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Cited by 316Cancer, Hypoxia, and MetabolismHepatocellular Carcinoma Treatment and PrognosisFerroptosis and cancer prognosis

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Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

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Bao, Macus Hao-Ran, Wong, Carmen Chak-Lui·2021·Cells
DOI 10.3390/cells10071715PMC PMC8304710
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Abstract

Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

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Figure 1 Hypoxic tumor microenvironment (TME) in hepatocellular carcinoma (HCC). A gradually decreasing gradient of partial pressure of O2 (pO2) in HCC from the blood vessel. Tumor regions that are close to the blood vessel are more oxygenated whereas regions away from the blood vessel are hypoxic. HCC treatments including arterial embolization transcatheter (TAE), arterial chemoembolization (TACE) and tyrosine kinase inhibitors (TKIs) inadvertently induced hypoxia in HCC.
Figure 1 Hypoxic tumor microenvironment (TME) in hepatocellular carcinoma (HCC). A gradually decreasing gradient of partial pressure of O2 (pO2) in HCC from the blood vessel. Tumor regions that are close to the blood vessel are more oxygenated whereas regions away from the blood vessel are hypoxic. HCC treatments including arterial embolization transcatheter (TAE), arterial chemoembolization (TACE) and tyrosine kinase inhibitors (TKIs) inadvertently induced hypoxia in HCC.CC BY · PubMed Central
Figure 2 Hypoxia-inducible factors (HIFs) divert metabolites from tricarboxylic acid cycle (TCA) cycle to glycolysis under hypoxia. (a) Under normoxia, glucose is converted to pyruvate during glycolysis. Pyruvate is then converted to acetyl coenzyme A (acetyl-CoA), which fuels the TCA cycle for maximum adenosine triphosphate (ATP) production with ample oxygen (O2) supply. (b) Under hypoxia, metabolism is switched from oxidative to glycolytic metabolism by HIF-dependent upregulation of pyruvate dehydrogenase kinase 1 (PDK1) and (lactate dehydrogenase A) LDHA. Lactate export is promoted to prevent excessive intracellular lactate accumulation, which may lead to cytoplasmic acidification. Serine synthesis pathway (SSP) and its downstream folate cycle are activated. Folate cycle produces a major antioxidant, nicotinamide adenine dinucleotide phosphate (NADPH), to counteract oxidative stress under hypoxia. Mitochondrial activity and biogenesis are suppressed to reduce mitochondrial reactive oxygen species (ROS) production. Genes or pathways highlighted in red: upregulated by HIFs. Genes or pathways highlighted in blue: downregulated by HIFs.
Figure 2 Hypoxia-inducible factors (HIFs) divert metabolites from tricarboxylic acid cycle (TCA) cycle to glycolysis under hypoxia. (a) Under normoxia, glucose is converted to pyruvate during glycolysis. Pyruvate is then converted to acetyl coenzyme A (acetyl-CoA), which fuels the TCA cycle for maximum adenosine triphosphate (ATP) production with ample oxygen (O2) supply. (b) Under hypoxia, metabolism is switched from oxidative to glycolytic metabolism by HIF-dependent upregulation of pyruvate dehydrogenase kinase 1 (PDK1) and (lactate dehydrogenase A) LDHA. Lactate export is promoted to prevent excessive intracellular lactate accumulation, which may lead to cytoplasmic acidification. Serine synthesis pathway (SSP) and its downstream folate cycle are activated. Folate cycle produces a major antioxidant, nicotinamide adenine dinucleotide phosphate (NADPH), to counteract oxidative stress under hypoxia. Mitochondrial activity and biogenesis are suppressed to reduce mitochondrial reactive oxygen species (ROS) production. Genes or pathways highlighted in red: upregulated by HIFs. Genes or pathways highlighted in blue: downregulated by HIFs.CC BY · PubMed Central
Figure 3 Electron transport chain (ETC). ETC is located at mitochondrial inner membrane (MIM). Electron donors produced from glycolysis and TCA cycle, nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), and succinate (glucose intermediate) donate electrons to the ETC. Electrons pass through ETC complex I to IV and finally to O2, the final electron accepter. Electron flow drives H+ export to the intermembrane space, creating a transmembrane electrical potential to drive ATP synthesis. Premature electron leakage leads to ROS accumulation, especially at complex I and complex III.
Figure 3 Electron transport chain (ETC). ETC is located at mitochondrial inner membrane (MIM). Electron donors produced from glycolysis and TCA cycle, nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), and succinate (glucose intermediate) donate electrons to the ETC. Electrons pass through ETC complex I to IV and finally to O2, the final electron accepter. Electron flow drives H+ export to the intermembrane space, creating a transmembrane electrical potential to drive ATP synthesis. Premature electron leakage leads to ROS accumulation, especially at complex I and complex III.CC BY · PubMed Central
Figure 4 HIF-induced metabolic reprogramming under hypoxia creates an immunosuppressive TME. HIF-mediated induction of lactate metabolism and adenosinergic metabolism leads to the accumulation of oncometabolites, including lactate, adenosine monophosphate (AMP) and adenosine at TME that inhibits anti-tumoral immune cells and promotes expansion of protumoral immune cells, resulting in an immunosuppressive TME that aids immune evasion of tumor cells.
Figure 4 HIF-induced metabolic reprogramming under hypoxia creates an immunosuppressive TME. HIF-mediated induction of lactate metabolism and adenosinergic metabolism leads to the accumulation of oncometabolites, including lactate, adenosine monophosphate (AMP) and adenosine at TME that inhibits anti-tumoral immune cells and promotes expansion of protumoral immune cells, resulting in an immunosuppressive TME that aids immune evasion of tumor cells.CC BY · PubMed Central

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Research works printed but not linked: 104

  1. Chen, 2017, Hypoxia inducible factors in hepatocellular carcinoma, Oncotarget, 8, 46691, 10.18632/oncotarget.17358 · DOI
  2. Li, 2017, Hypoxia induces universal but differential drug resistance and impairs anticancer mechanisms of 5-fluorouracil in hepatoma cells, Acta Pharmacol. Sin., 38, 1642, 10.1038/aps.2017.79 · DOI
  3. Cheng, 2009, Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial, Lancet Oncol., 10, 25, 10.1016/S1470-2045(08)70285-7 · DOI · Paper page
  4. Copur, 2008, Sorafenib in advanced hepatocellular carcinoma, N. Engl. J. Med., 359, 2498
  5. Ikeda, 2015, Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma, Clin. Cancer Res., 22, 1385, 10.1158/1078-0432.CCR-15-1354 · DOI
  6. Meyer, 2018, Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma, N. Engl. J. Med., 379, 54, 10.1056/NEJMoa1717002 · DOI
  7. Sangro, 2017, Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial, Lancet, 389, 2492, 10.1016/S0140-6736(17)31046-2 · DOI · Paper page
  8. Zhu, 2019, Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): A randomised, double-blind, placebo-controlled, phase 3 trial, Lancet Oncol., 20, 282, 10.1016/S1470-2045(18)30937-9 · DOI
  9. Shi, 2010, PD-1 and PD-L1 upregulation promotes CD8+ T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients, Int. J. Cancer, 128, 887, 10.1002/ijc.25397 · DOI
  10. Pesce, 2019, PD/1-PD-Ls Checkpoint: Insight on the Potential Role of NK Cells, Front. Immunol., 10, 1242, 10.3389/fimmu.2019.01242 · DOI
  11. Parry, 2005, CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms, Mol. Cell. Biol., 25, 9543, 10.1128/MCB.25.21.9543-9553.2005 · DOI · Paper page
  12. Vaupel, 2007, Detection and Characterization of Tumor Hypoxia Using pO2 Histography, Antioxid. Redox Signal., 9, 1221, 10.1089/ars.2007.1628 · DOI · Paper page
  13. Liu, 2013, Enhancement of cisplatin-based TACE by a hemoglobin-based oxygen carrier in an orthotopic rat HCC model, Artif. Cells Nanomed. Biotechnol., 42, 229, 10.3109/21691401.2013.808647 · DOI
  14. Riedl, 2008, Imaging Hypoxia in Orthotopic Rat Liver Tumors with Iodine 124–labeled Iodoazomycin Galactopyranoside PET, Radiology, 248, 561, 10.1148/radiol.2482071421 · DOI · Paper page
  15. Wada, 2006, Expression pattern of angiogenic factors and prognosis after hepatic resection in hepatocellular carcinoma: Importance of angiopoietin-2 and hypoxia-induced factor-1a, Liver Int., 26, 414, 10.1111/j.1478-3231.2006.01243.x · DOI · Paper page
  16. Amann, 2009, GLUT1 Expression Is Increased in Hepatocellular Carcinoma and Promotes Tumorigenesis, Am. J. Pathol., 174, 1544, 10.2353/ajpath.2009.080596 · DOI
  17. Guo, 2019, Combined Aberrant Expression of NDRG2 and LDHA Predicts Hepatocellular Carcinoma Prognosis and Mediates the Anti-tumor Effect of Gemcitabine, Int. J. Biol. Sci., 15, 1771, 10.7150/ijbs.35094 · DOI
  18. Huang, W.-J., Jeng, Y.-M., Lai, H.-S., Fong, I.-U., Sheu, F.-Y.B., Lai, P.-L., and Yuan, R.-H. (2015). Expression of Hypoxic Marker Carbonic Anhydrase IX Predicts Poor Prognosis in Resectable Hepatocellular Carcinoma. PLoS ONE, 10. · DOI
  19. Helmlinger, 1997, Interstitial pH and pO2 gradients in solid tumors in vivo: High-resolution measurements reveal a lack of correlation, Nat. Med., 3, 177, 10.1038/nm0297-177 · DOI
  20. Sun, 2009, Antisense Hypoxia-Inducible Factor-1α Augments Transcatheter Arterial Embolization in the Treatment of Hepatocellular Carcinomas in Rats, Hum. Gene Ther., 20, 314, 10.1089/hum.2008.164 · DOI
  21. Korotchkina, 2001, Site Specificity of Four Pyruvate Dehydrogenase Kinase Isoenzymes toward the Three Phosphorylation Sites of Human Pyruvate Dehydrogenase, J. Biol. Chem., 276, 37223, 10.1074/jbc.M103069200 · DOI · Paper page
  22. Korotchkina, 1995, Mutagenesis Studies of the Phosphorylation Sites of Recombinant Human Pyruvate Dehydrogenase. SITE-SPECIFIC REGULATION, J. Biol. Chem., 270, 14297, 10.1074/jbc.270.24.14297 · DOI
  23. Ma, 2014, 2-Methoxyestradiol synergizes with sorafenib to suppress hepatocellular carcinoma by simultaneously dysregulating hypoxia-inducible factor-1 and -2, Cancer Lett., 355, 96, 10.1016/j.canlet.2014.09.011 · DOI
  24. Semenza, 2012, Hypoxia-Inducible Factors in Physiology and Medicine, Cell, 148, 399, 10.1016/j.cell.2012.01.021 · DOI · Paper page
  25. Samanta, 2016, PHGDH Expression Is Required for Mitochondrial Redox Homeostasis, Breast Cancer Stem Cell Maintenance, and Lung Metastasis, Cancer Res., 76, 4430, 10.1158/0008-5472.CAN-16-0530 · DOI
  26. Coriat, 2012, Sorafenib-Induced Hepatocellular Carcinoma Cell Death Depends on Reactive Oxygen Species Production In Vitro and In Vivo, Mol. Cancer Ther., 11, 2284, 10.1158/1535-7163.MCT-12-0093 · DOI
  27. Clavo, 1995, Fluorodeoxyglucose uptake in human cancer cell lines is increased by hypoxia, J. Nucl. Med., 36, 1625
  28. Xia, 2019, Hypoxia-induced modulation of glucose transporter expression impacts 18F-fluorodeoxyglucose PET-CT imaging in hepatocellular carcinoma, Eur. J. Nucl. Med. Mol. Imaging, 47, 787, 10.1007/s00259-019-04638-4 · DOI
  29. Pedersen, 2002, Mitochondrial bound type II hexokinase: A key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention, Biochim. et Biophys. Acta (BBA) Bioenerg., 1555, 14, 10.1016/S0005-2728(02)00248-7 · DOI
  30. Gwak, 2005, Hypoxia stimulates proliferation of human hepatoma cells through the induction of hexokinase II expression, J. Hepatol., 42, 358, 10.1016/j.jhep.2004.11.020 · DOI
  31. Guo, 2015, MiR-199a-5p is negatively associated with malignancies and regulates glycolysis and lactate production by targeting hexokinase 2 in liver cancer, Hepatology, 62, 1132, 10.1002/hep.27929 · DOI
  32. Gao, 2019, Prognostic value of glucose transporter 3 expression in hepatocellular carcinoma, Oncol. Lett., 19, 691
  33. Li, 2019, Fructose-Bisphosphate Aldolase A Regulates Hypoxic Adaptation in Hepatocellular Carcinoma and Involved with Tumor Malignancy, Dig. Dis. Sci., 64, 3215, 10.1007/s10620-019-05642-2 · DOI
  34. Kunjithapatham, 2012, Glyceraldehyde-3-Phosphate Dehydrogenase: A Promising Target for Molecular Therapy in Hepatocellular Carcinoma, Oncotarget, 3, 940, 10.18632/oncotarget.623 · DOI
  35. Zhang, 2016, Prognostic significance of synergistic hexokinase-2 and beta2-adrenergic receptor expression in human hepatocelluar carcinoma after curative resection, BMC Gastroenterol., 16, 1, 10.1186/s12876-016-0474-8 · DOI
  36. Yoo, J.-J., Yu, S.J., Na, J., Kim, K., Cho, Y.Y., Lee, Y.B., Cho, E.J., Lee, J.-H., Kim, Y.J., and Youn, H. (2019). Hexokinase-II Inhibition Synergistically Augments the Anti-tumor Efficacy of Sorafenib in Hepatocellular Carcinoma. Int. J. Mol. Sci., 20. · DOI
  37. Schito, 2016, Hypoxia-Inducible Factors: Master Regulators of Cancer Progression, Trends Cancer, 2, 758, 10.1016/j.trecan.2016.10.016 · DOI · Paper page
  38. Cui, 2017, HIF1/2alpha mediates hypoxia-induced LDHA expression in human pancreatic cancer cells, Oncotarget, 8, 24840, 10.18632/oncotarget.15266 · DOI
  39. Chen, 2018, Aberrant MCT4 and GLUT1 expression is correlated with early recurrence and poor prognosis of hepatocellular carcinoma after hepatectomy, Cancer Med., 7, 5339, 10.1002/cam4.1521 · DOI
  40. Kim, 2006, HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia, Cell Metab., 3, 177, 10.1016/j.cmet.2006.02.002 · DOI · Paper page
  41. Papandreou, 2006, HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption, Cell Metab., 3, 187, 10.1016/j.cmet.2006.01.012 · DOI · Paper page
  42. Lai, 2016, NDUFA4L2 Fine-tunes Oxidative Stress in Hepatocellular Carcinoma, Clin. Cancer Res., 22, 3105, 10.1158/1078-0432.CCR-15-1987 · DOI
  43. Fukuda, 2007, HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells, Cell, 129, 111, 10.1016/j.cell.2007.01.047 · DOI · Paper page
  44. Wu, 2016, Correlation of PDK1 expression with clinicopathologic features and prognosis of hepatocellular carcinoma, OncoTargets Ther., 9, 5597, 10.2147/OTT.S110646 · DOI
  45. Ji, 2018, Up-Regulation of hsa-miR-210 Promotes Venous Metastasis and Predicts Poor Prognosis in Hepatocellular Carcinoma, Front. Oncol., 8, 569, 10.3389/fonc.2018.00569 · DOI
  46. Zhang, 2007, HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity, Cancer Cell, 11, 407, 10.1016/j.ccr.2007.04.001 · DOI · Paper page
  47. Liu, 2017, Glyceraldehyde-3-phosphate dehydrogenase promotes liver tumorigenesis by modulating phosphoglycerate dehydrogenase, Hepatology, 66, 631, 10.1002/hep.29202 · DOI
  48. Sun, 2015, cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions, Cell Res., 25, 429, 10.1038/cr.2015.33 · DOI
  49. Liu, 2016, Methylenetetrahydrofolate dehydrogenase 2 overexpression is associated with tumor aggressiveness and poor prognosis in hepatocellular carcinoma, Dig. Liver Dis., 48, 953, 10.1016/j.dld.2016.04.015 · DOI
  50. Lee, 2017, Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma, J. Clin. Investig., 127, 1856, 10.1172/JCI90253 · DOI
  51. Chiu, 2017, Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma, Nat. Commun., 8, 517, 10.1038/s41467-017-00530-7 · DOI · Paper page
  52. Ma, 2019, CD73 promotes hepatocellular carcinoma progression and metastasis via activating PI3K/AKT signaling by inducing Rap1-mediated membrane localization of P110beta and predicts poor prognosis, J. Hematol. Oncol., 12, 37, 10.1186/s13045-019-0724-7 · DOI
  53. Cao, 2006, Glucose uptake inhibitor sensitizes cancer cells to daunorubicin and overcomes drug resistance in hypoxia, Cancer Chemother. Pharmacol., 59, 495, 10.1007/s00280-006-0291-9 · DOI
  54. Shen, 2012, Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma, Br. J. Cancer, 108, 72, 10.1038/bjc.2012.559 · DOI
  55. Liang, 2013, Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma, Hepatology, 57, 1847, 10.1002/hep.26224 · DOI
  56. Tesori, 2015, The multikinase inhibitor Sorafenib enhances glycolysis and synergizes with glycolysis blockade for cancer cell killing, Sci. Rep., 5, 1, 10.1038/srep09149 · DOI
  57. Reyes, 2017, Sorafenib and 2-Deoxyglucose Synergistically Inhibit Proliferation of Both Sorafenib-Sensitive and -Resistant HCC Cells by Inhibiting ATP Production, Gene Expr., 17, 129, 10.3727/105221616X693855 · DOI
  58. Wei, 2019, Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC, Nat. Commun., 10, 1, 10.1038/s41467-019-12606-7 · DOI · Paper page
  59. Chang, 2015, Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression, Cell, 162, 1229, 10.1016/j.cell.2015.08.016 · DOI · Paper page
  60. Urasaki, Y., Heath, L., and Xu, C.W. (2012). Coupling of Glucose Deprivation with Impaired Histone H2B Monoubiquitination in Tumors. PLoS ONE, 7. · DOI
  61. Cao, Y., Rathmell, J.C., and MacIntyre, A.N. (2014). Metabolic Reprogramming towards Aerobic Glycolysis Correlates with Greater Proliferative Ability and Resistance to Metabolic Inhibition in CD8 versus CD4 T Cells. PLoS ONE, 9. · DOI
  62. Keating, 2016, Metabolic Reprogramming Supports IFN-gamma Production by CD56bright NK Cells, J. Immunol., 196, 2552, 10.4049/jimmunol.1501783 · DOI
  63. Wang, 2020, Glycolysis and Oxidative Phosphorylation Play Critical Roles in Natural Killer Cell Receptor-Mediated Natural Killer Cell Functions, Front. Immunol., 11, 202, 10.3389/fimmu.2020.00202 · DOI
  64. Bannoud, 2021, Hypoxia Supports Differentiation of Terminally Exhausted CD8 T Cells, Front. Immunol., 12, 660944, 10.3389/fimmu.2021.660944 · DOI
  65. Mah-Som, A., Rashidi, A., Keppel, M.P., Saucier, N., Moore, E., Alinger, J.B., Tripathy, S.K., Agarwal, S.K., Jeng, E.K., and Wong, H.C. (2017). Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control. JCI Insight, 2. · DOI
  66. Sonveaux, 2008, Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice, J. Clin. Investig., 118, 3930
  67. Sheng, 2012, Knockdown of lactate dehydrogenase A suppresses tumor growth and metastasis of human hepatocellular carcinoma, FEBS J., 279, 3898, 10.1111/j.1742-4658.2012.08748.x · DOI
  68. Lim, 2013, Inhibition of monocarboxylate transporter-4 depletes stem-like glioblastoma cells and inhibits HIF transcriptional response in a lactate-independent manner, Oncogene, 33, 4433, 10.1038/onc.2013.390 · DOI
  69. Feng, 2017, Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells, Oncogene, 36, 5829, 10.1038/onc.2017.188 · DOI
  70. Fischer, 2007, Inhibitory effect of tumor cell–derived lactic acid on human T cells, Blood, 109, 3812, 10.1182/blood-2006-07-035972 · DOI · Paper page
  71. Harmon, 2018, Lactate-Mediated Acidification of Tumor Microenvironment Induces Apoptosis of Liver-Resident NK Cells in Colorectal Liver Metastasis, Cancer Immunol. Res., 7, 335, 10.1158/2326-6066.CIR-18-0481 · DOI
  72. Chen, 2017, Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis, Proc. Natl. Acad. Sci. USA, 114, 580, 10.1073/pnas.1614035114 · DOI
  73. Comito, 2019, Lactate modulates CD4+ T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8/miR21 axis, Oncogene, 38, 3681, 10.1038/s41388-019-0688-7 · DOI
  74. Husain, 2013, Tumor-Derived Lactate Modifies Antitumor Immune Response: Effect on Myeloid-Derived Suppressor Cells and NK Cells, J. Immunol., 191, 1486, 10.4049/jimmunol.1202702 · DOI
  75. Watson, 2021, Metabolic support of tumour-infiltrating regulatory T cells by lactic acid, Nat. Cell Biol., 591, 645
  76. Renner, 2019, Restricting Glycolysis Preserves T Cell Effector Functions and Augments Checkpoint Therapy, Cell Rep., 29, 135, 10.1016/j.celrep.2019.08.068 · DOI
  77. Daneshmandi, S., Wegiel, B., and Seth, P. (2019). Blockade of Lactate Dehydrogenase-A (LDH-A) Improves Efficacy of Anti-Programmed Cell Death-1 (PD-1) Therapy in Melanoma. Cancers, 11. · DOI
  78. Dupuy, 2015, PDK1-Dependent Metabolic Reprogramming Dictates Metastatic Potential in Breast Cancer, Cell Metab., 22, 577, 10.1016/j.cmet.2015.08.007 · DOI · Paper page
  79. McFate, 2008, Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells, J. Biol. Chem., 283, 22700, 10.1074/jbc.M801765200 · DOI
  80. Tello, 2011, Induction of the Mitochondrial NDUFA4L2 Protein by HIF-1α Decreases Oxygen Consumption by Inhibiting Complex I Activity, Cell Metab., 14, 768, 10.1016/j.cmet.2011.10.008 · DOI
  81. Le, 2014, Complex IV subunit 1 defect predicts postoperative survival in hepatocellular carcinoma, Oncol. Lett., 7, 1430, 10.3892/ol.2014.1966 · DOI
  82. Li, 2019, Yin Yang 1 facilitates hepatocellular carcinoma cell lipid metabolism and tumor progression by inhibiting PGC-1beta-induced fatty acid oxidation, Theranostics, 9, 7599, 10.7150/thno.34931 · DOI
  83. Engel, 2020, Serine-dependent redox homeostasis regulates glioblastoma cell survival, Br. J. Cancer, 122, 1391, 10.1038/s41416-020-0794-x · DOI · Paper page
  84. To, 2015, Hypoxia is an effective stimulus for vesicular release of ATP from human umbilical vein endothelial cells, Placenta, 36, 759, 10.1016/j.placenta.2015.04.005 · DOI
  85. Adinolfi, 2017, Extracellular purines, purinergic receptors and tumor growth, Oncogene, 36, 293, 10.1038/onc.2016.206 · DOI
  86. Elwell, 2016, Hypoxia-Driven Adenosine Accumulation: A Crucial Microenvironmental Factor Promoting Tumor Progression, Advances in Experimental Medicine and Biology, Volume 876, 177, 10.1007/978-1-4939-3023-4_22 · DOI
  87. Ohta, 2006, A2A adenosine receptor protects tumors from antitumor T cells, Proc. Natl. Acad. Sci. USA, 103, 13132, 10.1073/pnas.0605251103 · DOI
  88. Beavis, 2013, Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors, Proc. Natl. Acad. Sci. USA, 110, 14711, 10.1073/pnas.1308209110 · DOI
  89. Stagg, 2011, CD73-Deficient Mice Have Increased Antitumor Immunity and Are Resistant to Experimental Metastasis, Cancer Res., 71, 2892, 10.1158/0008-5472.CAN-10-4246 · DOI
  90. Vijayan, 2017, Selective activation of anti-CD73 mechanisms in control of primary tumors and metastases, Oncoimmunology, 6, e1312044, 10.1080/2162402X.2017.1312044 · DOI
  91. Stagg, 2012, CD73-Deficient Mice Are Resistant to Carcinogenesis, Cancer Res., 72, 2190, 10.1158/0008-5472.CAN-12-0420 · DOI
  92. Sorrentino, 2015, Myeloid-derived suppressor cells contribute to A2B adenosine receptor-induced VEGF production and angiogenesis in a mouse melanoma model, Oncotarget, 6, 27478, 10.18632/oncotarget.4393 · DOI
  93. Csoka, 2012, Adenosine promotes alternative macrophage activation via A2A and A2B receptors, FASEB J., 26, 376, 10.1096/fj.11-190934 · DOI
  94. Perrot, 2019, Blocking antibodies targeting the CD39/CD73 immunosuppressive pathway unleash immune responses in combination cancer therapies, Cell Rep., 27, 2411, 10.1016/j.celrep.2019.04.091 · DOI
  95. Chiu, 2016, Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C-C motif) ligand 26, Hepatology, 64, 797, 10.1002/hep.28655 · DOI · Paper page
  96. Wong, 2012, Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis, J. Mol. Med., 90, 803, 10.1007/s00109-011-0855-y · DOI
  97. Scheuermann, 2009, Artificial ligand binding within the HIF2 PAS-B domain of the HIF2 transcription factor, Proc. Natl. Acad. Sci. USA, 106, 450, 10.1073/pnas.0808092106 · DOI · Paper page
  98. Xu, 2017, Increasing AR by HIF-2α inhibitor (PT-2385) overcomes the side-effects of sorafenib by suppressing hepatocellular carcinoma invasion via alteration of pSTAT3, pAKT and pERK signals, Cell Death Dis., 8, e3095, 10.1038/cddis.2017.411 · DOI
  99. Yang, 2016, Downregulation and pro-apoptotic effect of hypoxia-inducible factor 2 alpha in hepatocellular carcinoma, Oncotarget, 7, 34571, 10.18632/oncotarget.8952 · DOI
  100. Sun, 2012, Hypoxia inducible factor 2 alpha inhibits hepatocellular carcinoma growth through the transcription factor dimerization partner 3/ E2F transcription factor 1-dependent apoptotic pathway, Hepatology, 57, 1088, 10.1002/hep.26188 · DOI
  101. Fondevila, 2021, Prognostic and clinicopathological significance of hypoxia-inducible factors 1α and 2α in hepatocellular carcinoma: A systematic review with meta-analysis, Ther. Adv. Med. Oncol., 13, 1758835920987071
  102. Wang, 2017, HIF-2-dependent expression of stem cell factor promotes metastasis in hepatocellular carcinoma, Cancer Lett., 393, 113, 10.1016/j.canlet.2017.01.032 · DOI
  103. Bangoura, 2007, Prognostic significance of HIF-2alpha/EPAS1 expression in hepatocellular carcinoma, World J. Gastroenterol., 13, 3176, 10.3748/wjg.v13.i23.3176 · DOI
  104. Bao, 2021, Genome-wide CRISPR-Cas9 knockout library screening identified PTPMT1 in cardiolipin synthesis is crucial to survival in hypoxia in liver cancer, Cell Rep., 34, 108676, 10.1016/j.celrep.2020.108676 · DOI

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Authors
Bao, M. H.-R., & Wong, C. C.-L.
Affiliations
University of Hong Kong (HK)
Corresponding author
Wong, Carmen Chak-Lui
ORCID
Wong, Carmen Chak-Lui
Venue
Cells
Publisher
MDPI AG
Published
2021-07-06
Volume
10
Issue
7
Pages
1715
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells10071715
PMC
PMC8304710
OpenAlex
W3178403391
Cited by
316
References
121
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journal article
Language
en
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Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Program for Guangdong Introducing Innovative and Entrepreneurial Teams (2019BT02Y198)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
Keywords
hepatocellular carcinoma, tumor hypoxia, metabolic reprogramming, drug resistance, hypoxia-inducible factor, combination therapy, liver cancer treatment
MeSH terms
Sorafenib, Nivolumab, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Immune Checkpoint Inhibitors, Hypoxia, Antineoplastic Agents, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, Hypoxia-Inducible Factor 1, alpha Subunit, Metabolic Networks and Pathways, Tumor Microenvironment, Antibodies, Monoclonal, Humanized, Cellular Reprogramming

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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