Keck School Faculty

Keigo Machida, PhD
Keigo Machida, PhD
Associate Professor of Molecular Microbiology & Immunology
Molecular Microbiology and Immunology
HMR 503C 2011 Zonal Avenue Health Sciences Campus Los Angeles
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.

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

Regulation of HCV infection by Cellular Retinoic Acid Binding Proteins through the modulation of lipid droplet abundance J Virol. 2019 Feb 06. . View in PubMed

The 2-oxoglutarate carrier promotes liver cancer by sustaining mitochondrial GSH despite cholesterol loading Redox Biol. 2018 Apr; 14:164-177. . 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

Pluripotency transcription factors and Metabolic reprogramming of mitochondria in tumor-initiating stem-like cells Antioxid Redox Signal. 2017 Dec 19. . 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 Feb; 65(2):678-693. . View in PubMed

Hepatitis C virus has a genetically determined lymphotropism through co-receptor B72. Nat Commun. 2017 Jan 09; 8:13882. . 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

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

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

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

Osteopontin deficiency does not prevent but promotes alcoholic neutrophilic hepatitis in mice Hepatology. 2015 Jan; 61(1):129-40. . 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

FEBS Open Bio. 2014; 4:777-87. . View in PubMed

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

The TBC1D15 oncoprotein controls stem cell self-renewal through destabilization of the Numb-p53 complex PLoS One. 2013; 8(2):e57312. . View in PubMed

PPARs and Liver Disease PPAR Res. 2013; 2013:896412. . 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

J Biol Chem. 2012 May 25; 287(22):18036-43. . View in PubMed

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

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

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

J Immunol. 2010 Dec 01; 185(11):6985-98. . View in PubMed

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

J Virol. 2010 Nov; 84(21):11590-8. . View in PubMed

J Virol. 2010 Nov; 84(21):11590-8. . View in PubMed

Alcohol Clin Exp Res. 2010 Oct; 34(10):1675-86. . View in PubMed

Alcohol Clin Exp Res. 2010 Oct; 34(10):1675-86. . View in PubMed

J Virol. 2010 Aug; 84(16):7983-93. . View in PubMed

Hepatology. 2010 Aug; 52(2):480-92. . View in PubMed

Hepatology. 2010 Aug; 52(2):480-92. . View in PubMed

J Virol. 2010 Aug; 84(16):7983-93. . View in PubMed

Gastroenterol Res Pract. 2010; 2010:971270. . View in PubMed

Gastroenterol Res Pract. 2010; 2010:518674. . View in PubMed

Gastroenterol Res Pract. 2010; 2010:971270. . View in PubMed

Gastroenterol Res Pract. 2010; 2010:518674. . 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

Gastroenterology. 2009 Jul; 137(1):285-96, 296. e1-11. . View in PubMed

Gastroenterology. 2009 Jul; 137(1):285-96, 296. e1-11. . View in PubMed

Semin Liver Dis. 2009 May; 29(2):178-87. . View in PubMed

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

Proc Natl Acad Sci U S A. 2009 Feb 03; 106(5):1548-53. . View in PubMed

Proc Natl Acad Sci U S A. 2009 Feb 03; 106(5):1548-53. . View in PubMed

J Virol. 2008 Sep; 82(17):8838-48. . View in PubMed

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

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

Hepatology. 2006 Oct; 44(4):936-44. . View in PubMed

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

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