Gankyrin drives metabolic reprogramming to promote tumorigenesis, metastasis and drug resistance through activating β-catenin/c-Myc signaling in human hepatocellular carcinoma
Gankyrin drives metabolic reprogramming to promote tumorigenesis, metastasis and drug resistance through activating β-catenin/c-Myc signaling in human hepatocellular carcinoma
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Gankyrin 通过激活人肝细胞癌中的 β-catenin/c-Myc 信号传导来驱动代谢重编程，从而促进肿瘤发生、转移和耐药性
DOI：
10.1016/j.canlet.2018.11.030
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Zheng, Tongsen
中科院分区：
文献类型：
--
作者：
Liu, Ruiqi;Li, Yuejin;Zheng, Tongsen
Gankyrin在肝细胞癌（HCC）的发生和转移中起重要作用。我们首次研究了Gankyrin在体外和体内对糖酵解和多巴胺分解的影响，包括在患者来源的异种移植物中。我们报道Gankyrin通过上调转运蛋白和参与糖酵解和谷氨酰胺分解的酶（包括HK 2、GLUT 1、LDHA、PKM 2、ASCT 2和GLS 1）的表达，增加肝癌中葡萄糖消耗、乳酸产生、谷氨酰胺消耗和谷氨酸产生。我们进一步证明了Gankyrin通过激活β-连环蛋白信号传导上调c-Myc来驱动糖酵解和胞内胺解。重要的是，我们发现c-Myc介导的代谢重编程可能有助于Gankyrin诱导的肿瘤发生、转移和耐药性。c-Myc抑制剂与索拉非尼或瑞格非尼协同抑制具有高Gankyrin水平的HCC PDX肿瘤。我们在一组HCC活检标本中检测到Gankyrin和β-连环蛋白表达水平之间的显著相关性，这两个参数的组合是预后不良的更有力的预测因子。总的来说，我们的研究结果揭示了Gankyrin通过激活β-连环蛋白/c-Myc在糖酵解和β-氨基糖苷酶解中起重要调节作用，从而促进人类HCC的肿瘤发生、转移和耐药性。
Gankyrin plays important roles in tumorigenicity and metastasis of hepatocellular carcinoma (HCC). We have for the first time investigated the effects of Gankyrin on glycolysis and glutaminolysis both in vitro and in vivo, including in patient-derived xenografts. We reported Gankyrin increases glucose consumption, lactate production, glutamine consumption and glutamate production in HCC through upregulating the expression of the transporters and enzymes involved in glycolysis and glutaminolysis, including HK2, GLUT1, LDHA, PKM2, ASCT2 and GLS1. We further demonstrated that Gankyrin drives glycolysis and glutaminolysis through upregulating c-Myc via activating beta-catenin signaling. Importantly, we found c-Myc mediated metabolic reprogramming might contribute to the tumorigenicity, metastasis and drug resistance induced by Gankyrin. c-Myc inhibitor synergizes with Sorafenib or Regorafenib to suppress HCC PDX tumors with high Gankyrin levels. We detected a significant correlation between Gankyrin and beta-catenin expression levels in a cohort of HCC biopsies, and combination of these two parameters is a more powerful predictor of poor prognosis. Collectively, our results uncovered that Gankyrin functions as an essential regulator in glycolysis and glutaminolysis via activation of beta-catenin/c-Myc to promotes tumorigenesis, metastasis and drug resistance in human HCC.