ADIPOR2

Gene Summary

Gene:ADIPOR2; adiponectin receptor 2
Aliases: PAQR2, ACDCR2
Location:12p13.33
Summary:The adiponectin receptors, ADIPOR1 (MIM 607945) and ADIPOR2, serve as receptors for globular and full-length adiponectin (MIM 605441) and mediate increased AMPK (see MIM 602739) and PPAR-alpha (PPARA; MIM 170998) ligand activities, as well as fatty acid oxidation and glucose uptake by adiponectin (Yamauchi et al., 2003 [PubMed 12802337]).[supplied by OMIM, Mar 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:adiponectin receptor protein 2
Source:NCBIAccessed: 31 August, 2019

Ontology:

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 (1994-2019)
Graph generated 31 August 2019 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.

  • Smoking
  • Transforming Growth Factor beta
  • Transcription
  • Polycystic Ovary Syndrome
  • Stomach Cancer
  • Chromosome 12
  • Receptors, Leptin
  • Endometrial Cancer
  • Adipose Tissue
  • Case-Control Studies
  • Carcinoma
  • Genotype
  • Gene Expression
  • Cancer Gene Expression Regulation
  • Adiponectin
  • Immunohistochemistry
  • Colorectal Cancer
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases
  • Biomarkers, Tumor
  • Messenger RNA
  • Body Mass Index
  • Cell Proliferation
  • Neoplasm Invasiveness
  • Cell Surface Receptors
  • Up-Regulation
  • Young Adult
  • Genetic Predisposition
  • Epithelial Cells
  • Apoptosis
  • Receptors, Adiponectin
  • Risk Factors
  • AMP-Activated Protein Kinases
  • Single Nucleotide Polymorphism
  • Obesity
  • Immunoenzyme Techniques
  • Reproductive Techniques, Assisted
  • Breast Cancer
  • Western Blotting
  • Leptin
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: ADIPOR2 (cancer-related)

Cui E, Guo H, Shen M, et al.
Adiponectin inhibits migration and invasion by reversing epithelial‑mesenchymal transition in non‑small cell lung carcinoma.
Oncol Rep. 2018; 40(3):1330-1338 [PubMed] Free Access to Full Article Related Publications
Adiponectin is the most abundant adipokine in the tumor microenvironment. The role of this protein in tumor progression, however, remains controversial. In the present study, we aimed to investigate the effects of adiponectin on the abilities of migration and invasion in non‑small cell lung carcinoma (NSCLC). Using NSCLC cell lines, we examined the effects of adiponectin on cell migration and invasion using Transwell assays. Expression of epithelial‑mesenchymal transition markers was examined via microscopy and western blotting. We also performed a knockdown of Twist, AdipoR1 and AdipoR2 in NSCLC cells with siRNAs. The addition of adiponectin to NSCLC cells inhibited both the migration and invasion abilities. Furthermore, we found that NSCLC cells displayed increased epithelial marker expression and downregulation of mesenchymal marker expression following adiponectin administration. Twist AdipoR1 and AdipoR2 knockdown reversed the inhibitory effects of adiponectin on migration and invasion in NSCLC and epithelial‑mesenchymal transition. Exogenous adiponectin significantly impaired the migratory and invasive capacities of NSCLC cells through reversal of EMT, suggesting that adiponectin may be a novel promising therapeutic approach against NSCLC.

Babińska A, Pȩksa R, Świa Tkowska-Stodulska R, et al.
Expression of adiponectin and leptin receptors in adrenal incidentaloma patients with subclinical hormone secretion.
Cancer Biomark. 2018; 22(2):325-332 [PubMed] Related Publications
BACKGROUND: The role of adopokines in adrenal tumors' hormonal activity remains unclear. Obesity may induce arterial hypertension, disorders of carbohydrate metabolism, and is a risk factor of cardiovascular disease. In patients with subclinical hormone secretion by the adrenal cortex or medulla the risk of metabolic disease is increased.
OBJECTIVE: Authors of this retrospective study selected 78 patients with subclinical hormone secretion out of all adrenal incidentaloma patients hospitalized in the Department of Endocrinology and Internal Medicine between 1995 and 2014.
METHODS: The analyzed group comprised of 38 subclinical Cushing's syndrome (SCS), 40 incidentally discovered pheochromocytoma (PHEO) and 42 patients operated due to an adrenal tumor without pathological hormonal activity. Expression of adiponectin (AdipoR1, AdipoR2) and leptin (Ob-R) receptors in adrenal tumors was assessed in relation to body mass index (BMI) and hormonal activity.
RESULTS: We found statistically significant negative correlations between BMI and expression of all examined receptors in SCS patients (AdipoR1: p= 0.032; AdipoR2: p< 0.001; leptin Ob-R: p= 0.001). In PHEOs, BMI correlated negatively only with AdipoR2 (p= 0.014).
CONCLUSIONS: Data obtained show that the most significant factor associated with the expression of AdipoR1, AdipoR2 and leptin Ob-R receptors in the adrenal tumor tissue is BMI, not their hormonal activity.

Hoffmann M, Gogola J, Ptak A
Adiponectin Reverses the Proliferative Effects of Estradiol and IGF-1 in Human Epithelial Ovarian Cancer Cells by Downregulating the Expression of Their Receptors.
Horm Cancer. 2018; 9(3):166-174 [PubMed] Free Access to Full Article Related Publications
The expression of adiponectin receptors AdipoR1 and AdipoR2 has been reported in the human ovary and ovarian cancer tissues. Moreover, adiponectin has been reported to act as an anti-tumor factor by inhibiting cancer cell proliferation. Thus, we investigate whether adiponectin and its receptors influence ovarian cancer development. In the present study, we found that adiponectin was not expressed in the granulosa cell line (COV434), and epithelial ovarian cancer cell lines (OVCAR-3, SKOV-3, and Caov-3). Additionally, we found that AdipoR1 and AdipoR2 expression is lower in epithelial ovarian cancer cells than in granulosa tumor cells. Endogenous 17β-estradiol as well as exogenous estrogens, such as bisphenol A and its chlorinated and brominated analogs do not affect adiponectin receptor expression. We found that adiponectin inhibited the growth of OVCAR-3 and SKOV-3 cells, and that this effect was independent of apoptosis. Moreover, adiponectin reverses the stimulatory effects of 17β-estradiol and insulin-like growth factor 1 on cell proliferation by downregulating the expression of their receptors, whereas progesterone increased the sensitivity of cancer cells to adiponectin by upregulating AdipoR1 and AdipoR2 expression. These results suggest interactions between adiponectin and various ovarian steroid hormone and growth factor pathways in ovarian cancer cells.

Kokosar M, Benrick A, Perfilyev A, et al.
A Single Bout of Electroacupuncture Remodels Epigenetic and Transcriptional Changes in Adipose Tissue in Polycystic Ovary Syndrome.
Sci Rep. 2018; 8(1):1878 [PubMed] Free Access to Full Article Related Publications
A single bout of electroacupuncture results in muscle contractions and increased whole body glucose uptake in women with polycystic ovary syndrome (PCOS). Women with PCOS have transcriptional and epigenetic alterations in the adipose tissue and we hypothesized that electroacupuncture induces epigenetic and transcriptional changes to restore metabolic alterations. Twenty-one women with PCOS received a single bout of electroacupuncture, which increased the whole body glucose uptake. In subcutaneous adipose tissue biopsies, we identified treatment-induced expression changes of 2369 genes (Q < 0.05) and DNA methylation changes of 7055 individual genes (Q = 0.11). The largest increase in expression was observed for FOSB (2405%), and the largest decrease for LOC100128899 (54%). The most enriched pathways included Acute phase response signaling and LXR/RXR activation. The DNA methylation changes ranged from 1-16%, and 407 methylation sites correlated with gene expression. Among genes known to be differentially expressed in PCOS, electroacupuncture reversed the expression of 80 genes, including PPARγ and ADIPOR2. Changes in the expression of Nr4a2 and Junb are reversed by adrenergic blockers in rats demonstrating that changes in gene expression, in part, is due to activation of the sympathetic nervous system. In conclusion, low-frequency electroacupuncture with muscle contractions remodels epigenetic and transcriptional changes that elicit metabolic improvement.

Mociño-Rodríguez MD, Santillán-Benítez JG, Dozal-Domínguez DS, et al.
Expression of AdipoR1 and AdipoR2 Receptors as Leptin-Breast Cancer Regulation Mechanisms.
Dis Markers. 2017; 2017:4862016 [PubMed] Free Access to Full Article Related Publications
The development of breast cancer is influenced by the adipose tissue through the proteins leptin and adiponectin. However, there is little research concerning AdipoR1 and AdipoR2 receptors and the influence of leptin over them. The objective of this work was to analyze the expression of AdipoR1 and AdipoR2, modulated by differential concentrations of leptin in an obesity model (10 ng/mL, 100 ng/mL, and 1000 ng/mL) associated with breast cancer in MCF-7 and HCC1937 cell lines. Each cell line was characterized through immunohistochemistry, and the expression of AdipoR1 and AdipoR2 was analyzed by PCR in real time using TaqMan® probes. Leptin induced an increase in cell population of MCF-7 (23.8%, 10 ng/mL, 48 h) and HCC1937 (17.24%, 1000 ng/mL, 72 h). In MCF-7, the expression of AdipoR1 decreased (3.81%, 1000 ng/mL) and the expression of AdipoR2 increased by 13.74 times (10 ng/mL) with regard to the control. In HCC1937, the expression of AdipoR1 decreased by 86.28% (10 ng/mL), as well as the expression of AdipoR2 (50.3%, 100 ng/mL). In regard to the results obtained, it could be concluded that leptin has an effect over the expression of AdipoR1 and AdipoR2 mRNA.

Busch EL, Crous-Bou M, Prescott J, et al.
Adiponectin, Leptin, and Insulin-Pathway Receptors as Endometrial Cancer Subtyping Markers.
Horm Cancer. 2018; 9(1):33-39 [PubMed] Free Access to Full Article Related Publications
Developing a system of molecular subtyping for endometrial tumors might improve insight into disease etiology and clinical prediction of patient outcomes. High body mass index (BMI) has been implicated in development of endometrial cancer through hormonal pathways and might influence tumor expression of biomarkers involved in BMI-sensitive pathways. We evaluated whether endometrial tumor expression of 7 markers from BMI-sensitive pathways of insulin resistance could effectively characterize molecular subtypes: adiponectin receptor 1, adiponectin receptor 2, leptin receptor, insulin receptor (beta subunit), insulin receptor substrate 1, insulin-like growth factor 1 receptor, and insulin-like growth factor 2 receptor. Using endometrial carcinoma tissue specimens from a case-only prospective sample of 360 women from the Nurses' Health Study, we scored categorical immunohistochemical measurements of protein expression for each marker. Logistic regression was used to estimate associations between endometrial cancer risk factors, especially BMI, and tumor marker expression. Proportional hazard modeling was performed to estimate associations between marker expression and time to all-cause mortality as well as time to endometrial cancer-specific mortality. No association was observed between BMI and tumor expression of any marker. No marker was associated with time to either all-cause mortality or endometrial cancer-specific mortality in models with or without standard clinical predictors of patient mortality (tumor stage, grade, and histologic type). It did not appear that any of the markers evaluated here could be used effectively to define molecular subtypes of endometrial cancer.

Zhou L, Zhang HF, Ning W, et al.
Associations of adiponectin receptor 2 (AdipoR2) gene polymorphisms and AdipoR2 protein expression levels with the risk of colorectal cancer: A case-control study.
Mol Med Rep. 2017; 16(4):3983-3993 [PubMed] Free Access to Full Article Related Publications
The aim of the present study was to investigate the associations between adiponectin receptor 2 (AdipoR2) gene polymorphisms, AdipoR2 protein expression levels and the risk of colorectal cancer (CRC). From April 2012 to May 2015, 281 CRC patients (case group) admitted to the China‑Japan Friendship Hospital and 325 healthy control subjects (control group) were recruited for the study. Peripheral venous blood samples were collected and the DNA was extracted. Genotyping was performed using denaturing high‑performance liquid chromatography in the condition of partial degeneration. Linkage disequilibrium and haplotype were analyzed using SHEsis analysis software. AdipoR2 protein expression levels were detected by immunohistochemistry and logistic regression analysis was performed to determine the risk factors of CRC. The distribution of the TT genotype of AdipoR2 rs10773989 and the CC genotype of AdipoR2 rs1044471 was higher in the case group than in the control group (P<0.05). The AdipoR2 rs10773989 polymorphism was associated with the degree of tumor infiltration in CRC (P<0.05) and the AdipoR2 rs1044471 polymorphism was associated with the degree of differentiation and Dukes' staging in CRC (P<0.05). The CT haplotype was identified as a protective factor, while the TC haplotype was a risk factor in a healthy population. AdipoR2 protein expression was associated with the degree of differentiation, Dukes' staging, degree of tumor infiltration and lymphatic metastasis in CRC (all P<0.05). Logistic regression analysis demonstrated that the TT genotype of AdipoR2 rs10773989 and CC genotype of AdipoR2 rs1044471 were independent risk factors for CRC. The AdipoR2 rs10773989 and rs1044471 polymorphisms may be correlated with the susceptibility to CRC. In addition, the TC haplotype and AdipoR2 positive expression may increase the risk of CRC.

Yunusova NV, Spirina LV, Frolova AE, et al.
Association of IGFBP-6 Expression with Metabolic Syndrome and Adiponectin and IGF-IR Receptor Levels in Colorectal Cancer.
Asian Pac J Cancer Prev. 2016; 17(8):3963-9 [PubMed] Related Publications
PURPOSE: To assess IGFBP-6 expression in relation with the presence of the metabolic syndrome, adiponectin receptors (AdipoR1 and AdipoR2) and IGF-IR levels in colorectal adenocarcinoma cases.
MATERIALS AND METHODS: IGFBP-6 mRNA and protein levels were analyzed using real-time quantitative PCR and Western blotting in 46 patients. ELISA and ow cytometry were used for evaluation of AdipoR1, AdipoR2 and IGF-IR.
RESULTS: The results showed that IGFBP-6 mRNA expression and the IGFBP-6 content were higher in tumor tissue samples of colorectal cancer patients with and without the metabolic syndrome. In addition, IGFBP-6 mRNA expression was associated with tumor invasion (tumor size) and the IGFBP-6 protein level was associated with nodal status. Positive correlations and positive nonlinear relations were found between the IGFBP-6 level and the AdipoR1 and AdipoR2 contents in colorectal cancer patients.
CONCLUSIONS: The IGFBP-6 mRNA level and protein level were found to be associated with presence of the metabolic syndrome. Positive correlations indicated probable cross-talk between the IGF-IR-mediated and adiponectin-mediated signaling pathways in colorectal carcinomas. IGFBP-6 may be considered as a potential biomarker associated with lymphogenous metastasis and the metabolic syndrome in colorectal cancer.

Artimani T, Saidijam M, Aflatoonian R, et al.
Downregulation of adiponectin system in granulosa cells and low levels of HMW adiponectin in PCOS.
J Assist Reprod Genet. 2016; 33(1):101-10 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The purpose of the study was to investigate changes in adiponectin system expression in granulosa cells (GCs) and high molecular weight adiponectin levels in serum and follicular fluid (FF) of 40 women with polycystic ovary syndrome (PCOS) compared to those in 40 women with normal ovary function.
METHODS: Adiponectin (Adipo), adiponectin receptor 1 (AdipoR1), and adiponectin receptor 2 (AdipoR2) messenger RNA (mRNA) expression levels were measured using quantitative real-time polymerase chain reaction (qRT-PCR). High molecular weight (HMW) adiponectin protein concentration was evaluated by ELISA method. Data were analyzed using Student's t test and one-way ANOVA in SPSS 21 software. At oocyte retrieval, FF was aspirated and GCs were obtained from a pooled collection of FF per each patient.
RESULTS: PCR results showed expression of adiponectin, AdipoR1, AdipoR2, follicle-stimulating hormone receptor (FSHR), and luteinizing hormone receptor (LHR) in GCs. After controlling body mass index (BMI) values, qRT-PCR demonstrated a decreased expression of adiponectin system in GCs of PCOS patients compared to those in controls (p = 0.001). There was a strong positive correlation among AdipoR1 and AdipoR2 expression and also among FSH and LH receptor expression. (Both r = 0.8, p = 0.001). There were low levels of high molecular weight adiponectin in the serum of PCOS patients with controlled ovarian hyperstimulation (30.19 ± 4.3 ng/ml) compared to the controls (48.47 ± 5.9 ng/ml) and in the FF of PCOS patients with controlled ovarian hyperstimulation (7.86 ± 1.44 ng/ml) compared to the controls (14.22 ± 2.01 ng/ml; p = 0.02).
CONCLUSIONS: Lower expression of adiponectin and its receptors in GCs might be an important manifestation in gonadotropin-stimulated PCOS patients which could influence the physiologic adiponectin roles such as interaction with insulin and LH in induction of GC gene expression.

García V, Oróstica L, Poblete C, et al.
Endometria from Obese PCOS Women with Hyperinsulinemia Exhibit Altered Adiponectin Signaling.
Horm Metab Res. 2015; 47(12):901-9 [PubMed] Related Publications
Hyperandrogenemia, hyperinsulinemia, and obesity affect 60-70% of patients with Polycystic Ovarian Syndrome (PCOS), who exhibit an altered endometrial insulin signaling. The aim of the study was to evaluate whether hyperandrogenism, hyperinsulinism, and obesity present in PCOS patients impair the endometrial adiponectin signaling pathway. The ex vivo study was conducted on 27 samples from lean (n=9), obese (n=9), and obese-PCOS (n=9) patients. The in vitro assays were performed in immortalized human endometrial stromal cells stimulated with testosterone, insulin, or testosterone plus insulin. Serum steroid-hormones, adiponectin, glucose, and insulin; body mass index, free androgen index, ISI-Composite, and HOMA were evaluated in the 3 groups. Ex vivo and in vitro gene expression and protein content of adiponectin, AdipoR1, AdipoR2, and APPL1 were determined. Adiponectin serum levels were decreased in obese-PCOS patients compared to lean (78%) and obese (54%) controls (p<0.05). AdipoR1 protein and gene expression were increased in obese group vs. obese-PCOS and lean groups (2-fold, p<0.05). In turn, AdipoR2 protein and mRNA content was similar between the 3 groups. APPL1 protein levels were reduced in endometria from both obese groups, compared to lean group (6-fold, p<0.05). Testosterone plus insulin stimulation of T-HESC and St-T1b leads to a reduction of adiponectin, AdipoR1, AdipoR2, and APPL1 protein content in both endometrial cell lines (p<0.05), whereas, in the presence of testosterone or insulin alone, protein levels were similar to basal. Therefore, endometrial adiponectin-signaling pathway is impaired in hyperandrogenemic and hyperinsulinemic obese-PCOS patients, corroborated in the in vitro model, which could affect endometrial function and potentially the implantation process.

Tiwari A, Ocon-Grove OM, Hadley JA, et al.
Expression of adiponectin and its receptors is altered in epithelial ovarian tumors and ascites-derived ovarian cancer cell lines.
Int J Gynecol Cancer. 2015; 25(3):399-406 [PubMed] Related Publications
OBJECTIVES: Recent evidence suggests that higher body mass index is associated with a modest increase in ovarian cancer risk. Reduced serum levels of adiponectin are correlated with obesity and increased cancer risk. The objectives of the present study are to determine if expressions of adiponectin and its receptors, AdipoR1 and AdipoR2, are altered in epithelial ovarian tumors and ascites-derived ovarian cancer cell lines and to determine if plasma adiponectin levels are altered in the chicken model of ovarian cancer.
METHODS: Adiponectin, AdipoR1, and AdipoR2 mRNA concentrations in ovaries and chicken ovarian cancer (COVCAR) cell lines were determined by quantitative real-time polymerase chain reaction analysis. Existence of adiponectin isoforms in the ovaries and COVCAR cells was identified by nondenaturing gel electrophoresis. Adiponectin, AdipoR1, and AdipoR2 protein amounts were determined by Western blot analysis. Plasma total adiponectin levels were determined by an enzyme immunoassay.
RESULTS: Adiponectin, AdipoR1, and AdipoR2 mRNA concentrations were significantly lower in cancerous ovaries and COVCAR cell lines compared with normal ovaries and normal ovarian surface epithelial (NOSE) cells, respectively. Adiponectin in ovary and COVCAR cell lines appeared as a heavy-molecular-weight isoform that is greater than 720-kd mass. In addition, a lower-molecular-weight adiponectin isoform was found in COVCAR cells but not in NOSE cells. Adiponectin and AdipoR1 protein concentrations were not different in COVCAR cell lines compared with NOSE cells. However, AdipoR2 protein concentrations were significantly higher in cancerous ovaries but lower in COVCAR cell lines compared with normal ovaries and NOSE cells, respectively. Plasma adiponectin concentrations were not different in chickens that had ovarian carcinoma compared with control animals.
CONCLUSIONS: Expression of adiponectin in ovarian tumors and in metastatic ovarian tumor cells is likely to affect cellular metabolism and proliferation through activating AdipoR1 and/or AdipoR2. Plasma adiponectin levels may not be predictive of advanced stages of ovarian tumor in the chicken model.

Ayyildiz T, Dolar E, Ugras N, et al.
Adipo-R1 and adipo-R2 expression in colorectal adenomas and carcinomas.
Asian Pac J Cancer Prev. 2015; 16(1):367-72 [PubMed] Related Publications
BACKGROUND: Human adiponectin (ApN), a 30 kDa glycoprotein of 244-amino acids which is predominantly produced by adipocytes, exerts its effects via two receptors, namely adiponectin receptor-1 (adipo-R1) and adiponectin receptor-2 (adipo-R2) with differential binding affinity to globular adiponectin. Adiponectin receptor expression has been studied in several cancer tissues. However, there are no studies of colorectal adenomas which are considered to be precursors for colorectal carcinoma (CRC).
OBJECTIVES: In the present study, the expression of adipo-R1 and adipo-R2 was investigated immunohistochemically in colorectal adenomas and colorectal carcinoma tissues in an attempt to determine associations with these tumors.
MATERIALS AND METHODS: The study enrolled 50 CRC patients with tumor resection and 82 patients who were diagnosed with adenomatous polyps, classified as negative for neoplasia, low-grade dysplasia (L-GD) or high- grade dysplasia (H-GD).
RESULTS: Expression of both adipo-R1 and adipo-R2 was found to be significantly lower in the CRCs than in colorectal adenomas (tubular and tubulovillous, p=0.009 and p<0.001, respectively). Adipo-R1 and adipo-R2 expression was also significantly lower in the CRC group when compared with the groups of patients with low grade dysplasia, high-grade dysplasia or no neoplasia (p=0.012 and p<0.001, respectively). In addition, it was observed that adipo-R2 expression was generally positive in the non-neoplastic group irrespective of the adipo-R2 expression. In the L-GD, H-GD and CRC groups, the adipo-R2 result was positive whenever adipo-R1 result was positive but some patients with negative adipo-R1 had positive adipo-R2 (p<0.001, p=0.004, p<0.001, respectively).
CONCLUSIONS: This study indicated that ApN may play a role in the progression of colorectal adenomatous polyps to carcinoma through actions on adipo-R1 and adipo-R2 receptors.

Wu S, Zheng C, Chen S, et al.
Adiponectin signals through Adiponectin Receptor 1 to reverse imatinib resistance in K562 human chronic myeloid leukemia cells.
Biochem Biophys Res Commun. 2015; 456(1):367-72 [PubMed] Related Publications
Adiponectin, a member of adipokines, is a functional ligand for Adiponectin Receptor-1 (AdipoR1) and Adiponectin Receptor-2 (AdipoR2), and has been found to be linked to the risk of CML. Imatinib has undoubtedly revolutionised the management and outcome of chronic myeloid leukemia (CML), however imatinib resistance has been recognized as a major problem in CML therapy. In this study, we first established imatinib-resistant K562 CML cells, and then evaluated the effect of Adiponectin in reversing imatinib resistance. The data presented here demonstrated that Adiponectin was able to reverse K562 resistance to imatinib in vitro and in vivo. Additional data with molecular approaches suggested that the reversion of Adiponectin in imatinib resistance signals through AdipoR1 but not AdipoR2 to downregulate Bcr-Abl expression and effect in imatinib-resistant K562 CML cells. Taken together, our data showed that Adiponectin can reverse imatinib resistance in CML, and to a certain extent elucidate the mechanism of Adiponectin reversing imatinib resistance that may provide a new and promising approach in imatinib resistance management in CML therapy.

Guan G, Zhang D, Zheng Y, et al.
microRNA-423-3p promotes tumor progression via modulation of AdipoR2 in laryngeal carcinoma.
Int J Clin Exp Pathol. 2014; 7(9):5683-91 [PubMed] Free Access to Full Article Related Publications
Despite of the variety of combined modality treatments for laryngeal carcinoma have been introduced, the distance recurrence rate and 5-year overall survival rate over the past decades are still the major issues, underlining the importance to better understand the biological bases that contribute to disease progression. Here, we reported that miR-423-3p overexpressed in primary laryngeal carcinoma cell line where it plays a critical role in tumor progression. Suppression of miR-423-3p expression resulted in decreasing cell proliferation, clonogenicity, cell migration and invasion. By using in silico prediction algorithms for target identification, AdipoR2 (adiponectin receptor 2) and DUSP4 (MAP kinase phosphatase 2) were identified to be potential targets of miR-423-3p. Overexpression of miR-423-3p was associated with epigenetic silencing of AdipoR2 in human laryngeal carcinoma samples, which have been previously implicated in suppression of tumor proliferation and angiogenesis. Luciferase reporter assays and western blot further confirmed the direct interaction of miR-423-3p with AdipoR2. Our findings have demonstrated that miR-423-3p plays an important oncogenic role in laryngeal carcinoma progression, and further suggest that suppression of miR-423-3p expression might be useful for its clinical management.

Huang B, Cheng X, Wang D, et al.
Adiponectin promotes pancreatic cancer progression by inhibiting apoptosis via the activation of AMPK/Sirt1/PGC-1α signaling.
Oncotarget. 2014; 5(13):4732-45 [PubMed] Free Access to Full Article Related Publications
Adiponectin is an adipocyte-secreted adipokine with pleiotropic actions. Clinical evidence has shown that serum adiponectin levels are increased and that adiponectin can protect pancreatic beta cells against apoptosis, which suggests that adiponectin may play an anti-apoptotic role in pancreatic cancer (PC). Here, we investigated the effects of adiponectin on PC development and elucidated the underlying molecular mechanisms. Adiponectin deficiency markedly attenuated pancreatic tumorigenesis in vivo. We found that adiponectin significantly inhibited the apoptosis of both human and mouse pancreatic cancer cells via adipoR1, but not adipoR2. Furthermore, adiponectin can increase AMP-activated protein kinase (AMPK) phosphorylation and NAD-dependent deacetylase sirtuin-1 (Sirt1) of PC cells. Knockdown of AMPK or Sirt1 can increase the apoptosis in PC cells. AMPK up-regulated Sirt1, and Sirt1 can inversely phosphorylate AMPK. Further studies have shown that Sirt1 can deacetylate peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which can increase the expression levels of mitochondrial genes. Thus, adiponectin exerts potent anti-apoptotic effects on PC cells via the activation of AMPK/Sirt1/PGC1α signaling. Finally, adiponectin can elevate β-catenin levels. Taken together, these novel findings reveal an unconventional role of adiponectin in promoting pancreatic cancers, and suggest that the effects of adiponectin on tumorigenesis are highly tissue-dependent.

Ayyildiz T, Dolar E, Ugras N, et al.
Lack of any prognostic relationship between adiponectin receptor (Adipo R1/R2) expression for early/advanced stage gastric cancer.
Asian Pac J Cancer Prev. 2014; 15(11):4711-6 [PubMed] Related Publications
INTRODUCTION: Adiponectin (ApN) is a complement C1q-related protein, mainly secreted from adipose tissue, that signals through ApN receptor 1 (Adipo-R1) and ApN receptor 2 (Adipo-R2). Low serum ApN concentrations are associated with obesity-related malignancies. However, there are very few studies on any prognostic role of ApN receptors in gastric cancer.
OBJECTIVES: The aim of this study is to investigate the relationship between AdipoR1/R2 expression and early/advanced stage gastric cancer in terms of clinicopathologic characteristics and survival.
MATERIALS AND METHODS: Eighteen patients with early and 39 with advanced stage gastric cancer who underwent surgical gastric resection were included in this study.
RESULTS: Adipo-R1 expression was low in 2 of the 18 patients with early stage gastric cancer (11.1%), while 4 had low Adipo-R2 expression (22.2%). In those with advanced stage gastric cancer, 7 of 39 had low Adipo-R1 expression (17.9%) and 16 had low Adipo-R2 expression (41%). Adipo-R2 expression was significantly higher (p=0.011) in moderately differentiated tumors when compared to well-differentiated tumors. While there was nearly a statistically significant relationship between TNM stage (T, tumor size; N, regional lymph node; M, whether distant metastases exist) and Adipo-R2 expression (p=0.054), there was no relationship between Adipo-R1/-R2 expression with tumor stage and survival.
CONCLUSION: Adipo-R1/-R2 expression has no prognostic significance of in early/advanced stage gastric cancer.

Vetvik KK, Sonerud T, Lindeberg M, et al.
Globular adiponectin and its downstream target genes are up-regulated locally in human colorectal tumors: ex vivo and in vitro studies.
Metabolism. 2014; 63(5):672-81 [PubMed] Related Publications
OBJECTIVE: Low plasma adiponectin levels are linked to obesity, insulin resistance, and the risk of several types of malignancy. Despite the decline in circulating adiponectin concentrations, the increase in the expression of adiponectin receptors AdipoR1 and AdipoR2 is greater in cancerous than in normal colonic tissue. The purpose of this study was to obtain new information regarding local adiponectin signaling in the pathogenesis of colorectal cancer (CRC).
METHODS: We characterized the expressions of adiponectin and several of its downstream targets in paired samples of tumor tissue and adjacent noncancerous mucosa in 60 surgical patients with colorectal adenocarcinomas.
RESULTS: Adiponectin was expressed in both colorectal tumors and the adjacent mucosa. The expressions of adiponectin mRNA and its globular protein variant (gAd), adiponectin receptor type 1 and 5' AMP-activated protein kinase (AMPK) mRNA were significantly higher in colorectal tumors than in the adjacent mucosa. This finding was accompanied by increased mRNA expression of genes encoding proteins involved in fatty-acid trafficking and oxidation. The potential interference between adiponectin stimulation and AMPK activation through AMPK1 was examined in an in vitro model with the aid of silencing-RNA experiments. Furthermore, AMPK mRNA expression on tumors was positively correlated with a more advanced tumor stage in the patients.
CONCLUSION: We propose that the globular adiponectin-AMPK pathway functions in an autocrine manner in colorectal tumors, explaining some of the beneficial changes in cellular oxidative capacity in tumors in favor of tumorigenesis.

Comim FV, Hardy K, Franks S
Adiponectin and its receptors in the ovary: further evidence for a link between obesity and hyperandrogenism in polycystic ovary syndrome.
PLoS One. 2013; 8(11):e80416 [PubMed] Free Access to Full Article Related Publications
Polycystic ovary syndrome (PCOS), characterized by ovarian androgen excess, is the commonest endocrine disorder in women. Obesity increases androgen synthesis, a phenomenon attributed to the accompanying hyperinsulinemia. Our hypothesis was that adipokines, fat cell-derived hormones, play a direct role in modulating ovarian androgen secretion. Therefore, the aims of this study were to explore the effects of adipokines (in particular, adiponectin) on ovarian steroidogenesis and compare the expression of adiponectin receptors in ovaries from women with and without PCO. Sections of archived human ovaries (nine from women with normal ovaries and 16 with PCOS, classified histologically, with reference to menstrual history and ultrasound) were analysed by quantitative morphometry and the proportion of positive-labelling cells compared. In addition, studies of androgen production in relation to adipokine function in primary bovine theca cell culture were also performed. A significantly lower proportion of theca cells expressed adiponectin receptors 1 and 2 (AdipoR1, AdipoR2) in polycystic ovaries than in normal ovaries. In cultured theca cells, adiponectin suppressed androstenedione production and gene expression of LH receptor and key enzymes in the androgen synthesis pathway. Moreover, knockdown of genes for AdipoR1 and AdipoR2 was associated with increased androstenedione secretion by bovine theca cells. These results provide evidence for a direct link between fat cell metabolism and ovarian steroidogenesis, suggesting that disruption of adiponectin and/or its receptors plays a key role in pathogenesis of hyperandrogenism in PCOS.

Ye L, Zhang ZY, Du WD, et al.
Genetic analysis of ADIPOQ variants and gastric cancer risk: a hospital-based case-control study in China.
Med Oncol. 2013; 30(3):658 [PubMed] Related Publications
Single-nucleotide polymorphisms (SNPs) of adiponectin (ADIPOQ), adiponectin receptor 1 (ADIPOR1) and ADIPOR2 genes contribute to the risk and progression of cancers. Here, we investigated the associations between variants of these three genes and the risk of gastric cancer. We genotyped six ADIPOQ SNPs, nine ADIPOR1 SNPs and six ADIPOR2 SNPs using the Sequenom technique in a hospital-based case-control study of patients with gastric cancer and cancer-free controls in the Chinese Han population. We found associations of certain variants with location of gastric cancer. Rs16861205 with the minor allele A in ADIPOQ, rs10773989 with the minor allele C and rs1044471 with the minor allele T in ADIPOR2 presented significant associations with a decreased risk of cardia cancer (P = 0.024, OR 0.605, 95 % CI 0.390-0.938; P = 0.015, OR 0.699, 95 % CI 0.522-0.935; and P = 0.022, OR = 0.703, 95 % CI 0.519-0.951, respectively). ADIPOQ rs16861205 with minor allele A displayed an association with an increased risk of body cancer (P = 0.010, OR 1.821, 95 % CI 1.148-2.890). Further stratified analysis of the patients indicated that there were significant correlations for rs1342387A/G (P = 0.027) and rs16861205A/G (P = 0.000) with tumor location; rs16850799A/G (P = 0.004) and rs2058033C/A (P = 0.003) with invasion depth; rs16850799A/G (P = 0.019) with the tumor-node-metastasis stage; rs16850799A/G (P = 0.016), rs1501299A/C (P = 0.005) and rs1063538C/T (P = 0.017) with alcohol consumption; rs11612414A/G (P = 0.040) and rs12733285T/C (P = 0.005) with salted food; rs1063538C/T (P = 0.043) with family history of gastric cancer; and rs11612414A/G (P = 0.029) with gender. Adiponectin expression significantly correlated with gender (P = 0.014), alcohol consumption (P = 0.037), family history (P = 0.019) and invasion depth of primary tumor (P = 0.024). Our data suggested that variants of ADIPOQ may be genetic markers conferring susceptibility to gastric cancer subtypes. These findings need to be validated in a larger panel of samples from distinct populations.

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] Free Access to Full Article 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.

Kaklamani VG, Hoffmann TJ, Thornton TA, et al.
Adiponectin pathway polymorphisms and risk of breast cancer in African Americans and Hispanics in the Women's Health Initiative.
Breast Cancer Res Treat. 2013; 139(2):461-8 [PubMed] Free Access to Full Article Related Publications
Adiponectin, a protein secreted by the adipose tissue, is an endogenous insulin sensitizer with circulating levels that are decreased in obese and diabetic subjects. Recently, circulating levels of adiponectin have been correlated with breast cancer risk. Our previous work showed that polymorphisms of the adiponectin pathway are associated with breast cancer risk. We conducted the first study of adiponectin pathways in African Americans and Hispanics in the Women's Health Initiative SNP Health Association Resource cohort of 3,642 self-identified Hispanic women and 8,515 self-identified African American women who provided consent for DNA analysis. Single nucleotide polymorphisms (SNPs) from three genes were included in this analysis: ADIPOQ, ADIPOR1, and ADIPOR2. The genome-wide human SNP array 6.0 (909,622 SNPs) ( www.affymetrix.com ) was used. We found that rs1501299, a functional SNP of ADIPOQ that we previously reported was associated with breast cancer risk in a mostly Caucasian population, was also significantly associated with breast cancer incidence (HR for the GG/TG genotype: 1.23; 95 % CI 1.059-1.43) in African American women. We did not find any other SNPs in these genes to be associated with breast cancer incidence. This is the first study assessing the role of adiponectin pathway SNPs in breast cancer risk in African Americans and Hispanics. RS1501299 is significantly associated with breast cancer risk in African American women. As the rates of obesity and diabetes increase in African Americans and Hispanics, adiponectin and its functional SNPs may aid in breast cancer risk assessment.

Palin MF, Bordignon VV, Murphy BD
Adiponectin and the control of female reproductive functions.
Vitam Horm. 2012; 90:239-87 [PubMed] Related Publications
Adiponectin is the most abundant protein secreted by the white adipose tissue. It circulates at high levels in the bloodstream and its serum concentration is inversely correlated with body fat mass. The wide distribution of adiponectin receptors (AdipoR1, AdipoR2, and T-cadherin) in peripheral tissues and organs allows adiponectin to exert pleiotropic effects on whole-body metabolism. Besides its well-known antidiabetic, antiatherogenic, and anti-inflammatory properties, accumulating evidence suggests a direct role for adiponectin in reproductive tissues. The mammalian ovary and the ovarian follicle express AdipoR1 and AdipoR2, and treating pig granulosa cells with adiponectin induces changes characteristic of the periovulatory period. Moreover, additive effects are observed between adiponectin and insulin in induction of granulosa cell gene expression, thus suggesting that adiponectin actions on the ovary may be mediated through its insulin-sensitizing effects. Adiponectin receptors are also detected in the uterus. In women, higher AdipoR1 and AdipoR2 gene expression was observed during the mid-secretory phase of the menstrual cycle, suggesting that adiponectin is implicated in the endometrial changes in preparation for embryo implantation. Adiponectin receptors are found in oocytes and early developing pig, rabbit, and mice embryos, and it has been demonstrated that adiponectin can increase the success of porcine embryo development to the blastocyst stage in vitro. Moreover, adiponectin concentration is two to three times greater in human fetal circulation and in umbilical cord blood, compared to adult plasma. This further indicates a role for adiponectin in fetal growth. It has been further suggested that adipose-derived and locally produced adiponectin may act as a key neuromodulator of reproductive functions. For example, the inhibition of LH and GnRH release from rat pituitary and hypothalamic cells following treatment with adiponectin provides evidence that adiponectin may also act on the release of gonadotropins. Adipose tissue is now recognized as an important factor in the complex equation by which the nutritional status regulates female reproductive functions. For example, underweight women have delayed puberty and higher risk of premature delivery, whereas overweight and obese women have early puberty and are prone to develop polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and preeclampsia. Because hypoadiponectinemia is often associated with the abovementioned disorders, it has been suggested that this adipokine might play a role in the development of these pregnancy-related complications. Moreover, as these reproductive disorders often come with metabolic complications such as insulin and glucose resistance, the insulin-sensitizing effects of adiponectin may explain the observed association of this adipokine with PCOS, GDM, and preeclampsia. This review summarizes current knowledge on the role of adiponectin in female reproductive tissues and highlights mechanisms where information is available. We also discuss about the known and potential roles of adiponectin in the development of reproductive disorders.

Yamauchi N, Takazawa Y, Maeda D, et al.
Expression levels of adiponectin receptors are decreased in human endometrial adenocarcinoma tissues.
Int J Gynecol Pathol. 2012; 31(4):352-7 [PubMed] Related Publications
Adiponectin is a cytokine secreted by adipocytes, whose plasma levels are decreased in obesity. Adiponectin has insulin-sensitizing, antiatherogenic, and antidiabetogenic effects. It has been shown that adiponectin may also exert antineoplastic activity through suppression of tumor proliferation and neoangiogenesis and through induction of apoptosis. Recently, low adiponectin serum concentration has been found in obesity-related malignancies, including endometrial cancer. In addition, the expression of adiponectin receptors (AdipoR1 and AdipoR2) has been documented in several human cancer tissues, but the expression has previously not been assessed in human endometrial cancer tissues. In this study, we analyzed the immunohistochemical expression of AdipoR1 and AdipoR2 in a series of surgically resected human endometrioid adenocarcinoma tissues from a total of 141 cases. Decreased AdipoR1 or AdipoR2 expression was significantly associated with histological higher grade (P=0.0026 and 0.0004, respectively). Decreased expression of AdipoR1 was associated with myometrial invasion and lymph node metastasis of endometrioid adenocarcinoma (P=0.0039 and P=0.0069, respectively). AdipoR1 and AdipoR2 immunoexpression was significantly associated with the expression of the progesterone receptor, although it was not significantly correlated with the expression of the estrogen receptor, Ki-67 or p53. Our present study raises the possibility that decreased expression of adiponectin receptors is implicated in the development, invasion, and metastasis of human endometrioid adenocarcinoma. Our findings, moreover, indicate that adiponectin receptors could be considered as therapeutic targets for endometrioid adenocarcinoma. In adiponectin receptor-positive endometrioid adenocarcinoma, we think adiponectin-based anticancer therapy is useful; however, in histological high-grade endometrioid adenocarcinoma, in which the expression levels of adiponectin receptors are relatively low, adiponectin therapy supported by adiponectin receptor induction is needed.

Lu JP, Hou ZF, Duivenvoorden WC, et al.
Adiponectin inhibits oxidative stress in human prostate carcinoma cells.
Prostate Cancer Prostatic Dis. 2012; 15(1):28-35 [PubMed] Related Publications
BACKGROUND: Emerging data suggest that obesity increases the risk of aggressive prostate cancer (PC), but the mechanisms underlying this relationship remain to be fully elucidated. Oxidative stress (OS) is a key process in the development and progression of PC. Adiponectin, an adipocyte-specific hormone, circulates at relatively high levels in healthy humans, but at reduced levels in obese subjects. Moreover, case-control studies also document lower levels of serum adiponectin in PC patients compared with healthy individuals.
METHODS: Human 22Rv1 and DU-145 PC cell lines were examined for the generation of OS and detoxification of reactive oxygen species after treatment with adiponectin. Normality was confirmed using the Shapiro-Wilk test and results were analyzed using a one-way analysis of variance.
RESULTS: We demonstrate that adiponectin increased cellular anti-oxidative defense mechanisms and inhibited OS in a significant and dose-dependent manner. We show that adiponectin treatment decreased the generation of superoxide anion in both cell lines, whereas the transcript levels of NADPH oxidase (NOX)2 and NOX4 increased. We also found indications of an overall anti-oxidative effect, as the total anti-oxidative potential, catalase activity and protein levels, and manganese superoxide dismutase protein levels increased significantly (P<0.05) in both cell lines after treatment with adiponectin.
CONCLUSION: Lower levels of adiponectin in obese individuals may result in higher levels of prostatic OS, which may explain the clinical association between obesity, hypoadiponectinemia and PC.

Niu K, Asada M, Okazaki T, et al.
Adiponectin pathway attenuates malignant mesothelioma cell growth.
Am J Respir Cell Mol Biol. 2012; 46(4):515-23 [PubMed] Related Publications
Malignant mesothelioma (MM) is caused by exposure to asbestos. Because MM has a latency period, short survival time, and has a poor response to current therapeutic regimes, long-term preventive strategies are required to suppress the advance of pathological states after asbestos exposure. Accumulating evidence suggests that adiponectin plays a crucial role in the regulation of energy metabolism by increasing AMP-activated protein kinase (AMPK) activation. Several studies have indicated that the activation of AMPK decreases cyclooxygenase (COX)-2 expression. Because high COX-2 levels correlated with a worse prognosis and survival rate in MM, we examined whether the adiponectin pathway suppresses MM cell growth through the AMPK/COX-2 pathway. In vivo, dietary fish oil (a potential promoter of adiponectin) decreased the growth rate of MM, which was accompanied by an increase in adiponectin and phospho-AMPK levels, and a decrease in COX-2 level. In vitro, adiponectin significantly impaired the cell proliferation rate of MM cell lines. These effects partly involved induction of growth arrest and apoptosis to MM cells. MM cells expressed both adiponectin receptors 1 and 2 (AdipoR1 and -R2) at mRNA and proteins levels. These receptors were functional, because adiponectin activated AMPK. Adiponectin treatment also significantly down-regulated protein levels of COX-2 and its downstream prostaglandin E(2). Finally, inhibitory analysis of AdipoR1/R2 by small interfering RNA knockdown suggests that adiponectin enhances AMPK activity and impairs the cell proliferation rate of MM cells, mainly via AdipoR1. These findings suggest that the induction or supplementation of adiponectin is an important tactic for developing therapeutic strategies against MM.

Liu L, Zhong R, Wei S, et al.
Interactions between genetic variants in the adiponectin, adiponectin receptor 1 and environmental factors on the risk of colorectal cancer.
PLoS One. 2011; 6(11):e27301 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Metabolic syndrome traits play an important role in the development of colorectal cancer. Adipokines, key metabolic syndrome cellular mediators, when abnormal, may induce carcinogenesis.
METHODOLOGY/PRINCIPAL FINDINGS: To investigate whether polymorphisms of important adipokines, adiponectin (ADIPOQ) and its receptors, either alone or in combination with environmental factors, are implicated in colorectal cancer, a two-stage case-control study was conducted. In the first stage, we evaluated 24 tag single nucleotide polymorphisms (tag SNPs) across ADIPOQ ligand and two ADIPOQ receptors (ADIPOR1 and ADIPOR2) among 470 cases and 458 controls. One SNP with promising association was then analyzed in stage 2 among 314 cases and 355 controls. In our study, ADIPOQ rs1063538 was consistently associated with increased colorectal cancer risk, with an odds ratio (OR) of 1.94 (95%CI: 1.48-2.54) for CC genotype compared with TT genotype. In two-factor gene-environment interaction analyses, rs1063538 presented significant interactions with smoking status, family history of cancer and alcohol use, with ORs of 4.52 (95%CI: 2.78-7.34), 3.18 (95%CI: 1.73-5.82) and 1.97 (95%CI: 1.27-3.04) for smokers, individuals with family history of cancer or drinkers with CC genotype compared with non-smokers, individuals without family history of cancer or non-drinkers with TT genotype, respectively. Multifactor gene-environment interactions analysis revealed significant interactions between ADIPOQ rs1063538, ADIPOR1 rs1539355, smoking status and BMI. Individuals carrying one, two and at least three risk factors presented 1.18-fold (95%CI:0.89-fold to 1.58-fold), 1.87-fold (95%CI: 1.38-fold to 2.54-fold) and 4.39-fold (95%CI: 2.75-fold to 7.01-fold) increased colorectal cancer risk compared with those who without risk factor, respectively (P(trend) <0.0001).
CONCLUSIONS/SIGNIFICANCE: Our results suggest that variants in ADIPOQ may contribute to increased colorectal cancer risk in Chinese and this contribution may be modified by environmental factors, such as smoking status, family history of cancer and BMI.

Ozturk K, Avcu F, Ural AU
Aberrant expressions of leptin and adiponectin receptor isoforms in chronic myeloid leukemia patients.
Cytokine. 2012; 57(1):61-7 [PubMed] Related Publications
BACKGROUND: Leptin and adiponectin receptors mediate the role of leptin in stimulating the growth of leukemic cells and the protective function of adiponectin undertaken in several malignancies such as leukemia. In this study, we investigated the involvement of the expression of leptin and adiponectin receptors in chronic myeloid leukemia (CML) pathogenesis.
METHODS: The expression of leptin receptor isoforms, OB-Rt, OB-Ra, and OB-Rb, and the expression of adiponectin receptors, AdipoR1 and AdipoR2, were measured as mRNA levels in two CML cell lines (K562 and Meg-01) and 20 CML patients and 24 healthy controls by using RT-PCR.
RESULTS: OB-Rt and OB-Ra isoforms expression of the leptin receptors were found to be significantly lower in Meg-01 cell lines than K562 cells. All leptin receptors were downregulated in CML patients and more particularly OB-Rb level was found to be undetectably low in normal PBMC as well as in CML patients. AdipoR1 expression level was higher in Meg-01 than in K562, whereas AdipoR2 level was found to be unchanged in both cell lines. Interestingly, while AdipoR1 expression increased in CML patients, AdipoR2 decreased. Moreover, imatinib therapy did not affect both leptin and adiponectin isoform expressions.
CONCLUSION: While the decrease in leptin receptor levels in CML patients was confirmed, the increase in AdipoR1 levels and relevant decrease in AdipoR2 levels depicted their possible involvement in CML pathogenesis. This suggests different functions of adiponectin receptors in CML development.

Chen X, Xiang YB, Long JR, et al.
Genetic polymorphisms in obesity-related genes and endometrial cancer risk.
Cancer. 2012; 118(13):3356-64 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Obesity is associated with circulating levels of adiponectin and leptin and endometrial cancer risk. Little is known about whether single nucleotide polymorphisms (SNPs) in the genes that encode adiponectin (ADIPOQ), leptin (LEP), adiponectin receptor 1 (ADIPOR1), adiponectin receptor 2 (ADIPOR2), and leptin receptor (LEPR) are associated with endometrial cancer.
METHODS: The authors selected 87 tagging SNPs to capture common genetic variants in these 5 genes. These SNPs were evaluated in 1028 endometrial cancer cases and 1932 community controls recruited from Chinese women. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs).
RESULTS: Three of the 10 SNPs evaluated in the ADIPOQ gene were significantly associated with reduced cancer risk. The OR for women homozygous for the minor allele (A/A) for rs3774262 was 0.68 (95% CI, 0.48-0.97) compared with women homozygous for the major allele (G/G). Similar results were found for SNPs rs1063539 and rs12629945 in ADIPOQ, which were in linkage disequilibrium with rs3774262. These associations became nonsignificant after Bonferroni correction was applied. Controls with the minor allele A at rs3774262 had lower weight, smaller waist and hip circumferences, and lower body mass index than controls with the major allele G (all P < .05). Women homozygous for the minor allele (T/T) of rs2071045 in the LEP gene also had significantly lower risk (OR, 0.70; 95% CI, 0.54-0.90) than women homozygous for the major allele (C/C). No other SNPs in the LEP, ADIPOR1, ADIPOR2, or LEPR genes were found to be associated with cancer risk.
CONCLUSIONS: Although a chance finding cannot be ruled out, the consistency of findings for gene-endometrial cancer risk and gene-obesity measurements suggests that genetic polymorphisms in the ADIPOQ gene may play a role in endometrial cancer development.

Moon HS, Chamberland JP, Aronis K, et al.
Direct role of adiponectin and adiponectin receptors in endometrial cancer: in vitro and ex vivo studies in humans.
Mol Cancer Ther. 2011; 10(12):2234-43 [PubMed] Free Access to Full Article Related Publications
Low adiponectin levels are an independent risk factor for and mediate the effect of obesity on endometrial cancer in epidemiology studies. The direct or indirect mechanisms underlying these findings remain to be elucidated. We first examined the expression of adiponectin receptor 1 (AdipoR1) and 2 (AdipoR2) in normal human endometrium and in endometrial cancer tissues ex vivo. We then used KLE and RL95-2 human endometrial cancer cell lines in vitro to study relative expression of AdipoRs, to investigate the effect of adiponectin on activating intracellular signaling pathways, and to assess its potential to alter malignant properties. We report for the first time that the relative expression level of AdipoR1 is higher than AdipoR2 in human endometrial cancer tissue, but the expression of AdipoRs is not statistically different from nonneoplastic tissues. We also show for the first time in endometrial cancer cell lines in vitro that adiponectin suppresses endometrial cancer proliferation acting through AdipoRs. Adiponectin also increases the expression of the adaptor molecule LKB1, which is required for adiponectin-mediated activation of AMPK/S6 axis and modulation of cell proliferation, colony formation, adhesion, and invasion of KLE and RL95-2 cell lines. These novel mechanistic studies provide for the first time in vitro and ex vivo evidence for a causal role of adiponectin in endometrial cancer.

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