Gene Summary

Gene:LEPR; leptin receptor
Aliases: OBR, OB-R, CD295, LEP-R, LEPRD
Summary:The protein encoded by this gene belongs to the gp130 family of cytokine receptors that are known to stimulate gene transcription via activation of cytosolic STAT proteins. This protein is a receptor for leptin (an adipocyte-specific hormone that regulates body weight), and is involved in the regulation of fat metabolism, as well as in a novel hematopoietic pathway that is required for normal lymphopoiesis. Mutations in this gene have been associated with obesity and pituitary dysfunction. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. It is noteworthy that this gene and LEPROT gene (GeneID:54741) share the same promoter and the first 2 exons, however, encode distinct proteins (PMID:9207021).[provided by RefSeq, Nov 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:leptin receptor
Source:NCBIAccessed: 17 August, 2015


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: LEPR (cancer-related)

Wang Y, Yang H, Gao H, Wang H
The association between LEPR Q223R polymorphisms and breast cancer risk.
Breast Cancer Res Treat. 2015; 151(1):1-6 [PubMed] Related Publications
Recently, we have read with great interest the article entitled "The association between polymorphisms in the leptin receptor (LEPR) gene and risk of breast cancer: a systematic review and pooled analysis" published online by Wang et al. (Breast Cancer Res Treat 136:231-239, 2012). This article suggests that the A allele of LEPR gene rs1137101 variant was low-penetrant risk factor for developing breast cancer. The result is encouraging. Nevertheless, several key issues are worth noticing.

Lin HY, Shi H, Li CY, et al.
LEP and LEPR polymorphisms in non-Hodgkin lymphoma risk: a systematic review and pooled analysis.
J BUON. 2015 Jan-Feb; 20(1):261-8 [PubMed] Related Publications
PURPOSE: The purpose of this systematic meta-analysis was to evaluate the association between leptin (LEP) and leptin receptor (LEPR) gene polymorphisms and non-Hodgkin lymphoma (NHL) risk.
METHODS: All studies published up to July 2014 on the association between LEP and LEPR polymorphisms and NHL risk were identified by searching PubMed, Web of Science, EMBASE, and Google Scholar. Odds ratios (ORs) with 95% confidence intervals (CIs) for LEP and LEPR polymorphisms and NHL were calculated with fixed-effects and random-effects models.
RESULTS: LEP G2528A polymorphism was associated with increased, yet not statistically significant risk of NHL (homozygote comparison, OR=1.27, 95% CI=1.01-1.60, p=0.63; heterozygote comparison, OR=1.13, 95% CI=0.86-1.49, p=0.14; dominant model, OR=1.18, 95% CI=0.99-1.41, p=0.21; recessive model, OR=1.18, 95% CI=0.97-1.43, p=0.78; additive model, OR=1.14, 95% CI=1.01-1.28, p=0.52). Significant decrease of NHL risk was found in LEP A19G polymorphism, while no links were detected with the LEPR polymorphisms studied. In subgroup analysis, the pooled results showed that LEP A19G polymorphism was associated with decreased risk of follicular lymphoma (FL) (homozygote comparison, OR=0.56, 95% CI=0.37-0.85, p=0.69). However, no evidence of a significant association was observed in diffuse large B-cell lymphoma (DLBCL) for variant genotypes of all single nucleotide polymorphisms (SNPs).
CONCLUSIONS: LEP G2548A polymorphism contributes to NHL susceptibility. Also, our results provide evidence that LEP A19G polymorphism is associated with decreased risk of NHL, especially in FL. Further large-scale and well-designed studies are needed to confirm this association.

Alshaker H, Krell J, Frampton AE, et al.
Leptin induces upregulation of sphingosine kinase 1 in oestrogen receptor-negative breast cancer via Src family kinase-mediated, janus kinase 2-independent pathway.
Breast Cancer Res. 2014; 16(5):426 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Obesity is a known risk factor for breast cancer. Sphingosine kinase 1 (SK1) is an oncogenic lipid kinase that is overexpressed in breast tumours and linked with poor prognosis, however, its role in obesity-driven breast cancer was never elucidated.
METHODS: Human primary and secondary breast cancer tissues were analysed for SK1 and leptin receptor expression using quantitative real-time polymerase chain reaction (qRT-PCR) assay. Leptin-induced signalling was analysed in human oestrogen receptor (ER)-positive and negative breast cancer cells using Western blotting, qRT-PCR and radiolabelling assays.
RESULTS: Our findings show for the first time that human primary breast tumours and associated lymph node metastases exhibit a strong correlation between SK1 and leptin receptor expression (Pearson R = 0.78 and R = 0.77, respectively, P <0.001). Both these genes are elevated in metastases of ER-negative patients and show a significant increase in patients with higher body mass index (BMI). Leptin induces SK1 expression and activation in ER-negative breast cancer cell lines MDAMB-231 and BT-549, but not in ER-positive cell lines. Pharmacological inhibition and gene knockdown showed that leptin-induced SK1 activity and expression are mediated by activation of extracellular signal-regulated kinases 1/2 (ERK1/2) and Src family kinase (SFK) pathways, but not by the major pathways downstream of leptin receptor (LEPR) - janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Src-homology 2 domain-containing phosphatase 2 (SHP2) appeared to be key to SK1 activation, and may function as an adaptor protein between SFKs and LEPR. Importantly, leptin-induced breast cancer cell proliferation was abrogated by SK1-specific small interfering RNA (siRNA).
CONCLUSIONS: Overall, our findings demonstrate a novel SFK/ERK1/2-mediated pathway that links leptin signalling and expression of oncogenic enzyme SK1 in breast tumours and suggest the potential significance of this pathway in ER-negative breast cancer.

Ren H, Jia L, Zhao T, et al.
Hypoxia inducible factor (HIF)-1α directly activates leptin receptor (Ob-R) in pancreatic cancer cells.
Cancer Lett. 2014; 354(1):172-80 [PubMed] Related Publications
The aim of this study is to investigate the regulatory mechanism of leptin receptors (Ob-R) in pancreatic cancer. We found that the over-expression of hypoxia inducible factor (HIF-1)α and hypoxia up-regulated the expression of Ob-R in pancreatic cancer cells. When HIF-1α gene was silenced in vitro, the expression of Ob-R was significantly decreased. Xenograft mouse models showed that the inhibition of HIF-1α resulted in the concomitant decrease of Ob-R in vivo. In addition, HIF-1α expression was correlated with Ob-R in pancreatic cancer tissues by immunohistochemical staining. Clinical data showed that over-expression of HIF-1 was associated with pathological tumor node metastasis stage, lymph node metastasis and overall survival. HIF-1α directly bound to the hypoxia-responsive element (HRE) located in Ob-R gene promoter (-828/-832) and activated the transcription. Finally, we demonstrated that the silence of HIF-1α gene reversed the inhibitory effect of leptin/Ob-R in pancreatic cancer cells. Taken together, our results indicate that HIF-1α directly regulated Ob-R expression in pancreatic cancer, which might be a valuable therapeutic target for pancreatic cancer.

Pande M, Bondy ML, Do KA, et al.
Association between germline single nucleotide polymorphisms in the PI3K-AKT-mTOR pathway, obesity, and breast cancer disease-free survival.
Breast Cancer Res Treat. 2014; 147(2):381-7 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Obesity-related hormones and cytokines alter PI3 K-AKT-mTOR pathway activation in breast tumors contributing to poorer disease-free survival (DFS) and decreased responsiveness to tamoxifen and trastuzumab. We hypothesized that single nucleotide polymorphisms (SNPs) in candidate genes in the PI3 K-AKT-mTOR signaling pathway may act as genetic modifiers of breast cancer DFS. We analyzed the association of 106 tagging SNPs in 13 genes (ADIPOQ, IGF1, INS, IRS1, LEP, LEPR, LEPROT, PIK3CA, PIK3R5, PTEN, TSC1, TSC2, and AKT1) in the P13K-AKT-mTOR pathway with DFS in a sample of 1,019 women with stage I-II breast cancer. SNPs significantly associated with DFS in any genetic model (additive, dominant, or recessive) after correcting for false discovery rate (FDR = 0.10) were included in Cox proportional hazards multivariable analyses. After adjusting for race/ethnicity, age at diagnosis, tumor stage, and treatment, rs1063539 in ADIPOQ, rs11585329 in LEPR, and rs2519757 in TSC1 were associated with improved DFS, and rs1520220 in IGF1 and rs2677760 in PIK3CA were associated with worse DFS. The associations were not significantly modified by the type of systemic treatment received or body mass index. The SNPs were not associated with tumor characteristics such as tumor size, lymph node status, nuclear grade, or hormone receptor status. In this study, germline SNPs in the PI3 K-AKT-mTOR pathway were associated with breast cancer DFS and may be potential prognostic markers. Future studies are needed to replicate our results and to evaluate the relationship between these polymorphisms and activation of the PI3 K-AKT-mTOR pathway in breast tumors.

Unsal M, Kara N, Karakus N, et al.
Effects of leptin and leptin receptor gene polymorphisms on lung cancer.
Tumour Biol. 2014; 35(10):10231-6 [PubMed] Related Publications
Leptin (LEP), an adipocyte-derived cytokine, has been reported to participate in carcinogenesis. Elevated levels of systemic and pulmonary LEP are associated with diseases related to lung injury and lung cancer. The purpose of the present study was to investigate if the LEP and leptin receptor (LEPR) gene polymorphisms are associated with lung cancer in a cohort of Turkish population. One hundred and sixty-two lung cancer patients and 130 healthy controls were included in the study. The genotypes of LEP gene -2548G > A and LEPR gene Q223R polymorphisms were determined using polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP) analysis. The genotype frequencies of LEP -2548G > A polymorphism showed statistically significant differences between lung cancer patients and controls (p = 0.007). GA + AA genotypes and A allele of LEP -2548G > A polymorphism was found to be susceptibility factors for lung cancer (p = 0.003, odds ratio (OR) 2.32, 95 % confidence interval (CI) 1.32-4.10; p = 0.003, OR 1.65, 95 % CI 1.18-2.29, respectively). The genotype and allele frequencies of LEPR Q223R polymorphism did not show any statistically significant differences between lung cancer patients and controls (p = 0.782 and p = 0.762, respectively). Although AA-QQ and AA-QR combined genotypes of LEP -2548G > A-LEPR Q223R loci were significantly higher in lung cancer patients (p = 0.020 and p = 0.047, respectively), GG-QQ, GG-QR, and AA-RR combined genotypes were significantly higher in control group. As a result, susceptibility effects of LEP -2548G > A polymorphism alone or in combination with LEPR Q223R polymorphism on lung cancer were observed. Further studies are necessary to prove the association of LEP and LEPR gene polymorphisms with lung cancer.

Higurashi T, Endo H, Uchiyama T, et al.
Conditional knockout of the leptin receptor in the colonic epithelium revealed the local effects of leptin receptor signaling in the progression of colonic tumors in mice.
Carcinogenesis. 2014; 35(9):2134-41 [PubMed] Related Publications
Leptin, secreted by the adipose tissue and known to be related to obesity, is considered to be involved in the onset and progression of colorectal cancer. However, the exact role of leptin in colorectal carcinogenesis is still unclear, as several controversial reports have been published on the various systemic effects of leptin. The aim of this study was to clarify the local and precise roles of leptin receptor (LEPR)-mediated signaling in colonic carcinogenesis using intestinal epithelium-specific LEPRb conditional knockout (cKO) mice. We produced and used colonic epithelium-specific LEPRb cKO mice to investigate the carcinogen-induced formation of aberrant crypt foci (ACF) and tumors in the colon, using their littermates as control. There were no differences in the body weight or systemic condition between the control and cKO mice. The tumor sizes and number of large-sized tumors were significantly lower in the cKO mice as compared with those in the control mice. On the other hand, there was no significant difference in the proliferative activity of the normal colonic epithelial cells or ACF formation between the control and cKO mice. In the control mice, marked increase of the LEPRb expression level was observed in the colonic tumors as compared with that in the normal epithelium; furthermore, signal transducer and activator of transcription (STAT3) was activated in the tumor cells. These findings suggest that STAT3 is one of the important molecules downstream of LEPRb, and LEPRb/STAT3 signaling controls tumor cell proliferation. We demonstrated the importance of local/regional LEPR-mediated signaling in colorectal carcinogenesis.

Mu HJ, Zou J, Xie P, et al.
Association of leptin receptor Lys109Arg and Gln223Arg polymorphisms with increased risk of clear cell renal cell carcinoma.
Asian Pac J Cancer Prev. 2014; 15(10):4211-5 [PubMed] Related Publications
BACKGROUND: Although roles of genetic polymorphisms of leptin receptor (LEPR) gene in several cancers have been documented, the association between polymorphisms of LEPR and clear cell renal cell carcinoma (CC-RCC) remains unknown. The aim of this study was to explore any relation.
MATERIALS AND METHODS: The study population consisted of 77 patients with CC-RCC and 161 healthy control subjects. Polymorphism analyses of Lys109Arg and Gln223Arg were performed by direct DNA sequencing and PCR-restriction fragment length polymorphism approaches respectively.
RESULTS: Comparisons of allelic and genotypic frequencies in Lys109Arg and Gln223Arg showed no significant difference between the cases and controls. However, when evaluating the combined genotype of Lys109Arg and Gln223Arg, risk with GG/GG was increased (OR=1.85, 95%CI=1.04-3.30) and with GA/GG or GG/GA was decreased (OR=0.07, 95%CI=0.01-0.54; OR and 95%CI of the latter could not be calculated for a value of zero) . Furthermore, the G-G haplotype frequency of Lys109Arg and Gln223Arg in the cases was higher (OR=1.68; 95%CI=1.02-2.76). In contrast, the A-G and G-A haplotype frequencies in the cases were lower than those in the controls (OR=0.06; 95%CI=0.01 to 0.47; OR and 95%CI of the latter could not be calculated for a value of zero). In addition, the Lys109Arg A allele was in LD with the Gln223Arg A allele (d'=0.9399) in the CC-RCC subjects, but not in the controls.
CONCLUSIONS: Our data suggest that the GG/GG combined genotype and G-G haplotype of Lys109Arg and Gln223Arg can act as evaluating factors for CC-RCC risk.

Almeida MQ, Kaupert LC, Brito LP, et al.
Increased expression of ACTH (MC2R) and androgen (AR) receptors in giant bilateral myelolipomas from patients with congenital adrenal hyperplasia.
BMC Endocr Disord. 2014; 14:42 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Although chronic adrenocorticotropic hormone (ACTH) and androgen hyperstimulation are assumed to be involved in the pathogenesis of adrenal myelolipomas associated with poor-compliance patients with congenital adrenal hyperplasia (CAH), the expression of their receptors has not yet been demonstrated in these tumors so far.
METHODS: We analyzed Melanocortin 2 receptor (MC2R), Androgen Receptor (AR), Leptin (LEP), and Steroidogenic factor 1 (SF1) expression using real-time qRT-PCR in two giant bilateral adrenal myelolipomas from two untreated simple virilizing CAH cases and in two sporadic adrenal myelolipomas. In addition, the X-chromosome inactivation pattern and CAG repeat numbers in AR exon 1 gene were evaluated in the 4 cases.
RESULTS: The MC2R gene was overexpressed in myelolipomas from 3 out of 4 patients. AR overexpression was detected in 2 tumors: a giant bilateral myelolipoma in a CAH patient and a sporadic case. Simultaneous overexpression of AR and MC2R genes was found in two of the cases. Interestingly, the bilateral giant myelolipoma associated with CAH that had high androgen and ACTH levels but lacked MC2R and AR overexpression presented a significantly shorter AR allele compared with other tumors. In addition, X-chromosome inactivation pattern analysis showed a polyclonal origin in all tumors, suggesting a stimulatory effect as the trigger for tumor development.
CONCLUSION: These findings are the first evidence for MC2R or AR overexpression in giant bilateral myelolipomas from poor-compliance CAH patients.

Llanos AA, Brasky TM, Mathew J, et al.
Genetic variation in adipokine genes and associations with adiponectin and leptin concentrations in plasma and breast tissue.
Cancer Epidemiol Biomarkers Prev. 2014; 23(8):1559-68 [PubMed] Related Publications
BACKGROUND: Circulating adipokines may be associated with breast cancer risk. Genetic variants governing adipokines and adipokine receptors may also predict risk, but their effect on breast adipokine concentrations is unknown.
METHODS: We conducted a cross-sectional analysis of functional SNPs in 5 adipokine genes [adiponectin, leptin (LEP), and their receptors] among 85 cancer-free women who were undergoing reduction mammoplasty.
RESULTS: In multivariable-adjusted regression models, compared with the common GG genotype, the AA genotype of the LEP A19G SNP was associated with 27% lower plasma adiponectin [ratio, 0.73; 95% confidence interval (CI), 0.54-0.98] and leptin (ratio, 0.73; 95% CI, 0.55-0.96). Women with the AG genotype of LEP A19G had 39% lower breast leptin (ratio, 0.61; 95% CI, 0.39-0.97) compared with those with the GG genotype. No associations were observed for SNPs in the remaining genes.
CONCLUSIONS: Genetic variation in LEP may alter endogenous adipokine concentrations in circulation and in breast tissues.
IMPACT: These preliminary findings may support the hypothesis that genetic variation in adipokine genes modifies circulating adipokine concentrations and possibly leptin concentrations in local breast tissues, which may be associated with breast cancer risk.

Kuželová K, Grebeňová D, Holoubek A, et al.
Group I PAK inhibitor IPA-3 induces cell death and affects cell adhesivity to fibronectin in human hematopoietic cells.
PLoS One. 2014; 9(3):e92560 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
P21-activated kinases (PAKs) are involved in the regulation of multiple processes including cell proliferation, adhesion and migration. However, the current knowledge about their function is mainly based on results obtained in adherent cell types. We investigated the effect of group I PAK inhibition using the compound IPA-3 in a variety of human leukemic cell lines (JURL-MK1, MOLM-7, K562, CML-T1, HL-60, Karpas-299, Jurkat, HEL) as well as in primary blood cells. IPA-3 induced cell death with EC50 ranging from 5 to more than 20 μM. Similar range was found for IPA-3-mediated dephosphorylation of a known PAK downstream effector, cofilin. The cell death was associated with caspase-3 activation, PARP cleavage and apoptotic DNA fragmentation. In parallel, 20 μM IPA-3 treatment induced rapid and marked decrease of the cell adhesivity to fibronectin. Per contra, partial reduction of PAK activity using lower dose IPA-3 or siRNA resulted in a slight increase in the cell adhesivity. The changes in the cell adhesivity were also studied using real-time microimpedance measurement and by interference reflection microscopy. Significant differences in the intracellular IPA-3 level among various cell lines were observed indicating that an active mechanism is involved in IPA-3 transport.

Hogg K, Robinson WP, Beristain AG
Activation of endocrine-related gene expression in placental choriocarcinoma cell lines following DNA methylation knock-down.
Mol Hum Reprod. 2014; 20(7):677-89 [PubMed] Related Publications
Increasingly, placental DNA methylation is assessed as a factor in pregnancy-related complications, yet the transcriptional impact of such findings is not always clear. Using a proliferative in vitro placental model, the effect of DNA methylation loss on gene activation was evaluated at a number of genes selected for being differentially methylated in pre-eclampsia-associated placentae in vivo. We aimed to determine whether reduced DNA methylation at specific loci was associated with transcriptional changes at the corresponding gene, thus providing mechanistic underpinnings for previous clinical findings and to assess the degree of transcriptional response amongst our candidate genes. BeWo and JEG3 choriocarcinoma cells were exposed to 1 μM 5-Aza-2'-deoxycytidine (5-Aza-CdR) or vehicle control for 48 h, and re-plated and cultured for a further 72 h in normal media before cells were harvested for RNA and DNA. Bisulphite pyrosequencing confirmed that DNA methylation was reduced by ∼30-50% points at the selected loci studied in both cell lines. Gene activation, measured by qRT-PCR, was highly variable and transcript specific, indicating differential sensitivity to DNA methylation. Most notably, loss of DNA methylation at the leptin (LEP) promoter corresponded to a 200-fold and 40-fold increase in LEP expression in BeWo and JEG3 cells, respectively (P < 0.01). Transcripts of steroidogenic pathway enzymes CYP11A1 and HSD3B1 were up-regulated ∼40-fold in response to 5-Aza-CdR exposure in BeWo cells (P < 0.01). Other transcripts, including aromatase (CYP19), HSD11B2, inhibin (INHBA) and glucocorticoid receptor (NR3C1) were more moderately, although significantly, affected by loss of associated DNA methylation. These data present a mixed effect of DNA methylation changes at selected loci supporting cautionary interpretation of DNA methylation results in the absence of functional data.

Gu DL, Chen YH, Shih JH, et al.
Target genes discovery through copy number alteration analysis in human hepatocellular carcinoma.
World J Gastroenterol. 2013; 19(47):8873-9 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
High-throughput short-read sequencing of exomes and whole cancer genomes in multiple human hepatocellular carcinoma (HCC) cohorts confirmed previously identified frequently mutated somatic genes, such as TP53, CTNNB1 and AXIN1, and identified several novel genes with moderate mutation frequencies, including ARID1A, ARID2, MLL, MLL2, MLL3, MLL4, IRF2, ATM, CDKN2A, FGF19, PIK3CA, RPS6KA3, JAK1, KEAP1, NFE2L2, C16orf62, LEPR, RAC2, and IL6ST. Functional classification of these mutated genes suggested that alterations in pathways participating in chromatin remodeling, Wnt/β-catenin signaling, JAK/STAT signaling, and oxidative stress play critical roles in HCC tumorigenesis. Nevertheless, because there are few druggable genes used in HCC therapy, the identification of new therapeutic targets through integrated genomic approaches remains an important task. Because a large amount of HCC genomic data genotyped by high density single nucleotide polymorphism arrays is deposited in the public domain, copy number alteration (CNA) analyses of these arrays is a cost-effective way to reveal target genes through profiling of recurrent and overlapping amplicons, homozygous deletions and potentially unbalanced chromosomal translocations accumulated during HCC progression. Moreover, integration of CNAs with other high-throughput genomic data, such as aberrantly coding transcriptomes and non-coding gene expression in human HCC tissues and rodent HCC models, provides lines of evidence that can be used to facilitate the identification of novel HCC target genes with the potential of improving the survival of HCC patients.

Nejati-Koshki K, Akbarzadeh A, Pourhasan-Moghaddam M, et al.
Inhibition of leptin and leptin receptor gene expression by silibinin-curcumin combination.
Asian Pac J Cancer Prev. 2014; 14(11):6595-9 [PubMed] Related Publications
Leptin and its receptor are involved in breast carcinogenesis as mitogenic factors. Therefore, they could be considered as targets for breast cancer therapy. Expression of the leptin receptor gene could be modulated by leptin secretion. Silibinin and curcumin are herbal compounds with anti-cancer activity against breast cancer. The aim of this study was to assess their potential to inhibit of expression of the leptin gene and its receptor and leptin secretion. Cytotoxic effects of the two agents on combination on T47D breast cancer cells was investigated by MTT assay test after 24h treatment. With different concentrations the levels of leptin, leptin receptor genes expression were measured by reverse-transcription real-time PCR. Amount of secreted leptin in the culture medium was determined by ELISA. Data were statistically analyzed by one-way ANOVA test. The silibinin and curcumin combination inhibited growth of T47D cells in a dose dependent manner. There were also significant difference between control and treated cells in leptin expression and the quantity of secreted leptin with a relative decrease in leptin receptor expression. In conclusion, these herbal compounds inhibit the expression and secretion of leptin and it could probably be used as drug candidates for breast cancer therapy through leptin targeting in the future.

Zhang J, Dhakal IB, Zhang X, et al.
Genetic variability in energy balance and pancreatic cancer risk in a population-based case-control study in Minnesota.
Pancreas. 2014; 43(2):281-6 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
OBJECTIVES: Accumulating evidence suggests that energy imbalance plays a role in pancreatic carcinogenesis. However, it remains unclear whether single-nucleotide polymorphisms (SNPs) in genes regulating energy homeostasis influence pancreatic cancer risk. We investigated this question in a case-control study conducted from 1994 to 1998.
METHODS: Patients (n = 173) were ascertained from hospitals in the Twin Cities and Mayo Clinic, Minnesota. Control subjects (n = 476) were identified from the general population and frequency matched to patients by age and sex. Seven SNPs were evaluated in relation to pancreatic cancer using unconditional logistic regression.
RESULTS: After adjustment for confounders, the leucine/proline or proline/proline genotype of the neuropeptide Y (NPY) gene rs16139 was associated with a lower risk than the leucine/leucine genotype (odds ratio, 0.40 [95% confidence interval, 0.15-0.91]). Conversely, an increased risk was observed for the glycine/arginine or arginine/arginine genotype of the adrenoceptor β2, surface (ADRB2) gene rs1042713 as compared with the glycine/glycine genotype (odds ratio, 1.52 [95% confidence interval, 1.01-2.31]).
CONCLUSIONS: This study first reveals that SNPs in genes modulating energy intake (NPY) and energy expenditure (ADRB2) altered pancreatic cancer risk. If confirmed by other studies, our findings may shed new light on the etiology and prevention of pancreatic cancer.

Strong AL, Strong TA, Rhodes LV, et al.
Obesity associated alterations in the biology of adipose stem cells mediate enhanced tumorigenesis by estrogen dependent pathways.
Breast Cancer Res. 2013; 15(5):R102 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
INTRODUCTION: Obesity has been associated with increased incidence and mortality of breast cancer. While the precise correlation between obesity and breast cancer remains to be determined, recent studies suggest that adipose tissue and adipose stem cells (ASCs) influence breast cancer tumorigenesis and tumor progression.
METHODS: Breast cancer cells lines were co-cultured with ASCs (n = 24), categorized based on tissue site of origin and body mass index (BMI), and assessed for enhanced proliferation, alterations in gene expression profile with PCR arrays, and enhanced tumorigenesis in immunocompromised mice. The gene expression profile of ASCs was assess with PCR arrays and qRT-PCR and confirmed with Western blot analysis. Inhibitory studies were conducted by delivering estrogen antagonist ICI182,780, leptin neutralizing antibody, or aromatase inhibitor letrozole and assessing breast cancer cell proliferation. To assess the role of leptin in human breast cancers, Oncomine and Kaplan Meier plot analyses were conducted.
RESULTS: ASCs derived from the abdominal subcutaneous adipose tissue of obese subjects (BMI > 30) enhanced breast cancer cell proliferation in vitro and tumorigenicity in vivo. These findings were correlated with changes in the gene expression profile of breast cancer cells after co-culturing with ASCs, particularly in estrogen receptor-alpha (ESR1) and progesterone receptor (PGR) expression. Analysis of the gene expression profile of the four groups of ASCs revealed obesity induced alterations in several key genes, including leptin (LEP). Blocking estrogen signaling with ICI182,780, leptin neutralizing antibody, or letrozole diminished the impact of ASCs derived from obese subjects. Women diagnosed with estrogen receptor/progesterone receptor positive (ER+/PR+) breast cancers that also expressed high levels of leptin had poorer prognosis than women with low leptin expression.
CONCLUSION: ASCs isolated from the abdomen of obese subjects demonstrated increased expression of leptin, through estrogen stimulation, which increased breast cancer cell proliferation. The results from this study demonstrate that abdominal obesity induces significant changes in the biological properties of ASCs and that these alterations enhance ER+/PR+ breast cancer tumorigenesis through estrogen dependent pathways.

Han G, Zhao W, Wang L, et al.
Leptin enhances the invasive ability of glioma stem-like cells depending on leptin receptor expression.
Brain Res. 2014; 1543:1-8 [PubMed] Related Publications
Glioma stem-like cells have been demonstrated to have highly invasive activity, which is the major cause of glioma recurrence after therapy. Leptin plays a role in glioma invasion, however, whether and how leptin contributes to the biological properties of glioma stem-like cells, such as invasion, remains to be explored. In the current study, we aimed to explore the role of leptin during glioma stem-like cells invasion as well as the signaling pathway. We found that glioma stem-like cells exhibited high invasive potential, especially in the presence of leptin, Ob-R coexpressed with CD133 in glioma stem-like cells was showed to be responsible for leptin mediated invasion of glioma stem-like cells. Our results indicated that leptin served as a key intermediary linking the accumulation of excess adipokine to the invasion of glioma stem-like cells, which may be a novel therapeutic target for suppressing tumor invasion and recurrence.

Ikeda A, Shimizu T, Matsumoto Y, et al.
Leptin receptor somatic mutations are frequent in HCV-infected cirrhotic liver and associated with hepatocellular carcinoma.
Gastroenterology. 2014; 146(1):222-32.e35 [PubMed] Related Publications
BACKGROUND & AIMS: Hepatocellular carcinoma develops in patients with chronic hepatitis or cirrhosis via a stepwise accumulation of various genetic alterations. To explore the genetic basis of development of hepatocellular carcinoma in hepatitis C virus (HCV)-associated chronic liver disease, we evaluated genetic variants that accumulate in nontumor cirrhotic liver.
METHODS: We determined the whole exome sequences of 7 tumors and background cirrhotic liver tissues from 4 patients with HCV infection. We then performed additional sequencing of selected exomes of mutated genes, identified by whole exome sequencing, and of representative tumor-related genes on samples from 22 cirrhotic livers with HCV infection. We performed in vitro and in vivo functional studies for one of the mutated genes.
RESULTS: Whole exome sequencing showed that somatic mutations accumulated in various genes in HCV-infected cirrhotic liver tissues. Among the identified genes, the leptin receptor gene (LEPR) was one of the most frequently mutated in tumor and nontumor cirrhotic liver tissue. Selected exome sequencing analyses detected LEPR mutations in 12 of 22 (54.5%) nontumorous cirrhotic livers. In vitro, 4 of 7 (57.1%) LEPR mutations found in cirrhotic livers reduced phosphorylation of STAT3 to inactivate LEPR-mediated signaling. Moreover, 40% of Lepr-deficient (C57BL/KsJ-db/db) mice developed liver tumors after administration of thioacetamide compared with none of the control mice.
CONCLUSIONS: Based on analysis of liver tissue samples from patients, somatic mutations accumulate in LEPR in cirrhotic liver with chronic HCV infection. These mutations could disrupt LEPR signaling and increase susceptibility to hepatocarcinogenesis.

Prizment AE, Folsom AR, Dreyfus J, et al.
Plasma C-reactive protein, genetic risk score, and risk of common cancers in the Atherosclerosis Risk in Communities study.
Cancer Causes Control. 2013; 24(12):2077-87 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
PURPOSE: Many studies, including the Atherosclerosis Risk in Communities (ARIC) cohort, reported a positive association between plasma C-reactive protein (CRP)-a biomarker of low-grade chronic inflammation-and colorectal cancer risk, although it is unclear whether the association is causal. Our aims were to assess the associations of a CRP genetic risk score (CRP-GRS) created from single-nucleotide polymorphisms (SNPs) with colorectal cancer risk, as well as examine plasma CRP and CRP-GRS in relation to common cancers in the ARIC cohort.
METHODS: Cox proportional hazards models were used to prospectively estimate hazard ratios (HRs) and 95 % confidence interval (95 % CI) of total, colorectal, lung, prostate, and breast cancers in relation to: (1) CRP-GRS among 8,657 Whites followed in 1987-2006 and (2) log-transformed plasma CRP among 7,603 Whites followed in 1996-2006. A weighted CRP-GRS was comprised of 20 CRP-related SNPs located in/near CRP, APOC1, HNF1A, LEPR, and 16 other genes that were identified in genome-wide association studies.
RESULTS: After multivariable adjustment, one standard deviation increment of the CRP-GRS was associated with colorectal cancer risk (HR 1.19; 95 % CI 1.03-1.37), but not with any other cancer. One unit of log-transformed plasma CRP was associated with the risk of total, colorectal, lung, and breast cancers: HRs (95 % CIs) were 1.08 (1.01-1.15), 1.24 (1.01-1.51), 1.29 (1.08-1.54), and 1.27 (1.07-1.51), respectively. HRs remained elevated, although lost statistical significance for all but breast cancer, after excluding subjects with <2 years of follow-up.
CONCLUSIONS: The study corroborates a causative role of chronic low-grade inflammation in colorectal carcinogenesis.

Uddin S, Hussain AR, Khan OS, Al-Kuraya KS
Role of dysregulated expression of leptin and leptin receptors in colorectal carcinogenesis.
Tumour Biol. 2014; 35(2):871-9 [PubMed] Related Publications
Leptin is a multifunctional adipose-derived cytokine that plays a critical role in bodyweight homeostasis and energy balance. Plasma level of leptin is an indicator of the amount of energy stored in adipose tissues. Recently, leptin and leptin receptor dysregulation have been reported in a variety of malignant cells including colorectal cancers (CRCs). There are growing evidence that leptin may be the link between obesity and CRC carcinogenesis. Leptin influence the growth and proliferation of cancer cells via activation of various growth and survival signaling pathways including JAK/STAT, PI3-kinase/AKT, and/or MAP kinases. In this review, current understanding of leptin and its receptor's roles in the pathogenesis of colonogenic cancer has been described.

Zhang Y, Chen MB, Zhou XY, Hong XN
Lymphotoxin alpha (LTA) polymorphism is associated with prognosis of non-Hodgkin's lymphoma in a Chinese population.
PLoS One. 2013; 8(6):e66411 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Non-Hodgkin's lymphoma (NHL) has been widely reported to be associated with autoimmune and pro-inflammatory response, and genetic polymorphisms of candidate genes involved in autoimmune and pro-inflammatory response may influence the survival and prognosis of NHL patients. To evaluate the role of such genetic variations in prognosis of NHL, we conducted this study in a Chinese population.
METHODS: We used the TaqMan assay to genotype six single nucleotide polymorphisms (SNPs) (TNF rs1799964T>C, LTA rs1800683G>A, IL-10 rs1800872T>G, LEP rs2167270G>A, LEPR rs1327118C>G, TNFAIP8 rs1045241C>T) for 215 NHL cases. Kaplan-Meier analysis was performed to compare progression free survival among two common genotypes. Cox proportional hazard models were used to identify independent risk factors.
RESULTS: We observed that LTA rs1800683G>A was significantly associated with risk of progression or relapse in NHL patients (HR = 1.63, 95%CI = 1.06-2.51; P = 0.028), particularly in Diffuse large B cell lymphoma (DLBCL) cases (HR = 1.50, 95%CI = 1.10-2.04, P = 0.01). Both univariate and multivariate Cox regression analysis showed that in DLBCL patients, Ann Arbor stage III/IV, elevated LDH level before treatment and LTA rs1800683 AA genotype carrier were independent risk factors for progression or relapse. While in NK/T cell lymphoma, Ann Arbor stage III/IV and elevated β2-MG level before treatment indicated poorer prognosis.
CONCLUSIONS: The polymorphism of LTA rs1800683G>A contributes to NHL prognosis in a Chinese population. Further large-scale and well-designed studies are needed to confirm these results.

Li L, Lee KJ, Choi BC, Baek KH
Relationship between leptin receptor and polycystic ovary syndrome.
Gene. 2013; 527(1):71-4 [PubMed] Related Publications
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders, which is involved in the multi-system disease, and its etiology is still not clearly understood. It is currently considered that not only the genetic factors but also the environment factors play a crucial role in the pathogenesis of PCOS. Obesity plays an important role through the insulin, leptin and endocannabinoid system in the pathological process of PCOS, leading to more severe clinical manifestations. The aim of our present study is to investigate whether there is association between single nucleotide polymorphisms (SNPs) of Gln223Arg and Pro1019Pro in the leptin receptor gene (LEPR) and PCOS in a Korean population. Interestingly, a significant association was found between the Pro1019Pro in LEPR gene and PCOS, and a highly significant association was found between the Gln223Arg in LEPR gene and PCOS (P=0.033, OR=1.523, 95% confidence interval and P<0.0001, OR=0.446, 95% confidence interval). Moreover, genotype combination and haplotype analyses indicate that Gln223Arg and Pro1019Pro polymorphisms of LEPR are significantly associated with the risk of PCOS.

Mokrowiecka A, Sokolowska M, Luczak E, et al.
Adiponectin and leptin receptors expression in Barrett's esophagus and normal squamous epithelium in relation to central obesity status.
J Physiol Pharmacol. 2013; 64(2):193-9 [PubMed] Related Publications
UNLABELLED: Esophageal adenocarcinoma incidence is rapidly increasing which may be due to the growing incidence of Barrett's esophagus (BE) and obesity. The mechanisms linking obesity and progression of Barrett's carcinogenesis is poorly understood. The aim of the study was to evaluate the expression of adipokines receptors in BE and in normal squamous epithelium in the same patients in correlation with obesity parameters.
METHODS: Expression of adiponectin receptors 1 and 2 protein (AdipoR1, AdipoR2) as well as leptin receptor protein (ObR) in biopsies from 27 BE and normal squamous epithelium (N) in the same patients as well as in obese and normal controls were assessed with Western-blot analysis. These correlations were confirmed with the quantitative RT-PCR (qRT-PCR). AdipoR1 and ObR protein levels were similar in BE mucosa and squamous epithelium in the same patients in Western-blot analysis (2303 vs. 2448 OB units; 106927 vs. 103390, respectively; p>0.05). RT-PCR analysis confirmed this observation for AdipoR1, R2 and ObR genes expression (0.11±0.08 vs. 0.19±0.24, p=0.78; 0.24±0.36 vs. 0.33±0.49, p=0.5375; 0.71±0.8 vs. 1.33±2.95, p=1.0; respectively). Using linear correlation analysis we found the positive correlation between AdipoR1 expression in Barrett's epithelium compared to squamous epithelium in the same patients (N) (r=0.5; p=0.008) and between ObR expression in BE and N (r=0.8; p<0.001). The AdipoR1 and ObR protein levels were significantly higher in BE patients compared to controls and obese controls (2303 vs. 895 vs. 1674 and OD units, p<0.05).
CONCLUSIONS: in opposite to the prior hypothesis adiponectin and leptin receptors activation in BE may be not caused by obesity.

Delort L, Lequeux C, Dubois V, et al.
Reciprocal interactions between breast tumor and its adipose microenvironment based on a 3D adipose equivalent model.
PLoS One. 2013; 8(6):e66284 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Breast cancer has become the most common cancer among women in industrialized countries. Obesity is well established as a risk factor, in particular owing to the attendant secretion of the entities called adipokines; there is growing evidence for a role of cells and factors present in the mammary tumor microenvironment such as fibroblasts, preadipocytes, adipocytes and their secretions. To study how the microenvironment influences breast cancer growth, we developed a novel tridimensional adipose model epithelialized with normal human keratinocytes or with breast cancer cell lines. These mimicked a breast tumor in contact with an adipose microenvironment and allowed monitoring of the interactions between the cells. Leptin and adiponectin, two major adipokines, and their respective receptors, ObRt and AdipoR1, were expressed in the model, but not the second adiponectin receptor, AdipoR2. The differentiation of preadipocytes into adipocytes was greater when they were in contact with the breast cancer cell lines. The contact of breast cancer cell lines with the microenvironment completely modified their transcriptional programs by increasing the expression of genes involved in cell proliferation (cyclinD1, MAPK), angiogenesis (MMP9, VEGF) and hormonal pathways (ESR1, IL6). This tridimensional adipose model provides new insights into the interactions between breast cancer cells and their adipose microenvironment, and provides a tool to develop new drugs for the treatment of both cancer and obesity.

Liu L, Zhong R, Wei S, et al.
The leptin gene family and colorectal cancer: interaction with smoking behavior and family history of cancer.
PLoS One. 2013; 8(4):e60777 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Pathologic condition associated with metabolic syndrome traits seems to increase the risk of colorectal cancer. One mechanism underlying this relationship may involve the growth-promoting effects of the circulation hormones associated with obesity and insulin resistance, such as leptin.
METHODOLOGY/PRINCIPAL FINDINGS: A two-stage case-control study was used to explore the role of polymorphisms of Leptin (LEP) and Leptin receptor (LEPR), either alone or in combination with environmental factors in colorectal carcinogenesis. In stage 1, 20 single nucleotide polymorphisms (SNPs) that tag common SNPs in these two genes were genotyped among 470 cases and 458 controls. In stage 2, another population with 314 cases and 355 controls were genotyped for the two most promising SNPs from stage 1. LEPR rs12037879 only presented modestly increased colorectal cancer risk, with odds ratios of 1.41 (95% confidence interval [CI] 1.13-1.76) and 1.74 (95%CI 1.08-2.81) for GA and AA genotype when compared with GG genotype in combined population. Smokers carrying LEPR rs12037879 A allele presented 1.67-fold (95%CI 1.39-fold to 2.01-fold) increased colorectal cancer risk when compared with non-smokers carrying GG genotype in combined analysis. Individuals with family history of cancer harboring LEPR rs12037879 A allele showed 1.52-fold (95%CI: 1.24-fold to 1.86-fold) increased colorectal cancer risk, compared with individuals without family history of cancer harboring GG genotype. Multifactor gene-environment interaction analysis revealed significant interactions among LEPR rs12037879, LEPR rs6690625, smoking status and family history of cancer, exhibiting a gradient of increased colorectal cancer risk along with the increasing number of risk factors (P = 9.82 × 10(-10)).
CONCLUSIONS/SIGNIFICANCE: Our research supports that polymorphisms in LEPR may be associated with marginal increase in the risk for colorectal cancer. Moreover, this association could be strengthened by cigarette smoking and family history of cancer.

Dallal C, Garte S, Ragin C, et al.
Plasma leptin levels, LEPR Q223R polymorphism and mammographic breast density: a cross-sectional study.
Int J Biol Markers. 2013 Apr-Jun; 28(2):161-7 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Obesity is associated with breast cancer in post-menopausal women, and breast density is a marker of breast cancer risk. Leptin is produced by the adipose tissue, acts through receptors that are polymorphic in nature, and is considered a cancer growth factor. The relationship between body mass index, leptin, leptin receptors and breast density is not well studied. A cross-sectional analysis in 392 post-menopausal healthy women was conducted; participants provided permission to obtain copies of their most recent screening mammogram. Non-fasting plasma leptin levels were determined using a commercially available leptin ELISA kit. Analysis of the Q223R genotypes of the LEPR gene were performed by PCR followed by restriction fragment length polymorphism analysis using DNA extracted from buffy coat samples. A statistically significant positive relationship was observed between leptin levels and body mass index (p<0.0001); leptin was significantly positively associated with mammography total breast area and non-dense breast area (p<0.0001), while it was inversely associated with percent breast density (p<0.0001). Leptin levels varied across the LEPR Q223R polymorphism, and were higher in women homozygous for the AA variant. Percent breast density decreased across the LEPR Q223R genotype, with lower percent density in women with the AA genotype. When dense area was considered according to quartiles of leptin and stratified by LEPR Q223R, a significant inverse trend between leptin levels and dense breast area was observed only among women with the G/G genotype (p-trend<0.001). After adjustment for possible confounders, leptin levels were significantly inversely associated with percent breast density (p=0.01). A significant interaction between body mass index and leptin levels on percent breast density was observed (p=0.03). These findings suggest that the association between leptin and breast density may vary by LEPR Q223R genotype, and that body mass index and leptin may act in an interactive way in determining breast density.

Newman G, Gonzalez-Perez RR
Leptin-cytokine crosstalk in breast cancer.
Mol Cell Endocrinol. 2014; 382(1):570-82 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Despite accumulating evidence suggesting a positive correlation between leptin levels, obesity, post-menopause and breast cancer incidence, our current knowledge on the mechanisms involved in these relationships is still incomplete. Since the cloning of leptin in 1994 and its receptor (OB-R) 1 year later by Friedman's laboratory (Zhang et al., 1994) and Tartaglia et al. (Tartaglia et al., 1995), respectively, more than 22,000 papers related to leptin functions in several biological systems have been published (Pubmed, 2012). The ob gene product, leptin, is an important circulating signal for the regulation of body weight. Additionally, leptin plays critical roles in the regulation of glucose homeostasis, reproduction, growth and the immune response. Supporting evidence for leptin roles in cancer has been shown in more than 1000 published papers, with almost 300 papers related to breast cancer (Pubmed, 2012). Specific leptin-induced signaling pathways are involved in the increased levels of inflammatory, mitogenic and pro-angiogenic factors in breast cancer. In obesity, a mild inflammatory condition, deregulated secretion of proinflammatory cytokines and adipokines such as IL-1, IL-6, TNF-α and leptin from adipose tissue, inflammatory and cancer cells could contribute to the onset and progression of cancer. We used an in silico software program, Pathway Studio 9, and found 4587 references citing these various interactions. Functional crosstalk between leptin, IL-1 and Notch signaling (NILCO) found in breast cancer cells could represent the integration of developmental, proinflammatory and pro-angiogenic signals critical for leptin-induced breast cancer cell proliferation/migration, tumor angiogenesis and breast cancer stem cells (BCSCs). Remarkably, the inhibition of leptin signaling via leptin peptide receptor antagonists (LPrAs) significantly reduced the establishment and growth of syngeneic, xenograft and carcinogen-induced breast cancer and, simultaneously decreased the levels of VEGF/VEGFR2, IL-1 and Notch. Inhibition of leptin-cytokine crosstalk might serve as a preventative or adjuvant measure to target breast cancer, particularly in obese women. This review is intended to present an update analysis of leptin actions in breast cancer, highlighting its crosstalk to inflammatory cytokines and growth factors essential for tumor development, angiogenesis and potential role in BCSC.

Erkasap N, Ozkurt M, Erkasap S, et al.
Leptin receptor (Ob-R) mRNA expression and serum leptin concentration in patients with colorectal and metastatic colorectal cancer.
Braz J Med Biol Res. 2013; 46(3):306-10 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
The objective of the present study was to investigate the effect of leptin on the progression of colorectal carcinoma to metastatic disease by analyzing the serum leptin concentration and Ob-R gene expression in colon cancer tissues. Tissue samples were obtained from 31 patients who underwent surgical resection for colon (18 cases) and metastatic colon (13 cases) cancer. Serum leptin concentration was determined by an enzyme-linked immunosorbent assay (ELISA) and Ob-R mRNA expression by real-time polymerase chain reaction (RT-PCR) for both groups. ELISA data were analyzed by the Student t-test and RT-PCR data were analyzed by the Mann-Whitney U-test. RT-PCR results demonstrated that mRNA expression of Ob-R in human metastatic colorectal cancer was higher than in local colorectal cancer tissues. On the other hand, mean serum leptin concentration was significantly higher in local colorectal cancer patients compared to patients with metastatic colorectal cancer. The results of the present study suggest a role for leptin in the progression of colon cancer to metastatic disease without weight loss. In other words, significantly increased Ob-R mRNA expression and decreased serum leptin concentration in patients with metastatic colon cancer indicate that sensitization to leptin activity may be a major indicator of metastasis to the colon tissue and the determination of leptin concentration and leptin gene expression may be used to aid the diagnosis.

Binai NA, Carra G, Löwer J, et al.
Differential gene expression in ERα-positive and ERα-negative breast cancer cells upon leptin stimulation.
Endocrine. 2013; 44(2):496-503 [PubMed] Related Publications
In postmenopausal women, adipositas represents a serious risk factor for cancer development and progression. White adipose tissue secretes the 16 kDa hormone leptin which plays a key role in the regulation of appetite and metabolism. An increasing number of reports indicate that leptin also interferes with signal transduction pathways implicated in the development of breast cancer. In our previous study, we identified the estrogen receptor alpha (ERα) as a relevant enhancer of leptin-induced signal transduction leading to transactivation of signal transducer and activator of transcription 3 (Stat3). The purpose of this study is the investigation of specific target gene expression in response to leptin-mediated Stat3 signaling. We performed a comprehensive microarray analysis of ERα-positive and ERα-negative MDA-MB-231 cells upon leptin treatment and identified 49 genes which showed a significant ERα-dependent regulation in leptin-treated MDA-MB-231 cells. There was no intersection with genes which were merely up- or downregulated by ERα expression and only 9 and 11 genes overlapping targets which were regulated by leptin stimulation either in ERα-expressing or ERα-negative MDA-MB-231 cells, respectively. To demonstrate the specificity, expression of three target genes was validated by quantitative real-time PCR. In conclusion, these data imply that leptin can induce a different set of target genes dependent on ERα expression, which might contribute to the development and progression of cancer diseases.

Saini RK, Kaneko I, Jurutka PW, et al.
1,25-dihydroxyvitamin D(3) regulation of fibroblast growth factor-23 expression in bone cells: evidence for primary and secondary mechanisms modulated by leptin and interleukin-6.
Calcif Tissue Int. 2013; 92(4):339-53 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Fibroblast growth factor-23 (FGF23) is a circulating hormone that acts to correct hyperphosphatemic states by inhibiting renal phosphate reabsorption and to prevent hypervitaminosis D by feedback repressing 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) biosynthesis. FGF23 gene expression in the osteoblast/osteocyte is induced by the nuclear vitamin D receptor (VDR) bound to 1,25(OH)2D3, but cycloheximide sensitivity of this induction suggests that it may occur largely via secondary mechanisms requiring cooperating transcription factors. We therefore sought to identify 1,25(OH)2D3-regulated transcription factors that might impact FGF23 expression. Although neither leptin nor interleukin-6 (IL-6) alone affects FGF23 expression, leptin treatment was found to potentiate 1,25(OH)2D3 upregulation of FGF23 in UMR-106 cells, whereas IL-6 treatment blunted this upregulation. Genomic analyses revealed conserved binding sites for STATs (signal transduction mediators of leptin and IL-6 action) along with transcription factor ETS1 in human and other mammalian FGF23 genes. Further, STAT3, STAT1, ETS1, and VDR mRNAs were induced in a dose-dependent manner by 1,25(OH)2D3 in UMR-106 cells. Bioinformatic analysis identified nine potential VDREs in a genomic interval containing human FGF23. Six of the putative VDREs were capable of mediating direct transcriptional activation of a heterologous reporter gene when bound by a 1,25(OH)2D3-liganded VDR complex. A model is proposed wherein 1,25(OH)2D3 upregulates FGF23 production directly via multiple VDREs and indirectly via induction of STAT3, ETS1, and VDR transcription factors that are then activated via cell surface and intracellular signaling to cooperate in the induction of FGF23 through DNA looping and generation of euchromatin architecture.

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