专家论坛

肝癌代谢重编程研究及其临床应用进展

  • 1侯怡然 ,
  • 1李宝莉 ,
  • 2邢金良 ,
  • 3李积彬
展开
  • 1延安大学医学院药理学教研室,陕西 延安 716000;2空军军医大学生理与病理生理学教研室, 西安 710032;3空军军医大学基础医学院教学实验中心, 西安 710032

网络出版日期: 2021-04-12

基金资助

中国科协青年人才托举工程(2018QNRC001)

Metabolic reprogramming in liver cancer and its potential clinical implications

  • 1HOU Yi-ran ,
  • 1LI Bao-li ,
  • 2XING Jin-liang ,
  • 3LI Ji-bin
Expand
  • 1Department of Pharmacology, Medical College of Yan’an University, Yan’an 716000, Shaanxi, China; 2Department of Physiology and Pathophysiology, Air Force Military Medical University, Xi’an  710023,  China; 3 Experimental Teaching Center of Basic Medicine, Air Force Military Medical University, Xi’an  710023,   China

Online published: 2021-04-12

摘要

肝癌是我国常见的恶性肿瘤之一,其恶性程度高、发病隐匿,缺乏特异性的早期诊断与治疗标志物。肝癌的发生发展与其代谢过程密切相关。与其他大多数肿瘤细胞类似,肝癌细胞的代谢过程较正常肝细胞发生了诸多显著改变,具体表现在糖酵解异常活跃、脂肪酸从头合成增强而氧化减弱、谷氨酰胺分解代谢加快等。这些代谢的异常改变为肝癌细胞提供了中间物质与能量,以满足其快速生长、增殖与转移所需。同时,参与肝癌细胞不同代谢过程中的多种酶与信号分子也在其中发挥着不可替代的作用,因此调控上述代谢过程中关键的代谢酶及通路被认为是肝癌诊断与治疗的重要靶点。近年来,关于肝癌细胞代谢重编程及其临床应用研究取得了令人瞩目的进展。同时,寻找新型标志物分子也一直是肝癌研究领域的重点。本文主要围绕肝癌细胞的糖、脂、氨基酸及核苷酸代谢过程中发生的异常改变及其背后的分子机理进行了综述,同时对肝癌诊断与治疗标志物分子的潜在临床应用价值进行总结与展望。

关键词: 肝癌; 代谢; 诊断; 治疗

本文引用格式

1侯怡然 , 1李宝莉 , 2邢金良 , 3李积彬 . 肝癌代谢重编程研究及其临床应用进展[J]. 肿瘤代谢与营养电子杂志, 2019 , 6(3) : 295 -300 . DOI: 10.16689/j.cnki.cn11-9349/r.2019.03.005

Abstract

Liver cancer is one of the most common malignant tumors in China, which is characterized by high degree of malignancy, insidious onset and lack of specific markers for early diagnosis and treatment. The development of liver cancer is  its metabolic process. Similar to most other tumor cells, the metabolic process of liver cancer cells has undergone many significant changes compared to normal hepatocytes, such as abnormal activity of glycolysis, increased de novo synthesis of fatty acids and decreased oxidation, and accelerated glutamine catabolism. These abnormal changes in metabolism provide intermediate substances and energy for the rapid growth, proliferation and metastasis of liver cancer cells. At the same time, a variety of enzymes and signaling molecules involved in different metabolic processes also play an irreplaceable role in liver cancer. Therefore, the key metabolic enzymes and pathways that regulate the above metabolic processes are important targets for the diagnosis and treatment of liver cancer. In recent years, the reprogramming of liver cancer cells and its clinical application have made remarkable progress. In addition, the research for new markers has been the focus of liver cancer. This paper focuses on the abnormal changes of glucose, lipid, amino acid and nucleotide metabolism and its molecular mechanism and the potential clinical application value of metabolic marker molecules will be summarized and prospected.

参考文献

1.Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018.  CA Cancer J Clin. 2018;68(1):7-30.
2.Bacon BR, Adams PC, Kowdley KV, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American association for the study of liver diseases. Hepatology. 2011;54(1):328-343.
3.Teng R, Liu Z, Tang H, et al. HSP60 silencing promotes Warburg-like phenotypes and switches the mitochondrial function from ATP production to biosynthesis in ccRCC cells. Redox Biol. 2019;24:101218.
4.Amann T, Hellerbrand C. GLUT1 as a therapeutic target in hepatocellular carcinoma. Expert Opin Ther Tar. 2009;13(12):1411-1427.
5.Kim YH, Jeong DC, Pak K, et al. SLC2A2 (GLUT2) as a novel prognostic factor for hepatocellular carcinoma. Oncotarget. 2017;8(40):68381-68392.
6.Lis P, Dylag M, Niedzwiecka K, et al. The HK2 dependent “Warburg effect” and mitochondrial oxidative phosphorylation in cancer: targets for effective therapy with 3-bromopyruvate. Molecules. 2016;21(12):E1292.
7.Yoo JJ, Yu SJ, Na J, et al. Hexokinase-II inhibition synergistically augments the anti-tumor efficacy of Sorafenib in hepatocellular carcinoma. Int J Mol Sci. 2019;20(6):E1292.
8.Lu DH, Lv WW, Li WX, et al. High PKM2 expression is independently correlated with decreased overall survival in hepatocellular carcinoma. Oncol Lett. 2018;16(3):3603-3610.
9.Li SS, Fitch WM, Pan YC, et al. Evolutionary relationships of vertebrate lactate dehydrogenase isozymes A4 (muscle), B4 (heart), and C4 (testis). J Biol Chem. 1983;258(11):7029-7032.
10.Faloppi L, Bianconi M, Memeo R, et al. Lactate dehydrogenase in hepatocellular carcinoma: something old, something new. Biomed Res Int. 2016;2016:7196280.
11.Semenza GL, Roth PH, Fang HM, et al. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem. 1994;269(38):23757-23763.
12.Dang CV. MYC on the path to cancer. Cell. 2012;149(1):22-35.
13.Wong KK, Engelman JA, Cantley LC. Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev. 2010;20(1):87-90.
14.Robey RB, Hay N. Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and AKT. Oncogene. 2006;25(34):4683-4696.
15.Kohn AD, Summers SA, Birnbaum MJ, et al. Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J Biol Chem. 1996;271(49):31372-31378.
16.Huang Q, Li J, Xing J, et al. CD147 promotes reprogramming of glucose metabolism and cell proliferation in HCC cells by inhibiting the p53-dependent signaling pathway. J Hepatol. 2014;61(4):859-866.
17.Cao D, Song X, Che L, et al. Both de novo synthetized and exogenous fatty acids support the growth of hepatocellular carcinoma cells. Liver Int. 2017;37(1):80-89.
18.Krammer J, Digel M, Ehehalt F, et al. Overexpression of CD36 and acyl-CoA synthetases FATP2, FATP4 and ACSL1 increases fatty acid uptake in human hepatoma cells. Int J Med Sci. 2011;8(7):599-614.
19.Nath A, Li I, Roberts LR, et al. Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma. Sci Rep. 2015;5:14752.
20.Santos CR, Schulze A. Lipid metabolism in cancer. FEBS J. 2012;279(15):2610-2623.
21.Duncan AL, Robinson AJ, Walker JE. Cardiolipin binds selectively but transiently to conserved lysine residues in the rotor of metazoan ATP synthases. Proc Natl Acad Sci U S A. 2016;113(31):8687-8692.
22.Nakagawa H, Hayata Y, Kawamura S, et al. Lipid metabolic reprogramming in hepatocellular carcinoma. Cancers (Basel). 2018;10(11).pii:E447.
23.Zu XY, Zhang QH, Liu JH, et al. ATP citrate lyase inhibitors as novel cancer therapeutic agents. Recent Pat Anticancer Drug Discov. 2012;7(2):154-167.
24.Wang MD, Wu H, Fu GB, et al. Acetyl-coenzyme A carboxylase alpha promotion of glucose-mediated fatty acid synthesis enhances survival of hepatocellular carcinoma in mice and patients. Hepatology. 2016;63(4):1272-1286.
25.Lally JSV, Ghoshal S, DePeralta DK, et al. Inhibition of acetyl-CoA carboxylase by phosphorylation or the inhibitor ND-654 suppresses lipogenesis and hepatocellular carcinoma. Cell Metab. 2019;29(1):174-182.e5.
26.Li L, Pilo GM, Li X, et al. Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans. J Hepatol. 2016;64(2):333-341.
27.Budhu A, Roessler S, Zhao X, et al. Integrated metabolite and gene expression profiles identify lipid biomarkers associated with progression of hepatocellular carcinoma and patient outcomes. Gastroenterology. 2013;144(5):1066-1075.e1.
28.Horton JD. Sterol regulatory element-binding proteins: transcriptional activators of lipid synthesis. Biochem Soc Trans. 2002;30(6):1091-1095.
29.Li C, Yang W, Zhang J, et al. SREBP-1 has a prognostic role and contributes to invasion and metastasis in human hepatocellular carcinoma. Int J Mol Sci. 2014;15(5):7124-7138.
30.Calvisi DF, Wang C, Ho C, et al. Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology. 2011;140(3):1071-1083.
31.Liu G, Kuang S, Cao R, et al. Sorafenib kills liver cancer cells by disrupting SCD1-mediated synthesis of monounsaturated fatty acids via the ATP-AMPK-mTOR-SREBP1 signaling pathway. FASEB J. 2019;33(9):10089-10103.
32.Li J, Huang Q, Long X, et al. CD147 reprograms fatty acid metabolism in hepatocellular carcinoma cells through Akt/mTOR/SREBP1c and P38/PPARalpha pathways. J Hepatol. 2015;63(6):1378-1389.
33.Montero J, Morales A, Llacuna L, et al. Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma. Cancer Res. 2008;68(13):5246-5256.
34.Zhao Z, Zhong L, He K, et al. Cholesterol attenuated the progression of DEN-induced hepatocellular carcinoma via inhibiting SCAP mediated fatty acid de novo synthesis. Biochem Biophys Res Commun. 2019;509(4):855-861.
35.Fujiwara N, Nakagawa H, Enooku K, et al. CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity. Gut. 2018;67(8):1493-1504.
36.Huang J, Viswakarma N, Yu S, et al. Progressive endoplasmic reticulum stress contributes to hepatocarcinogenesis in fatty acyl-CoA oxidase 1-deficient mice. Am J Pathol. 2011;179(2):703-713.
37.Chiu M, Tardito S, Pillozzi S, et al. Glutamine depletion by crisantaspase hinders the growth of human hepatocellular carcinoma xenografts. Br J Cancer. 2014;111(6):1159-1167.
38.Jin L, Alesi GN, Kang S. Glutaminolysis as a target for cancer therapy. Oncogene. 2016;35(28):3619-3625.
39.Sun HW, Yu XJ, Wu WC, et al. GLUT1 and ASCT2 as predictors for prognosis of hepatocellular carcinoma. PLoS One. 2016;11(12):e0168907.
40.Kumar A, Giri S, Shaha C. Sestrin2 facilitates glutamine-dependent transcription of PGC-1alpha and survival of liver cancer cells under glucose limitation. FEBS J. 2018;285(7):1326-1345.
41.DeBerardinis RJ, Cheng T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 2010;29(3):313-324.
42.Cox AG, Hwang KL, Brown KK, et al. Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Nat Cell Biol. 2016;18(8):886-896.
43.Wang JB, Erickson JW, Fuji R, et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010;18(3):207-219.
44.Suzuki S, Tanaka T, Poyurovsky MV, et al. Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci U S A. 2010;107(16):7461-7466.
45.Xi J, Sun Y, Zhang M, et al. GLS1 promotes proliferation in hepatocellular carcinoma cells via AKT/GSK3beta/CyclinD1 pathway. Exp Cell Res. 2019;381(1):1-9.
46.Li B, Cao Y, Meng G, et al. Targeting glutaminase 1 attenuates stemness properties in hepatocellular carcinoma by increasing reactive oxygen species and suppressing Wnt/beta-catenin pathway. EBioMedicine. 2019;39:239-254.
47.Zhang J, Wang C, Chen M, et al. Epigenetic silencing of glutaminase 2 in human liver and colon cancers. BMC Cancer. 2013;13:601.
48.Liu J, Zhang C, Lin M, et al. Glutaminase 2 negatively regulates the PI3K/AKT signaling and shows tumor suppression activity in human hepatocellular carcinoma. Oncotarget. 2014;5(9):2635-2647.
49.Sun L, Song L, Wan Q, et al. cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions. Cell Res. 2015;25(4):429-444.
50.Zhu J, Thompson CB. Metabolic regulation of cell growth and proliferation. Nat Rev Mol Cell Biol. 2019;20(7):436-450.
51.Ciou SC, Chou YT, Liu YL, et al. Ribose-5-phosphate isomerase A regulates hepatocarcinogenesis via PP2A and ERK signaling. Int J Cancer. 2015;137(1):104-115.
52.Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245-1255.
53.Talbot JN, Fartoux L, Balogova S, et al. Detection of hepatocellular carcinoma with PET/CT: a prospective comparison of 18F-fluorocholine and 18F-FDG in patients with cirrhosis or chronic liver disease. J Nucl Med. 2010;51(11):1699-1706.
54.Di Tommaso L, Franchi G, Park YN, et al. Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis. Hepatology. 2007;45(3):725-734.
55.Zhou J, Yu L, Gao X, et al. Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. J Clin Oncol. 2011;29(36):4781-4788.
56.Li L, Chen J, Chen X, et al. Serum miRNAs as predictive and preventive biomarker for pre-clinical hepatocellular carcinoma. Cancer Lett. 2016;373(2):234-240.
57.Liu YX, Feng JY, Sun MM, et al. Aspirin inhibits the proliferation of hepatoma cells through controlling GLUT1-mediated glucose metabolism. Acta Pharmacol Sin. 2019;40(1):122-132.
58.Dai W, Wang F, Lu J, et al. By reducing hexokinase 2, resveratrol induces apoptosis in HCC cells addicted to aerobic glycolysis and inhibits tumor growth in mice. Oncotarget. 2015;6(15):13703-13717.
59.Reyes RK, Motiwala T, Jacob ST. Regulation of glucose metabolism in hepatocarcinogenesis by microRNAs. Gene Expr. 2014;16(2):85-92.
60.Jiang JX, Gao S, Pan YZ, et al. Overexpression of microRNA-125b sensitizes human hepatocellular carcinoma cells to 5-fluorouracil through inhibition of glycolysis by targeting hexokinase II. Mol Med Rep. 2014;10(2):995-1002.
61.Shang R, Wang J, Sun W, et al. RRAD inhibits aerobic glycolysis, invasion, and migration and is associated with poor prognosis in hepatocellular carcinoma. Tumour Biol. 2016;37(4):5097-5105.
62.Savic LJ, Chapiro J, Duwe G, et al. Targeting glucose metabolism in cancer: new class of agents for loco-regional and systemic therapy of liver cancer and beyond? Hepat Oncol. 2016;3(1):19-28.
63.Ma MKF, Lau EYT, Leung DHW, et al. Stearoyl-CoA desaturase regulates sorafenib resistance via modulation of ER stress-induced differentiation. J Hepatol. 2017;67(5):979-990.
64.Treiber G. mTOR inhibitors for hepatocellular cancer: a forward-moving target. Expert Rev Anticancer Ther. 2009;9(2):247-261.
65.Koeberle D, Dufour JF, Demeter G, et al. Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC):a randomized multicenter, multinational phase II trial (SAKK 77/08 and SASL 29). Ann Oncol. 2016;27(5):856-861.
66.Abdelmonsif DA, Sultan AS, El-Hadidy WF, et al. Targeting AMPK, mTOR and beta-catenin by combined metformin and aspirin therapy in HCC: an appraisal in Egyptian HCC patients. Mol Diagn Ther. 2018;22(1):115-127.
67.Ko E, Seo HW, Jung ES, et al. PI3Kdelta is a therapeutic target in hepatocellular carcinoma. Hepatology. 2018;68(6):2285-2300.
68.Li H, Li CW, Li X, et al. MET inhibitors promote liver tumor evasion of the immune response by stabilizing PDL1. Gastroenterology. 2019;156(6):1849-1861.e13.
69.Wang C, Tong Y, Wen Y, et al. Hepatocellular carcinoma-associated protein TD26 interacts and enhances sterol regulatory element-binding protein 1 activity to promote tumor cell proliferation and growth. Hepatology. 2018;68(5):1833-1850.
70.Jiang Y, Sun A, Zhao Y, et al. Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature. 2019;567(7747):257-261.
文章导航

/