Retinoic Acid Receptor Responder Research Articles

Characterization of RARRES1 Expression on Circulating Tumor Cells as Unfavorable Prognostic Marker in Resected Pancreatic Ductal Adenocarcinoma Patients.

Simple SummaryOur explorative study used a microfluidic-based approach for circulating tumor cell (CTC) detection in 55 pancreatic ductal adenocarcinoma (PDAC) patients before treatment initiation (baseline) and during follow-up (FUP). For the first time, we assessed the expression of retinoic acid receptor responder 1 (RARRES1) on CTCs. CTCs were detected in 25.5% of patients at baseline, while the detection rate during FUP was higher (45.5%). Especially high CTC counts during FUP in resected patients were associated with early tumor relapse (p = 0.02). Combining CTC detection and RARRES1 protein expression showed that RARRES1-positive patients with high CTCs counts after curative operation during FUP had a worse prognosis (p = 0.001). In conclusion, RARRES1 is a new marker of interest for further research investigations on subtypes of CTCs in PDAC.Background: In pancreatic ductal adenocarcinoma (PDAC), the characterization of circulating tumor cells (CTCs) opens new insights into cancer metastasis as the leading cause of cancer-related death. Here, we focused on the expression of retinoic acid receptor responder 1 (RARRES1) on CTCs as a novel marker for treatment failure and early relapse. Methods: The stable isotope labeling of amino acids in cell culture (SILAC)—approach was applied for identifying and quantifying new biomarker proteins in PDAC cell lines HPDE and its chemoresistant counterpart, L3.6pl-Res. Fifty-five baseline and 36 follow-up (FUP) peripheral blood samples were processed via a marker-independent microfluidic-based CTC detection approach using RARRES1 as an additional marker. Results: SILAC-based proteomics identified RARRES1 as an abundantly expressed protein in more aggressive chemoresistant PDAC cells. At baseline, CTCs were detected in 25.5% of all PDAC patients, while FUP analysis (median: 11 months FUP) showed CTC detection in 45.5% of the resected patients. CTC positivity (≥3 CTC) at FUP was significantly associated with short recurrence-free survival (p = 0.002). Furthermore, detection of RARRES1 positive CTCs was indicative of an even earlier relapse after surgery (p = 0.001). Conclusions: CTC detection in resected PDAC patients during FUP is associated with a worse prognosis, and RARRES1 expression might identify an aggressive subtype of CTCs that deserves further investigation.

Amniotic fluid biomarkers predict the severity of congenital cytomegalovirus infection.

BACKGROUNDCytomegalovirus (CMV) is the most common intrauterine infection, leading to infant brain damage. Prognostic assessment of CMV-infected fetuses has remained an ongoing challenge in prenatal care, in the absence of established prenatal biomarkers of congenital CMV (cCMV) infection severity. We aimed to identify prognostic biomarkers of cCMV-related fetal brain injury.METHODSWe performed global proteome analysis of mid-gestation amniotic fluid samples, comparing amniotic fluid of fetuses with severe cCMV with that of asymptomatic CMV-infected fetuses. The levels of selected differentially excreted proteins were further determined by specific immunoassays.RESULTSUsing unbiased proteome analysis in a discovery cohort, we identified amniotic fluid proteins related to inflammation and neurological disease pathways, which demonstrated distinct abundance in fetuses with severe cCMV. Amniotic fluid levels of 2 of these proteins — the immunomodulatory proteins retinoic acid receptor responder 2 (chemerin) and galectin-3–binding protein (Gal-3BP) — were highly predictive of the severity of cCMV in an independent validation cohort, differentiating between fetuses with severe (n = 17) and asymptomatic (n = 26) cCMV, with 100%–93.8% positive predictive value, and 92.9%–92.6% negative predictive value (for chemerin and Gal-3BP, respectively). CONCLUSIONAnalysis of chemerin and Gal-3BP levels in mid-gestation amniotic fluids could be used in the clinical setting to profoundly improve the prognostic assessment of CMV-infected fetuses.FUNDINGIsrael Science Foundation (530/18 and IPMP 3432/19); Research Fund – Hadassah Medical Organization.

Socioeconomic disparity in cardiovascular disease: Possible biological pathways based on a proteomic approach

Background and aimsLarge social disparities in the occurrence of cardiovascular disease (CVD) have been documented but the underlying biological mechanisms are largely unknown. We investigated a panel of biomarkers linked to CVD to improve our understanding and quantify the biological pathways in socioeconomic disparity in CVD and their mediation through behavioural and biological risk factors. MethodsWe included 1142 participants from the Copenhagen City Heart Study aged 55–64 years. Socioeconomic position (SEP) was defined by the length of education and household income. Blood samples were analysed for 184 biomarkers (Olink). Pearson's correlation analysis and linear regression with multivariate adjustment for CVD risk factors were performed. ResultsThe median length of education was 10 (IQR 7–11) years and associated with age, sex, BMI, smoking, blood pressure, physical activity and income. 48 biomarkers were significantly correlated (p < 0.05) to the length of education. The strongest negative associations were seen for interleukin-6 (IL-6), metalloproteinase 12, growth/differentiation factor 15 (GDF-15), retinoic acid receptor responder protein 2 (RARRES2), leptin (LEP), von Willebrand factor (vWF), and renin (REN) (all p < 0.0001) while the strongest positive associations were seen for chymotrypsin, paraoxonase, epidermal growth factor receptor (EGFR) and brother of CDO (cell adhesion and platelet activation) (all p < 0.001). Proportion mediated by CVD risk factors ranged from <1% to 100%. After multivariate adjustment, 14 biomarkers remained significantly associated with education. ConclusionsSEP was associated with multiple biomarkers, indicating pathways involving inflammation (IL-6, RARRES2), platelet-activation (vWF, IL-6), blood pressure (REN, LEP) and Mitogen-activated protein kinase cascade (GDF-15, EGFR) may contribute to the socioeconomic differences in CVD.

Involvement of miR-769-5p/Retinoic Acid Receptor Responder 1 Axis in the Progression of Osteosarcoma: Characterization of Potential Therapeutic Targets

Introduction: This study aimed to detect the function of retinoic acid receptor responder 1 (RARRES1) and its regulator miR-769-5p in the growth and mobility of osteosarcoma cells. Methods: The Gene Expression Omnibus database was applied to analyze RARRES1 and miR-769-5p expression, and the survival rate of osteosarcoma patients. The target association between miR-769-5p and RARRES1 was speculated by miRWalk, TargetScan, and miRanda Web sites, as well as affirmed by dual luciferase assay. RARRES1 expression was tested by quantitative real-time polymerase chain reaction and Western blot. The malignant properties of MG-63 and U2OS cells were assessed by a series of biological experiments. Results: RARRES1 was lowly expressed in osteosarcoma patients, which resulted in unfavorable survival. Depletion of RARRES1 promoted the viability and mobility of osteosarcoma cells. Moreover, miR-769-5p was affirmed as an upstream regulator of RARRES1 and negatively regulated RARRES1 expression. miR-769-5p upregulation accelerated the viability and mobility of osteosarcoma cells, which can be blocked by RARRES1 overexpression. miR-769-5p inhibitor suppressed the effect of malignant viability and mobility of osteosarcoma cells, while this suppressive effect was abolished by depleting RARRES1. Discussion/Conclusion: miR-769-5p promoted cell viability, invasion, and migration by reducing RARRES1 expression in osteosarcoma cells, which might provide novel targets for the treatment of osteosarcoma.

Loss of RARRES1 function Promotes Follicular Lymphomagenesis and Inhibits B cell Differentiation in Mice.

Retinoic acid receptor responder 1 (RARRES1) is among the most commonly methylated loci in multiple cancers. RARRES1 regulates mitochondrial and fatty acid metabolism, stem cell differentiation, and survival of immortalized cell lines in vitro. Here, we created constitutive Rarres1 knockout (Rarres1-/-) mouse models to study RARRES1 function in vivo. Rarres1-/- embryonic fibroblasts regulated tubulin glutamylation, cell metabolism, and survival, recapitulating RARRES1 function in immortalized cell lines. In two mouse strains, loss of Rarres1 led to a markedly increased dose-dependent incidence of follicular lymphoma (FL). Prior to lymphoma formation, Rarres1-/- B cells have compromised activation, maturation, differentiation into antibody-secreting plasma cells, and cell cycle progression. Rarres1 ablation increased B cell survival and led to activation of the unfolded protein response (UPR) and heat shock response (HSR). Rarres1 deficiency had differential effects on cellular metabolism, with increased bioenergetic capacity in fibroblasts, and minor effects on bioenergetics and metabolism in B cells. These findings reveal that RARRES1 is a bona fide tumor suppressor in vivo and the deletion in mice promotes cell survival, and reduces B cell differentiation with B cell autonomous and non-autonomous functions.

Expression of chemerin in intestinal mucosa of calves with comparable expression level with other antimicrobial proteins.

Neonatal calves are highly susceptible to infectious disorders including diarrhea. Therefore, epithelial innate immunity, including antimicrobial peptides/proteins (AMPs), is important during the early stage of their lives. Chemerin, a multifunctional protein that was originally identified as a chemokine, possesses a potent antimicrobial activity. The present study investigated the expression levels of chemerin in the gastrointestinal (GI) tract of growing calves. Chemerin and its coding gene, retinoic acid receptor responder protein 2 (RARRES2), were highly expressed in duodenum, jejunum, and ileum compared with other parts of the GI tract. Immunohistochemistry demonstrated that chemerin-producing cells were localized in the crypt of the intestinal mucosa. Finally, the expression level of RARRES2 was higher compared with those of other major AMPs in duodenum, although it was lower compared with that of enteric β-defensin but mostly higher than those of other AMPs in jejunum and ileum at various ages in calves. The expression levels of RARRES2 were not influenced by the age of calves in duodenum and jejunum, whereas a higher expression level of RARRES2 in ileum was observed in younger calves. This study revealed that chemerin is produced in the small intestine of calves and has the potential to contribute to the gut epithelial barrier system.

Autocrine and paracrine effects of a novel podocyte gene, RARRES1

Retinoic acid receptor responder protein 1 (RARRES1) has been identified as a novel gene for the regulation of podocyte function, and its expression is increased in glomerular disease and associated with disease progression. Increased expression of RARRES1 in podocytes leads to apoptosis through an autocrine effect. Möller-Hackbarth etal. recently found that RARRES1 expression is increased in the endothelial cells in some diseased kidneys to promote podocyte injury, likely through a paracrine effect.

Retinoic acid receptor responder1 promotes development of glomerular diseases via the Nuclear Factor-κB signaling pathway

Inflammatory pathways are activated in most glomerular diseases but molecular mechanisms driving them in kidney tissue are poorly known. We identified retinoic acid receptor responder 1 (Rarres1) as a highly podocyte-enriched protein in healthy kidneys. Studies in podocyte-specific knockout animals indicated that Rarres1 was not needed for the normal development or maintenance of the glomerulus filtration barrier and did not modulate the outcome of kidney disease in a model of glomerulonephritis. Interestingly, we detected an induction of Rarres1 expression in glomerular and peritubular capillary endothelial cells in IgA and diabetic kidney disease, as well as in ANCA-associated vasculitis. Analysis of publicly available RNA data sets showed that the induction of Rarres1 expression was a common molecular mechanism in chronic kidney diseases. A conditional knock-in mouse line, overexpressing Rarres1 specifically in endothelial cells, did not show any obvious kidney phenotype. However, the overexpression promoted the progression of kidney damage in a model of glomerulonephritis. In line with this, conditional knock-out mice, lacking Rarres1 in endothelial cells, were partially protected in the disease model. Mechanistically, Rarres1 promoted inflammation and fibrosis via transcription factor Nuclear Factor-κB signaling pathway by activating receptor tyrosine kinase Axl. Thus, induction of Rarres1 expression in endothelial cells is a prevalent molecular mechanism in human glomerulopathies and this seems to have a pathogenic role in driving inflammation and fibrosis via the Nuclear Factor-κB signaling pathway.

Single Nucleotide Polymorphism rs17173608 in the Chemerin Encoding Gene: Is It a Predictor of Insulin Resistance and Severity of Coronary Artery Disease in Non-Obese Type 2 Diabetes?

(1) Background: Chemerin, or the RARRES2 (Retinoic Acid Receptor Responder 2) gene, is found to be associated with an increased incidence of insulin resistance, endothelial dysfunction, type 2 diabetes (T2D), and coronary artery disease (CAD). This study investigates associations of RARRES2 rs17173608 with insulin resistance and the severity of CAD in non-obese T2D patients in relation to the clinical and genetic factors. (2) Methods: A total of 300 patients with T2D and CAD were recruited in this study. The associations of insulin resistance and the severity of CAD with RARRES2 rs17173608 and clinical factors were assessed. The genotyping procedures were performed using the TaqMan method. The significant associations (p ≤ 0.05) from preliminary tests were employed to carry out the secondary analysis. (3) Results: RARRES2 rs17173608 (TT, TG, and GG polymorphisms in the preliminary analysis; TG and GG polymorphisms in a secondary analysis) was associated with insulin resistance and the severity of CAD in both the preliminary and secondary analysis (all p-values were < 0.05). Additionally, in the secondary analysis, FPG and ACEI were also associated with insulin resistance and the severity of CAD (all p-values were < 0.05). (4) Conclusion: From the preliminary findings, rs17173608 is a significant predictor of insulin resistance and the severity of CAD.

Proteomic alterations in the plasma of Beagle dogs induced by Toxocara canis infection

Toxocara canis causes ocular larva migrans and visceral larva migrans in humans. Knowledge about the molecular mechanism of T. canis-hosts interaction is limited. The proteomic alterations in the plasma of Beagle dogs induced by T. canis infection were studied by the quantitative mass spectrometry-based data-independent acquisition (DIA). 418, 414 and 411 plasma proteins were identified at 24 h post-infection (hpi), 96 hpi and 36 days post-infection (dpi), including 6, 5 and 23 proteins with differential abundance, respectively. At 24 hpi, the altered proteins, retinoic acid receptor responder protein 2 (RARRES2), WD repeat-containing protein 1 (WDR1), moesin and filamin-A, may participate in pro-inflammatory reaction or promote larvae migration. At 96 hpi, the altered protein C and fibroleukin may maintain the stability of the coagulation system to protect the lung. At 36 dpi, the alterations of C-reactive protein (CRP), ficolin (FCN), complement factor H-related protein 5 (CFHR5) and other complements can affect the three traditional complement system, including the classic pathway, lectin pathway and alternative pathway. These proteins may play important roles in the interaction between T. canis and its definitive hosts. Further study on these altered proteins triggered by T. canis infection may discovery novel therapeutic or diagnostic targets for toxocariasis. Significance of the studyToxocara canis is one of the globally distributed soil-transmitted helminths, which causes ocular larva migrans and visceral larva migrans in humans and a wide range of warm-blooded animals. T. canis adapts to different microenvironments by resisting and adjusting various biological processes of the hosts. Knowledge about the molecular mechanism of T. canis-hosts interaction is limited. Plasma proteins are good marker for monitoring the occurrence and development of diseases. The proteomic alterations in the plasma of Beagle dogs induced by T. canis infection were studied by the quantitative mass spectrometry-based data-independent acquisition (DIA) in this study. A total of 418, 414 and 411 plasma proteins were identified at 24 h post-infection (hpi), 96 hpi and 36 days post-infection, respectively. Ten protein with differential abundances were validated by using parallel reaction monitoring (PRM). Collectively, our deep proteomic analysis of plasma revealed that proteins alterations were affected by disease development, and proteomic analysis is an ideal method for quantifying changes in circulating factors on a global scale in response to pathophysiological perturbations such as T. canis infection.

Chemerin Reactivates PTEN and Suppresses PD-L1 in Tumor Cells via Modulation of a Novel CMKLR1-mediated Signaling Cascade.

Chemerin (retinoic acid receptor responder 2, RARRES2) is an endogenous leukocyte chemoattractant that recruits innate immune cells through its receptor, ChemR23. RARRES2 is widely expressed in nonhematopoietic tissues and often downregulated across multiple tumor types compared with normal tissue. Recent studies show that augmenting chemerin in the tumor microenvironment significantly suppresses tumor growth, in part, by immune effector cells recruitment. However, as tumor cells express functional chemokine/chemoattractant receptors that impact their phenotype, we hypothesized that chemerin may have additional, tumor-intrinsic effects. We investigated the effect of exogenous chemerin on human prostate and sarcoma tumor lines. Key signaling pathway components were elucidated using qPCR, Western blotting, siRNA knockdown, and specific inhibitors. Functional consequences of chemerin treatment were evaluated using in vitro and in vivo studies. We show for the first time that human tumors exposed to exogenous chemerin significantly upregulate PTEN expression/activity, and concomitantly suppress programmed death ligand-1 (PD-L1) expression. CMKLR1 knockdown abrogated chemerin-induced PTEN and PD-L1 modulation, exposing a novel CMKLR1/PTEN/PD-L1 signaling cascade. Targeted inhibitors suggested signaling was occurring through the PI3K/AKT/mTOR pathway. Chemerin treatment significantly reduced tumor migration, while significantly increasing T-cell-mediated cytotoxicity. Chemerin treatment was as effective as both PD-L1 knockdown and the anti-PD-L1 antibody, atezolizumab, in augmenting T-cell-mediated tumor lysis. Forced expression of chemerin in human DU145 tumors significantly suppressed in vivo tumor growth, and significantly increased PTEN and decreased PD-L1 expression. Collectively, our data show a novel link between chemerin, PTEN, and PD-L1 in human tumor lines, which may have a role in improving T-cell-mediated immunotherapies.

Soluble RARRES1 induces podocyte apoptosis to promote glomerular disease progression.

Using the Nephrotic Syndrome Study Network Consortium data set and other publicly available transcriptomic data sets, we identified retinoic acid receptor responder protein 1 (RARRES1) as a gene whose expression positively correlated with renal function decline in human glomerular disease. The glomerular expression of RARRES1, which is largely restricted to podocytes, increased in focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD). TNF-α was a potent inducer of RARRES1 expression in cultured podocytes, and transcriptomic analysis showed the enrichment of cell death pathway genes with RARRES1 overexpression. The overexpression of RARRES1 indeed induced podocyte apoptosis in vitro. Notably, this effect was dependent on its cleavage in the extracellular domain, as the mutation of its cleavage site abolished the apoptotic effect. Mechanistically, the soluble RARRES1 was endocytosed and interacted with and inhibited RIO kinase 1 (RIOK1), resulting in p53 activation and podocyte apoptosis. In mice, podocyte-specific overexpression of RARRES1 resulted in marked glomerular injury and albuminuria, while the overexpression of RARRES1 cleavage mutant had no effect. Conversely, podocyte-specific knockdown of Rarres1 in mice ameliorated glomerular injury in the setting of adriamycin-induced nephropathy. Our study demonstrates an important role and the mechanism of RARRES1 in podocyte injury in glomerular disease.

The yin and yang of retinoic acid signaling in kidney diseases.

Retinoic acid (RA) signaling is involved in various physiological and pathological conditions, including development, tumorigenesis, inflammation, and tissue damage and repair. In kidneys, the beneficial effect of RA has been reported in multiple disease models, such as glomerulosclerosis, renal fibrosis, and acute kidney injury. In this issue of the JCI, Chen et al. report a pathway activated by RA signaling that is mediated by the retinoic acid receptor responder protein 1 (RARRES1). Specifically, RARRES1, which is proteolytically cleaved to release the extracellular domain, was endocytosed by podocytes to induce apoptosis and glomerular dysfunction kidney disease. These findings unveil the contrasting aspects, a Janus face, of RA signaling that may guide its therapeutic use.

The methylation status of the chemerin promoter region located from \u2212\u2009252 to +\u2009258\xa0bp regulates constitutive but not acute-phase cytokine-inducible chemerin expression levels

Chemerin is a chemoattractant protein with adipokine properties encoded by the retinoic acid receptor responder 2 (RARRES2) gene. It has gained more attention in the past few years due to its multilevel impact on metabolism and immune responses. However, mechanisms controlling the constitutive and regulated expression of RARRES2 in a variety of cell types remain obscure. To our knowledge, this report is the first to show that DNA methylation plays an important role in the cell-specific expression of RARRES2 in adipocytes, hepatocytes, and B lymphocytes. Using luciferase reporter assays, we determined the proximal fragment of the RARRES2 gene promoter, located from − 252 to + 258 bp, to be a key regulator of transcription. Moreover, we showed that chemerin expression is regulated in murine adipocytes by acute-phase cytokines, interleukin 1β and oncostatin M. In contrast with adipocytes, these cytokines exerted a weak, if any, response in mouse hepatocytes, suggesting that the effects of IL-1β and OSM on chemerin expression is specific to fat tissue. Together, our findings highlight previously uncharacterized mediators and mechanisms that control chemerin expression.

Prognostic Value of Serum Retinoic Acid Receptor Responder Protein 2 (RARRES2) in Chronic Hepatitis C Patients

Abstract Background: Adipocytokines play an important role in the development of metabolic abnormality and fibrogenesis in Chronic Hepatitis C virus (CHC) infection. The prognosis of CHC is still ill-defined. Liver biopsy for staging liver injury comprises variable risks. Many biochemical markers that mirror liver injury progression have been suggested. Aim of Study: The aim of this work is to measure the levels of serum Retinoic Acid Receptor Responder Protein 2 (RARRES2) and leptin in normal weight female CHC patients, as well as to study the correlation between these cytokines and the markers of liver damage, to assess the prognosis of chronic hepatitis C. Subjects and Methods: This study included 100 normal weight (BMI <25) female subjects; 50 patients of CHC, aged (43.50±6.31), and 50 healthy controls, aged (44.32±5.10). CHC was confirmed by the Polymerase Chain Reaction (PCR). Laboratory investigations included albumin, bilirubin, pro-thrombin time (the Child Pugh score), fasting glucose, fasting insulin, insulin resistance (HOMA-IR), alanine aminotrans-ferase (ALT), aspartate aminotransferase (AST), AST/ALT and Alkaline Phosphatase (ALP) activities along with serum RARRES2, leptin and alpha-fetoprotein. Results: Serum RARRES2, leptin, total bilirubin, pro-thrombin time (INR), ALT and AST activities were significantly higher, and albumin was significantly lower in the normal weight female CHC patients compared to the control. A significant negative correlation between each of RARRES2 and leptin with albumin; and a significant positive correlation between RARRES2 and INR; indicate that these adipokines increase as liver function worsens. Conclusion: The serum levels of RARRES2 and leptin may be considered additional non-invasive markers of prog-nostic significance in CHC patients.

The associations among RARRES2 rs17173608 gene polymorphism, serum chemerin, and non-traditional lipid profile in patients with metabolic syndrome

BackgroundThe adipokine chemerin retinoic acid receptor responder protein 2 (RARRES2) has been associated with insulin resistance, type II diabetes mellitus (T2DM), obesity, and metabolic syndrome (MetS). The impact of RARRES2 rs17173608 gene polymorphism on MetS and chemerin levels is not completely elucidated. This study included 100 patients with MetS and 68 healthy subjects (non-MetS group). The RARRES2 rs17173608 gene variant was analyzed by tetra amplification refractory mutation system polymerase chain reaction (T-ARMS-PCR). Circulating chemerin levels were determined by ELISA. Serum urea, creatinine, fasting blood glucose, glycated hemoglobin, and traditional lipid profile were measured by colorimetric methods. The estimated glomerular filtration rate (eGFR) and non-traditional lipid parameters were calculated.ResultsSerum chemerin levels were significantly higher in MetS than in non-MetS subjects, type II diabetics (T2DM) than non-diabetics, and overweight compared to lean subjects, but it did not differ significantly between patients with and without hypertension. Strikingly, newly diagnosed diabetic patients had significantly higher serum chermerin levels. Correlation and multiple linear regression analysis showed that serum chemerin levels and non-traditional lipid parameters were correlated significantly with the clinical criteria of MetS. Genotyping and allelic frequency distribution of RARRES2 rs17173608 gene polymorphism showed its significant association with MetS. The TT genotype of RARRES2 rs17173608 SNP was more distributed in T2DM in comparison with non-diabetics, and it was associated significantly with higher serum chemerin and higher glycated hemoglobin levels. RARRES2 rs17173608 GG genotype and G allele frequency were less distributed in T2DM patients than in non-diabetic patients.ConclusionsThe RARRES2 rs17173608 SNP might have an impact on chemerin levels and lipid parameters. The GG genotype and G allele may have a protective role towards the risk of T2DM but not for MetS. Serum chemerin and non-traditional lipid profile are significantly associated with MetS.

Association of the 7q36.1 region gene variant rs4721 with risk of breast cancer in Iranian-Azeri population

Breast cancer (BC) after non-melanoma skin cancer is the most current malignancy of women. According to World Health Organization (WHO) statistics, female BC is the fifth leading cause of death (627,000 deaths, 6.6%) and 76% of prevalent malignancies in Iranian women. Chemerin (retinoic acid receptor responder 2, RARRES2 or tazarotene induced gene 2, TIG2), as an inflammatory adipocytokine associated with autocrine and paracrine chemotaxis for leukocyte populations expressing ChemR23. The role of this gene in different cancers have been evaluated. The current studied group included 250 women with BC and 250 healthy women. Genotypes were determined by direct Sanger sequencing to determine T > G (rs4721) polymorphism in the 3′ UTR of the chemerin gene. Genotype frequencies of patients were 36.0%GG, 40.8%GT and 23.2%TT. Frequencies of G and T alleles were 56.4% and 43.6 in patients and 49% and 51% in healthy individuals, respectively. In healthy women, genotype frequencies of GG, GT and TT were 26%, 46% and 30%, respectively. The association between genotype and grade, size, stage and lymph was significant (p < .05) but there were no association between genotype and tumor type, side of the tumor and age of the patients (p > .05). To date, in our knowledge, no study has been conducted in the relation between chemerin rs4721 polymorphism and the risk of breast cancer. Our study is the first to demonstrate a significant correlation between BC risk and homozygote GG genotype of rs4721 polymorphism in Iranian-Azeri population.

Peptide-Carbon Quantum Dots conjugate, Derived from Human Retinoic Acid Receptor Responder Protein 2, against Antibiotic-Resistant Gram Positive and Gram Negative Pathogenic Bacteria.

Antibiotic-resistant bacterial infections have become global issues for public health, which increases the utter need to develop alternatives to antibiotics. Here, the HSER (Homo sapiens retinoic acid receptor) peptide was designed from retinoic acid receptor responder protein 2 of Homo sapiens, and was conjugated with synthesized CQDs (carbon quantum dots) for enhanced antibacterial activity in combination, as individually they are not highly effective. The HSER–CQDs were characterized using spectrophotometer, HPLC coupled with electrospray-ionization quadrupole time-of-flight mass spectrometer (ESI–qTOF) mass spectrometer, zeta potential, zeta size, and FTIR. Thereafter, the antibacterial activity against Vancomycin-Resistant Staphylococcus aureus (VRSA) and Escherichia coli (carbapenem resistant) was studied using growth curve analysis, further supported by microscopic images showing the presence of cell debris and dead bacterial cells. The antibacterial mechanism of HSER–CQDs was observed to be via cell wall disruption and also interaction with gDNA (genomic DNA). Finally, toxicity test against normal human epithelial cells showed no toxicity, confirmed by microscopic analysis. Thus, the HSER–CQDs conjugate, having high stability and low toxicity with prominent antibacterial activity, can be used as a potential antibacterial agent.

Transcriptomic changes and potential regulatory mechanism of intrauterine human chorionic gonadotropin co-cultured with peripheral blood mononuclear cells infusion in mice with embryonic implantation dysfunction.

This study aimed to explore whether intrauterine infusion of peripheral blood mononuclear cells (PBMCs) could induce favorable transcriptomic changes in the endometrium for embryo implantation and the potential mechanism. Twenty-one mice were randomly divided to five groups, including a normal pregnancy (NP) group, an embryo implantation dysfunction (EID) group, an EID with human chorionic gonadotropin (hCG) group, an EID with PBMCs group, and an EID with hCG co-cultured with PBMCs group. The endometrium in the implantation window from mice were collected and determined by RNA sequencing (RNA-Seq), and the expression of significantly different genes with high degree of coincidence was recommended and validated by quantitative real-time polymerase chain reaction (qRT-PCR). There were totally 1,366 up-regulated and 1,374 down-regulated genes in the EID mice compared with the normal pregnant mice. We selected (fold change ≥2, P<0.05) and verified the candidate genes associated with embryo implantation, immune response and other reproductive processes in previous reports by qRT-PCR. Leukemia inhibitory factor (LIF), solute carrier family 15 member 2 (SLC15A2), retinoic acid receptor responder 1 (RARRES1), vascular cell adhesion molecule 1 (VCAM1) were down-regulated and musculin (MSC), chemokine (C-X-C motif) ligand 14 (CXCL14) were up-regulated significantly in EID group (P<0.05), and the synergistic effects of hCG were seen. In addition, the expression of glucocorticoid receptor (GR)-β in PBMCs of NP mice was higher than that of EID mice, and up-regulated GR-β in EID mice could significantly increase the expression of LIF, SLC15A2, RARRES1 and VCAM1, and decrease the expression of CXCL14 and MSC, which indicated GR-β might be a transcriptional factor of the six genes above. Intrauterine PBMCs perfusion might improve the performance of impaired endometrial receptivity by regulating LIF, SLC15A2, RARRES1, VCAM1, MSC as well as CXCL14, and hCG could enhance the effect of PBMCs. In addition, GR-β, as a transcriptional factor, could regulate the six genes in PBMCs.

Abstract 2846: Chemerin, as a serum biomarker, promotes tumorigenesis and metastasis in oral squamous cell carcinoma

Abstract Chemerin encoded by retinoic acid receptor responder 2 (RARRES2) has been found to be related with malignant tumors, but its causal role in the development of oral squamous cell carcinoma (OSCC) is largely unexplored. In the present study, clinical data showed that higher serum levels of chemerin were observed in OSCC patients compared to the healthy and significantly decreased after tumor resection, and were positively associated with advanced tumor stage and lymph node metastasis. The expression level of chemerin was positive correlated with the migration and invasion of OSCC cell lines. Recombinant chemerin dose-dependently enhanced the migration, invasion and proliferation of OSCC cells in vitro, and shRNA targeting RARRES2 inhibited chemerin expression, OSCC cells metastasis and proliferation in vitro and vivo. Additionally, Chemerin activated the Manganese superoxide dismutase (SOD2) activity and increased intracellular H2O2, led to a significant decrease of E-cadherin expression and a dramatically increasing expression of p-ERK1/2, Slug, Vimentin and N-cadherin. This study suggested that chemerin was a novel biomarker for OSCC patients. Chemerin promoted the tumorigenesis and metastasis of OSCC and would be a new therapeutic target for OSCC. Keywords: Chemerin; Oral squamous cell carcinoma; Tumorgenesis; Metastasis; SOD2 Citation Format: Anxun Wang. Chemerin, as a serum biomarker, promotes tumorigenesis and metastasis in oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2846.