses aerobic glycolysis and proliferation of nasopharyngeal carcinoma via the Wnt/β-catenin-Lin28/let7-PDK1 cascade.
Chibby suppresses aerobic glycolysis and proliferation of nasopharyngeal carcinoma via the Wnt/β-catenin-Lin28/let7-PDK1 cascade.
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Chibby 通过 Wnt/β-catenin-Lin28/let7-PDK1 级联抑制鼻咽癌的有氧糖酵解和增殖
DOI：
10.1186/s13046-018-0769-4
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发表时间：
2018-05-15
期刊：
影响因子：
--
通讯作者：
Yang SY
中科院分区：
文献类型：
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作者：
Cai CF;Ye GD;Shen DY;Zhang W;Chen ML;Chen XX;Han DX;Mi YJ;Luo QC;Cai WY;Yang SY
有氧糖酵解或所谓的瓦尔堡效应在多种癌症中的研究已经取得了很大进展，但瓦尔堡效应在鼻咽癌（NPC）中的调控机制尚未完全确定。使用NPC细胞的基因表达模式来测试Chibby和β-catenin表达之间的关联。将Chibby siRNA和过表达载体转染鼻咽癌细胞，下调或上调Chibby的表达。进行功能丧失和获得测定以研究Chibby在NPC细胞中的作用。Western印迹、细胞增殖、葡萄糖摄取、乳酸释放、ATP水平和O2消耗测定用于确定Chibby调节潜在靶点的机制。最后，采用免疫组化法检测Chibby、β-Catenin和PDK1在鼻咽癌组织中的表达。我们观察到β-catenin相关拮抗剂Chibby在鼻咽癌细胞系中表达下调，并抑制Wnt/β-catenin信号通路诱导的瓦尔堡效应。机制研究表明，Chibby通过参与葡萄糖代谢的重要酶丙酮酸脱氢酶激酶1（PDK1）调节鼻咽癌细胞有氧糖酵解。此外，Chibby通过Wnt/β-Catenin-Lin28/let7-PDK1级联反应抑制NPC的有氧糖酵解。Chibby和PDK1在Wnt/β-Catenin信号通路诱导鼻咽癌细胞增殖中起重要作用。最后，组织样品的免疫染色测定提供了Chibby、Wnt/β-连环蛋白信号传导和PDK1之间的重要临床相关性。我们的研究揭示了Chibby表达与肿瘤有氧糖酵解的相关性，这突出了Wnt/β-catenin通路在NPC能量代谢调控中的重要性。这些结果表明，Chibby和PDK1是NPC治疗的潜在靶点。本文的在线版本（10.1186/s13046 - 018 - 0769 - 4）包含补充材料，可供授权用户使用。
Great progress has been achieved in the study of the aerobic glycolysis or the so-called Warburg effect in a variety of cancers; however, the regulation of the Warburg effect in Nasopharyngeal carcinoma (NPC) has not been completely defined. Gene expression pattern of NPC cells were used to test associations between Chibby and β-catenin expression. Chibby siRNAs and over-expression vector were transfected into NPC cells to down-regulate or up-regulate Chibby expression. Loss- and gain-of function assays were performed to investigate the role of Chibby in NPC cells. Western blot, cell proliferation, Glucose uptake, Lactate release, ATP level, and O2 consumption assays were used to determine the mechanism of Chibby regulation of underlying targets. Finally, immunohistochemistry assay of fresh NPC and nasopharyngeal normal tissue sample were used to detect the expression of Chibby, β-Catenin, and PDK1 by immunostaining. We observed that Chibby, a β-catenin-associated antagonist, is down-regulated in nasopharyngeal carcinoma cell lines and inhibits Wnt/β-Catenin signaling induced Warburg effect. Mechanism study revealed that Chibby regulates aerobic glycolysis in NPC cells through pyruvate dehydrogenase kinase 1(PDK1), an important enzyme involved in glucose metabolism. Moreover, Chibby suppresses aerobic glycolysis of NPC via Wnt/β-Catenin-Lin28/let7-PDK1 cascade. Chibby and PDK1 are critical for Wnt/β-Catenin signaling induced NPC cell proliferation both in vitro and in vivo. Finally, immunostaining assay of tissue samples provides an important clinical relevance among Chibby, Wnt/β-Catenin signaling and PDK1. Our study reveals an association between Chibby expression and cancer aerobic glycolysis, which highlights the importance of Wnt/β-catenin pathway in regulation of energy metabolism of NPC. These results indicate that Chibby and PDK1 are the potential target for NPC treatment. The online version of this article (10.1186/s13046-018-0769-4) contains supplementary material, which is available to authorized users.