Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma

Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proli...

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Published inBiomedicines Vol. 9; no. 11; p. 1639
Main Authors Sun, Eun Jin, Wankell, Miriam, Palamuthusingam, Pranavan, McFarlane, Craig, Hebbard, Lionel
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 08.11.2021
MDPI
Subjects
1-Phosphatidylinositol 3-kinase
Akt
AKT protein
Angiogenesis
Apoptosis
Autophagy
Cancer therapies
Cell cycle
Cell growth
clinical trials
Cyclic AMP response element-binding protein
Diabetes
Drug resistance
Fibroblasts
Forkhead protein
Glycogen
Glycogen synthase kinase 3
HCC
Hepatitis B
Hepatitis C
Hepatocellular carcinoma
Industrialized nations
Kinases
Lipogenesis
Liver cancer
Liver diseases
MDM2 protein
Metabolism
mTOR
NF-κB protein
p53 Protein
Phagocytosis
PI3K
Proteins
Regulation
Review
Sarcoma
Signal transduction
TOR protein
Vascular endothelial growth factor
United States > US
Online AccessGet full text
ISSN2227-9059
2227-9059
DOI10.3390/biomedicines9111639

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Abstract Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proliferation, apoptosis, and metabolism. Importantly, deregulation of the PI3K/Akt/mTOR pathway leading to activation is common in HCC and is hence the subject of intense investigation and the focus of current therapeutics. In this review article, we consider the role of this pathway in the pathogenesis of HCC, focusing on its downstream effectors such as glycogen synthase kinase-3 (GSK-3), cAMP-response element-binding protein (CREB), forkhead box O protein (FOXO), murine double minute 2 (MDM2), p53, and nuclear factor-κB (NF-κB), and the cellular processes of lipogenesis and autophagy. In addition, we provide an update on the current ongoing clinical development of agents targeting this pathway for HCC treatments.
AbstractList Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proliferation, apoptosis, and metabolism. Importantly, deregulation of the PI3K/Akt/mTOR pathway leading to activation is common in HCC and is hence the subject of intense investigation and the focus of current therapeutics. In this review article, we consider the role of this pathway in the pathogenesis of HCC, focusing on its downstream effectors such as glycogen synthase kinase-3 (GSK-3), cAMP-response element-binding protein (CREB), forkhead box O protein (FOXO), murine double minute 2 (MDM2), p53, and nuclear factor-κB (NF-κB), and the cellular processes of lipogenesis and autophagy. In addition, we provide an update on the current ongoing clinical development of agents targeting this pathway for HCC treatments.
Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proliferation, apoptosis, and metabolism. Importantly, deregulation of the PI3K/Akt/mTOR pathway leading to activation is common in HCC and is hence the subject of intense investigation and the focus of current therapeutics. In this review article, we consider the role of this pathway in the pathogenesis of HCC, focusing on its downstream effectors such as glycogen synthase kinase-3 (GSK-3), cAMP-response element-binding protein (CREB), forkhead box O protein (FOXO), murine double minute 2 (MDM2), p53, and nuclear factor-κB (NF-κB), and the cellular processes of lipogenesis and autophagy. In addition, we provide an update on the current ongoing clinical development of agents targeting this pathway for HCC treatments.Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proliferation, apoptosis, and metabolism. Importantly, deregulation of the PI3K/Akt/mTOR pathway leading to activation is common in HCC and is hence the subject of intense investigation and the focus of current therapeutics. In this review article, we consider the role of this pathway in the pathogenesis of HCC, focusing on its downstream effectors such as glycogen synthase kinase-3 (GSK-3), cAMP-response element-binding protein (CREB), forkhead box O protein (FOXO), murine double minute 2 (MDM2), p53, and nuclear factor-κB (NF-κB), and the cellular processes of lipogenesis and autophagy. In addition, we provide an update on the current ongoing clinical development of agents targeting this pathway for HCC treatments.
Author Wankell, Miriam
Hebbard, Lionel
Sun, Eun Jin
Palamuthusingam, Pranavan
McFarlane, Craig
AuthorAffiliation 3 Institute of Surgery, The Townsville University Hospital, Townsville, QLD 4811, Australia; Pranavan.Palamuthusingam@health.qld.gov.au
5 Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW 2145, Australia
2 College of Medicine and Dentistry, James Cook University, Townsville, QLD 4811, Australia
1 Centre for Molecular Therapeutics, Department of Molecular and Cell Biology, Australian Institute of Tropical Medicine and Health, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD 4811, Australia; eunjin.sun@my.jcu.edu.au (E.J.S.); miriam.wankell@jcu.edu.au (M.W.); craig.mcfarlane@jcu.edu.au (C.M.)
4 Mater Hospital, Townsville, QLD 4811, Australia
AuthorAffiliation_xml – name: 2 College of Medicine and Dentistry, James Cook University, Townsville, QLD 4811, Australia
– name: 4 Mater Hospital, Townsville, QLD 4811, Australia
– name: 3 Institute of Surgery, The Townsville University Hospital, Townsville, QLD 4811, Australia; Pranavan.Palamuthusingam@health.qld.gov.au
– name: 1 Centre for Molecular Therapeutics, Department of Molecular and Cell Biology, Australian Institute of Tropical Medicine and Health, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD 4811, Australia; eunjin.sun@my.jcu.edu.au (E.J.S.); miriam.wankell@jcu.edu.au (M.W.); craig.mcfarlane@jcu.edu.au (C.M.)
– name: 5 Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW 2145, Australia
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  surname: Sun
  fullname: Sun, Eun Jin
– sequence: 2
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  orcidid: 0000-0002-7056-8887
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Cites_doi 10.1002/jcp.20474
10.1101/gad.1256804
10.1016/j.cell.2008.06.028
10.1038/cr.2014.57
10.1074/jbc.M405522200
10.1038/onc.2013.266
10.1056/NEJMoa1915745
10.1038/s12276-021-00570-6
10.1093/annonc/mdz394.029
10.1172/JCI0215593
10.1136/flgastro-2013-100403
10.1016/j.cell.2017.10.037
10.3390/ijms15057124
10.1038/onc.2008.313
10.1016/j.jhep.2018.04.010
10.1073/pnas.1522163112
10.1159/000485384
10.1016/S0140-6736(18)30207-1
10.1016/S0092-8674(00)80696-0
10.1038/cddis.2016.423
10.1016/j.cell.2007.06.009
10.1158/1078-0432.CCR-20-3407
10.1002/hep.29466
10.1016/j.cell.2010.06.011
10.1016/j.jhep.2020.07.036
10.3322/caac.21492
10.1038/s41580-018-0033-y
10.1136/gutjnl-2019-318934
10.5732/cjc.013.10057
10.1101/gad.1617608
10.1158/0008-5472.CAN-06-1377
10.1016/j.tibs.2011.03.006
10.1097/MD.0000000000010214
10.1093/ajcp/aqx132
10.1128/MCB.22.16.5962-5974.2002
10.1073/pnas.2003193118
10.1158/0008-5472.CAN-06-4149
10.1016/j.bbamcr.2019.118635
10.1038/s41416-019-0650-z
10.1158/1535-7163.MCT-08-0013
10.1016/j.jhep.2019.09.010
10.1016/S0092-8674(00)00171-9
10.1016/j.patbio.2010.01.005
10.1016/S0140-6736(16)31012-1
10.1185/03007995.2010.506375
10.1056/NEJMoa1717002
10.1016/S0140-6736(17)31046-2
10.1007/s00109-011-0735-5
10.1053/j.gastro.2008.02.090
10.1038/43466
10.1007/s00018-020-03525-8
10.1038/nri.2017.142
10.1016/j.ccell.2017.11.011
10.3389/fgene.2018.00002
10.1016/j.jhep.2018.12.001
10.1001/jama.2014.7189
10.1016/j.jhep.2013.11.031
10.1093/annonc/mdw054
10.1016/j.canlet.2019.08.003
10.1038/ncb1101-973
10.1038/cgt.2016.68
10.1038/s41419-020-03233-y
10.1016/j.cell.2011.06.034
10.1016/j.ejca.2012.11.008
10.1056/NEJMoa0708857
10.1007/s10637-014-0169-3
10.1038/onc.2016.363
10.1158/0008-5472.CAN-03-2089
10.1016/j.pharmthera.2014.11.016
10.1002/hep.25899
10.1016/j.molcel.2018.04.024
10.1002/hep.29367
10.1097/01.tp.0000252780.42104.95
10.1158/1078-0432.CCR-04-0941
10.1038/nrc3204
10.1002/hep.29018
10.1016/j.cell.2005.04.014
10.1038/nature04723
10.3389/fonc.2014.00064
10.1101/gad.1662308
10.1016/S1470-2045(08)70285-7
10.3390/cancers10010018
10.1016/j.cmet.2011.06.002
10.1038/s12276-019-0308-1
10.1053/j.gastro.2008.08.008
10.1186/s12885-019-6110-6
10.1016/j.canlet.2008.12.031
10.3892/ol.2017.5557
10.1038/nrgastro.2010.213
10.1159/000508568
10.1016/S1097-2765(01)00323-9
10.3390/cells8121597
10.1002/hep.26420
10.2174/0929867321666131228205703
10.3390/cancers13123026
10.1038/s41388-017-0046-6
10.1128/MCB.06159-11
10.1016/j.bbrc.2015.11.122
10.1073/pnas.181181198
10.1016/j.cub.2009.09.058
10.1158/1078-0432.CCR-07-4774
10.1016/j.cell.2017.04.001
10.1038/cr.2013.166
10.1080/15548627.2019.1709762
10.1038/sj.onc.1202659
10.1155/2017/4629495
10.1016/j.bbamcr.2011.03.013
10.1016/S0140-6736(16)32453-9
10.1074/jbc.273.22.13375
10.18632/oncotarget.13786
10.1074/jbc.M109745200
10.1016/j.bbcan.2019.188314
10.1053/j.gastro.2019.11.312
10.3390/cancers12113166
10.1038/ncb2152
10.1101/cshperspect.a006098
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References Yao (ref_8) 1999; 18
Bray (ref_4) 2018; 68
Golabi (ref_18) 2018; 97
Li (ref_88) 2017; 65
Mayo (ref_66) 2001; 98
Dong (ref_57) 2017; 8
Mancinelli (ref_40) 2017; 2017
Zhang (ref_52) 2012; 56
Vousden (ref_62) 2000; 103
Komatsu (ref_94) 2006; 441
Kim (ref_91) 2004; 279
Sangro (ref_115) 2017; 389
Franke (ref_30) 2008; 27
Kovach (ref_48) 2006; 206
Meyer (ref_111) 2018; 379
Taniguchi (ref_78) 2018; 18
Hay (ref_56) 2011; 1813
Feng (ref_70) 2007; 67
Ogawara (ref_65) 2002; 277
Beurel (ref_41) 2015; 148
Guri (ref_93) 2017; 32
Lin (ref_14) 2020; 9
DeYoung (ref_73) 2008; 22
Song (ref_58) 2020; 19
Fondevila (ref_24) 2019; 51
Finn (ref_113) 2020; 382
Faivre (ref_22) 2020; 72
Li (ref_87) 2014; 15
Liu (ref_15) 2019; 70
Mauriz (ref_54) 2014; 21
Finn (ref_110) 2018; 69
Lee (ref_90) 2017; 171
Zhu (ref_119) 2014; 312
Liu (ref_11) 2006; 66
Evangelisti (ref_39) 2020; 1867
Abramovitch (ref_50) 2004; 64
Sanyal (ref_5) 2010; 26
Peterson (ref_89) 2011; 146
Ozes (ref_79) 1999; 401
Maehama (ref_32) 1998; 273
Montella (ref_6) 2011; 11
Sever (ref_27) 2015; 5
Russell (ref_98) 2014; 24
Kew (ref_64) 2010; 58
Ding (ref_114) 2015; 112
Marrero (ref_25) 2008; 134
Budanov (ref_71) 2008; 134
Wang (ref_118) 2008; 14
Koeberle (ref_120) 2016; 27
Nie (ref_99) 2016; 7
Ahn (ref_59) 2018; 149
Ryu (ref_100) 2021; 53
Fang (ref_44) 2019; 463
Mendoza (ref_103) 2011; 36
Manning (ref_34) 2017; 169
Kane (ref_81) 2002; 22
Eslam (ref_7) 2020; 158
Xue (ref_102) 2020; 16
Sahin (ref_9) 2004; 10
Maeda (ref_83) 2005; 121
Casak (ref_112) 2021; 27
Wang (ref_51) 2013; 58
Czech (ref_31) 2000; 100
Bruix (ref_109) 2017; 389
Thomas (ref_117) 2018; 94
Wu (ref_82) 2009; 278
Matter (ref_124) 2014; 60
Llovet (ref_13) 2008; 359
Kancherla (ref_63) 2018; 9
Brugarolas (ref_72) 2004; 18
Laplante (ref_85) 2009; 19
Lemmon (ref_29) 2010; 141
Xu (ref_101) 2013; 6
Sieghart (ref_12) 2007; 83
Kudo (ref_21) 2020; 69
Kudo (ref_108) 2018; 391
Wang (ref_2) 2016; 388
ref_60
Dieterle (ref_33) 2014; 33
Yang (ref_55) 2021; 11
Park (ref_53) 2016; 469
Cheng (ref_107) 2009; 10
Koundouros (ref_86) 2020; 122
Luedde (ref_76) 2011; 8
Kim (ref_96) 2011; 13
Estes (ref_19) 2018; 67
Yecies (ref_92) 2011; 14
Dyson (ref_16) 2014; 5
Dan (ref_80) 2008; 22
Yang (ref_106) 2017; 13
Yu (ref_47) 2014; 7
Singh (ref_37) 2018; 37
Zhou (ref_67) 2001; 3
Alers (ref_97) 2012; 32
Yau (ref_116) 2019; 30
Chibaya (ref_68) 2021; 118
Stambolic (ref_69) 2001; 8
Luo (ref_75) 2021; 74
Gedaly (ref_104) 2012; 32
Shneor (ref_49) 2017; 24
Knox (ref_122) 2015; 33
ref_38
Perkins (ref_77) 2012; 12
Anwanwan (ref_20) 2020; 1873
He (ref_43) 2018; 70
Villanueva (ref_10) 2008; 135
Wilhelm (ref_23) 2008; 7
Porta (ref_123) 2014; 4
ref_105
Choo (ref_121) 2013; 49
Khan (ref_28) 2013; 32
Horton (ref_84) 2002; 109
ref_45
ref_42
Hansen (ref_95) 2018; 19
ref_1
ref_3
Manning (ref_26) 2007; 129
Liang (ref_61) 2020; 11
Kim (ref_36) 2017; 36
Gao (ref_35) 2014; 24
Steven (ref_46) 2020; 77
Chalasani (ref_17) 2018; 67
Maddocks (ref_74) 2011; 89
References_xml – volume: 206
  start-page: 411
  year: 2006
  ident: ref_48
  article-title: Role of cyclic-AMP responsive element binding (CREB) proteins in cell proliferation in a rat model of hepatocellular carcinoma
  publication-title: J. Cell. Physiol.
  doi: 10.1002/jcp.20474
– volume: 18
  start-page: 2893
  year: 2004
  ident: ref_72
  article-title: Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex
  publication-title: Genes Dev.
  doi: 10.1101/gad.1256804
– volume: 134
  start-page: 451
  year: 2008
  ident: ref_71
  article-title: p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling
  publication-title: Cell
  doi: 10.1016/j.cell.2008.06.028
– volume: 11
  start-page: 159
  year: 2011
  ident: ref_6
  article-title: HCC, diet and metabolic factors: Diet and HCC
  publication-title: Hepat. Mon.
– volume: 24
  start-page: 785
  year: 2014
  ident: ref_35
  article-title: Akt: A new activation mechanism
  publication-title: Cell Res.
  doi: 10.1038/cr.2014.57
– ident: ref_1
– volume: 279
  start-page: 51999
  year: 2004
  ident: ref_91
  article-title: Regulatory role of glycogen synthase kinase 3 for transcriptional activity of ADD1/SREBP1c
  publication-title: J. Biol. Chem.
  doi: 10.1074/jbc.M405522200
– volume: 33
  start-page: 3043
  year: 2014
  ident: ref_33
  article-title: PDK1 controls upstream PI3K expression and PIP3 generation
  publication-title: Oncogene
  doi: 10.1038/onc.2013.266
– volume: 382
  start-page: 1894
  year: 2020
  ident: ref_113
  article-title: Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma
  publication-title: N. Engl. J. Med.
  doi: 10.1056/NEJMoa1915745
– volume: 6
  start-page: 711
  year: 2013
  ident: ref_101
  article-title: UNC51-like kinase 1 as a potential prognostic biomarker for hepatocellular carcinoma
  publication-title: Int. J. Clin. Exp. Pathol.
– volume: 53
  start-page: 369
  year: 2021
  ident: ref_100
  article-title: GSK3B induces autophagy by phosphorylating ULK1
  publication-title: Exp. Mol. Med. Med.
  doi: 10.1038/s12276-021-00570-6
– volume: 30
  start-page: v874
  year: 2019
  ident: ref_116
  article-title: CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC)
  publication-title: Ann. Oncol.
  doi: 10.1093/annonc/mdz394.029
– volume: 109
  start-page: 1125
  year: 2002
  ident: ref_84
  article-title: SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver
  publication-title: J. Clin. Investig.
  doi: 10.1172/JCI0215593
– volume: 5
  start-page: 211
  year: 2014
  ident: ref_16
  article-title: Non-alcoholic fatty liver disease: A practical approach to diagnosis and staging
  publication-title: Frontline Gastroenterol.
  doi: 10.1136/flgastro-2013-100403
– volume: 171
  start-page: 1545
  year: 2017
  ident: ref_90
  article-title: Post-transcriptional Regulation of De Novo Lipogenesis by mTORC1-S6K1-SRPK2 Signaling
  publication-title: Cell
  doi: 10.1016/j.cell.2017.10.037
– volume: 15
  start-page: 7124
  year: 2014
  ident: ref_87
  article-title: SREBP-1 has a prognostic role and contributes to invasion and metastasis in human hepatocellular carcinoma
  publication-title: Int. J. Mol. Sci.
  doi: 10.3390/ijms15057124
– volume: 27
  start-page: 6473
  year: 2008
  ident: ref_30
  article-title: PI3K/Akt: Getting it right matters
  publication-title: Oncogene
  doi: 10.1038/onc.2008.313
– volume: 69
  start-page: 353
  year: 2018
  ident: ref_110
  article-title: Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: Additional analyses from the phase III RESORCE trial
  publication-title: J. Hepatol.
  doi: 10.1016/j.jhep.2018.04.010
– volume: 112
  start-page: 15713
  year: 2015
  ident: ref_114
  article-title: BRD4 is a novel therapeutic target for liver fibrosis
  publication-title: Proc. Natl. Acad. Sci. USA
  doi: 10.1073/pnas.1522163112
– volume: 94
  start-page: 329
  year: 2018
  ident: ref_117
  article-title: A Randomized Phase II Open-Label Multi-Institution Study of the Combination of Bevacizumab and Erlotinib Compared to Sorafenib in the First-Line Treatment of Patients with Advanced Hepatocellular Carcinoma
  publication-title: Oncology
  doi: 10.1159/000485384
– volume: 391
  start-page: 1163
  year: 2018
  ident: ref_108
  article-title: Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial
  publication-title: Lancet
  doi: 10.1016/S0140-6736(18)30207-1
– volume: 100
  start-page: 603
  year: 2000
  ident: ref_31
  article-title: PIP2 and PIP3: Complex Roles at the Cell Surface
  publication-title: Cell
  doi: 10.1016/S0092-8674(00)80696-0
– ident: ref_3
– volume: 7
  start-page: e2563
  year: 2016
  ident: ref_99
  article-title: Regulation of ER stress-induced autophagy by GSK3β-TIP60-ULK1 pathway
  publication-title: Cell Death Dis.
  doi: 10.1038/cddis.2016.423
– volume: 129
  start-page: 1261
  year: 2007
  ident: ref_26
  article-title: AKT/PKB signaling: Navigating downstream
  publication-title: Cell
  doi: 10.1016/j.cell.2007.06.009
– volume: 27
  start-page: 1836
  year: 2021
  ident: ref_112
  article-title: FDA Approval Summary: Atezolizumab Plus Bevacizumab for the Treatment of Patients with Advanced Unresectable or Metastatic Hepatocellular Carcinoma
  publication-title: Clin. Cancer Res.
  doi: 10.1158/1078-0432.CCR-20-3407
– volume: 67
  start-page: 123
  year: 2018
  ident: ref_19
  article-title: Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease
  publication-title: Hepatology
  doi: 10.1002/hep.29466
– volume: 141
  start-page: 1117
  year: 2010
  ident: ref_29
  article-title: Cell signaling by receptor tyrosine kinases
  publication-title: Cell
  doi: 10.1016/j.cell.2010.06.011
– volume: 74
  start-page: 96
  year: 2021
  ident: ref_75
  article-title: p53 haploinsufficiency and increased mTOR signalling define a subset of aggressive hepatocellular carcinoma
  publication-title: J. Hepatol.
  doi: 10.1016/j.jhep.2020.07.036
– volume: 68
  start-page: 394
  year: 2018
  ident: ref_4
  article-title: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
  publication-title: CA Cancer J. Clin.
  doi: 10.3322/caac.21492
– volume: 19
  start-page: 579
  year: 2018
  ident: ref_95
  article-title: Autophagy as a promoter of longevity: Insights from model organisms
  publication-title: Nat. Rev. Mol. Cell Biol.
  doi: 10.1038/s41580-018-0033-y
– volume: 69
  start-page: 1492
  year: 2020
  ident: ref_21
  article-title: Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial
  publication-title: Gut
  doi: 10.1136/gutjnl-2019-318934
– volume: 32
  start-page: 253
  year: 2013
  ident: ref_28
  article-title: Targeting the PI3K-AKT-mTOR signaling network in cancer
  publication-title: Chin. J. Cancer
  doi: 10.5732/cjc.013.10057
– volume: 22
  start-page: 239
  year: 2008
  ident: ref_73
  article-title: Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling
  publication-title: Genes Dev.
  doi: 10.1101/gad.1617608
– volume: 66
  start-page: 11851
  year: 2006
  ident: ref_11
  article-title: Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5
  publication-title: Cancer Res.
  doi: 10.1158/0008-5472.CAN-06-1377
– volume: 36
  start-page: 320
  year: 2011
  ident: ref_103
  article-title: The Ras-ERK and PI3K-mTOR pathways: Cross-talk and compensation
  publication-title: Trends Biochem. Sci.
  doi: 10.1016/j.tibs.2011.03.006
– volume: 97
  start-page: e0214
  year: 2018
  ident: ref_18
  article-title: Components of metabolic syndrome increase the risk of mortality in nonalcoholic fatty liver disease (NAFLD)
  publication-title: Medicine (Baltimore)
  doi: 10.1097/MD.0000000000010214
– volume: 149
  start-page: 117
  year: 2018
  ident: ref_59
  article-title: Overexpression of Forkhead Box O3a and Its Association With Aggressive Phenotypes and Poor Prognosis in Human Hepatocellular Carcinoma
  publication-title: Am. J. Clin. Pathol.
  doi: 10.1093/ajcp/aqx132
– volume: 22
  start-page: 5962
  year: 2002
  ident: ref_81
  article-title: Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription
  publication-title: Mol. Cell Biol.
  doi: 10.1128/MCB.22.16.5962-5974.2002
– volume: 118
  start-page: e2003193118
  year: 2021
  ident: ref_68
  article-title: Mdm2 phosphorylation by Akt regulates the p53 response to oxidative stress to promote cell proliferation and tumorigenesis
  publication-title: Proc. Natl. Acad. Sci. USA
  doi: 10.1073/pnas.2003193118
– volume: 67
  start-page: 3043
  year: 2007
  ident: ref_70
  article-title: The regulation of AMPK beta1, TSC2, and PTEN expression by p53: Stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways
  publication-title: Cancer Res. Res.
  doi: 10.1158/0008-5472.CAN-06-4149
– volume: 1867
  start-page: 118635
  year: 2020
  ident: ref_39
  article-title: Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer
  publication-title: Biochim. Biophys. Acta (BBA)—Mol. Cell Res.
  doi: 10.1016/j.bbamcr.2019.118635
– volume: 122
  start-page: 4
  year: 2020
  ident: ref_86
  article-title: Reprogramming of fatty acid metabolism in cancer
  publication-title: Br. J. Cancer
  doi: 10.1038/s41416-019-0650-z
– volume: 7
  start-page: 3129
  year: 2008
  ident: ref_23
  article-title: Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling
  publication-title: Mol. Cancer Ther.
  doi: 10.1158/1535-7163.MCT-08-0013
– volume: 72
  start-page: 342
  year: 2020
  ident: ref_22
  article-title: Molecular therapies for HCC: Looking outside the box
  publication-title: J. Hepatol.
  doi: 10.1016/j.jhep.2019.09.010
– volume: 103
  start-page: 691
  year: 2000
  ident: ref_62
  article-title: p53: Death Star
  publication-title: Cell
  doi: 10.1016/S0092-8674(00)00171-9
– volume: 58
  start-page: 273
  year: 2010
  ident: ref_64
  article-title: Epidemiology of chronic hepatitis B virus infection, hepatocellular carcinoma, and hepatitis B virus-induced hepatocellular carcinoma
  publication-title: Pathol. Biol.
  doi: 10.1016/j.patbio.2010.01.005
– volume: 388
  start-page: 1459
  year: 2016
  ident: ref_2
  article-title: Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: A systematic analysis for the Global Burden of Disease Study 2015
  publication-title: Lancet
  doi: 10.1016/S0140-6736(16)31012-1
– volume: 26
  start-page: 2183
  year: 2010
  ident: ref_5
  article-title: Population-based risk factors and resource utilization for HCC: US perspective
  publication-title: Curr. Med. Res. Opin.
  doi: 10.1185/03007995.2010.506375
– volume: 379
  start-page: 54
  year: 2018
  ident: ref_111
  article-title: Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma
  publication-title: N. Engl. J. Med.
  doi: 10.1056/NEJMoa1717002
– volume: 389
  start-page: 2492
  year: 2017
  ident: ref_115
  article-title: Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial
  publication-title: Lancet
  doi: 10.1016/S0140-6736(17)31046-2
– volume: 89
  start-page: 237
  year: 2011
  ident: ref_74
  article-title: Metabolic regulation by p53
  publication-title: J. Mol. Med.
  doi: 10.1007/s00109-011-0735-5
– volume: 134
  start-page: 1752
  year: 2008
  ident: ref_25
  article-title: Diagnosis and Treatment of Hepatocellular Carcinoma
  publication-title: Gastroenterology
  doi: 10.1053/j.gastro.2008.02.090
– volume: 401
  start-page: 82
  year: 1999
  ident: ref_79
  article-title: NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase
  publication-title: Nature
  doi: 10.1038/43466
– volume: 77
  start-page: 4049
  year: 2020
  ident: ref_46
  article-title: What turns CREB on? And off? And why does it matter?
  publication-title: Cell. Mol. Life Sci.
  doi: 10.1007/s00018-020-03525-8
– volume: 18
  start-page: 309
  year: 2018
  ident: ref_78
  article-title: NF-κB, inflammation, immunity and cancer: Coming of age
  publication-title: Nat. Rev. Immunol.
  doi: 10.1038/nri.2017.142
– volume: 32
  start-page: 807
  year: 2017
  ident: ref_93
  article-title: mTORC2 Promotes Tumorigenesis via Lipid Synthesis
  publication-title: Cancer Cell
  doi: 10.1016/j.ccell.2017.11.011
– volume: 9
  start-page: 2
  year: 2018
  ident: ref_63
  article-title: Genomic Analysis Revealed New Oncogenic Signatures in TP53-Mutant Hepatocellular Carcinoma
  publication-title: Front. Genet.
  doi: 10.3389/fgene.2018.00002
– volume: 70
  start-page: 674
  year: 2019
  ident: ref_15
  article-title: The trends in incidence of primary liver cancer caused by specific etiologies: Results from the Global Burden of Disease Study 2016 and implications for liver cancer prevention
  publication-title: J. Hepatol.
  doi: 10.1016/j.jhep.2018.12.001
– volume: 312
  start-page: 57
  year: 2014
  ident: ref_119
  article-title: Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: The EVOLVE-1 randomized clinical trial
  publication-title: JAMA
  doi: 10.1001/jama.2014.7189
– volume: 60
  start-page: 855
  year: 2014
  ident: ref_124
  article-title: Targeting the mTOR pathway in hepatocellular carcinoma: Current state and future trends
  publication-title: J. Hepatol.
  doi: 10.1016/j.jhep.2013.11.031
– volume: 27
  start-page: 856
  year: 2016
  ident: ref_120
  article-title: 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)
  publication-title: Ann. Oncol.
  doi: 10.1093/annonc/mdw054
– volume: 463
  start-page: 11
  year: 2019
  ident: ref_44
  article-title: Inhibition of GSK-3beta activity suppresses HCC malignant phenotype by inhibiting glycolysis via activating AMPK/mTOR signaling
  publication-title: Cancer Lett.
  doi: 10.1016/j.canlet.2019.08.003
– volume: 3
  start-page: 973
  year: 2001
  ident: ref_67
  article-title: HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation
  publication-title: Nat. Cell Biol.
  doi: 10.1038/ncb1101-973
– volume: 24
  start-page: 64
  year: 2017
  ident: ref_49
  article-title: Stable knockdown of CREB, HIF-1 and HIF-2 by replication-competent retroviruses abrogates the responses to hypoxia in hepatocellular carcinoma
  publication-title: Cancer Gene Ther.
  doi: 10.1038/cgt.2016.68
– volume: 11
  start-page: 1017
  year: 2020
  ident: ref_61
  article-title: Hypoxia induces sorafenib resistance mediated by autophagy via activating FOXO3a in hepatocellular carcinoma
  publication-title: Cell Death Dis.
  doi: 10.1038/s41419-020-03233-y
– volume: 146
  start-page: 408
  year: 2011
  ident: ref_89
  article-title: mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway
  publication-title: Cell
  doi: 10.1016/j.cell.2011.06.034
– volume: 49
  start-page: 999
  year: 2013
  ident: ref_121
  article-title: A Phase 1 dose-finding and pharmacodynamic study of rapamycin in combination with bevacizumab in patients with unresectable hepatocellular carcinoma
  publication-title: Eur. J. Cancer
  doi: 10.1016/j.ejca.2012.11.008
– volume: 359
  start-page: 378
  year: 2008
  ident: ref_13
  article-title: Sorafenib in Advanced Hepatocellular Carcinoma
  publication-title: N. Engl. J. Med.
  doi: 10.1056/NEJMoa0708857
– volume: 33
  start-page: 241
  year: 2015
  ident: ref_122
  article-title: A phase II trial of bevacizumab plus temsirolimus in patients with advanced hepatocellular carcinoma
  publication-title: Investig. New Drugs
  doi: 10.1007/s10637-014-0169-3
– volume: 36
  start-page: 2191
  year: 2017
  ident: ref_36
  article-title: mTORC1 and mTORC2 in cancer and the tumor microenvironment
  publication-title: Oncogene
  doi: 10.1038/onc.2016.363
– volume: 64
  start-page: 1338
  year: 2004
  ident: ref_50
  article-title: A pivotal role of cyclic AMP-responsive element binding protein in tumor progression
  publication-title: Cancer Res.
  doi: 10.1158/0008-5472.CAN-03-2089
– volume: 148
  start-page: 114
  year: 2015
  ident: ref_41
  article-title: Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases
  publication-title: Pharmacol. Ther.
  doi: 10.1016/j.pharmthera.2014.11.016
– volume: 56
  start-page: 2051
  year: 2012
  ident: ref_52
  article-title: Hepatitis B virus X protein modulates oncogene Yes-associated protein by CREB to promote growth of hepatoma cells
  publication-title: Hepatology
  doi: 10.1002/hep.25899
– volume: 70
  start-page: 949
  year: 2018
  ident: ref_43
  article-title: mTORC1 Promotes Metabolic Reprogramming by the Suppression of GSK3-Dependent Foxk1 Phosphorylation
  publication-title: Mol. Cell
  doi: 10.1016/j.molcel.2018.04.024
– volume: 67
  start-page: 328
  year: 2018
  ident: ref_17
  article-title: The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases
  publication-title: Hepatology
  doi: 10.1002/hep.29367
– volume: 83
  start-page: 425
  year: 2007
  ident: ref_12
  article-title: Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation
  publication-title: Transplantation
  doi: 10.1097/01.tp.0000252780.42104.95
– volume: 10
  start-page: 8421
  year: 2004
  ident: ref_9
  article-title: mTOR and P70 S6 kinase expression in primary liver neoplasms
  publication-title: Clin. Cancer Res.
  doi: 10.1158/1078-0432.CCR-04-0941
– volume: 12
  start-page: 121
  year: 2012
  ident: ref_77
  article-title: The diverse and complex roles of NF-κB subunits in cancer
  publication-title: Nat. Rev. Cancer
  doi: 10.1038/nrc3204
– volume: 65
  start-page: 1936
  year: 2017
  ident: ref_88
  article-title: Inhibition of the sterol regulatory element-binding protein pathway suppresses hepatocellular carcinoma by repressing inflammation in mice
  publication-title: Hepatology
  doi: 10.1002/hep.29018
– volume: 121
  start-page: 977
  year: 2005
  ident: ref_83
  article-title: IKKβ Couples Hepatocyte Death to Cytokine-Driven Compensatory Proliferation that Promotes Chemical Hepatocarcinogenesis
  publication-title: Cell
  doi: 10.1016/j.cell.2005.04.014
– volume: 441
  start-page: 880
  year: 2006
  ident: ref_94
  article-title: Loss of autophagy in the central nervous system causes neurodegeneration in mice
  publication-title: Nature
  doi: 10.1038/nature04723
– volume: 4
  start-page: 64
  year: 2014
  ident: ref_123
  article-title: Targeting PI3K/Akt/mTOR Signaling in Cancer
  publication-title: Front. Oncol.
  doi: 10.3389/fonc.2014.00064
– volume: 22
  start-page: 1490
  year: 2008
  ident: ref_80
  article-title: Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK
  publication-title: Genes Dev.
  doi: 10.1101/gad.1662308
– volume: 10
  start-page: 25
  year: 2009
  ident: ref_107
  article-title: 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
  publication-title: Lancet Oncol.
  doi: 10.1016/S1470-2045(08)70285-7
– ident: ref_38
  doi: 10.3390/cancers10010018
– volume: 14
  start-page: 21
  year: 2011
  ident: ref_92
  article-title: Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways
  publication-title: Cell Metab.
  doi: 10.1016/j.cmet.2011.06.002
– volume: 51
  start-page: 1
  year: 2019
  ident: ref_24
  article-title: Anti-tumoral activity of single and combined regorafenib treatments in preclinical models of liver and gastrointestinal cancers
  publication-title: Exp. Mol. Med.
  doi: 10.1038/s12276-019-0308-1
– volume: 11
  start-page: 1797
  year: 2021
  ident: ref_55
  article-title: Role of Forkhead Box O Proteins in Hepatocellular Carcinoma Biology and Progression (Review)
  publication-title: Front. Oncol.
– volume: 135
  start-page: 1972
  year: 2008
  ident: ref_10
  article-title: Pivotal role of mTOR signaling in hepatocellular carcinoma
  publication-title: Gastroenterology
  doi: 10.1053/j.gastro.2008.08.008
– ident: ref_60
  doi: 10.1186/s12885-019-6110-6
– volume: 278
  start-page: 145
  year: 2009
  ident: ref_82
  article-title: NF-κB inhibition in human hepatocellular carcinoma and its potential as adjunct to sorafenib based therapy
  publication-title: Cancer Lett.
  doi: 10.1016/j.canlet.2008.12.031
– volume: 13
  start-page: 1041
  year: 2017
  ident: ref_106
  article-title: Targeting the Ras/Raf/MEK/ERK pathway in hepatocellular carcinoma
  publication-title: Oncol. Lett.
  doi: 10.3892/ol.2017.5557
– volume: 8
  start-page: 108
  year: 2011
  ident: ref_76
  article-title: NF-κB in the liver--linking injury, fibrosis and hepatocellular carcinoma
  publication-title: Nat. Rev. Gastroenterol. Hepatol.
  doi: 10.1038/nrgastro.2010.213
– volume: 9
  start-page: 563
  year: 2020
  ident: ref_14
  article-title: The Burden and Trends of Primary Liver Cancer Caused by Specific Etiologies from 1990 to 2017 at the Global, Regional, National, Age, and Sex Level Results from the Global Burden of Disease Study 2017
  publication-title: Liver Cancer
  doi: 10.1159/000508568
– volume: 7
  start-page: 873
  year: 2014
  ident: ref_47
  article-title: Cyclic adenosine monophosphate-responsive element-binding protein activation predicts an unfavorable prognosis in patients with hepatocellular carcinoma
  publication-title: Onco Targets Ther.
– volume: 8
  start-page: 317
  year: 2001
  ident: ref_69
  article-title: Regulation of PTEN transcription by p53
  publication-title: Mol. Cell
  doi: 10.1016/S1097-2765(01)00323-9
– ident: ref_42
  doi: 10.3390/cells8121597
– volume: 58
  start-page: 1011
  year: 2013
  ident: ref_51
  article-title: Mutual interaction between YAP and CREB promotes tumorigenesis in liver cancer
  publication-title: Hepatology
  doi: 10.1002/hep.26420
– volume: 21
  start-page: 1231
  year: 2014
  ident: ref_54
  article-title: FoxO proteins: Regulation and molecular targets in liver cancer
  publication-title: Curr. Med. Chem.
  doi: 10.2174/0929867321666131228205703
– ident: ref_105
  doi: 10.3390/cancers13123026
– volume: 37
  start-page: 1142
  year: 2018
  ident: ref_37
  article-title: Dual role of autophagy in hallmarks of cancer
  publication-title: Oncogene
  doi: 10.1038/s41388-017-0046-6
– volume: 32
  start-page: 2
  year: 2012
  ident: ref_97
  article-title: Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: Cross talk, shortcuts, and feedbacks
  publication-title: Mol. Cell Biol.
  doi: 10.1128/MCB.06159-11
– volume: 469
  start-page: 363
  year: 2016
  ident: ref_53
  article-title: Inhibition of cyclic AMP response element-directed transcription by decoy oligonucleotides enhances tumor-specific radiosensitivity
  publication-title: Biochem. Biophys. Res. Commun.
  doi: 10.1016/j.bbrc.2015.11.122
– volume: 98
  start-page: 11598
  year: 2001
  ident: ref_66
  article-title: A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus
  publication-title: Proc. Natl. Acad. Sci. USA
  doi: 10.1073/pnas.181181198
– volume: 19
  start-page: R1046
  year: 2009
  ident: ref_85
  article-title: An emerging role of mTOR in lipid biosynthesis
  publication-title: Curr. Biol.
  doi: 10.1016/j.cub.2009.09.058
– volume: 14
  start-page: 5124
  year: 2008
  ident: ref_118
  article-title: Effect of Rapamycin Alone and in Combination with Sorafenib in an Orthotopic Model of Human Hepatocellular Carcinoma
  publication-title: Clin. Cancer Res.
  doi: 10.1158/1078-0432.CCR-07-4774
– volume: 169
  start-page: 381
  year: 2017
  ident: ref_34
  article-title: AKT/PKB Signaling: Navigating the Network
  publication-title: Cell
  doi: 10.1016/j.cell.2017.04.001
– volume: 24
  start-page: 42
  year: 2014
  ident: ref_98
  article-title: Autophagy regulation by nutrient signaling
  publication-title: Cell Res.
  doi: 10.1038/cr.2013.166
– volume: 16
  start-page: 1823
  year: 2020
  ident: ref_102
  article-title: The role of the key autophagy kinase ULK1 in hepatocellular carcinoma and its validation as a treatment target
  publication-title: Autophagy
  doi: 10.1080/15548627.2019.1709762
– volume: 18
  start-page: 3181
  year: 1999
  ident: ref_8
  article-title: PTEN/MMAC1 mutations in hepatocellular carcinomas
  publication-title: Oncogene
  doi: 10.1038/sj.onc.1202659
– volume: 2017
  start-page: 4629495
  year: 2017
  ident: ref_40
  article-title: Multifaceted Roles of GSK-3 in Cancer and Autophagy-Related Diseases
  publication-title: Oxid. Med. Cell. Longev.
  doi: 10.1155/2017/4629495
– volume: 1813
  start-page: 1965
  year: 2011
  ident: ref_56
  article-title: Interplay between FOXO, TOR, and Akt
  publication-title: Biochim. Biophys. Acta
  doi: 10.1016/j.bbamcr.2011.03.013
– volume: 389
  start-page: 56
  year: 2017
  ident: ref_109
  article-title: Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial
  publication-title: Lancet
  doi: 10.1016/S0140-6736(16)32453-9
– volume: 273
  start-page: 13375
  year: 1998
  ident: ref_32
  article-title: The Tumor Suppressor, PTEN/MMAC1, Dephosphorylates the Lipid Second Messenger, Phosphatidylinositol 3,4,5-Trisphosphate*
  publication-title: J. Biol. Chem.
  doi: 10.1074/jbc.273.22.13375
– volume: 32
  start-page: 2531
  year: 2012
  ident: ref_104
  article-title: The role of PI3K/mTOR inhibition in combination with sorafenib in hepatocellular carcinoma treatment
  publication-title: Anticancer Res.
– volume: 19
  start-page: 3181
  year: 2020
  ident: ref_58
  article-title: High expression of FOXO3 is associated with poor prognosis in patients with hepatocellular carcinoma
  publication-title: Oncol. Lett.
– volume: 8
  start-page: 1703
  year: 2017
  ident: ref_57
  article-title: FOXO1 inhibits the invasion and metastasis of hepatocellular carcinoma by reversing ZEB2-induced epithelial-mesenchymal transition
  publication-title: Oncotarget
  doi: 10.18632/oncotarget.13786
– volume: 277
  start-page: 21843
  year: 2002
  ident: ref_65
  article-title: Akt enhances Mdm2-mediated ubiquitination and degradation of p53
  publication-title: J. Biol. Chem.
  doi: 10.1074/jbc.M109745200
– volume: 1873
  start-page: 188314
  year: 2020
  ident: ref_20
  article-title: Challenges in liver cancer and possible treatment approaches
  publication-title: Biochim. Biophys. Acta (BBA)—Rev. Cancer
  doi: 10.1016/j.bbcan.2019.188314
– volume: 158
  start-page: 1999
  year: 2020
  ident: ref_7
  article-title: MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease
  publication-title: Gastroenterology
  doi: 10.1053/j.gastro.2019.11.312
– ident: ref_45
  doi: 10.3390/cancers12113166
– volume: 13
  start-page: 132
  year: 2011
  ident: ref_96
  article-title: AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1
  publication-title: Nat. Cell Biol.
  doi: 10.1038/ncb2152
– volume: 5
  start-page: a006098
  year: 2015
  ident: ref_27
  article-title: Signal transduction in cancer
  publication-title: Cold Spring Harb. Perspect. Med.
  doi: 10.1101/cshperspect.a006098
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Snippet Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains...
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SubjectTerms 1-Phosphatidylinositol 3-kinase
Akt
AKT protein
Angiogenesis
Apoptosis
Autophagy
Cancer therapies
Cell cycle
Cell growth
clinical trials
Cyclic AMP response element-binding protein
Diabetes
Drug resistance
Fibroblasts
Forkhead protein
Glycogen
Glycogen synthase kinase 3
HCC
Hepatitis B
Hepatitis C
Hepatocellular carcinoma
Industrialized nations
Kinases
Lipogenesis
Liver cancer
Liver diseases
MDM2 protein
Metabolism
mTOR
NF-κB protein
p53 Protein
Phagocytosis
PI3K
Proteins
Regulation
Review
Sarcoma
Signal transduction
TOR protein
Vascular endothelial growth factor
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Title Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma
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