Human Heme Oxygenase-1 Induced by Interleukin-6 via JAK/STAT3 Pathways Is a Tumor Suppressor Gene in Hepatoma Cells.

Kun-Chun Chiang,Shu-Yuan Hsu,Tsui-Hsia Feng,Kang-Shuo Chang,Hsin-Ching Sung,Mei Chao,Horng-Heng Juang

doi:10.3390/antiox9030251

Abstract

Heme oxygenase-1 (HO-1) has several important roles in hepatocytes in terms of anti-inflammation, anti-apoptosis, and antioxidant properties. Interleukin-6 (IL-6) is a pleiotropic cytokine associated with liver regeneration and protection against injury. The aim of this study was to determine the potential crosstalk between HO-1 and IL-6, and to elucidate the signaling pathways involved in the induction of HO-1 by IL-6 in human hepatoma cells. Ectopic overexpression of HO-1 not only attenuated cell proliferation in vitro and in vivo, but also blocked the reactive oxygen species (ROS) induced by H2O2 and the pyocyanin in HepG2 or Hep3B cells. IL-6 expression was negatively regulated by HO-1, while IL-6 induced signal transducer and activator of transcription 3 (STAT3) phosphorylation and HO-1 gene expression in HepG2 cells. The co-transfected HO-1 reporter vector and a protein inhibitor of the activated STAT3 (PIAS3) expression vector blocked the IL-6-induced HO-1 reporter activity. Both interferon γ and interleukin-1β treatments induced STAT1 but not STAT3 phosphorylation, which had no effects on the HO-1 expression. Treatments of AG490 and luteolin blocked the JAK/STAT3 signaling pathways which attenuated IL-6 activation on the HO-1 expression. Our results indicated that HO-1 is the antitumor gene induced by IL-6 through the IL-6/JAK/STAT3 pathways; moreover, a feedback circuit may exist between IL-6 and HO-1 in hepatoma cells.

Highlights

Heme oxygenase-1 (HO-1) is an inducible enzyme that can degrade toxic heme into carbon monoxide (CO), ferrous iron, and biliverdin [1]
The thymidine incorporation assays revealed that overexpression of heme oxygenase (HO)-1 in HepG2 (Figure 1B) and Hep3B (Figure 1C) cells downregulated cell proliferation
The Matrigel invasion assays indicated that HO-1 overexpression blocked 75% of cell invasion compared to HO-1 mock-transfected Hep3B cells (Figure 1D)

Summary

Introduction

Heme oxygenase-1 (HO-1) is an inducible enzyme that can degrade toxic heme into carbon monoxide (CO), ferrous iron, and biliverdin [1]. Recent studies have shown that HO-1 is involved in the improvements of several events, such oxidation stress, airway inflammation, functions of adipocytes, obesity, steatohepatitis, atherosclerosis, diabetes mellitus, brain hemorrhage, as well as neuroprotection [3,4,5,6,7,8]. This is especially essential in the health maintenance of the liver which contains about 15% of body heme [9,10,11,12]. Several studies have extensively demonstrated the positive role of HO-1 in cancer progress [14,15,16]

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