Epigenetic Inhibition of Nuclear Receptor Small Heterodimer Partner Is Associated With and Regulates Hepatocellular Carcinoma Growth

He, Ning; Park, Kyungtae; Zhang, Yuxia; Huang, Jiansheng; Lu, Shan; Wang, Li

doi:10.1053/j.gastro.2008.01.006

Cited by 95 publications

(97 citation statements)

References 27 publications

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“…As LRH-1 haplo-insufficient mice have reduced tumor development in two different models of intestinal tumor formation, it is likely that LRH-1 contributes to CRC development via the regulation of cell-cycle progression, in addition to the here-proposed function in tumor immune escape via the synthesis of GC. In support of this notion is a recent finding that the LRH-1 antagonist small heterodimer partner (SHP) is frequently downregulated in hepatocellular carcinoma by epigenetic silencing, which is associated with increased tumor growth (He et al, 2008). Also, in CRC uniform LRH-1 expression was frequently observed, whereas in the normal mucosa it remained restricted to the proliferating cells of the crypts.…”

Section: Extra-adrenal Glucocorticoid Synthesis In Colon Cancermentioning

confidence: 86%

Colon cancer cells produce immunoregulatory glucocorticoids

et al. 2011

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Glucocorticoids (GC) have important anti-inflammatory and pro-apoptotic activities. Initially thought to be exclusively produced by the adrenal glands, there is now increasing evidence for extra-adrenal sources of GCs. We have previously shown that the intestinal epithelium produces immunoregulatory GCs and that intestinal steroidogenesis is regulated by the nuclear receptor liver receptor homolog-1 (LRH-1). As LRH-1 has been implicated in the development of colon cancer, we here investigated whether LRH-1 regulates GC synthesis in colorectal tumors and whether tumor-produced GCs suppress T-cell activation. Colorectal cancer cell lines and primary tumors were found to express steroidogenic enzymes and regulatory factors required for the de novo synthesis of cortisol. Both cell lines and primary tumors constitutively produced readily detectable levels of cortisol, as measured by radioimmunoassay, thin-layer chromatography and bioassay. Whereas overexpression of LRH-1 significantly increased the expression of steroidogenic enzymes and the synthesis of cortisol, downregulation or inhibition of LRH-1 effectively suppressed these processes, indicating an important role of LRH-1 in colorectal tumor GC synthesis. An immunoregulatory role of tumor-derived GCs could be further confirmed by demonstrating a suppression of T-cell activation. This study describes for the first time cortisol synthesis in a non-endocrine tumor in humans, and suggests that the synthesis of bioactive GCs in colon cancer cells may account as a novel mechanism of tumor immune escape.

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Section: Extra-adrenal Glucocorticoid Synthesis In Colon Cancermentioning

confidence: 86%

Colon cancer cells produce immunoregulatory glucocorticoids

et al. 2011

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“…More studies are warranted about whether miR-421 can regulate FXR by targeting 5 0 -UTR or ORF of FXR mRNA. Besides involved in the regulation of bile acid, lipid, and glucose metabolisms, recent studies have shown that FXR can protect against tumorigenesis and inhibit cell growth in several cancers including HCC (23)(24)(25). Usually, FXR regulates cell proliferation and/or apoptosis through the function of its target genes.…”

Section: Discussionmentioning

confidence: 99%

“…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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“…SHP is considered a tumor suppressor [80] in addition to a metabolic regulator [81] . SHP null mice spontaneously develop HCC at 12 to 15 months of age [82] , and SHP expression is diminished in human HCC samples and cell lines [23,83] . SHP represses tumor growth via the inhibition of cellular proliferation [82,83] and the activation of apoptotic signals [84,85] .…”

Section: Fxr-regulated Target Genes and Liver Cancermentioning

confidence: 99%

“…SHP null mice spontaneously develop HCC at 12 to 15 months of age [82] , and SHP expression is diminished in human HCC samples and cell lines [23,83] . SHP represses tumor growth via the inhibition of cellular proliferation [82,83] and the activation of apoptotic signals [84,85] . He et al observed that SHP was downregulated by promoter hypermethylation, which is an important epigenetic event during HCC development [83] .…”

Section: Fxr-regulated Target Genes and Liver Cancermentioning

confidence: 99%

FXR and liver carcinogenesis

2014

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Farnesoid X receptor (FXR) is a member of the nuclear receptor family and a ligand-modulated transcription factor. In the liver, FXR has been considered a multi-functional cell protector and a tumor suppressor. FXR can suppress liver carcinogenesis via different mechanisms: 1) FXR maintains the normal liver metabolism of bile acids, glucose and lipids; 2) FXR promotes liver regeneration and repair after injury; 3) FXR protects liver cells from death and enhances cell survival; 4) FXR suppresses hepatic inflammation, thereby preventing inflammatory damage; and 5) FXR can directly increase the expression of some tumor-suppressor genes and repress the transcription of several oncogenes. However, inflammation and epigenetic silencing are known to decrease FXR expression during tumorigenesis. The reactivation of FXR function in the liver may be a potential therapeutic approach for patients with liver cancer.

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Epigenetic Inhibition of Nuclear Receptor Small Heterodimer Partner Is Associated With and Regulates Hepatocellular Carcinoma Growth

Cited by 95 publications

References 27 publications

Colon cancer cells produce immunoregulatory glucocorticoids

Colon cancer cells produce immunoregulatory glucocorticoids

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

FXR and liver carcinogenesis

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