title: Up-regulation of Foxo4 mediated by hepatitis B virus X protein confers resistance to oxidative stress-induced cell death.
abstract: The hepatitis B virus X (HBX) protein, a regulatory protein of the hepatitis B virus (HBV), has been shown to generate reactive oxygen species (ROS) in human liver cell lines; however, the mechanism by which cells protect themselves under this oxidative stress is poorly understood. Here, we show that HBX induces the up-regulation of Forkhead box class O 4 (Foxo4) not only in Chang cells stably expressing HBX (Chang-HBX) but also in primary hepatic tissues from HBX-transgenic mice. HBX also increased ROS, but reduction of the abundance of ROS using N-acetylcystein (NAC) diminished the levels of Foxo4. Elevated Foxo4 was also detected in nuclei of Chang-HBX cells but not in Chang cells stably expressing the vector (Chang-Vec), suggesting that HBX activates the transcriptional activity of Foxo4. When we examined whether HBX bypasses JNK signaling that targets Foxo4, we found that the activity of JNK but not of ERK is required for the up-regulation of Foxo4 even in the presence of HBX. Furthermore, the reduction of Foxo4 levels using siRNA or a JNK inhibitor rendered Chang-HBX cells sensitive to apoptosis under oxidative stress, suggesting that up-regulation of Foxo4 mediated by HBX enhances resistances to oxidative stress-induced cell death. Accordingly, we propose that Foxo4 may be a useful target for suppression in the treatment of HBV-associated hepatocellular carcinoma cells.
authors.affiliation: WCU Department of Cogno-Mechatronics Engineering, BK21 Nanofusion Technology Team, Pusan National University, Busan, Republic of Korea.
authors.forename: Ratakorn
authors.initials: R
authors.lastname: Srisuttee
authors.forename: Sang Seok
authors.initials: SS
authors.lastname: Koh
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Park
authors.forename: Il-Rae
authors.initials: IR
authors.lastname: Cho
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Min
authors.forename: Byung Hak
authors.initials: BH
authors.lastname: Jhun
authors.forename: Dae-Yeul
authors.initials: DY
authors.lastname: Yu
authors.forename: Sun
authors.initials: S
authors.lastname: Park
authors.forename: Do Yun
authors.initials: DY
authors.lastname: Park
authors.forename: Mi Ock
authors.initials: MO
authors.lastname: Lee
authors.forename: Diego H
authors.initials: DH
authors.lastname: Castrillon
authors.forename: Randal N
authors.initials: RN
authors.lastname: Johnston
authors.forename: Young-Hwa
authors.initials: YH
authors.lastname: Chung
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000235:genetics*; D021381:Protein Transport / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D051858:Forkhead Transcription Factors; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D048670:MAP Kinase Kinase 4