Skip to main content

Advertisement

SpringerLink
Log in

Correlation of hepatitis C virus-mediated endoplasmic reticulum stress with autophagic flux impairment and hepatocarcinogenesis

  • Original Paper
  • Published:
Medical Molecular Morphology Aims and scope Submit manuscript

Abstract

Hepatitis C virus (HCV) infection has been known to use autophagy for its replication. However, the mechanisms by which HCV modulates autophagy remain controversial. We used HCV-Japanese fulminant hepatitis-1-infected Huh7 cells. HCV infection induced the accumulation of autophagosomes. Morphological analyses of monomeric red fluorescent protein (mRFP)-green fluorescent protein (GFP) tandem fluorescent-tagged LC3 transfection showed HCV infection impaired autophagic flux. Autophagosome-lysosome fusion assessed by transfection of mRFP- or GFP-LC3 and immunostaining of lysosomal-associated membrane protein 1 was inhibited by HCV infection. Decrease of HCV-induced endoplasmic reticulum (ER) stress by 4-phenylbutyric acid, a chemical chaperone, improved the HCV-mediated autophagic flux impairment. HCV infection-induced oxidative stress and subsequently DNA damage, but not apoptosis. Furthermore, HCV induced cytoprotective effects against the cellular stress by facilitating the formation of cytoplasmic inclusion bodies as shown by p62 expression and by modulating keratin protein expression and activated nuclear factor erythroid 2-related factor 2. HCV eradication by direct-acting antivirals improved autophagic flux, but DNA damage persisted. In conclusion, HCV-induced ER stress correlates with autophagic flux impairment. Decrease of ER stress is considered to be a promising therapeutic strategy for HCV-related chronic liver diseases. However, we should be aware that the risk of hepatocarcinogenesis remains even after HCV eradication.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

HCV:

Hepatitis C virus

HCC:

Hepatocellular carcinoma

ER:

Endoplasmic reticulum

JFH1:

Japanese fulminant hepatitis-1

NS:

Nonstructural

IFN:

Interferon

DMEM:

Dulbecco’s modified Eagle’s medium

4PBA:

4-Phenylbutyric acid

3MA:

3-Methyladenine

SOF:

Sofosbuvir

DCV:

Daclatasvir

DMSO:

Dimethyl sulfoxide

K:

Keratin

CHOP:

C/EBP homologous protein

XBP1:

X-box binding protein 1

SREBP1c:

Sterol regulatory element binding protein 1c

Nrf2:

Nuclear factor erythroid 2-related factor 2

HNE:

Hydroxyl-2-nonenal

γ-H2AX:

Gamma-H2AX

53BP1:

p53-binding protein 1

Atg:

Autophagy-related gene

SOD1:

Superoxide dismutase 1

eIF2α:

Eukaryotic initiation factor 2α

JNK:

c-Jun N-terminal kinase

CREB:

cAMP response element-binding protein

PARP:

Poly-ADP-ribose-polymerase

LC3:

Microtubule-associated protein light chain 3

Keap1:

Kelch-like ECH-associated protein 1

HO-1:

Heme oxygenase-1

Rubicon:

RUN domain and cysteine-rich domain containing, Beclin1-interacting protein

Lamp1:

Lysosomal-associated membrane protein 1

PFA:

Paraformaldehyde

PBS:

Phosphate-buffered saline

PI:

Propidium iodide

mRFP:

Monomeric red fluorescent protein

GFP:

Green fluorescent protein

tf-LC3:

Tandem fluorescent-tagged LC3

ROS:

Reactive oxygen species

H2DCFDA:

2′, 7′-Dichlorodihydrofluorescein diacetate

MDB:

Mallory-Denk body

DAAs:

Direct-acting antivirals

PI3K:

Phosphoinositide 3-kinase

References

  1. Moradpour D, Penin F, Rice CM (2007) Replication of hepatitis C virus. Nat Rev Microbiol 5:453–463

    Article  CAS  PubMed  Google Scholar 

  2. Lok AS, Seeff LB, Morgan TR, di isceqlie AM, Sterling RK, Curto TM, Everson GT, Lindsay KL, Lee WM, Bonkovsky HL, Dienstag JL, Ghany MG, Morishima C, Goodman ZD; HALT-C Trial Group (2009) Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology 136:138-148

  3. Mizushima N, Yoshimori T (2007) How to interpret LC3 immunoblotting. Autophagy 3:542–545

    Article  CAS  PubMed  Google Scholar 

  4. Kaizuka T, Morishita H, Hama Y, Tsukamoto S, Matsui T, Toyota Y, Kodama A, Ishihara T, Mizushima T, Mizushima N (2016) An autophagic flux probe that releases an internal control. Mol Cell 64:835–849

    Article  CAS  PubMed  Google Scholar 

  5. Sir D, Kuo CF, Tian Y, Liu HM, Huang EJ, Jung JU, Machida K, Ou JH (2012) Replication of hepatitis C virus RNA on autophagosomal membranes. J Biol Chem 287:18036–18043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fahmy AM, Labonté P (2017) The autophagy elongation complex (ATG5-12/16L1) positively regulates HCV replication and is required for wild-type membranous web formation. Sci Rep 7:40351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, Murthy K, Habermann A, Kräusslich HG, Mizokami M, Bartenschlager R, Liang TJ (2005) Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 11:791–796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhong J, Gastaminza P, Cheng G, Kapadia S, Kato T, Burton DR, Wieland SF, Uprichard SL, Wakita T, Chisari FV (2005) Robust hepatitis C virus infection in vitro. Proc Natl Acad Sci USA 102:9294–9299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hara Y, Yanatori I, Ikeda M, Kiyokage E, Nishina S, Toida K, Kishi F, Kato N, Imamura M, Chayama K, Hino K (2014) Hepatitis C virus core protein suppresses mitophagy by interacting with parkin in the context of mitochondrial depolarization. Am J Pathol 184:3026–3039

    Article  CAS  PubMed  Google Scholar 

  10. Kato N, Mori K, Abe K, Dansako H, Kuroki M, Ariumi Y, Wakita T, Ikeda M (2009) Efficient replication systems for hepatitis C virus using a new human hepatoma cell line. Virus Res 146:41–50

    Article  CAS  PubMed  Google Scholar 

  11. Dansako H, Hiramoto H, Ikeda M, Wakita T, Kato N (2014) Rab18 is required for viral assembly of hepatitis C virus through trafficking of the core protein to lipid droplets. Virology 462–463:166–174

    Article  PubMed  CAS  Google Scholar 

  12. Miyagawa K, Oe S, Honma Y, Izumi H, Baba R, Harada M (2016) Lipid-induced endoplasmic reticulum stress impairs selective autophagy at the step of autophagosome-lysosome fusion in hepatocytes. Am J Pathol 186:1861–1873

    Article  CAS  PubMed  Google Scholar 

  13. Mizushima N, Yoshimori T, Levine B (2010) Methods in mammalian autophagy research. Cell 140:313–326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yoshimori T, Yamamoto A, Moriyama Y, Futai M, Tashiro Y (1991) Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells. J Biol Chem 266:17707–17712

    Article  CAS  PubMed  Google Scholar 

  15. Harada M, Sakisaka S, Yoshitake M, Kin M, Ohishi M, Shakado S, Mimura Y, Noguchi K, Sata M, Tanikawa K (1996) Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPases, inhibits the receptor-mediated endocytosis of asialoglycoproteins in isolated rat hepatocytes. J Hepatol 24:594–603

    Article  CAS  PubMed  Google Scholar 

  16. Eskelinen EL, Tanaka Y, Saftig P (2003) At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol 13:137–145

    Article  CAS  PubMed  Google Scholar 

  17. Hanada S, Harada M, Kumemura H, Bishr Omary M, Koga H, Kawaguchi T, Taniguchi E, Yoshida T, Hisamoto T, Yanagimoto C, Maeyama M, Ueno T, Sata M (2007) Oxidative stress induces the endoplasmic reticulum stress and facilitates inclusion formation in cultured cells. J Hepatol 47:93–102

    Article  CAS  PubMed  Google Scholar 

  18. Sir D, Chen WL, Choi J, Wakita T, Yen TS, Ou JH (2008) Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response. Hepatology 48:1054–1061

    Article  CAS  PubMed  Google Scholar 

  19. Kim JY, Wang L, Lee J, Ou JJ (2017) Hepatitis C virus induces the localization of lipid rafts to autophagosomes for its RNA replication. J Virol 91:e00541-e617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chusri P, Kumthip K, Hong J, Zhu C, Duan X, Jilg N, Fusco DN, Brisac C, Schaefer EA, Cai D, Peng LF, Maneekarn N, Lin W, Chung RT (2016) HCV induces transforming growth factor β1 through activation of endoplasmic reticulum stress and the unfolded protein response. Sci Rep 6:22487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Taguwa S, Kambara H, Fujita N, Noda T, Yoshimori T, Koike K, Moriishi K, Matsuura Y (2011) Dysfunction of autophagy participates in vacuole formation and cell death in cells replicating hepatitis C virus. J Virol 85:13185–13194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yamamoto A, Tagawa Y, Yoshimori T, Moriyama Y, Masaki R, Tashiro Y (1998) Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct Funct 23:33–42

    Article  CAS  PubMed  Google Scholar 

  23. Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, Maejima I, Shirahama-Noda K, Ichimura T, Isobe T, Akira S, Noda T, Yoshimori T (2009) Two Beclin 1-binding proteins, Atg 14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 11:385–396

    Article  CAS  PubMed  Google Scholar 

  24. Wang L, Tian Y, Ou JH (2015) HCV induces the expression of Rubicon and UVRAG to temporally regulate the maturation of autophagosomes and viral replication. PLoS Pathog 11:e1004764

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Itakura E, Kishi C, Inoue K, Mizushima N (2008) Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 19:5360–5372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shrivastava S, Bhanja Chowdhury J, Steele R, Ray R, Ray RB (2012) Hepatitis C virus upregulates Beclin1 for induction of autophagy and activates mTOR signaling. J Virol 86:8705–9712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Guévin C, Manna D, Bélanger C, Konan KV, Mak P, Labonté P (2010) Autophagy protein ATG5 interacts transiently with the hepatitis C virus RNA polymerase (NS5B) early during infection. Virology 405:1–7

    Article  PubMed  CAS  Google Scholar 

  28. Su WC, Chao TC, Huang YL, Weng SC, Jeng KS, Lai MM (2011) Rab5 and class III phosphoinositide 3-kinase Vps34 are involved in hepatitis C virus NS4B-induced autophagy. J Virol 85:10561–10571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kimura S, Noda T, Yoshimori T (2007) Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy 3:452–460

    Article  CAS  PubMed  Google Scholar 

  30. Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y, Peng J, Mi N, Zhao Y, Liu Z, Wan F, Hailey DW, Oorschot V, Klumperman J, Baehrecke EH, Lenardo MJ (2010) Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465:942–946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mauthe M, Orhon I, Rocchi C, Zhou X, Luhr M, Hijlkema KJ, Coppes RP, Engedal N, Mari M, Reggiori F (2018) Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy 14:1435–1455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Seglen PO, Gordon PB (1982) 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Natl Acad Sci USA 79:1889–1892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tsutsumi T, Matsuda M, Aizaki H, Moriya K, Miyoshi H, Fujie H, Shintani Y, Yotsuyanagi H, Miyamura T, Suzuki T, Koike K (2009) Proteomics analysis of mitochondrial proteins reveals overexpression of a mitochondrial protein chaperon, prohibitin, in cells expressing hepatitis C virus core protein. Hepatology 50:378–386

    Article  CAS  PubMed  Google Scholar 

  34. Negro F, Sanyal AJ (2009) Hepatitis C virus, steatosis and lipid abnormalities: clinical and pathogenic data. Liver Int 29(Suppl 2):26–37

    Article  CAS  PubMed  Google Scholar 

  35. Lerat H, Kammoun HL, Hainault I, Mérour E, Higgs MR, Callens C, Lemon SM, Foufelle F, Pawlotsky JM (2009) Hepatitis C virus proteins induce lipogenesis and defective triglyceride secretion in transgenic mice. J Biol Chem 284:33466–33474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ (2009) Autophagy regulates lipid metabolism. Nature 458:1131–1135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Vescovo T, Romagnoli A, Perdomo AB, Corazzari M, Ciccosanti F, Alonzi T, Nardacci R, Ippolito G, Tripodi M, Garcia-Monzon C, Lo Iacono O, Piacentini M, Fimia GM (2012) Autophagy protects cells from HCV-induced defects in lipid metabolism. Gastroenterology 142:644–653

    Article  CAS  PubMed  Google Scholar 

  38. Rakoski MO, Brown MB, Fontana RJ, Bonkovsky HL, Brunt EM, Goodman ZD, Lok AS, Omary MB; HALT-C Trial Group (2011) Mallory-Denk bodies are associated with outcomes and histologic features in patients with chronic hepatitis C. Clin Gastroenterol Hepatol 9:902–909

    Article  Google Scholar 

  39. Honma Y, Sato-Morita M, Katsuki Y, Mihara H, Baba R, Harada M (2018) Trehalose activates autophagy and decreases proteasome inhibitor-induced endoplasmic reticulum stress and oxidative stress-mediated cytotoxicity in hepatocytes. Hepatol Res 48:94–105

    Article  CAS  PubMed  Google Scholar 

  40. Zatloukal K, French SW, Stumptner C, Strnad P, Harada M, Toivola DM, Cadrin M, Omary MB (2007) From Mallory to Mallory-Denk bodies: what, how and why? Exp Cell Res 313:2033–2049

    Article  CAS  PubMed  Google Scholar 

  41. Harada M, Strnad P, Resurreccion EZ, Ku NO, Omary MB (2007) Keratin 18 overexpression but not phosphorylation or filament organization blocks mouse Mallory body formation. Hepatology 45:88–96

    Article  CAS  PubMed  Google Scholar 

  42. Kwan R, Hanada S, Harada M, Sternad P, Li DH, Omary MB (2012) Keratin 8 phosphorylation regulates its transamidation and hepatocyte Mallory-Denk body formation. FASEB J 26:2318–2326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ku NO, Sternad P, Zhong BH, Tao GZ, Omary MB (2007) Keratins let liver live: Mutations predispose to liver disease and crosslinking generates Mallory-Denk bodies. Hepatology 46:1639–1649

    Article  CAS  PubMed  Google Scholar 

  44. Kamegaya Y, Hiasa Y, Zukerberg L, Fowler N, Blackard JT, Lin W, Choe WH, Schmidt EV, Chung RT (2005) Hepatitis C virus acts as a tumor accelerator by blocking apoptosis in a mouse model of hepatocarcinogenesis. Hepatology 41:660–667

    Article  PubMed  Google Scholar 

  45. Harada M, Hanada S, Toivola DM, Ghori N, Omary MB (2008) Autophagy activation by rapamycin eliminates mouse Mallory-Denk bodies and blocks their proteasome inhibitor-mediated formation. Hepatology 47:2026–2035

    Article  CAS  PubMed  Google Scholar 

  46. Kageyama S, Sou YS, Uemura T, Kametaka S, Saito T, Ishimura R, Kouno T, Bedford L, Mayer RJ, Lee MS, Yamamoto M, Waguri S, Tanaka K, Komatsu M (2014) Proteasome dysfunction activates autophagy and the Keap1-Nrf2 pathway. J Biol Chem 289:24944–24955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jeong SW, Jang JY, Chung RT (2012) Hepatitis C virus and hepatocarcinogenesis. Clin Mol Hepatol 18:347–356

    Article  PubMed  PubMed Central  Google Scholar 

  48. Lemon SM, McGivern DR (2012) Is hepatitis C virus carcinogenic? Gastroenterology 142:1274–1278

    Article  PubMed  Google Scholar 

  49. Hino K, Nishina S, Hara Y (2013) Iron metabolic disorder in chronic hepatitis C: mechanisms and relevance to hepatocarcinogenesis. J Gastroenterol Hepatol 28(Suppl 4):93–98

    Article  CAS  PubMed  Google Scholar 

  50. Sharma A, Singh K, Almasan A (2012) Histone H2AX phosphorylation: a marker for DNA damage. Methods Mol Biol 920:613–626

    Article  CAS  PubMed  Google Scholar 

  51. Panier S, Boulton SJ (2014) Double-strand break repair: 53BP1 comes into focus. Nat Rev Mol Cell Biol 15:7–18

    Article  CAS  PubMed  Google Scholar 

  52. Siddiqui MS, François M, Fenech MF, Leifert WR (2015) Persistent γH2AX: A promising molecular marker of DNA damage and aging. Mutat Res Rev Mutat Res 766:1–19

    Article  CAS  PubMed  Google Scholar 

  53. Ichimura Y, Waguri S, Sou YS, Kageyama S, Hasegawa J, Ishimura R, Saito T, Yang Y, Kouno T, Fukutomi T, Hoshii T, Hirao A, Takagi K, Mizushima T, Motohashi H, Lee MS, Yoshimori T, Tanaka K, Yamamoto M, Komatsu M (2013) Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol Cell 51:618–631

    Article  CAS  PubMed  Google Scholar 

  54. Ioannou GN, Green PK, Berry K (2017) HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma. J Hepatol S0168–8287:32273

    Google Scholar 

  55. Waziry R, Hajarizadeh B, Grebely J, Amin J, Law M, Danta M, George J, Dore GJ (2017) Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression. J Hepatol 67:1204–1212

    Article  CAS  PubMed  Google Scholar 

  56. Conti F, Buonfiglioli F, Scuteri A, Crespi C, Bolondi L, Caraceni P, Foschi FG, Lenzi M, Mazzella G, Verucchi G, Andreone P, Brillanti S (2016) Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol 65:727–733

    Article  CAS  PubMed  Google Scholar 

  57. Saito T, Ichimura Y, Taguchi K, Suzuki T, Mizushima T, Takagi K, Hirose Y, Nagahashi M, Iso T, Fukutomi T, Ohishi M, Endo K, Uemura T, Nishito Y, Okuda S, Obata M, Kouno T, Imamura R, Tada Y, Obata R, Yasuda D, Takahashi K, Fujimura T, Pi J, Lee MS, Ueno T, Ohe T, Mashino T, Wakai T, Kojima H, Okabe T, Nagano T, Motohashi H, Waguri S, Soga T, Yamamoto M, Tanaka K, Komatsu M (2016) p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming. Nat Commun 7:12030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Menegon S, Columbano A, Giordano S (2016) The Dual Roles of NRF2 in Cancer. Trends Mol Med 22:578–593

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

Lamp1 antibody was a kind gift from J.T. August (Johns Hopkins University). GFP-LC3 was a kind gift from Dr. Yoshimori (Osaka University).

Funding

This work was supported in part by JSPS KAKENHI Grant Number 18K07988, Grant-in-aid for Scientific Research (C) 22591052, the Research Program on Hepatitis from the Japan Agency for Medical Research and Development (AMED).

Author information

Authors and Affiliations

  1. Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan

    Yuichi Honma, Koichiro Miyagawa, Tsuguru Hayashi, Masashi Kusanaga, Noriyoshi Ogino, Sota Minami, Shinji Oe & Masaru Harada

  2. Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan

    Yuichi Hara & Keisuke Hino

  3. Department of Persistent and Oncogenic Viruses, Center for Chronic Viral Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

    Masanori Ikeda

Authors
  1. Yuichi Honma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Koichiro Miyagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuichi Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tsuguru Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masashi Kusanaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Noriyoshi Ogino
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sota Minami
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shinji Oe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masanori Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Keisuke Hino
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Masaru Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yuichi Honma or Masaru Harada.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (pdf 1044 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Honma, Y., Miyagawa, K., Hara, Y. et al. Correlation of hepatitis C virus-mediated endoplasmic reticulum stress with autophagic flux impairment and hepatocarcinogenesis. Med Mol Morphol 54, 108–121 (2021). https://doi.org/10.1007/s00795-020-00271-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00795-020-00271-5

Keywords

Search

Navigation