Faculty

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Keigo Machida, PhD
Associate Professor of Molecular Microbiology & Immunology
Molecular Microbiology and Immunology
HMR 503A 2011 Zonal Avenue Health Sciences Campus Los Angeles
+1 323 442 2692

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

The 2-oxoglutarate carrier promotes liver cancer by sustaining mitochondrial GSH despite cholesterol loading. Redox Biol. 2017 Sep 14; 14:164-177. View in: PubMed

Wnt/ß-catenin activation and macrophage induction during liver cancer development following steatosis. Oncogene. 2017 Jul 03. View in: PubMed

Existence of cancer stem cells in hepatocellular carcinoma: myth or reality? Hepatol Int. 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 B7. 2. Nat Commun. 2017 Jan 09; 8:13882. View in: PubMed

Existence of cancer stem cells in hepatocellular carcinoma: myth or reality? Hepatol Int. Existence of cancer stem cells in hepatocellular carcinoma: myth or reality? Hepatol Int. 2016 Dec 18. 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

TGF-ß/ß2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome. J Clin Invest. 2016 Feb 1; 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

Iterative tyrosine phosphorylation controls non-canonical domain utilization in Crk. Oncogene. 2015 Aug 6; 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

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 1; 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

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

Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers. Nat Commun. 2015; 6:7839. 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

HCV infection enhances Th17 commitment, which could affect the pathogenesis of autoimmune diseases. PLoS One. 2014; 9(6):e98521. 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

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

Reciprocal regulation by TLR4 and TGF-ß in tumor-initiating stem-like cells. J Clin Invest. 2013 Jul 1; 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 7; 287(50):41922-30. 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 Apr; 7(4):771-81. 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

Hepatitis C virus translation preferentially depends on active RNA replication. PLoS One. 2012; 7(8):e43600. 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

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. 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

Proteins that bind the Src homology 3 domain of CrkI have distinct roles in Crk transformation. Oncogene. 2010 Dec 2; 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

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 1; 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

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

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

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

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 1; 183(9):5964-76. View in: PubMed

Hepatitis C virus and disrupted interferon signaling promote lymphoproliferation via type II CD95 and interleukins. Gastroenterology. 2009 Jul; 137(1):285-96, 296. 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 1; 199(5):726-36. 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

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 3; 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

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 species. VI. 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

Sterol constituents from two edible mushrooms, Lentinula edodes and Tricholoma matsutake. Chem Pharm Bull (Tokyo). 2000 May; 48(5):749-51. View in: PubMed

Studies of the constituents of Gardenia species. II. 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 1; 185(1):65-70. 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

Long-chain alkyl ester of AMP acts as an antagonist of glucose-induced signal transduction that mediates activation of plasma membrane proton pump in Saccharomyces cerevisiae. Microbiology. 2000 Feb; 146 ( Pt 2):377-84. 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

[Active pulmonary tuberculosis in patients with lung cancer]. Kekkaku. 1999 Nov; 74(11):797-802. View in: PubMed

UK-2A, B, C and D, novel antifungal antibiotics from Streptomyces sp. 517-02. 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

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 SPECT. MRI 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

[Double cancer in small cell lung cancer patients treated with intensive chemotherapy with or without radiation therapy]. Nihon Kyobu Shikkan Gakkai Zasshi. 1991 Nov; 29(11):1432-8. 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

Resistance to Rickettsia tsutsugamushi and persistence of infection in different wild rodents. Jpn J Exp Med. 1990 Aug; 60(4):241-5. 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

[Evaluation of image quality and lesion detectability on I-123 IMP brain SPECT]. Kaku Igaku. 1990 Apr; 27(4):323-32. View in: PubMed

[Prospective study to assess the clinical efficacy of bone scintigraphy--comparative study of the efficacy in breast carcinoma and prostate carcinoma]. Radioisotopes. 1988 Nov; 37(11):608-14. View in: PubMed

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[Prospective study to assess the clinical efficacy of bone scintigraphy--ROC analysis]. Radioisotopes. 1988 Mar; 37(3):148-54. View in: PubMed

Combination chemotherapy for small cell carcinoma of the lung: evaluation of four-drug combination of cyclophosphamide, vincristine, methotrexate, and procarbazine. Acta Med Okayama. 1983 Apr; 37(2):147-53. View in: PubMed

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