Autophagy and liver cancer
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Autophagy is a highly conserved catabolic process that degrades cytosolic proteins and organelles via formation of autophagosomes that fuse with lysosomes to form autolysosomes, whereby autophagic cargos are degraded. Numerous studies have demonstrated that autophagy plays a critical role in the regulation of liver physiology and homeostasis, and impaired autophagy leads to the pathogenesis of various liver diseases such as viral hepatitis, alcohol associated liver diseases (AALD), non-alcoholic fatty liver diseases (NAFLD), and liver cancer. Recent evidence indicates that autophagy may play a dual role in liver cancer: inhibiting early tumor initiation while promoting progression and malignancy of already formed liver tumors. In this review, we summarized the progress of current understanding of how hepatic viral infection, alcohol consumption and diet-induced fatty liver diseases impair hepatic autophagy. We also discussed how impaired autophagy promotes liver tumorigenesis, and paradoxically how autophagy is required to promote the malignancy and progression of liver cancer. Understanding the molecular mechanisms underlying how autophagy differentially affects liver cancer development and progression may help to design better therapeutic strategies for prevention and treatment of liver cancer.
Abstract
Autophagy is a highly conserved catabolic process that degrades cytosolic proteins and organelles via formation of autophagosomes that fuse with lysosomes to form autolysosomes, whereby autophagic cargos are degraded. Numerous studies have demonstrated that autophagy plays a critical role in the regulation of liver physiology and homeostasis, and impaired autophagy leads to the pathogenesis of various liver diseases such as viral hepatitis, alcohol associated liver diseases (AALD), non-alcoholic fatty liver diseases (NAFLD), and liver cancer. Recent evidence indicates that autophagy may play a dual role in liver cancer: inhibiting early tumor initiation while promoting progression and malignancy of already formed liver tumors. In this review, we summarized the progress of current understanding of how hepatic viral infection, alcohol consumption and diet-induced fatty liver diseases impair hepatic autophagy. We also discussed how impaired autophagy promotes liver tumorigenesis, and paradoxically how autophagy is required to promote the malignancy and progression of liver cancer. Understanding the molecular mechanisms underlying how autophagy differentially affects liver cancer development and progression may help to design better therapeutic strategies for prevention and treatment of liver cancer.
참고문헌 (134)
- Klionsky DJ, "Autophagy as a regulated pathway of cellular degradation", Science, 290, pp.1717~1721 (2000)
- Parzych KR, "An overview of autophagy : morphology, mechanism, and regulation", Antioxid Redox Signal, 20, pp.460~473 (2014)
- Mizushima N, "Autophagy fights disease through cellular self-digestion", Nature, 451, pp.1069~1075 (2008)
- White E, "The role for autophagy in cancer", J Clin Invest, 125, pp.42~46 (2015)
- Yang JD, "Hepatocellular carcinoma : a global view", Nat Rev Gastroenterol Hepatol, 7, pp.448~458 (2010)
- Bray F, "Global cancer statistics 2018 : GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries", CA Cancer J Clin, 68, pp.394~424 (2018)
- Xu J, "Trends in liver cancer mortality among adults aged 25 and over in the United States, 2000-2016", NCHS Data Brief, (314), pp.1~8 (2018)
- Farazi PA, "Hepatocellular carcinoma pathogenesis : from genes to environment", Nat Rev Cancer, 6, pp.674~687 (2006)
- Chao X, "Role and mechanisms of autophagy in alcoholinduced liver injury", Adv Pharmacol, 85, pp.109~131 (2019)
- Ma X, "Role and mechanisms of mitophagy in liver diseases", Cells, 9, pp.837~ (2020)
- Yang L, "Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance", Cell Metab, 11, pp.467~478 (2010)
- Sir D, "Autophagy by hepatitis B virus and for hepatitis B virus", Autophagy, 6, pp.548~549 (2010)
- Sir D, "Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response", Hepatology, 48, pp.1054~1061 (2008)
- Chao X, "Impaired TFEB-mediated lysosome biogenesis and autophagy promote chronic ethanol-induced liver injury and steatosis in mice", Gastroenterology, 155, pp.865~879.e12 (2018)
- Liang XH, "Induction of autophagy and inhibition of tumorigenesis by beclin 1", Nature, 402, pp.672~676 (1999)
- Qu X, "Promotion of tumorigenesis by heterozygous disruption of the beclin 1autophagy gene", J Clin Invest, 112, pp.1809~1820 (2003)
- Yue Z, "Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor", Proc Natl Acad Sci U S A, 100, pp.15077~15082 (2003)
- Qiu DM, "The expression of beclin-1, an autophagic gene, in hepatocellular carcinoma associated with clinical pathological and prognostic significance", BMC Cancer, 14, pp.327~ (2014)
- Kuma A, "The role of autophagy during the early neonatal starvation period", Nature, 432, pp.1032~1036 (2004)
- Komatsu M, "Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice", J Cell Biol, 169, pp.425~434 (2005)
- Takamura A, "Autophagy-deficient mice develop multiple liver tumors", Genes Dev, 25, pp.795~800 (2011)
- Inami Y, "Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells", J Cell Biol, 193, pp.275~284 (2011)
- Ni HM, "Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy", J Hepatol, 61, pp.617~625 (2014)
- Ding WX, "Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy", Mol Cancer Ther, 8, pp.2036~2045 (2009)
- Ding WX, "Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome", Autophagy, 4, pp.141~150 (2008)
- Chen N, "Autophagy and tumorigenesis", FEBS Lett, 584, pp.1427~1435 (2010)
- Mathew R, "Autophagy suppresses tumorigenesis through elimination of p62", Cell, 137, pp.1062~1075 (2009)
- Vessoni AT, "Autophagy and genomic integrity", Cell Death Differ, 20, pp.1444~1454 (2013)
- Tian Y, "Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis", Cell Death Differ, 22, pp.1025~1034 (2015)
- Ni HM, "Liver-specific loss of Atg5 causes persistent activation of Nrf2and protects against acetaminophen-induced liver injury", Toxicol Sci, 127, pp.438~450 (2012)
- Yang H, "Sequestosome 1", p62 protein is associated with autophagic removal of excess hepatic endoplasmic reticulum in mice, 2016, pp.291, 18663~18674
- Ni HM, "Dual roles of mammalian target of rapamycin in regulating liver injury and tumorigenesis in autophagy-defective mouse liver", Hepatology, 70, pp.2142~2155 (2019)
- Khambu B, "HMGB1promotes ductular reaction and tumorigenesis in autophagydeficient livers", J Clin Invest, 128, pp.2419~2435 (2018)
- Lee YA, "Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap", Nat Commun, 9, pp.4962~ (2018)
- Yang H, "Emerging Players in autophagy deficiency-induced liver injury and tumorigenesis", Gene Expr, 19, pp.229~234 (2019)
- Martinotti S, "Emerging roles for HMGB1protein in immunity, inflammation, and cancer", Immunotargets Ther, 4, pp.101~109 (2015)
- Sims GP, "HMGB1 and RAGE in inflammation and cancer", Annu Rev Immunol, 28, pp.367~388 (2010)
- Arriazu E, "Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury", Gut, 66, pp.1123~1137 (2017)
- Wang H, "HMG-1 as a late mediator of endotoxin lethality in mice", Science, 285, pp.248~251 (1999)
- Zhao B, "TEAD mediates YAPdependent gene induction and growth control", Genes Dev, 22, pp.1962~1971 (2008)
- Zhao B, "Both TEAD-binding and WW domains are required for the growth stimulation and oncogenic transformation activity of yes-associated protein", Cancer Res, 69, pp.1089~1098 (2009)
- Saxton RA, "mTOR signaling in growth, metabolism, and disease", Cell, 169, pp.361~371 (2017)
- Matter MS, "Targeting the mTOR pathway in hepatocellular carcinoma : current state and future trends", J Hepatol, 60, pp.855~865 (2014)
- Hu TH, "Expression and prognostic role of tumor suppressor gene PTEN", MMAC1, Cancer, pp.2003, 97[DOI]
- Ho DWH, "TSC1", 2 mutations define a molecular subset of HCC with aggressive behaviour and treatment implication, 2017, pp.66, 1496~1506
- Kenerson HL, "Akt and mTORC1 have different roles during liver tumorigenesis in mice", Gastroenterology, 144, pp.1055~1065 (2013)
- Abraham RT, "The mammalian target of rapamycin signaling pathway : twists and turns in the road to cancer therapy", Clin Cancer Res, 13, pp.3109~3114 (2007)
- Chiang GG, "Targeting the mTOR signaling network in cancer", Trends Mol Med, 13, pp.433~442 (2007)
- Liu K, "Mitophagy controls the activities of tumor suppressor p53 to regulate hepatic cancer stem cells", Mol Cell, 68, pp.281~292.e5 (2017)
- Qian H, "A PINK1-mediated mitophagy pathway decides the fate of tumors-to be benign or malignant?", Autophagy, 14, pp.563~566 (2018)
- Li X, "Autophagy and autophagy-related proteins in cancer", Mol Cancer, 19, pp.12~ (2020)
- Barnard RA, "Autophagy inhibition delays early but not late-stage metastatic disease", J Pharmacol Exp Ther, 358, pp.282~293 (2016)
- Guo JY, "Autophagy-mediated tumor promotion", Cell, 155, pp.1216~1219 (2013)
- White E, "Deconvoluting the context-dependent role for autophagy in cancer", Nat Rev Cancer, 12, pp.401~410 (2012)
- Ding WX, "Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability", Am J Pathol, 171, pp.513~524 (2007)
- Ding WX, "Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival", J Biol Chem, 282, pp.4702~4710 (2007)
- Song J, "Hypoxiainduced autophagy contributes to the chemoresistance of hepatocellular carcinoma cells", Autophagy, 5, pp.1131~1144 (2009)
- Degenhardt K, "Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis", Cancer Cell, 10, pp.51~64 (2006)
- Perera RM, "Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism", Nature, 524, pp.361~365 (2015)
- Yang S, "Pancreatic cancers require autophagy for tumor growth", Genes Dev, 25, pp.717~729 (2011)
- Guo JY, "Autophagy suppresses progression of K-rasinduced lung tumors to oncocytomas and maintains lipid homeostasis", Genes Dev, 27, pp.1447~1461 (2013)
- Strohecker AM, "Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors", Cancer Discov, 3, pp.1272~1285 (2013)
- Rosenfeldt MT, "p53 status determines the role of autophagy in pancreatic tumour development", Nature, 504, pp.296~300 (2013)
- Santanam U, "Atg7 cooperates with Pten loss to drive prostate cancer tumor growth", Genes Dev, 30, pp.399~407 (2016)
- Poillet-Perez L, "Autophagy maintains tumour growth through circulating arginine", Nature, 563, pp.569~573 (2018)
- Dillon BJ, "Incidence and distribution of argininosuccinate synthetase deficiency in human cancers : a method for identifying cancers sensitive to arginine deprivation", Cancer, 100, pp.826~833 (2004)
- Yang A, "Autophagy sustains pancreatic cancer growth through both cell-autonomous and nonautonomous mechanisms", Cancer Discov, 8, pp.276~287 (2018)
- Sousa CM, "Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion", Nature, 536, pp.479~483 (2016)
- Endo S, "Autophagy is required for activation of pancreatic stellate cells, associated with pancreatic cancer progression and promotes growth of pancreatic tumors in mice", Gastroenterology, 152, pp.1492~1506.e24 (2017)
- Yamamoto K, "Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I", Nature, 581, pp.100~105 (2020)
- Yamamoto K, "Selective autophagy of MHC-I promotes immune evasion of pancreatic cancer", Autophagy, 16, pp.1524~1525 (2020)
- Pankiv S, "p62", SQSTM1 binds directly to Atg8, J Biol Chem, pp.2007, 282[DOI]
- Ichimura Y, "Structural basis for sorting mechanism of p62 in selective autophagy", J Biol Chem, 283, pp.22847~22857 (2008)
- Katsuragi Y, "p62", SQSTM1 functions as a signaling hub and an autophagy adaptor, 2015, pp.282, 4672~4678
- Manley S, "Role of p62", SQSTM1 in liver physiology and pathogenesis, 2013, pp.238, 525~538
- Komatsu M, "Physiological significance of selective degradation of p62 by autophagy", FEBS Lett, 584, pp.1374~1378 (2010)
- Sánchez-Martín P, "p62", SQSTM1-steering the cell through health and disease, 2018, pp.131, jcs222836~
- Jakobi AJ, "Structural basis of p62", SQSTM1 helical filaments, their presence in p62 bodies and role in cargo recognition in the cell, 2020, pp.11, 440~
- Wilson MI, "PB1 domainmediated heterodimerization in NADPH oxidase and signaling complexes of atypical protein kinase C with Par6 and p62", Mol Cell, 12, pp.39~50 (2003)
- Duran A, "p62 is a key regulator of nutrient sensing in the mTORC1 pathway", Mol Cell, 44, pp.134~146 (2011)
- Katsuragi Y, "Regulation of the Keap1–Nrf2pathway by p62", SQSTM1, 2016, pp.1, 54~61
- Komatsu M, "The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1", Nat Cell Biol, 12, pp.213~223 (2010)
- Ichimura Y, "Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy", Mol Cell, 51, pp.618~631 (2013)
- Jain A, "p62", SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription, 2010, pp.285, 22576~22591
- Isogai S, "Crystal structure of the ubiquitin-associated(UBA)domain of p62and its interaction with ubiquitin", J Biol Chem, 286, pp.31864~31874 (2011)
- Taniguchi K, "p62", SQSTM1-Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer, 2016, pp.590, 2375~2397
- Umemura A, "p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells", Cancer Cell, 29, pp.935~948 (2016)
- Duran A, "p62", SQSTM1 by binding to vitamin D receptor inhibits hepatic stellate cell activity, fibrosis, and liver cancer, 2016, pp.30, 595~609
- Saito T, "p62", Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming, 2016, pp.7, 12030~
- Aishima S, "p62+ hyaline inclusions in intrahepatic cholangiocarcinoma associated with viral hepatitis or alcoholic liver disease", Am J Clin Pathol, 134, pp.457~465 (2010)
- Xiang X, "Expression of P62 in hepatocellular carcinoma involving hepatitis B virus infection and aflatoxin B1 exposure", Cancer Med, 6, pp.2357~2369 (2017)
- Menk M, "Chronic alcohol consumption inhibits autophagy and promotes apoptosis in the liver", Int J Med Sci, 15, pp.682~688 (2018)
- Fukushima H, "Formation of p62-positive inclusion body is associated with macrophage polarization in non-alcoholic fatty liver disease", Hepatol Res, 48, pp.757~767 (2018)
- González-Rodríguez A, "Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD", Cell Death Dis, 5, pp.e1179~ (2014)
- Bartolini D, "Nrf2-p62autophagy pathway and its response to oxidative stress in hepatocellular carcinoma", Transl Res, 193, pp.54~71 (2018)
- Settembre C, "Signals from the lysosome : a control centre for cellular clearance and energy metabolism", Nat Rev Mol Cell Biol, 14, pp.283~296 (2013)
- Settembre C, "A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB", EMBO J, 31, pp.1095~1108 (2012)
- Settembre C, "TFEB links autophagy to lysosomal biogenesis", Science, 332, pp.1429~1433 (2011)
- Palmieri M, "mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases", Nat Commun, 8, pp.14338~ (2017)
- Li Y, "Protein kinase C controls lysosome biogenesis independently of mTORC1", Nat Cell Biol, 18, pp.1065~1077 (2016)
- Sha Y, "STUB1 regulates TFEB-induced autophagy-lysosome pathway", EMBO J, 36, pp.2544~2552 (2017)
- Medina DL, "Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB", Nat Cell Biol, 17, pp.288~299 (2015)
- Wang Y, "Acetyltransferase GCN5 regulates autophagy and lysosome biogenesis by targeting TFEB", EMBO Rep, 21, pp.e48335~ (2020)
- Bao J, "Deacetylation of TFEB promotes fibrillar Aβ degradation by upregulating lysosomal biogenesis in microglia", Protein Cell, 7, pp.417~433 (2016)
- Tanaka M, "Modeling alveolar soft part sarcoma unveils novel mechanisms of metastasis", Cancer Res, 77, pp.897~907 (2017)
- Ploper D, "MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells", Proc Natl Acad Sci U S A, 112, pp.E420~E429 (2015)
- Mendel L, "Comprehensive study of three novel cases of TFEB-amplified renal cell carcinoma and review of the literature : Evidence for a specific entity with poor outcome", Genes Chromosomes Cancer, 57, pp.99~113 (2018)
- Argani P, "A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11. 2;q23)", Oncogene, 22, pp.5374~5378 (2003)
- Clark J, "Fusion of splicing factor genes PSF and NonO(p54nrb)to the TFE3 gene in papillary renal cell carcinoma", Oncogene, 15, pp.2233~2239 (1997)
- Di Malta C, "Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth", Science, 356, pp.1188~1192 (2017)
- Sancak Y, "Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids", Cell, 141, pp.290~303 (2010)
- Schmidt LS, "FLCN : the causative gene for Birt-Hogg-Dubé syndrome", Gene, 640, pp.28~42 (2018)
- Tsun ZY, "The folliculin tumor suppressor is a GAP for the RagC", D GTPases that signal amino acid levels to mTORC1, 2013, pp.52, 495~505
- Baba M, "Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse model : Erk1", 2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys, 2008, pp.100, 140~154
- Napolitano G, "A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dubé syndrome", Nature (2020)[DOI]
- Chao X, "Insufficient autophagy : a novel autophagic flux scenario uncovered by impaired liver TFEB-mediated lysosomal biogenesis from chronic alcohol-drinking mice", Autophagy, 14, pp.1646~1648 (2018)
- Zhang Z, "The unfolded protein response regulates hepatic autophagy by sXBP1-mediated activation of TFEB", Autophagy (2020)[DOI]
- Michalopoulos GK, "The regenerative altruism of hepatocytes and cholangiocytes", Cell Stem Cell, 23, pp.11~12 (2018)
- Deng X, "Chronic liver injury induces conversion of biliary epithelial cells into hepatocytes", Cell Stem Cell, 23, pp.114~122.e3 (2018)
- Schaub JR, "De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation", Nature, 557, pp.247~251 (2018)
- Pastore N, "TFEB regulates murine liver cell fate during development and regeneration", Nat Commun, 11, pp.2461~ (2020)
- Chalhoub N, "PTEN and the PI3-kinase pathway in cancer", Annu Rev Pathol, 4, pp.127~150 (2009)
- Mora A, "PDK1, the master regulator of AGC kinase signal transduction", Semin Cell Dev Biol, 15, pp.161~170 (2004)
- Sarbassov DD, "Phosphorylation and regulation of Akt", PKB by the rictor-mTOR complex, 2005, pp.307, 1098~1101
- Engelman JA, "The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism", Nat Rev Genet, 7, pp.606~619 (2006)
- Manning BD, "Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase", akt pathway, 2002, pp.10, 151~162
- Inoki K, "TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling", Nat Cell Biol, 4, pp.648~657 (2002)
- Inoki K, "TSC2 mediates cellular energy response to control cell growth and survival", Cell, 115, pp.577~590 (2003)
- Hawley SA, "Complexes between the LKB1 tumor suppressor, STRAD alpha", beta and MO25 alpha, J Biol, pp.2003, 2[DOI]
- Woods A, "LKB1 is the upstream kinase in the AMP-activated protein kinase cascade", Curr Biol, 13, pp.2004~2008 (2003)
- Hemminki A, "A serine", threonine kinase gene defective in Peutz-Jeghers syndrome, 1998, pp.391, 184~187
- Horie Y, "Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas", J Clin Invest, 113, pp.1774~1783 (2004)
- Ueno T, "Loss of Pten, a tumor suppressor, causes the strong inhibition of autophagy without affecting LC3 lipidation", Autophagy, 4, pp.692~700 (2008)
- Menon S, "Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice", Sci Signal, 5, pp.ra24~ (2012)
