Orphan receptor small heterodimer partner suppresses tumorigenesis by modulating cyclin D1 expression and cellular proliferation†

Zhang, Yuxia; Xu, Ping; Park, Kyungtae; Choi, Yunhee; Moore, David D.; Wang, Li

doi:10.1002/hep.22342

Cited by 112 publications

(132 citation statements)

References 24 publications

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“…For example, SHP, a typical target gene of FXR, has been shown to suppress cell proliferation and promote apoptosis (23). It is reported that the expression of SHP was downregulated in human HCC, and mice with SHP deficiency developed spontaneous liver tumors (24,26). The accumulating data suggest that FXR may be a pharmaceutical target for the treatment of the associated cancers including HCC.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Human Farnesoid X Receptor by miR-421 Promotes Proliferation and Migration of Hepatocellular Carcinoma Cells

Zhang

Gong

Dai

et al. 2012

Molecular Cancer Research

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The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is highly expressed in liver, kidney, adrenal gland, and intestine. It plays an important role in regulating the progression of several cancers including hepatocellular carcinoma (HCC). So it is necessary to study the regulation of FXR. In this study, we found that the expression of miR-421 was inversely correlated with FXR protein level in HCC cell lines. Treatment with miR-421 mimic repressed FXR translation. The reporter assay revealed that miR-421 targeted 3 0 untranslated region of human FXR mRNA. Furthermore, downregulation of FXR by miR-421 promoted the proliferation, migration, and invasion of HCC cells. These results suggest that miR-421 may serve as a novel molecular target for manipulating FXR expression in hepatocyte and for the treatment of HCC. Mol Cancer Res; 10(4); 516-22. Ó2012 AACR. IntroductionThe farnesoid X receptor (FXR) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily that is mainly expressed in liver, intestine, kidney, and adrenal gland (1). Ligand-activated FXR binds to response elements of target genes either as a classical FXRRXRa (retinoid X receptor alpha) heterodimer or as a monomer (2-4). FXR plays an important role in regulating the metabolisms of bile acid, cholesterol, triglyceride, and glucose (5). Recent studies show that FXR is also involved in the regulation of liver regeneration and protection against the liver carcinogenesis (6). Therefore, FXR has received increasing attention as a therapeutic target for the treatments of certain metabolic diseases and liver carcinoma.As a multiple functional transcriptional factor, FXR regulates so many target genes, but its own regulation is not well known. It has been reported that several transcriptional coregulators, including PGC-1a, Brg-1, p300, CARM1, PRMT1, and ASCOM, can potentially modulate FXR expression (7). Moreover, glucose and insulin (8) as well as the cytokines tumor necrosis factor-a and interleukin-1 (9) have also been identified to regulate FXR level. Recently, posttranslational modifications, such as phosphorylation,

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Section: Discussionmentioning

confidence: 99%

Downregulation of Human Farnesoid X Receptor by miR-421 Promotes Proliferation and Migration of Hepatocellular Carcinoma Cells

Zhang

Gong

Dai

et al. 2012

Molecular Cancer Research

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“…Therefore, chronic deregulation of SHP expression may lead to pathologic consequences and favor liver disease. The potential negative consequences of SHP deregulation can be extrapolated from studies with liver-specific SHP-transgenic and SHP-deficient mice (Wang et al, 2003;Boulias et al, 2005;Park et al, 2008;Zhang et al, 2008Zhang et al, , 2010Zhang et al, , 2014Chanda et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

Repression of the Nuclear Receptor Small Heterodimer Partner by Steatotic Drugs and in Advanced Nonalcoholic Fatty Liver Disease

et al. 2015

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The small heterodimer partner (SHP) (NR0B2) is an atypical nuclear receptor that lacks a DNA-binding domain. It interacts with and inhibits many transcription factors, affecting key metabolic processes, including bile acid, cholesterol, fatty acid, and drug metabolism. Our aim was to determine the influence of steatotic drugs and nonalcoholic fatty liver disease (NAFLD) on SHP expression and investigate the potential mechanisms. SHP was found to be repressed by steatotic drugs (valproate, doxycycline, tetracycline, and cyclosporin A) in cultured hepatic cells and the livers of different animal models of NAFLD: iatrogenic (tetracycline-treated rats), genetic (glycine N-methyltransferase-deficient mice), and nutritional (mice fed a methionine-and choline-deficient diet). Among the different transcription factors investigated, CCAATenhancer-binding protein a (C/EBPa) showed the strongest dominant-repressive effect on SHP expression in HepG2 and human hepatocytes. Reporter assays revealed that the inhibitory effect of C/EBPa and steatotic drugs colocalize between 2340 and 2509 base pair of the SHP promoter, and mutation of a predicted C/EBPa response element at 2473 base pair abolished SHP repression by both C/EBPa and drugs. Moreover, inhibition of major stress signaling pathways demonstrated that the mitogen-activated protein kinase kinase 1/2 pathway activates, while the phosphatidylinositol 3 kinase pathway represses SHP in a C/EBP-dependent manner. We conclude that SHP is downregulated by several steatotic drugs and in advanced NAFLD. These conditions can activate signals that target C/EBPa and consequently repress SHP, thus favoring the progression and severity of NAFLD.

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“…SHP KO mice are known to have various phenotypes, such as mild defects in bile acid homeostasis, 18 repression of osteoblast differentiation and decreases in bone mass, 36 enhancement of hepatocyte proliferation and transformation, 37 and susceptibility to endotoxin-induced sepsis. 17 However, no clear cardiac phenotypes have been reported.…”

Section: Discussionmentioning

confidence: 99%

Small Heterodimer Partner Blocks Cardiac Hypertrophy by Interfering With GATA6 Signaling

Nam

Kim

Joung

et al. 2014

Circulation Research

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Cardiac hypertrophy is an increase in the individual cellular volume of the heart and is an adaptive response to exogenous stresses. The increase in cellular volume is associated with reactivation of the fetal gene program, which is finely regulated by diverse cardiac transcription factors.1 Specifically, GATA4, GATA6, myocyte enhancer factor 2C, nuclear factor of activated T cells, NK2 homeobox 5, and serum response factor have been shown to be involved in the development of cardiac hypertrophy.1 GATA4 and GATA6 are heart-specific transcription factors that regulate pathological cardiac hypertrophy in association with atrial natriuretic factor (ANF) expression.2,3 Transgenic mice that overexpress GATA4 in the heart show cardiac hypertrophy, 4 and GATA4 activity is regulated by physical interaction with other transcription factors, such as serum response factor, NK2 homeobox 5, and myocyte enhancer factor 2.5-7 GATA6 also induces pathological cardiac hypertrophy, which was demonstrated by recent studies of cardiac-specific overexpression of GATA6 in mice. 3In addition to effects as transcription factors, some of these factors also act as nuclear receptors that provide signal-mediated responsiveness to endogenous or exogenous ligands. For example, peroxisome proliferator-activated receptor-α or steroid receptors respond to a ligand and then mediate diverse cellular events as well as metabolic regulation.8,9 Not surprisingly, these nuclear receptors also play important roles in various organs, and therapeutic applications of their modulators are growing. The nuclear receptors are classified depending on their structural similarities. Interestingly, 1 group of nuclear receptors is termed the orphan nuclear receptors. In contrast with the other nuclear receptors that have endogenous ligands

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Orphan receptor small heterodimer partner suppresses tumorigenesis by modulating cyclin D1 expression and cellular proliferation†

Cited by 112 publications

References 24 publications

Downregulation of Human Farnesoid X Receptor by miR-421 Promotes Proliferation and Migration of Hepatocellular Carcinoma Cells

Downregulation of Human Farnesoid X Receptor by miR-421 Promotes Proliferation and Migration of Hepatocellular Carcinoma Cells

Repression of the Nuclear Receptor Small Heterodimer Partner by Steatotic Drugs and in Advanced Nonalcoholic Fatty Liver Disease

Small Heterodimer Partner Blocks Cardiac Hypertrophy by Interfering With GATA6 Signaling

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