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HBV-induced ROS accumulation promotes hepatocarcinogenesis through Snail-mediated
epigenetic silencing of SOCS3
#MMPMID26794444
Yuan K
; Lei Y
; Chen HN
; Chen Y
; Zhang T
; Li K
; Xie N
; Wang K
; Feng X
; Pu Q
; Yang W
; Wu M
; Xiang R
; Nice EC
; Wei Y
; Huang C
Cell Death Differ
2016[Apr]; 23
(4
): 616-27
PMID26794444
show ga
Interleukin-6 (IL-6) has been demonstrated to be involved in Hepatitis B virus
(HBV)-associated hepatocarcinogenesis through activation of the STAT3 pathway.
The sustained activation of the IL-6/STAT3 pathway is frequently associated with
repression of SOCS3, which is both a target gene and a negative regulator of
STAT3. However, the silencing mechanism of SOCS3 in hepatocellular carcinoma
(HCC) remains to be elucidated. Here, we showed that the repression of SOCS3 and
sustained activation of IL-6/STAT3 pathway in HBV-producing HCC cells were caused
by HBV-induced mitochondrial ROS accumulation. Mechanistic studies revealed that
ROS-mediated DNA methylation resulted in the silencing of SOCS3. Decreased SOCS3
expression significantly promoted the proliferation of HCC cells and growth of
tumor xenografts in mice. Further studies revealed that HBV-induced ROS
accumulation upregulated the expression of the transcription factor, Snail, which
bound to the E-boxes of SOCS3 promoter and mediated the epigenetic silencing of
SOCS3 in association with DNMT1 and HDAC1. In addition, we found that the
expression of Snail and SOCS3 were inversely correlated in HBV-associated HCC
patients, suggesting that SOCS3 and/or Snail could be used as prognostic markers
in HCC pathogenesis. Taken together, our data show that HBV-induced mitochondrial
ROS production represses SOCS3 expression through Snail-mediated epigenetic
silencing, leading to the sustained activation of IL-6/STAT3 pathway and
ultimately contributing to hepatocarcinogenesis.
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