Circulating Adiponectin and Risk of Endometrial Cancer

<div><p>Background</p><p>Adiponectin is an insulin-sensitizing hormone produced by adipocytes. It has been suggested to be involved in endometrial tumorigenesis. Published data have shown inconsistent results for the association between circulating adiponectin levels and endometrial cancer. In this study, we conducted a meta-analysis to evaluate the predictive value of circulating adiponectin levels on the development of endometrial cancer.</p><p>Methods</p><p>PubMed, Embase, ISI web of knowledge, and Cochrane databases were searched for all eligible studies, and the summary relative risk (SRR) was calculated. Additionally, we performed dose-response analysis with eight eligible studies.</p><p>Results</p><p>A total of 1,955 cases and 3,458 controls from 12 studies were included. The SRR for the ‘highest’ vs ‘lowest’ adiponectin levels indicated high adiponectin level reduced the risk of endometrial cancer [SRR = 0.40, 95% confidence interval (CI), 0.33–0.66]. Results from the subgroup analyses were consistent with the overall analysis. The SRR for each 1 µg/ml increase of adiponectin indicated a 3% reduction in endometrial cancer risk (95% CI: 2%–4%), and a 14% reduction for each increase of 5 µg/ml (95% CI: 9%–19%). No evidence of publication bias was found.</p><p>Conclusions</p><p>This meta-analysis demonstrates that low level of circulating adiponectin is a risk factor for endometrial cancer.</p></div

Forest plot of the ‘highest’ vs the ‘lowest’ category of circulating adiponectin and endometrial cancer risk.

<p>RR, relative risk; CI, confidence interval.</p

Characteristics of studies included in the meta-analysis.

<p>RR, relative risk; CI, confidence interval; DR, dose-response; HB, hospital-based; NA, not applicable; RIA, radioimmunoassay; BMI, body mass index; pre, premenopause; post, postmenopause; HRT, hormone replacement therapy; PB, population-based; ELISA, enzyme-linked immunosorbent assay; EPIC, European Prospective Investigation into Cancer and Nutrition cohort study; NHS, Nurses’ Health Study; FIT, the Fracture Intervention Trial; HOMA-IR, the homeostasis model assessment of insulin resistance; QUICKI, quantitative insulin sensitivity check index; PLCO, Prostate, Lung, Colorectal and Ovarian cancer screening trial.</p><p>Characteristics of studies included in the meta-analysis.</p

Characteristics of lung cancer and esophageal squamous cell carcinoma (ESCC) patients and healthy controls.

<p>Abbreviations: SQC, squamous cell carcinoma; SCC, small-cell carcinoma.</p><p>Two-sided χ² test for categorical variables.</p

Forest plot of lung cancer risk associated with the rs401681 polymorphism.

<p>Stratification analysis by histology type revealed that rs401681 T genotypes were associated with a significantly reduced risk of both adenocarcinoma and squamous cell carcinoma.</p

Genotype and allele frequencies of the rs401681 polymorphism in lung cancer and esophageal squamous cell carcinoma (ESCC) patients and healthy controls.

<p>^a Two-sided χ² test of the difference in the genotype frequency distribution between cases and controls.</p><p>^b Two-sided χ² test of the distribution of combined genotypes (CT+TT).</p><p>cTwo-sided χ² test of the allele distribution.</p><p>The observed genotype frequency among the control subjects conformed to Hardy–Weinberg equilibrium (p²+2pq+q² = 1)(<i>P</i> = 0.805).</p

Association between the rs401681 polymorphism and the susceptibility to lung cancer and esophageal squamous cell carcinoma (ESCC).

<p>Abbreviations: OR, odds ratio; CI, confidence interval; DOM, dominant model (CT/TT vs. CC); REC, recessive model (TT vs. CC/CT); ADD, additive model (2*TT+CT vs. 2*CC+CT).</p><p>^a Crude ORs and <i>P</i> values were estimated in a logistic regression model without any adjustment.</p><p>^b Adjusted for age, sex and smoking and alcohol status.</p

The expression of RBP2, E-cadherin, N-cadherin and snail in normal lung tissues and lung cancer tissues.

<p>A. Immunohistochemistrical analysis of RBP2, E-cadherin, N-cadherin and snail (magnification × 200). RBP2, N-cadherin and snail were strongly positive in both adenocarcinoma and squamous carcinoma samples, whereas E-cadherin was weakly stained or unstained. B. Western blot analysis of the RBP2 protein. N = normal lung tissue, C = lung cancer tissue. C. Real-time PCR analysis of RBP2 mRNA. The level of RBP2 mRNA was higher in the lung cancer tissues than in the normal lung tissues (<i>P</i> = 0.0011). *<i>P</i> < 0.05 and **<i>P</i> < 0.01. </p

The migratory behaviors of both Beas2B and A549 cells.

<p>A. Transwell invasion analysis (magnification × 200). B. The number of invaded cells. More Beas2B cells invaded after transfection with the pcDNA3-HA-RBP2 plasmid (<i>P</i> = 0.0011), whereas the number of invaded A549 cells significantly decreased when treated with RBP2 siRNA2 (<i>P</i> = 0.0005). *<i>P</i> < 0.05, **<i>P</i> < 0.01 and ***<i>P</i> < 0.001. C. The number of migrated cells. The number of migrated Beas2B cells significantly increased when transfected with the pcDNA3-HA-RBP2 plasimid (<i>P</i> = 0.0010), whereas fewer A549 cells migrated into the center space when transfected with RBP2 siRNA2 (<i>P</i> = 0.0014). *<i>P</i> < 0.05, **<i>P</i> < 0.01 and ***<i>P</i> < 0.001. D. Wound healing assays (magnification × 100). </p

The expression of RBP2, E-cadherin, N-cadherin and snail in both Beas2B and A549 cells.

<p>A. Western blot analysis of RBP2, E-cadherin, N-cadherin and snail expression in the Beas2B, SK-MES-1 and A549 cells. When the Beas2B cells were transfected with the pcDNA3-HA-RBP2 plasmid, the levels of RBP2, N-cadherin and snail proteins increased, and the level of E-cadherin protein decreased. When the SK-MES-1 and A549 cells were transfected with RBP2 siRNA2, the levels of RBP2, N-cadherin and snail proteins were increased, and the level of E-cadherin protein decreased. B. Real-time analysis of the levels of E-cadherin, N-cadherin and snail mRNAs in the Beas2B cells. The level of E-cadherin mRNA was higher in the Beas2B cells treated with the pcDNA3-HA-RBP2 plasmid than in the control Beas2B cells (<i>P</i> = 0.0005), but the levels of N-cadherin and snail mRNAs were lower (N-cadherin, <i>P</i> = 0.0063; snail, <i>P</i> = 0.0101). *<i>P</i> < 0.05, **<i>P</i> < 0.01 and ***<i>P</i> < 0.001. C. Real-time analysis of the levels of E-cadherin, N-cadherin and snail mRNAs in the A549 cells. The level of E-cadherin mRNA was lower in the A549 cells treated with RBP2 siRNA2 than in the control A549 cells (<i>P</i> = 0.0007), but the levels of N-cadherin and snail mRNAs were higher (N-cadherin, <i>P</i> = 0.0037; snail, <i>P</i> = 0.0014). *<i>P</i> < 0.05, **<i>P</i> < 0.01 and ***<i>P</i> < 0.001.</p