Nasopharyngeal carcinoma (NPC) is a subtype of head and neck cancer with dismal prognosis and high relapse rate. The role of long non-coding RNAs (lncRNAs) in NPC has become a research hotspot in recent years. This study aimed to interrogate the function and mechanism of lncRNA MSC antisense RNA 1 (MSC-AS1) in NPC.

Our previous genome-wide association studies showed that DNA methyltransferase 1 (DNMT1) is associated with increased susceptibility to type 2 diabetes (T2D) in Han Chinese individuals. Here, we aimed to further evaluate the role of DNMT1 in T2D. We performed a genome-wide DNA methylation array and found that the nuclear receptor subfamily 4 group A member 1 (NR4A1) promoter was hypermethylated in patients with T2D and in a mouse model of T2D. Moreover, DNA hypermethylation of the NR4A1 promoter reduced NR4A1 mRNA expression. Transient transfection of human NR4A1 into RIN-m5F and 293T cells caused DNMT1 inhibition and induced insulin receptor activation. NR4A1knockdown by shRNA resulted in overexpression of DNMT1 and inhibition of insulin receptor, suggesting that the NR4A1 gene is involved in the epigenetics pathway. Furthermore, T2D model mice treated with the DNMT1 inhibitor aurintricarboxylic acid (ATA) showed reduced activation of DNMT1 in pancreatic β cells; this effect reversed the changes in NR4A1 expression and decreased blood glucose in T2D model mice. Thus, our results showed for the first time that DNMT1 caused NR4A1 DNA hypermethylation and blocked insulin signaling in patients with T2D. Importantly, ATA therapy may be useful for decreasing blood glucose levels by reversing NR4A1-dependent insulin signaling. These findings improve our understanding of the crucial roles of these regulatory elements in human T2D.

Sustained elevation of sympathetic activity is an important contributor to pathological cardiac hypertrophy, ventricular arrhythmias, and left ventricular contractile dysfunction in chronic heart failure. The orphan nuclear receptor NR4A2 is an immediate early-response gene activated in the heart under β-adrenergic stimulation. The goal of this study was to identify the transcriptional remodeling events induced by increased NR4A2 expression in cardiomyocytes and their impact on the physiological response of those cells to sustained β-adrenergic stimulation. Treatment of adult rat ventricular myocytes with isoproterenol induced a rapid (<4 h) increase in NR4A2 levels that was accompanied by a transient (<24 h) increase in nuclear localization of the transcription factor. Adenovirus-mediated overexpression of NR4A2 to similar levels modulated the expression of genes linked to adrenoceptor signaling, calcium signaling, cell growth and proliferation and counteracted the increase in protein synthesis rate and cell surface area mediated by chronic isoproterenol stimulation. Consistent with those findings, NR4A2 overexpression also blocked the phosphorylative activation of growth-related kinases ERK1/2, Akt, and p70 S6 kinase. Prominent among the transcriptional changes induced by NR4A2 was the upregulation of the dual-specificity phosphatases DUSP2 and DUSP14, two known inhibitors of ERK1/2. Pretreatment of NR4A2-overexpressing cardiomyocytes with the DUSP inhibitor BCI [(E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one] prevented the inhibition of ERK1/2 following isoproterenol stimulation. In conclusion, our results suggest that NR4A2 acts as a novel negative feedback regulator of the β-adrenergic receptor-mediated growth response in cardiomyocytes and this at least partly through DUSP-mediated inhibition of ERK1/2 signaling.

Allergic rhinitis (AR) is a common chronic disease characterized by inflammation of the nasal mucosa. Long non-coding RNA (LncRNA) has been reported to be involved in the pathogenesis of various diseases. However, the biological roles of lncRNA Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) in AR are still unclear. The mRNA levels of NEAT1, miR-511, and Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) were detected by RT-qPCR. The protein levels of exosomal markers were examined by western blot. ELISA was used to assess the levels of GM-CSF, eotaxin-1, and MUC5AC. The cell viability and apoptosis were evaluated by CCK-8 and TUNEL assays. In this study, we found that the NEAT1 level was highly expressed in AR and IL-13-treated HNECs. NEAT1 interference significantly suppressed levels of GM-CSF, eotaxin-1, and MUC5AC and apoptosis rate, but promoted the viability of IL-13-treated human nasal epithelial cells (HNECs). Moreover, exosomes containing NEAT1 induced inflammatory cytokine production and apoptosis, while NEAT1 depletion abrogated these effects. In addition, NEAT1 directly interacted with miR-511, and the inhibition of miR-511 partially restored the inhibitory effects of NEAT1 silencing on inflammatory cytokine, mucus production, and apoptosis in IL-13-stimulated HNECs. Furthermore, miR-511 could bind to the 3'UTR of NR4A2, and the inhibition of miR-511 increased levels of inflammatory factors and apoptosis rate, which was counteracted by depleting NR4A2. In conclusion, our data revealed that exosomal NEAT1 contributed to the pathogenesis of AR through the miR-511/NR4A2 axis. These findings might offer novel strategies for the prevention and treatment of AR.

Apoptosis is characterized by distinct morphological and biochemical changes that occur upon activation of a family of serine proteases known as caspases. Reactive oxygen species (ROS) induce apoptosis in many cell systems. Nuclear receptor subfamily 4, group A, member 1 (NR4A1) has been shown to induce apoptosis in a number of cell lineages, but can also paradoxically act as a death inhibitory factor. In the current study, we focused on the potential role of NR4A1 in hydrogen peroxide (H2O2)-induced apoptosis of normal human umbilical cord fibroblast (HUC-F2) cells.

Emerging reports uncover that long noncoding RNAs (lncRNAs) help regulate intervertebral disc degeneration (IVDD). Here, we probe the function of lncRNA nuclear receptor subfamily 2 group F member 1 antisense RNA 1 (NR2F1-AS1) in IVDD. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was applied to verify the expression of NR2F1-AS1 and miR-145-5p in nucleus pulposus (NP) tissues from IVDD patients or NP cells dealt with IL-1β or TNF-α. Flow cytometry or the TdT-mediated dUTP nick end labeling (TUNEL) assay was performed to validate the apoptosis of NP cells with selective regulation of NR2F1-AS1 and miR-145-5p. ECM-related genes, FOXO1, Bax, and Bcl2 were evaluated by qRT-PCR or Western blot (WB). The targeted relationships between NR2F1-AS1 and miR-145-5p, miR-145-5p and FOXO1 were testified by the dual-luciferase reporter assay and the RNA immunoprecipitation (RIP) assay. Our outcomes substantiated that NR2F1-AS1 was up-regulated, while miR-145-5p was down-regulated in intervertebral disc tissues of IVDD patients or NP cells treated with IL-1β or TNF-α. Besides, overexpressing NR2F1-AS1 intensified ECM degradation and NP cell apoptosis induced by IL-1β, while knocking down NR2F1-AS1 or up-regulating miR-145-5p reversed IL-1β-mediated effects in NP cells. Meanwhile, NR2F1-AS1 choked miR-145-5p and abated its effects in NP cells. This study confirms that NR2F1-AS1 modulates IVDD progression by up-regulating the FOXO1 pathway through the sponge of miR-145-5p as a competitive endogenous RNA (ceRNA).

BACKGROUND Nuclear receptor subfamily 4 group A member 1 (Nr4a1) has been increasingly investigated in association with type 2 diabetes mellitus (T2DM). This study aimed to explore its efficacy with liver kinase B1 (LKB1) and potential signaling pathways in T2DM. MATERIAL AND METHODS A T2DM model in rats was established by high-fat diet and injection of 30 mg/kg streptozotocin. The ectopic expression of Nr4a1 or in combination with LKB1 was performed in T2DM rats to probe their effects on T2DM. Then, the weight and indicators of blood lipid and blood glucose in normal rats and T2DM rats were measured. The volume change of adipocytes and the size of lipid droplets in white adipose tissue (WAT) were observed by hematoxylin-eosin staining and oil red O staining, respectively. We also measured levels of Nr4a1, LKB1, and adenosine monophosphate-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/Nuclear factor-kappa B (NF-kappaB) axis-related proteins. RESULTS In T2DM rats, Nr4a1 was highly expressed, and body weight, blood lipid and blood glucose were increased, and the volume of adipocytes and the size of lipid droplets in WAT were increased, which were all reversed by low expression of Nr4a1. After treatment with Nr4a1 and LKB1 together, T2DM rats showed decreased levels of blood lipid, blood glucose, and reduced volume of adipocytes and lipid droplet size in WAT, with activated AMPK/SIRT1 signaling pathway and inhibited NF-kappaB. CONCLUSIONS Our results highlight that interaction of Nr4a1 and LKB1 can mitigate T2DM by activating the AMPK/SIRT1 signaling pathway and inhibiting NF-kappaB activation. This may offer new insight for T2DM treatment.

Hepatoblastoma is a kind of extreme malignancy frequently diagnosed in children. Although surgical resection is considered as the first-line treatment for hepatoblastoma, a relatively large population of patients have lost the preferred opportunity for surgery. Administration of locoregional ablation enables local tumor control but with the deficiency of insufficient ablation, residual tumor, and rapid progression. In this study, we integrated 219 hepatoblastoma and 121 non-cancer liver tissues to evaluate the expression of NR2F6, from which a higher NR2F6 level was found in hepatoblastoma compared with non-cancer livers with a standard mean difference (SMD) of 1.04 (95% CI: 0.79, 1.29). The overexpression of NR2F6 also appeared to be an efficient indicator in distinguishing hepatoblastoma tissues from non-cancer liver tissues from the indication of a summarized AUC of 0.90, with a pooled sensitivity of 0.76 and a pooled specificity of 0.89. Interestingly, nude mouse xenografts provided direct evidence that overexpressed NR2F6 was also detected in residual tumor compared to untreated hepatoblastoma. Chromatin immunoprecipitation-binding data in HepG2 cells and transcriptome analysis of HepG2 xenografts were combined to identify target genes regulated by NR2F6. We finally selected 150 novel target genes of NR2F6 in residual tumor of incomplete ablation, and these genes appeared to be associated with the biological regulation of lipid metabolism-related pathway. Accordingly, targeting NR2F6 holds a therapeutic promise in treating residual recurrent hepatoblastoma after incomplete ablation.

BACKGROUND This study was designed to investigate the role of long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in the proliferation as well as apoptosis of human umbilical vein endothelial cells (HUVECs), to offer a basis for therapy of hypertension. MATERIAL AND METHODS The lncRNA MALAT1 expression, hsa-miR-124-3p, hsa-miR-135a-5p, hsa-miR-135b-5p, and hsa-miR-455-5p in plasma were measured from 230 patients with hypertension and 230 non-hypertensive controls. The mechanism for lncRNA MALAT1 modulating the proliferation and apoptosis of HUVECs was explored by cell transfection, Cell Counting Kit-8 (CCK-8), quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and dual-luciferase reporter assays. RESULTS The expression of hsa-miR-124-3p and hsa-miR-135a-5p was reduced and the expression of lncRNA MALAT1 was increased in the plasma of hypertensive patients. Moreover, the plasma levels of hsa-miR-124-3p and hsa-miR-135a-5p of hypertensive patients were negatively correlated with lncRNA MALAT1 (r=-0.64, -0.72; P<0.01, P<0.01, respectively). The level of nuclear receptor subfamily 3, group C, member 2 (NR3C2) protein was negatively correlated with hsa-miR-124-3p and hsa-miR-135a-5p (r=-0.74, -0.84; P<0.01, P<0.01, respectively). The proliferation of HUVECs was inhibited after the inhibition of MALAT. Additionally, after knocking down MALAT, the levels of hsa-miR-124-3p and hsa-miR-135a-5p in HUVECs were markedly increased, while the expression level of NR3C2 protein was decreased. The apoptotic rate of HUVECs after the transfection of MALAT1 small interfering RNA (si-MALAT1) (3.64±0.21%) was significantly reduced compared to that of transfected si-MALAT1 no template control (NC) (3.76±0.19%) and the control group (10.51±1.24%). CONCLUSIONS LncRNA MALAT1 regulates proliferation and apoptosis of HUVECs through the hsa-miR-124-3p/NR3C2 and/or hsa-miR-135a-5p/NR3C2 axis.

Orphan Receptor of Nuclear Receptor superfamily is the one with no known endogenous ligands. Many of these orphan receptors are associated with different types of diseases and therefore deserve special attention to find the potential ligands they would be associated with. The major task of molecular pharmacology is the deorphanization of the large number of nuclear receptors with unidentified endogenous agonists. The deorphanization provides a promising research for new therapeutics. The Testicular Receptor 4 being negative modulator to other members of the nuclear receptor superfamily, is one of the Orphan members of this family and is associated with prostate cancer, breast cancer, sickle cell anemia and joint diseases. The knowledge that related receptors of the same family often have ligands with similar structural features has helped us to utilize the chemogenomic approach to deorphanize the orphan receptor. Chemogenomics approach involves screening of known ligands of a protein family having analogous domain architecture for identification of new leads for existing protein family members. The deorphanization involved the database homology searching, followed by domain identification, active site prediction, sequence and structure comparative studies. A ligand library set was prepared based on these studies and was used to deorphanize the receptor. The molecular docking study conducted using PyRx revealed that estradiol and tretinion as a potential ligand for Testicular Receptor 4.

Nuclear receptor subfamily 4 group A member 2 (NR4A2) is an orphan nuclear receptor that is over-expressed in cancer and promotes cell proliferation, migration, transformation, and chemoresistance. Increased expression and function of NR4A2 have been attributed to various signaling pathways, but little is known about microRNA (miRNA) regulation of NR4A2 in cancer. To investigate the posttranscriptional regulation of NR4A2, we used a 3' untranslated region (UTR) reporter screen and identified miR-34 as a putative regulator of NR4A2. By using computer predictions, we identified and confirmed an miRNA recognition element in the 3' UTR of NR4A2 that was responsible for miR-34-mediated suppression. We next demonstrated that overexpression of exogenous miR-34 or activation of the p53 pathway, which regulates endogenous miR-34 expression, decreased NR4A2 expression. Consistent with previous reports, overexpression of NR4A2 blocked the induction of p53 target genes, including mir-34a. This was a phenotypic effect, as NR4A2 overexpression could rescue cells from p53-induced inhibition of proliferation. In summary, our results are the first characterization of a cancer-related miRNA capable of regulating NR4A2 and suggest a network and possible feedback mechanism involving p53, miR-34, and NR4A2.

Cushing disease (CD) is a life-threatening disorder attributed to excess pituitary tumor-derived adrenocorticotrophic hormone (ACTH) and adrenal steroid secretion caused by pituitary tumors. Whereas CD was first described in 1932, the underlying genetic basis driving tumor growth and ACTH secretion remains unsolved. Here, we show that testicular orphan nuclear receptor 4 (TR4, nuclear receptor subfamily 2, group C, member 2) is overexpressed in human corticotroph tumors as well as in human and mouse corticotroph tumor cell lines. Forced overexpression of TR4 in both human and murine tumor cells increased proopiomelanocortin transcription, ACTH secretion, cellular proliferation, and tumor invasion rates in vitro. Conversely, knockdown of TR4 expression reversed all phenotypes. Mechanistically, we show that TR4 transcriptionally activates proopiomelanocortin through binding of a direct repeat 1 response element in the promoter, and that this is enhanced by MAPK-mediated TR4 phosphorylation. In vivo, TR4 overexpression promotes murine corticotroph tumor growth as well as enhances ACTH and corticosterone production, whereas TR4 knockdown decreases circulating ACTH and corticosterone levels in mice harboring ACTH-secreting tumors. Our findings directly link TR4 to the etiology of corticotroph tumors, hormone secretion, and cell growth as well as identify it as a potential target in the treatment of CD.

Obesity is a severe disease worldwide. Mitochondrial autophagy (mitophagy) may be related to metabolic abnormalities in obese individuals, but the mechanism is still unclear. We aimed to investigate whether nuclear receptors NR1D1 and ULK1 influence obesity by affecting mitophagy. In vitro model was established by inducing 3T3-L1 cells differentiation. MTT was detected cell viability. ELISA was tested triglyceride (TG). Oil red O staining was performed to detect lipid droplets. Flow cytometry was measured mtROS. ChIP and Dual-luciferase reporter assay were verified NR1D1 bind to ULK1. LC3 level was detected by IF. After differentiation medium treatment, cell viability was decreased, TG content and lipid droplets were increased Moreover, NR1D1 expression was reduced in Model group. NR1D1 overexpression was increased cell viability, reduced TG content and lipid droplets. Subsequently, NR1D1 inhibited TOM20 and mtROS, whereas, Parkin and PINK1 were accelerated. NR1D1 overexpression facilitated LC3 expression, whereas ULK1 knockdown was reversed the effect of NR1D1 overexpression. Liensinine also reversed the effect of NR1D1 overexpression, that is, cell viability was reduced, mtROS, TG content and lipid droplets were increased. The combination of nuclear receptor NR1D1 and ULK1 promoted mitophagy in adipocytes to alleviate obesity, which provided new target and strategy for obesity treatment.Abbreviations: Mitochondrial autophagy (mitophagy), triglyceride (TG), Uncoordinated-51 like autophagy activating kinase 1 (ULK1), Nuclear receptor subfamily 1 group D member 1 (NR1D1), American Type Culture Collection (ATCC), fetal bovine serum (FBS), 3-isobutyl-1-methylxanthine (IBMX), dexamethasone (DEX), short hairpin RNA ULK1 (sh-ULK1), wild-type (WT), mutant (MUT), Enzyme-linked immunosorbent assay (ELISA), mitochondrial reactive oxygen species (mtROS), Chromatin immunoprecipitation (ChIP), Quantitative real-time PCR (qRT-PCR), Immunofluorescence (IF), standard deviation (SD).

Nuclear receptors (NRs) are a superfamily of transcription factors which sense hormonal signals or nutrients to regulate various biological events, including development, reproduction, and metabolism. Here, this study identifies nuclear receptor subfamily 2, group F, member 6 (NR2F6), as an important regulator of hepatic triglyceride (TG) homeostasis and causal factor in the development of non-alcoholic fatty liver disease (NAFLD). Adeno-associated virus (AAV)-mediated overexpression of NR2F6 in the liver promotes TG accumulation in lean mice, while hepatic-specific suppression of NR2F6 improves obesity-associated hepatosteatosis, insulin resistance, and methionine and choline-deficient (MCD) diet-induced non-alcoholic steatohepatitis (NASH). Mechanistically, the fatty acid translocase CD36 is identified as a transcriptional target of NR2F6 to mediate its steatotic role. NR2F6 is able to bind directly onto the CD36 promoter region in hepatocytes and increases the enrichment of nuclear receptor coactivator 1 (SRC-1) and histone acetylation at its promoter. Of pathophysiological significance, NR2F6 is significantly upregulated in the livers of obese mice and NAFLD patients. Moreover, treatment with metformin decreases NR2F6 expression in obese mice, resulting in suppression of CD36 and reduced hepatic TG contents. Therefore, these results provide evidence for an unpredicted role of NR2F6 that contributes to liver steatosis and suggest that NR2F6 antagonists may present a therapeutic strategy for reversing or treating NAFLD/NASH pathogenesis.

Shear stress, particularly low and oscillatory shear stress, plays a critical pathophysiological role in vascular remodeling-related cardiovascular diseases. Growing evidence suggests that the orphan nuclear receptor Nur77 [also known as TR3 or nuclear receptor subfamily 4, group A, member 1 (NR4A1)] is expressed in diseased human vascular tissue and plays an important role in vascular physiology and pathology. In the present study, we used a mouse model of flow-dependent remodeling by partial ligation of the left common carotid artery (LCCA) to define the exact role of Nur77 in vascular remodeling induced by low shear stress. Following vascular remodeling, Nur77 was highly expressed in neointimal vascular smooth muscle cells (VSMCs) in the ligated carotid arteries. The reactive oxygen species (ROS) levels were elevated in the remodeled arteries in vivo and in primary rat VSMCs in vitro following stimulation with platelet-derived growth factor (PDGF). Further in vitro experiments revealed that Nur77 expression was rapidly increased in the VSMCs following stimulation with PDGF and H2O2, whereas treatment with N-acetyl cysteine (NAC, a ROS scavenger) reversed the increase in the protein level of Nur77 induced by H2O2. Moreover, Nur77 overexpression markedly inhibited the proliferation and migration of VSMCs, induced by PDGF. Finally, to determine the in vivo role of Nur77 in low shear stress-induced vascular remodeling, wild-type (WT) and Nur77-deficient mice were subjected to partial ligation of the LCCA. Four weeks following surgery, in the LCCAs of the Nur77‑deficient mice, a significant increase in the intima-media area and carotid intima-media thickness was noted, as well as more severe elastin disruption and collagen deposition compared to the WT mice. Immunofluorescence staining revealed an increase in VSMC proliferation [determined by the expression of proliferating cell nuclear antigen (PCNA)] and matrix metalloproteinase 9 (MMP-9) production in the Nur77-deficient mice. There was no difference in the number of intimal apoptotic cells between the groups. Taken together, our results indicate that Nur77 may be a sensor of oxidative stress and an inhibitor of vascular remodeling induced by low shear stress. Nur77, as well as its downstream cell signals, may thus be a potential therapeutic target for the suppression of vascular remodeling.

The present study evaluated expression patterns of chemokine (C-C motif) ligand 2 gene/Monocyte chemoattractant protein-1 gene (CCL2/MCP-1), prostaglandin F2 alpha receptor gene (PTGFR) and immediate early genes including nuclear receptor subfamily 4, group A, member 1 (NR4A1), early growth response 1 (EGR1) and FBJ murine osteosarcoma viral oncogene homolog (FOS) in cells of the bovine corpus luteum after intrauterine infusion of a low dose of prostaglandin F2α (PGF2A) aimed at enhancing our understanding of the mechanisms of luteolysis. Holstein dairy cows were superovulated (>6 corpora lutea [CL]) and on day 9 of the estrous cycle were infused with a low dose of PGF2A (0.5 mg PGF2A in 0.25 ml phosphate buffered saline) into the greater curvature of the uterine horn ipsilateral to the CL. Ultrasound-guided biopsy samples of different CL were collected at 0 min, 15 min, 30 min, 1h, 2h and 6h after PGF2A infusion. Expression profiles and localization of mRNA for PTGFR, CCL2/MCP-1, and immediate early genes (NR4A1, EGR1 and FOS), were investigated by using qPCR and in situ hybridization. The concentrations of early response genes including FOS, NR4A1, and EGR1 exhibited the greatest increase at 30 min after PGF2A, compared to other time points. Expression profile of CCL2 mRNA increased gradually after intrauterine infusion of PGF2A with maximal up-regulation for CCL2 at 6h. Abundance of PTGFR mRNA only increased at 15 min and significantly decreased at 6h, compared to 0 min. Cellular localizations of all studied genes except CCL2 (primarily localized to apparent immune cells) were predominantly visualized in large luteal cells. Interestingly, early response genes demonstrated a changing profile in cellular localization with initial responses appearing to be in both large luteal cells and endothelial cells, although no staining for PTGFR mRNA was observed in endothelial cells. Later, sustained responses, were only observed in large luteal cells, although PTGFR mRNA was decreasing in large luteal cells over time after PGF2A. The involvement of the immune system was also highlighted by the immediate increases in CCL2 mRNA that became much greater over time as there was an apparent influx of CCL2-positive immune cells. Thus, the temporal and cell-specific localization patterns for the studied mRNA demonstrate the complex pathways that are responsible for initiation of luteolysis in the bovine CL.

The neural cell adhesion molecule (NCAM) is the major carrier of polysialic acid (PSA) which modulates NCAM functions of neural cells at the cell surface. In previous studies, we have shown that stimulation of cultured neurons with surrogate NCAM ligands leads to the generation and nuclear import of PSA-lacking and -carrying NCAM fragments. Here, we show that the nuclear import of the PSA-carrying NCAM fragment is mediated by positive cofactor 4 and cofilin, which we identified as novel PSA-binding proteins. In the nucleus, the PSA-carrying NCAM fragment interacts via PSA with PC4 and cofilin, which are involved in RNA polymerase II-dependent transcription. Microarray analysis revealed that the nuclear PSA-carrying and -lacking NCAM fragments affect expression of different genes. By qPCR and immunoblot analysis we verified that the nuclear PSA-carrying NCAM fragment increases mRNA and protein expression of nuclear receptor subfamily 2 group F member 6, whereas the PSA-lacking NCAM fragment increases mRNA and protein expression of low density lipoprotein receptor-related protein 2 and α-synuclein. Differential gene expression evoked by nuclear NCAM fragments without and with PSA indicates that PSA-carrying and -lacking NCAM play different functional roles in the nervous system.

Nuclear receptor subfamily 5 group A member 2 (Nr5a2) is widely involved in the physiological and pathological processes of the pancreas. However, the cytological and molecular evidence regarding how Nr5a2 implicated in acute pancreatitis (AP) remains insufficient. Here, we explored this problem by using cellular AP model in both normal and Nr5a2 silenced AR42J pancreatic acinar cells. An in vitro cellular model of AP was established by stimulating AR42J cells with caerulein (CAE) for 24 h. Reduced Nr5a2 expression was observed in the CAE-treated cells. Nr5a2 silencing led to AP-like inflammation, with increased interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α mRNA levels. In the cellular AP model, Nr5a2 silencing further increased IL-1β, IL-6, and TNF-α mRNA levels, as well as amylase activity. In addition, we found that Nr5a2 silencing did not affect IL-10 level under physiological conditions but inhibited the anti-inflammatory response of IL-10 in AP model. Moreover, in CAE-induced pancreatic inflammation, Nr5a2 silencing increased the apoptosis and necrosis of acinar cells and inhibited the proliferation of acinar cells, which has not been shown previously. Further experiments showed, for the first time, that Nr5a2 silencing downregulated the expression of β-catenin and its downstream target gene T-cell factor (TCF)-4 in the cellular AP model but increased the expression of nuclear factor (NF)-κB. In conclusion, in CAE-induced pancreatic inflammation, lower Nr5a2 level leads to downregulation of β-catenin and its downstream target gene TCF-4 and upregulation of NF-κB, which exacerbates the inflammatory response and cell damage and inhibits the proliferation and regeneration of acinar cells.

Accumulation of fatty acids and neutral lipids in nonadipose tissues is cytotoxic. We recently showed that ERBB2-positive breast cancer cells produce significantly high amounts of fats, because of overexpression of the peroxisome proliferator-activated receptor (PPAR)gamma-binding protein and the nuclear receptor NR1D1 (nuclear receptor subfamily 1, group D, member 1; Rev-erbalpha). These genes upregulate de novo fatty acid synthesis, which is a critical pathway for the energy production and survival of these cells. NR1D1 and PPARgamma-binding protein are functionally related to PPARgamma, a well established positive regulator of adipogenesis and lipid storage.

Pregnane X receptor (PXR), which is a member of the nuclear receptor protein family (nuclear receptor subfamily 1 group I member 2 [NR 1I2]), mediates the drug-resistance in the hepatocellular carcinoma (HCC) via enhancing the expression of drug-resistance-related genes which accelerate the clearance of antitumor drugs, eg, sorafenib. However, there are few reports on miRNA targeting PXR participating in the epigenetic regulation of PXR in HCC cells.