Gankyrin drives metabolic reprogramming to promote tumorigenesis, metastasis and drug resistance through activating β-catenin/c-Myc signaling in human hepatocellular carcinoma
Autor: | Ruiqi Liu, Shuangjia Wang, Yanqiao Zhang, Chunhui Zhang, Lianxin Liu, Shuli Tang, Meng Zhou, Jiguang Han, Jianhua Nie, Boshi Sun, Binlin Lin, Huawen Shi, Lantian Tian, Li Wu, Yingjian Liang, Yuejin Li, Benjie Xu, Tongsen Zheng, Jiabei Wang, Guangyu Wang, Kunmei Gong |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Sorafenib Male Cancer Research Proteasome Endopeptidase Complex Carcinoma Hepatocellular Gankyrin PKM2 medicine.disease_cause Metastasis Proto-Oncogene Proteins c-myc 03 medical and health sciences Mice 0302 clinical medicine Cell Line Tumor Proto-Oncogene Proteins medicine Animals Humans Glycolysis Neoplasm Metastasis beta Catenin Glutaminolysis biology Chemistry Liver Neoplasms medicine.disease Cellular Reprogramming digestive system diseases Gene Expression Regulation Neoplastic 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Catenin biology.protein Cancer research Carcinogenesis Neoplasm Transplantation medicine.drug Signal Transduction |
Zdroj: | Cancer letters. 443 |
ISSN: | 1872-7980 |
Popis: | 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 β-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 β-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 β-catenin/c-Myc to promotes tumorigenesis, metastasis and drug resistance in human HCC. |
Databáze: | OpenAIRE |
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