Wnt信号通路在胚胎发育中发挥重要作用，而它的失调可导致多种恶性肿瘤。Wnt信号通路可介导Snail依赖的上皮-间叶组织转变（EMT）。而EMT可导致肿瘤的侵袭和转移。5月25日Cancer Research 杂志在线发表了Su Yeon Lee等人的研究论文揭示了Wnt/Snail肿瘤发生和发展中的新功能。
研究证实，Wnt通过抑制细胞色素氧化酶C（COX）的三个亚基：COXVIc, COXVIIa, 和 COXVIIc的表达，抑制线粒体呼吸及COX活力。此外，Wnt还可通过增加葡萄糖的消耗和乳酸的生成，并且诱导丙酮酸羧化酶来调节糖代谢向糖酵解的方向倾斜。Wnt诱导线粒体抑制和糖酵解作用增加是通过经典的β-catenin/T细胞因子4 (TCF4)/Snail途径实现的。
这些研究发现，揭示了Wnt/Snail信号途径在肿瘤生长和进展过程中调节线粒体呼吸和糖代谢的新功能。他们还进一步证实短发卡RNA（shRNA）介导的EMT诱导因子E-cadherin下调，可抑制线粒体呼吸并通过激活Snail上调糖酵解作用。这提示，EMT可有助于Wnt/Snail对线粒体呼吸和糖代谢的调节。(生物谷.Bioon.com)
doi:10.1158/0008-5472.CAN-12-0006
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Wnt/Snail Signaling Regulates Cytochrome C Oxidase and Glucose Metabolism
Su Yeon Lee,Hyun Min Jeon,Min Kyung Ju et al.
Abstract
Wnt signaling plays a critical role in embryonic development, and its deregulation is closely linked to the occurrence of a number of malignant tumors, including breast and colon cancer. It induces Snail-dependent epithelial-to-mesenchymal transition (EMT), which is responsible for tumor invasion and metastasis. In this study, we demonstrate that Wnt suppresses mitochondrial respiration and cytochrome C oxidase (COX) activity by inhibiting the expression of 3 COX subunits, namely, COXVIc, COXVIIa, and COXVIIc. In addition, Wnt induces a glycolytic switch via increased glucose consumption and lactate production, with induction of pyruvate carboxylase (PC), a key enzyme of anaplerosis. Wnt-induced mitochondrial repression and glycolytic switch occur by the canonical β-catenin/T-cell factor 4 (TCF4)/Snail pathway. These findings provide a new function for Wnt/Snail signaling in the regulation of mitochondrial respiration (via COX gene expression) and glucose metabolism (via PC gene expression) in tumor growth and progression. We further demonstrate that short hairpin RNA (shRNA)-mediated knockdown of E-cadherin, which can induce EMT, represses mitochondrial respiration and induces a glycolytic switch via Snail activation, indicating that EMT may contribute to Wnt/Snail regulation of mitochondrial respiration and glucose metabolism.
