Induction of SOCS3 by liver X receptor suppresses the proliferation of hepatocellular carcinoma cells.

Haojun Xiong,Bo Li,Yan Zhang,Shan Chen,Jintao He,Fan Yang,Fengtian He,Xinzhe Li,Zhenhong Ni,Yijun Zeng,Bingbo Chen,Kai Zhao

doi:10.18632/oncotarget.19321

Abstract

Liver X receptor (LXR), a member of nuclear receptor superfamily, is involved in the regulation of glucose, lipid and cholesterol metabolism. Recently, it has been reported that LXR suppress different kinds of cancers including hepatocellular carcinoma (HCC). However, the corresponding mechanism is still not well elucidated. In the present study, we found that activation of LXR downregulated cyclin D1 while upregulated p21 and p27 by elevating the level of suppressor of cytokine signaling 3 (SOCS3), leading to the cell cycle arrest at G1/S phase and growth inhibition of HCC cells. Moreover, we demonstrated that LXRα (not LXRβ) mediated the induction of SOCS3 in HCC cells. Subsequently, we showed that LXR activation enhanced the mRNA stability of SOCS3, but had no significant influence on the transcriptional activity of SOCS3 gene promoter. The experiments in nude mice revealed that LXR agonist inhibited the growth of xenograft tumors and enhanced SOCS3 expression in vivo. These results indicate that “LXRα-SOCS3-cyclin D1/p21/p27” is a novel pathway by which LXR exerts its anti-HCC effects, suggesting that the pathway may be a new potential therapeutic target for HCC treatment.

Highlights

Liver X receptor (LXR) belongs to a subgroup of ligand-activated nuclear receptor superfamily [1]
Reexpression of suppressor of cytokine signaling 3 (SOCS3) by LXR agonists led to cell cycle arrest through increasing p21 and p27 and decreasing cyclin D1, which resulted in the growth inhibition of hepatocellular carcinoma (HCC) cells
We showed that the expression of SOCS3 in HCC tissues was dramatically decreased, which was in line with the previous report [26]

Summary

Introduction

Liver X receptor (LXR) belongs to a subgroup of ligand-activated nuclear receptor superfamily [1]. LXR contain two isoforms, LXRα ( known as NR1H3) and LXRβ ( known as NR1H2) [2]. The expression profile of LXR isoforms in human organs are quite different, LXRα is highly expressed in the liver, intestine, kidney and adipose tissues whereas LXRβ is ubiquitously expressed in almost all tissues at a low concentration [3]. Previous reports have shown that LXR plays an important role in the regulation of lipid metabolism as it can promote the expression of key genes (SREBP-1c, ChREBP, FASN et al) critical for hepatic lipogenesis [4]. LXR activation can reduce the body load of cholesterol through upregulating important genes (ABCA1, ABCG1, ABCG5 and ABCG8) involved in reverse cholesterol transport [5].

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