Keigo Machida, PhD

Associate Professor of Molecular Microbiology & Immunology

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Overview

Hepatitis C Virus (HCV) is a “silent stalker” in infected people, who can develop hepatocellular carcinomas (HCC) decades later. Our short-term goal is to study three areas:

(i) Host-pathogen interactions to identify the mechanism of HCV-associated HCC

(ii) Molecular virology of lymphotropic HCV in viral persistence and pathogenesis

(iii) Cancer biology in liver oncogenesis generated from tumor-initiating cells (TICs: “bad seeds” of treatment-resistant HCC) induced by interactions between environmental factors (alcohol, obesity) and HCV.

Our lab’s long-term goal is to test new therapeutic modalities for HCC in HCV-infected patients with alcoholism and/or obesity.

Our experience and resources on TICs have provided a unique opportunity to functionally dissect the alcohol-mediated self-renewal of liver TICs via TLR4 signaling. The p53 tumor suppressor acts as a barrier against stem cell proliferation, and inactivation of p53, or its stabilizing partner NUMB (cell fate decision molecule), leads to expansion of TICs. Although treatment efficacy of HCV has been dramatically improved in recent years, the incidence of HCV-associated HCC keeps rising due to the prevalence of obesity, alcoholism and illicit drug usage in HCV patients. Thus, we will continue our research on the development of new therapeutic modalities for HCC.

Awards

  • American Cancer Society (ACS) : Research Scholar, 2011-2016
  • Liver Meeting of AASLD: Presidential Poster of Distinction, 2008
  • Research Center for Liver Diseases : USC Research Center for Liver Diseases Pilot Funding Award, 2007-2007
  • Asian Pacific Association for the Study of the Liver (APASL): Young Investigator Award, 2007
  • Japan Society for the Promotion of Science: Scholarship, 1998-2001

Publications

  • NOTCH localizes to mitochondria through the TBC1D15-FIS1 interaction and is stabilized via blockade of E3 ligase and CDK8 recruitment to reprogram tumor-initiating cells Exp Mol Med. 2024 Feb; 56(2):461-477. . View in PubMed
  • Protocol for generation of humanized HCC mouse model and cancer-driver mutations using CRISPR-Cas9 STAR Protoc. 2023 Dec 15; 4(4):102389. . View in PubMed
  • Polycomb repressive complex 2 binds and stabilizes NANOG to suppress differentiation-related genes to promote self-renewal iScience. 2023 Jul 21; 26(7):107035. . View in PubMed
  • MSI2 promotes translation of multiple IRES-containing oncogenes and virus to induce self-renewal of tumor initiating stem-like cells Cell Death Discov. 2023 Apr 28; 9(1):141. . View in PubMed
  • LIN28 and histone H3K4 methylase induce TLR4 to generate tumor-initiating stem-like cells iScience. 2023 Mar 17; 26(3):106254. . View in PubMed
  • Profiling of Circulating Tumor Cells for Screening of Selective Inhibitors of Tumor-Initiating Stem-Like Cells Adv Sci (Weinh). 2023 05; 10(14):e2206812. . View in PubMed
  • ß-CATENIN stabilizes HIF2 through lncRNA and inhibits intravenous immunoglobulin immunotherapy Front Immunol. 2023; 14:1204907. . View in PubMed
  • Gut-derived Endotoxin-TLR4 Signaling Drives MYC-Ig Translocation to Promote Lymphoproliferation through c-JUN and STAT3 Activation Mol Cancer Res. 2023 02 01; 21(2):155-169. . View in PubMed
  • Hepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 – ß-catenin cascade to promote liver tumorigenesis Nat Commun. 2023 05 08; 14(1):2651. . View in PubMed
  • GRP78 Inhibitor YUM70 Suppresses SARS-CoV-2 Viral Entry, Spike Protein Production and Ameliorates Lung Damage Viruses. 2023 05 06; 15(5). . View in PubMed
  • The stress-inducible ER chaperone GRP78/BiP is upregulated during SARS-CoV-2 infection and acts as a pro-viral protein Nat Commun. 2022 Nov 14; 13(1):6551. . View in PubMed
  • c-JUN inhibits mTORC2 and glucose uptake to promote self-renewal and obesity iScience. 2022 Jun 17; 25(6):104325. . View in PubMed
  • Immunotherapy and Microbiota for Targeting of Liver Tumor-Initiating Stem-like Cells Cancers (Basel). 2022 May 12; 14(10). . View in PubMed
  • Activated and nonactivated MSCs increase survival in humanized mice after acute liver injury through alcohol binging Hepatol Commun. 2022 07; 6(7):1549-1560. . View in PubMed
  • A review of alcohol-pathogen interactions: New insights into combined disease pathomechanisms Alcohol Clin Exp Res. 2022 03; 46(3):359-370. . View in PubMed
  • State of the art treatment of hepatitis B virus hepatocellular carcinoma and the role of hepatitis B surface antigen post-liver transplantation and resection Liver Int. 2022 02; 42(2):288-298. . View in PubMed
  • DNMT and EZH2 inhibitors synergize to activate therapeutic targets in hepatocellular carcinoma Cancer Lett. 2022 11 01; 548:215899. . View in PubMed
  • HCV and tumor-initiating stem-like cells Front Physiol. 2022; 13:903302. . View in PubMed
  • The chaperone GRP78 is a host auxiliary factor for SARS-CoV-2 and GRP78 depleting antibody blocks viral entry and infection J Biol Chem. 2021 Jan-Jun; 296:100759. . View in PubMed
  • Cell fate, metabolic reprogramming and lncRNA of tumor-initiating stem-like cells induced by alcohol Chem Biol Interact. 2020 May 25; 323:109055. . View in PubMed
  • p53 destabilizing protein skews asymmetric division and enhances NOTCH activation to direct self-renewal of TICs Nat Commun. 2020 06 17; 11(1):3084. . View in PubMed
  • Transcriptional regulation of autophagy-lysosomal function in BRAF-driven melanoma progression and chemoresistance Nat Commun. 2019 04 12; 10(1):1693. . View in PubMed
  • Regulation of Hepatitis C Virus Infection by Cellular Retinoic Acid Binding Proteins through the Modulation of Lipid Droplet Abundance J Virol. 2019 04 15; 93(8). . View in PubMed
  • Pluripotency Transcription Factors and Metabolic Reprogramming of Mitochondria in Tumor-Initiating Stem-like Cells Antioxid Redox Signal. 2018 Apr 10; 28(11):1080-1089. . View in PubMed
  • The 2-oxoglutarate carrier promotes liver cancer by sustaining mitochondrial GSH despite cholesterol loading Redox Biol. 2018 04; 14:164-177. . View in PubMed
  • NANOG-Dependent Metabolic Reprogramming and Symmetric Division in Tumor-Initiating Stem-like Cells Adv Exp Med Biol. 2018; 1032:105-113. . View in PubMed
  • Mitophagy Controls the Activities of Tumor Suppressor p53 to Regulate Hepatic Cancer Stem CellsMol Cell. 2017 Oct 19; 68(2):281-292. e5. . View in PubMed
  • Existence of cancer stem cells in hepatocellular carcinoma: myth or reality? Hepatol Int. 2017 Mar; 11(2):143-147.. View in PubMed
  • Loss of the transforming growth factor-ß effector ß2-Spectrin promotes genomic instability Hepatology. 2017 02; 65(2):678-693. . View in PubMed
  • Wnt/ß-catenin activation and macrophage induction during liver cancer development following steatosis Oncogene. 2017 10 26; 36(43):6020-6029. . View in PubMed
  • Hepatitis C virus has a genetically determined lymphotropism through co-receptor B72. Nat Commun. 2017 01 09; 8:13882. . View in PubMed
  • TLR4 Signaling via NANOG Cooperates With STAT3 to Activate Twist1 and Promote Formation of Tumor-Initiating Stem-Like Cells in Livers of Mice Gastroenterology. 2016 Mar; 150(3):707-19. . View in PubMed
  • TGF-ß/ß2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome J Clin Invest. 2016 Feb; 126(2):527-42. . View in PubMed
  • NANOG Metabolically Reprograms Tumor-Initiating Stem-like Cells through Tumorigenic Changes in Oxidative Phosphorylation and Fatty Acid Metabolism Cell Metab. 2016 Jan 12; 23(1):206-19. . View in PubMed
  • NUMB phosphorylation destabilizes p53 and promotes self-renewal of tumor-initiating cells by a NANOG-dependent mechanism in liver cancer Hepatology. 2015 Nov; 62(5):1466-79. . View in PubMed
  • Iterative tyrosine phosphorylation controls non-canonical domain utilization in Crk Oncogene. 2015 Aug 06; 34(32):4260-9. . View in PubMed
  • Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers Nat Commun. 2015 Aug 03; 6:7839. . View in PubMed
  • Smad7 regulates compensatory hepatocyte proliferation in damaged mouse liver and positively relates to better clinical outcome in human hepatocellular carcinoma Clin Sci (Lond). 2015 Jun; 128(11):761-74. . View in PubMed
  • Phosphorylation of Dok1 by Abl family kinases inhibits CrkI transforming activity Oncogene. 2015 May 14; 34(20):2650-9. . View in PubMed
  • Osteopontin deficiency does not prevent but promotes alcoholic neutrophilic hepatitis in mice Hepatology. 2015 Jan; 61(1):129-40. . View in PubMed
  • TLR4-dependent tumor-initiating stem cell-like cells (TICs) in alcohol-associated hepatocellular carcinogenesis Adv Exp Med Biol. 2015; 815:131-44. . View in PubMed
  • Alcohol, TLR4-TGF-ß antagonism, and liver cancer Hepatol Int. 2014 Sep; 8 Suppl 2:408-12. . View in PubMed
  • Oncogenic signaling pathways and origins of tumor-initiating stem-like cells of hepatocellular carcinomas induced by hepatitis C virus, alcohol and/or obesity Hepatol Int. 2014 Jul; 8(3):330-8. . View in PubMed
  • Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-induced acute liver failure FEBS Open Bio. 2014; 4:777-87. . View in PubMed
  • HCV infection enhances Th17 commitment, which could affect the pathogenesis of autoimmune diseases PLoS One. 2014; 9(6):e98521. . View in PubMed
  • Reciprocal regulation by TLR4 and TGF-ß in tumor-initiating stem-like cells J Clin Invest. 2013 Jul; 123(7):2832-49. . View in PubMed
  • Tumor-initiating stem-like cells and drug resistance: carcinogenesis through Toll-like receptors, environmental factors, and virus Drug Deliv Transl Res. 2013 Apr; 3(2):152-64. . View in PubMed
  • PPARs and Liver Disease PPAR Res. 2013; 2013:896412. . View in PubMed
  • The TBC1D15 oncoprotein controls stem cell self-renewal through destabilization of the Numb-p53 complex PLoS One. 2013; 8(2):e57312. . View in PubMed
  • Transient activation of the PI3K-AKT pathway by hepatitis C virus to enhance viral entry J Biol Chem. 2012 Dec 07; 287(50):41922-30. . View in PubMed
  • Mitochondrial GSH determines the toxic or therapeutic potential of superoxide scavenging in steatohepatitis J Hepatol. 2012 Oct; 57(4):852-9. . View in PubMed
  • Replication of hepatitis C virus RNA on autophagosomal membranes J Biol Chem. 2012 May 25; 287(22):18036-43. . View in PubMed
  • Mouse intragastric infusion (iG) model Nat Protoc. 2012 Mar 29; 7(4):771-81. . View in PubMed
  • Cancer stem cells generated by alcohol, diabetes, and hepatitis C virus J Gastroenterol Hepatol. 2012 Mar; 27 Suppl 2:19-22. . View in PubMed
  • Morphogens and hepatic stellate cell fate regulation in chronic liver disease J Gastroenterol Hepatol. 2012 Mar; 27 Suppl 2:94-8. . View in PubMed
  • Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells Proc Natl Acad Sci U S A. 2012 Jan 17; 109(3):829-34. . View in PubMed
  • A super TLR agonist to improve efficacy of dendritic cell vaccine in induction of anti-HCV immunity PLoS One. 2012; 7(11):e48614. . View in PubMed
  • Hepatitis C virus translation preferentially depends on active RNA replication PLoS One. 2012; 7(8):e43600. . View in PubMed
  • Phosphorylation of Crk on tyrosine 251 in the RT loop of the SH3C domain promotes Abl kinase transactivation Oncogene. 2011 Nov 17; 30(46):4645-55. . View in PubMed
  • Inhibition of RIG-I-mediated signaling by Kaposi’s sarcoma-associated herpesvirus-encoded deubiquitinase ORF64 J Virol. 2011 Oct; 85(20):10899-904. . View in PubMed
  • Lymphotropic HCV strain can infect human primary naïve CD4+ cells and affect their proliferation and IFN-? secretion activity. J Gastroenterol. 2011 Feb; 46(2):232-41.. View in PubMed
  • Alcohol induces RNA polymerase III-dependent transcription through c-Jun by co-regulating TATA-binding protein (TBP) and Brf1 expression J Biol Chem. 2011 Jan 28; 286(4):2393-401. . View in PubMed
  • Hepatitis C virus-related lymphomagenesis in a mouse model ISRN Hematol. 2011; 2011:167501. . View in PubMed
  • Proteins that bind the Src homology 3 domain of CrkI have distinct roles in Crk transformation Oncogene. 2010 Dec 02; 29(48):6378-89. . View in PubMed
  • Hepatitis C virus inhibits DNA damage repair through reactive oxygen and nitrogen species and by interfering with the ATM-NBS1/Mre11/Rad50 DNA repair pathway in monocytes and hepatocytes J Immunol. 2010 Dec 01; 185(11):6985-98. . View in PubMed
  • Ethanol-induced HO-1 and NQO1 are differentially regulated by HIF-1alpha and Nrf2 to attenuate inflammatory cytokine expression J Biol Chem. 2010 Nov 12; 285(46):35359-73. . View in PubMed
  • Hepatitis C virus egress and release depend on endosomal trafficking of core protein J Virol. 2010 Nov; 84(21):11590-8. . View in PubMed
  • Alcohol and hepatitis C virus–interactions in immune dysfunctions and liver damage Alcohol Clin Exp Res. 2010 Oct; 34(10):1675-86. . View in PubMed
  • c-Jun mediates hepatitis C virus hepatocarcinogenesis through signal transducer and activator of transcription 3 and nitric oxide-dependent impairment of oxidative DNA repair Hepatology. 2010 Aug; 52(2):480-92. . View in PubMed
  • Polo-like kinase 1 is involved in hepatitis C virus replication by hyperphosphorylating NS5A J Virol. 2010 Aug; 84(16):7983-93. . View in PubMed
  • TLRs, Alcohol, HCV, and Tumorigenesis Gastroenterol Res Pract. 2010; 2010:518674. . View in PubMed
  • Toll-like receptor signaling in liver diseases Gastroenterol Res Pract. 2010; 2010:971270. . View in PubMed
  • Hepatitis C virus causes uncoupling of mitotic checkpoint and chromosomal polyploidy through the Rb pathway J Virol. 2009 Dec; 83(23):12590-600. . View in PubMed
  • Ethanol augments RANTES/CCL5 expression in rat liver sinusoidal endothelial cells and human endothelial cells via activation of NF-kappa B, HIF-1 alpha, and AP-1 J Immunol. 2009 Nov 01; 183(9):5964-76. . View in PubMed
  • Hepatitis C virus and disrupted interferon signaling promote lymphoproliferation via type II CD95 and interleukinsGastroenterology. 2009 Jul; 137(1):285-96296. e1-11. . View in PubMed
  • “Second hit” models of alcoholic liver disease Semin Liver Dis. 2009 May; 29(2):178-87. . View in PubMed
  • SYNCRIP (synaptotagmin-binding, cytoplasmic RNA-interacting protein) is a host factor involved in hepatitis C virus RNA replication Virology. 2009 Apr 10; 386(2):249-56. . View in PubMed
  • Hepatitis C virus infection of T cells inhibits proliferation and enhances fas-mediated apoptosis by down-regulating the expression of CD44 splicing variant 6 J Infect Dis. 2009 Mar 01; 199(5):726-36. . View in PubMed
  • Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog Proc Natl Acad Sci U S A. 2009 Feb 03; 106(5):1548-53. . View in PubMed
  • Association of hepatitis C virus replication complexes with microtubules and actin filaments is dependent on the interaction of NS3 and NS5A J Virol. 2008 Sep; 82(17):8838-48. . View in PubMed
  • Hepatitis C virus (HCV)-induced immunoglobulin hypermutation reduces the affinity and neutralizing activities of antibodies against HCV envelope protein J Virol. 2008 Jul; 82(13):6711-20. . View in PubMed
  • Hepatitis C virus NS3/4A protein interacts with ATM, impairs DNA repair and enhances sensitivity to ionizing radiation Virology. 2008 Jan 20; 370(2):295-309. . View in PubMed
  • Bulk electronic structure of the antiferromagnetic superconducting phase in ErNi2B2C Phys Rev Lett. 2008 Jan 11; 100(1):017003. . View in PubMed
  • Therapeutic control of hepatitis C virus: the role of neutralizing monoclonal antibodies Curr Top Microbiol Immunol. 2008; 317:1-38. . View in PubMed
  • Hepatitis C virus infects T cells and affects interferon-gamma signaling in T cell lines Virology. 2007 Apr 25; 361(1):161-73. . View in PubMed
  • HCV core expression in hepatocytes protects against autoimmune liver injury and promotes liver regeneration in mice Hepatology. 2006 Oct; 44(4):936-44. . View in PubMed
  • Hepatitis C virus triggers mitochondrial permeability transition with production of reactive oxygen species, leading to DNA damage and STAT3 activation J Virol. 2006 Jul; 80(14):7199-207. . View in PubMed
  • Hepatitis C virus induces toll-like receptor 4 expression, leading to enhanced production of beta interferon and interleukin-6 J Virol. 2006 Jan; 80(2):866-74. . View in PubMed
  • Hepatitis C virus E2-CD81 interaction induces hypermutation of the immunoglobulin gene in B cells J Virol. 2005 Jul; 79(13):8079-89. . View in PubMed
  • Hepatitis C virus infection activates the immunologic (type II) isoform of nitric oxide synthase and thereby enhances DNA damage and mutations of cellular genes J Virol. 2004 Aug; 78(16):8835-43. . View in PubMed
  • Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes Proc Natl Acad Sci U S A. 2004 Mar 23; 101(12):4262-7. . View in PubMed
  • Cynomolgus monkey did not hyperacutely reject skin xenograft of N-acetylglucosaminyltransferase III gene transgenic pig Transplant Proc. 2003 Feb; 35(1):518. . View in PubMed
  • Secoiridoid glycosides from Gentiana scabra J Nat Prod. 2001 Dec; 64(12):1574-5. . View in PubMed
  • Intranephron localization and regulation of the V1a vasopressin receptor during chronic metabolic acidosis and dehydration in rats Pflugers Arch. 2001 Aug; 442(5):652-61. . View in PubMed
  • Studies on the constituents of Catalpa speciesVI. Monoterpene glycosides from the fallen leaves of Catalpa ovata G. Don. Chem Pharm Bull (Tokyo). 2001 Jun; 49(6):732-6. . View in PubMed
  • Hyaluronan activates cell motility of v-Src-transformed cells via Ras-mitogen-activated protein kinase and phosphoinositide 3-kinase-Akt in a tumor-specific manner Mol Biol Cell. 2001 Jun; 12(6):1859-68. . View in PubMed
  • New sterols and triterpenoids from four edible mushrooms Chem Pharm Bull (Tokyo). 2001 May; 49(5):589-94. . View in PubMed
  • Inhibition of cytochrome c release in Fas-mediated signaling pathway in transgenic mice induced to express hepatitis C viral proteins J Biol Chem. 2001 Apr 13; 276(15):12140-6. . View in PubMed
  • Secoiridoid glycosides from the flower buds of Lonicera japonica Phytochemistry. 2000 Dec; 55(8):879-81. . View in PubMed
  • Structures of new ceramides from the fruit bodies of Grifola frondosa Chem Pharm Bull (Tokyo). 2000 Sep; 48(9):1356-8. . View in PubMed
  • Protective effects of alpha-tocopherol and beta-carotene on para-nonylphenol-induced inhibition of cell growth, cellular respiration and glucose-induced proton extrusion of bacteria FEMS Microbiol Lett. 2000 Jun 15; 187(2):161-5. . View in PubMed
  • Studies of the constituents of Gardenia speciesII. Terpenoids from Gardeniae Fructus. Chem Pharm Bull (Tokyo). 2000 May; 48(5):746-8. . View in PubMed
  • Protective effect of antioxidants against para-nonylphenol-induced inhibition of cell growth in Saccharomyces cerevisiae FEMS Microbiol Lett. 2000 Apr 01; 185(1):65-70. . View in PubMed
  • v-Src suppresses SHPS-1 expression via the Ras-MAP kinase pathway to promote the oncogenic growth of cells Oncogene. 2000 Mar 23; 19(13):1710-8. . View in PubMed
  • Clustered cysteine residues in the kinase domain of v-Src: critical role for protein stability, cell transformation and sensitivity to herbimycin A Oncogene. 2000 Jan 13; 19(2):273-9. . View in PubMed
  • Farnesol-induced generation of reactive oxygen species dependent on mitochondrial transmembrane potential hyperpolarization mediated by F(0)F(1)-ATPase in yeast FEBS Lett. 1999 Nov 26; 462(1-2):108-12. . View in PubMed
  • Ras pathway is required for the activation of MMP-2 secretion and for the invasion of src-transformed 3Y1 Oncogene. 1999 Nov 11; 18(47):6555-63. . View in PubMed
  • Lung cancer in patients who had received thoracoplasty for pulmonary tuberculosis Jpn J Clin Oncol. 1999 Nov; 29(11):541-5. . View in PubMed
  • UK-2A, B, C and D, novel antifungal antibiotics from Streptomyces sp517-02. IV. Comparative studies of UK-2A with antimycin A3 on cytotoxic activity and reactive oxygen species generation in LLC-PK1 cells. J Antibiot (Tokyo). 1999 May; 52(5):480-4. . View in PubMed
  • Hyaluronan activates mitogen-activated protein kinase via Ras-signaling pathway Int J Oncol. 1999 Apr; 14(4):733-8. . View in PubMed
  • Farnesol-induced generation of reactive oxygen species via indirect inhibition of the mitochondrial electron transport chain in the yeast Saccharomyces cerevisiae J Bacteriol. 1998 Sep; 180(17):4460-5. . View in PubMed
  • Isolation of RNA aptamers specific to the NS3 protein of hepatitis C virus from a pool of completely random RNA Virology. 1997 Oct 27; 237(2):270-82. . View in PubMed
  • [Diagnostic accuracy of 201T1 SPECTMRI in brain diseases and inter-reader variance of diagnostic performance]. Kaku Igaku. 1996 Sep; 33(9):943-52. . View in PubMed
  • Dietary analysis of Japanese patients with chronic pancreatitis in stable conditions J Gastroenterol. 1994 Dec; 29(6):756-62. . View in PubMed
  • Seasonal development of Leptotrombidium pallidum (Acari: Trombiculidae) observed by experimental rearing in the natural environment J Med Entomol. 1993 Mar; 30(2):320-5. . View in PubMed
  • Molecular analysis of genetic mutation in electrophoretic variant of human lactate dehydrogenase-A(M) subunit Biochem Int. 1992 Sep; 27(6):1051-7. . View in PubMed
  • Aggregated distribution of infective spots composed of Leptotrombidium pallidum, highly prevalent with Rickettsia tsutsugamushi, demonstrated by sentinel voles, Microtus montebelli, on the ground Jpn J Exp Med. 1990 Dec; 60(6):325-35. . View in PubMed
  • A missense mutation found in human lactate dehydrogenase-B (H) variant gene Biochem Biophys Res Commun. 1990 Apr 30; 168(2):672-6. . View in PubMed