Thyroid hormone protects hepatocytes from HBx-induced carcinogenesis by enhancing mitochondrial turnover

Abstract

Infection by hepatitis B virus (HBV) accounts for 50-80% of hepatocellular carcinoma (HCC) development worldwide, in which the HBV-encoded X protein (HBx) has critical role in the induction of carcinogenesis. Several studies have shown that thyroid hormone (TH) suppresses HCC development and protects hepatocytes from HBx-induced damage, thus it is of interest to examine whether TH can protect hepatocytes from HBx-induced carcinogenesis. By treating HBx- transgenic mice with or without TH, we confirmed the protective effects of TH on HBx-induced hepatocarcinogenesis, which was achieved via reduction of reactive oxygen species (ROS) inflicted DNA damage. We further found that TH induced biogenesis of mitochondria (MITO) and autophagy of HBx-targeted MITO simultaneously, consequently leading to suppression of HBx-promoted ROS and carcinogenesis. Using microarray data analysis, this protective effect of TH was found to be mediated via activation of PTEN-induced kinase 1 (PINK1) in hepatocytes. PINK1, in turn, activated and recruited Parkin, an E3 ligase, to ubiquitinate MITO-associated HBx protein and trigger selective mitophagy. The pathological significance of the TH/PINK1 pathway in liver protection was confirmed by the concomitant decrease in expression of both TR and PINK1 in matched HCC tumor tissues and negatively correlated with aggressive progression of cancer and poor prognosis. Our data indicate that TH/PINK1/Parkin pathway has a critical role in protecting hepatocytes from HBx-induced carcinogenesis. Notably, several liver-targeting therapeutic derivatives of TH facilitating prevention or therapy of steatosis have been identified. Furthermore, our proof-of-concept experiments suggest that application of T constitutes an effective novel therapeutic or preventive option for HCC. Thus, the utilization of the agonists of TRs could be the meaningful strategy in liver relative diseases, ranging from simple hepatic steatosis to HCC.

Impact of the Interaction of Hepatitis B Virus with Mitochondria and Associated Proteins

“…They further demonstrated that TH abolished HBx-mediated upregulation of transcription factors, phospho-STAT3, c-Jun, NF-κB, and AP-1 through the increase of mROS and the reduction of ∆ψm, and these results are consistent with others reports [35,37,69]. These TH/PINK1/Parkin signaling effects on the reduction of HBx-mediated HCC are correlated with clinical cases [69]. HBx promotes stem/progenitor cell markers in HBx-transgenic mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) [70].…”

“…Chi et al investigated the mitochondrial localization of HBx with its effect on mROS and ∆ψm, which correlated with their data from HBx transgenic mice and clinical HBV-mediated HCC patients [69]. HBx-induced carcinogenesis in HBx transgenic mice and predominantly localized into mitochondria in stably expressing HepG2 cells and interacted with PINK1 and parkin [69]. Thyroid hormone (TH) simultaneously induces mitochondrial biogenesis and autophagy of HBx-targeted mitochondria through PINK1 induction to suppress HBx-promoted ROS generation and carcinogenesis [69].…”

“…This phenomenon has been confirmed in HBV-replicating HepG2.2.2.15 cell line [67,68]. Chi et al investigated the mitochondrial localization of HBx with its effect on mROS and ∆ψm, which correlated with their data from HBx transgenic mice and clinical HBV-mediated HCC patients [69]. HBx-induced carcinogenesis in HBx transgenic mice and predominantly localized into mitochondria in stably expressing HepG2 cells and interacted with PINK1 and parkin [69].…”

“…HBx-induced carcinogenesis in HBx transgenic mice and predominantly localized into mitochondria in stably expressing HepG2 cells and interacted with PINK1 and parkin [69]. Thyroid hormone (TH) simultaneously induces mitochondrial biogenesis and autophagy of HBx-targeted mitochondria through PINK1 induction to suppress HBx-promoted ROS generation and carcinogenesis [69]. They further demonstrated that TH abolished HBx-mediated upregulation of transcription factors, phospho-STAT3, c-Jun, NF-κB, and AP-1 through the increase of mROS and the reduction of ∆ψm, and these results are consistent with others reports [35,37,69].…”

“…Thyroid hormone (TH) simultaneously induces mitochondrial biogenesis and autophagy of HBx-targeted mitochondria through PINK1 induction to suppress HBx-promoted ROS generation and carcinogenesis [69]. They further demonstrated that TH abolished HBx-mediated upregulation of transcription factors, phospho-STAT3, c-Jun, NF-κB, and AP-1 through the increase of mROS and the reduction of ∆ψm, and these results are consistent with others reports [35,37,69]. These TH/PINK1/Parkin signaling effects on the reduction of HBx-mediated HCC are correlated with clinical cases [69].…”