Fangyuan Dong1,2,3,4, Rongkun Li5, Jiaofeng Wang1,2,3,4, Yan Zhang1, Jianfeng Yao1, Shu-Heng Jiang6, Xiaona Hu7,8,9,10, Mingxuan Feng11, Zhijun Bao12,13,14,15. 1. Department of Gastroenterology, Huadong Hospital, Shanghai Medical College, Fudan University, No.221 Yan'an West Road, Shanghai, 200040, P.R. China. 2. Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, 200040, P.R. China. 3. Research Center on Aging and Medicine, Fudan University, Shanghai, 200040, P.R. China. 4. Department of Geriatrics, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, P.R. China. 5. Institute of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China. 6. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, P.R. China. 7. Department of Gastroenterology, Huadong Hospital, Shanghai Medical College, Fudan University, No.221 Yan'an West Road, Shanghai, 200040, P.R. China. huxnfd@hotmail.com. 8. Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, 200040, P.R. China. huxnfd@hotmail.com. 9. Research Center on Aging and Medicine, Fudan University, Shanghai, 200040, P.R. China. huxnfd@hotmail.com. 10. Department of Geriatrics, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, P.R. China. huxnfd@hotmail.com. 11. Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, P.R. China. heartsfool@sohu.com. 12. Department of Gastroenterology, Huadong Hospital, Shanghai Medical College, Fudan University, No.221 Yan'an West Road, Shanghai, 200040, P.R. China. zhijunbao@fudan.edu.cn. 13. Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, 200040, P.R. China. zhijunbao@fudan.edu.cn. 14. Research Center on Aging and Medicine, Fudan University, Shanghai, 200040, P.R. China. zhijunbao@fudan.edu.cn. 15. Department of Geriatrics, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, P.R. China. zhijunbao@fudan.edu.cn.
Abstract
BACKGROUND: Reprogrammed glucose metabolism, also known as the Warburg effect, which is essential for tumor progression, is regarded as a hallmark of cancer. MAP17, a small 17-kDa non-glycosylated membrane protein, is frequently dysregulated in human cancers. However, its role in hepatocellular carcinoma (HCC) remains largely unknown. METHODS: Immunohistochemistry was used to analyze the expression pattern of MAP17 in HCC. Loss-of-function and gain-of-function studies were performed to investigate the oncogenic roles of MAP17 in vitro and in vivo. RNA sequencing, co-immunoprecipitation, immunofluorescence and western blotting were used to study the molecular mechanism of MAP17 affecting the tumor growth and glycolytic phenotype of HCC. RESULTS: An integrative analysis showed that MAP17, a small 17-kDa non-glycosylated membrane protein, is significantly related to the glycolytic phenotype of hepatocellular carcinoma (HCC). Firstly, we found that MAP17 expression is hypoxia-dependent and predicts a poor prognosis in HCC. Genetic silencing of MAP17 reduced the rate of glucose uptake, lactate release, extracellular acidification rate, and expression of glycolytic genes. Ectopic expression of wild type MAP17 but not its PDZ binding domain mutant MAP17-PDZm increased tumor glycolysis. Further research showed that MAP17 knockdown markedly retarded in vivo tumor growth in HCC. Importantly, attenuation of tumor glycolysis by galactose largely hijacked the growth-promoting role of MAP17 in HCC cells. RNA sequencing analysis revealed that MAP17 knockdown leads to transcriptional changes in the ROS metabolic process, cell surface receptor signaling, cell communication, mitotic cell cycle progression, and regulation of cell differentiation. Mechanistically, MAP17 exerted an increased tumoral phenotype associated with an increase in reactive oxygen species (ROS), which activates downstream effectors AKT and HIF1α to enhance the Warburg effect. In HCC clinical samples, there is a close correlation between MAP17 expression and HIF1α or phosphorated level of AKT. CONCLUSIONS: Our results show that MAP17 is a novel glycolytic regulator, and targeting MAP17/ROS pathway may be an alternative approach for the prevention and treatment of HCC.
BACKGROUND: Reprogrammed glucose metabolism, also known as the Warburg effect, which is essential for tumor progression, is regarded as a hallmark of cancer. MAP17, a small 17-kDa non-glycosylated membrane protein, is frequently dysregulated in humancancers. However, its role in hepatocellular carcinoma (HCC) remains largely unknown. METHODS: Immunohistochemistry was used to analyze the expression pattern of MAP17 in HCC. Loss-of-function and gain-of-function studies were performed to investigate the oncogenic roles of MAP17 in vitro and in vivo. RNA sequencing, co-immunoprecipitation, immunofluorescence and western blotting were used to study the molecular mechanism of MAP17 affecting the tumor growth and glycolytic phenotype of HCC. RESULTS: An integrative analysis showed that MAP17, a small 17-kDa non-glycosylated membrane protein, is significantly related to the glycolytic phenotype of hepatocellular carcinoma (HCC). Firstly, we found that MAP17 expression is hypoxia-dependent and predicts a poor prognosis in HCC. Genetic silencing of MAP17 reduced the rate of glucose uptake, lactate release, extracellular acidification rate, and expression of glycolytic genes. Ectopic expression of wild type MAP17 but not its PDZ binding domain mutant MAP17-PDZm increased tumor glycolysis. Further research showed that MAP17 knockdown markedly retarded in vivo tumor growth in HCC. Importantly, attenuation of tumor glycolysis by galactose largely hijacked the growth-promoting role of MAP17 in HCC cells. RNA sequencing analysis revealed that MAP17 knockdown leads to transcriptional changes in the ROS metabolic process, cell surface receptor signaling, cell communication, mitotic cell cycle progression, and regulation of cell differentiation. Mechanistically, MAP17 exerted an increased tumoral phenotype associated with an increase in reactive oxygen species (ROS), which activates downstream effectors AKT and HIF1α to enhance the Warburg effect. In HCC clinical samples, there is a close correlation between MAP17 expression and HIF1α or phosphorated level of AKT. CONCLUSIONS: Our results show that MAP17 is a novel glycolytic regulator, and targeting MAP17/ROS pathway may be an alternative approach for the prevention and treatment of HCC.
Authors: Ghassan K Abou-Alfa; Tim Meyer; Ann-Lii Cheng; Anthony B El-Khoueiry; Lorenza Rimassa; Baek-Yeol Ryoo; Irfan Cicin; Philippe Merle; YenHsun Chen; Joong-Won Park; Jean-Frederic Blanc; Luigi Bolondi; Heinz-Josef Klümpen; Stephen L Chan; Vittorina Zagonel; Tiziana Pressiani; Min-Hee Ryu; Alan P Venook; Colin Hessel; Anne E Borgman-Hagey; Gisela Schwab; Robin K Kelley Journal: N Engl J Med Date: 2018-07-05 Impact factor: 91.245
Authors: Jia Xu; Tiphaine C Martin; Royce W Zhou; Alexis L Zachem; John He; Sait Ozturk; Deniz Demircioglu; Ankita Bansal; Andrew P Trotta; Bruno Giotti; Berkley Gryder; Yao Shen; Xuewei Wu; Saul Carcamo; Kaitlyn Bosch; Benjamin Hopkins; Alexander Tsankov; Randolph Steinhagen; Drew R Jones; John Asara; Jerry E Chipuk; Rachel Brody; Steven Itzkowitz; Iok In Christine Chio; Dan Hasson; Emily Bernstein; Ramon E Parsons Journal: Nat Commun Date: 2022-10-17 Impact factor: 17.694