HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression

Wonchung Lim, Soon Hwan Kwon, Hyeseon Cho, Sujeong Kim, Seungmin Lee, Wang-Shick Ryu, Hyeseong Cho

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Chronic inflammation can be a major risk factor for cancer development and may contribute to the high worldwide incidence of hepatocellular carcinoma (HCC). Cyclooxygenase-2 (COX-2) is known to be an important mediator of inflammatory responses; however, its link to hepatitis B virus (HBV)-mediated inflammatory responses has not been established. Here, we demonstrate that the expression of COX-2 mRNA and protein was significantly elevated in cells transfected by HBV replicon but not in cells transfected by HBV genome lacking the HBx gene. Notably, COX-2 induction was correlated with HBx's ability to increase reactive oxygen species (ROS) levels. Consistently with this, antioxidant treatment and ectopic expression of manganese superoxide dismutase or catalase completely abolished COX-2 induction. Interestingly, a mitochondria localization-defective mutant of HBx (HBxΔ68-117) neither increased intracellular ROS levels nor induced COX-2 expression. HBx 68-117, which encodes only amino acids 68-117 and is sufficient for mitochondria localization, increased ROS levels but did not induce COX-2 expression. Similarly, HBx targeting to the outer membrane of mitochondria (Mito-HBx) increased ROS but also failed to increase COX-2 expression, suggesting that other cytoplasmic signaling pathways are involved in HBx-mediated COX-2 induction. Indeed, inhibition of cytoplasmic calcium signaling by cyclosporine A, blocking mitochondrial permeability transition pore, and herbimycin, and inhibition of calcium-dependent tyrosine kinase suppressed HBV-mediated COX-2 induction. Thus, the data indicate that both mitochondrial ROS and cytoplasmic calcium signaling are necessary for the COX-2 induction. Our studies revealed a pathophysiological link between HBV infection and hepatic inflammation, and this chain of events might contribute to early steps in HBV-associated liver carcinogenesis.

Original languageEnglish
Pages (from-to)359-369
Number of pages11
JournalJournal of Molecular Medicine
Volume88
Issue number4
DOIs
Publication statusPublished - 2010 Apr 1

Fingerprint

Cyclooxygenase 2
Hepatitis B virus
Reactive Oxygen Species
Mitochondria
Calcium Signaling
Inflammation
Replicon
Liver
Virus Diseases
Protein-Tyrosine Kinases
Catalase
Cyclosporine
Superoxide Dismutase
Hepatocellular Carcinoma
Carcinogenesis
Antioxidants
Genome
Calcium
Amino Acids
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

Lim, Wonchung ; Kwon, Soon Hwan ; Cho, Hyeseon ; Kim, Sujeong ; Lee, Seungmin ; Ryu, Wang-Shick ; Cho, Hyeseong. / HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression. In: Journal of Molecular Medicine. 2010 ; Vol. 88, No. 4. pp. 359-369.
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abstract = "Chronic inflammation can be a major risk factor for cancer development and may contribute to the high worldwide incidence of hepatocellular carcinoma (HCC). Cyclooxygenase-2 (COX-2) is known to be an important mediator of inflammatory responses; however, its link to hepatitis B virus (HBV)-mediated inflammatory responses has not been established. Here, we demonstrate that the expression of COX-2 mRNA and protein was significantly elevated in cells transfected by HBV replicon but not in cells transfected by HBV genome lacking the HBx gene. Notably, COX-2 induction was correlated with HBx's ability to increase reactive oxygen species (ROS) levels. Consistently with this, antioxidant treatment and ectopic expression of manganese superoxide dismutase or catalase completely abolished COX-2 induction. Interestingly, a mitochondria localization-defective mutant of HBx (HBxΔ68-117) neither increased intracellular ROS levels nor induced COX-2 expression. HBx 68-117, which encodes only amino acids 68-117 and is sufficient for mitochondria localization, increased ROS levels but did not induce COX-2 expression. Similarly, HBx targeting to the outer membrane of mitochondria (Mito-HBx) increased ROS but also failed to increase COX-2 expression, suggesting that other cytoplasmic signaling pathways are involved in HBx-mediated COX-2 induction. Indeed, inhibition of cytoplasmic calcium signaling by cyclosporine A, blocking mitochondrial permeability transition pore, and herbimycin, and inhibition of calcium-dependent tyrosine kinase suppressed HBV-mediated COX-2 induction. Thus, the data indicate that both mitochondrial ROS and cytoplasmic calcium signaling are necessary for the COX-2 induction. Our studies revealed a pathophysiological link between HBV infection and hepatic inflammation, and this chain of events might contribute to early steps in HBV-associated liver carcinogenesis.",
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HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression. / Lim, Wonchung; Kwon, Soon Hwan; Cho, Hyeseon; Kim, Sujeong; Lee, Seungmin; Ryu, Wang-Shick; Cho, Hyeseong.

In: Journal of Molecular Medicine, Vol. 88, No. 4, 01.04.2010, p. 359-369.

Research output: Contribution to journalArticle

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AU - Lim, Wonchung

AU - Kwon, Soon Hwan

AU - Cho, Hyeseon

AU - Kim, Sujeong

AU - Lee, Seungmin

AU - Ryu, Wang-Shick

AU - Cho, Hyeseong

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