A prospective study of soluble receptor for advanced glycation end products and adipokines in association with pancreatic cancer in postmenopausal women

Abstract

Advanced glycation end products (AGEs) dysregulate adipokines and induce inflammation by binding to their adipocyte receptor (RAGE). Soluble RAGE (sRAGE) prevents AGEs/RAGE signaling. We performed a nested case–control study of the association between sRAGE, adipokines, and incident pancreatic cancer risk in the prospective Women's Health Initiative Study. We individually matched controls (n = 802) to cases (n = 472) on age, race, and blood draw date. We evaluated serum concentrations of sRAGE, adiponectin, leptin, monocyte chemotactic protein 1 (MCP1), and plasminogen activator inhibitor‐1 (PAI1) using immunoassay. We used conditional logistic regression model to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for pancreatic cancer over biomarker quartiles (Q1–Q4). We used principal component analysis to create two composite biomarkers and performed a confirmatory factor analysis to examine the association between composite biomarker scores (CBS) and pancreatic cancer risk. Baseline serum sRAGE concentrations were inversely associated with pancreatic cancer risk (aORQ4 vs. Q1 = 0.70, 95% CI: 0.50–0.99). High MCP1 (aOR Q4 vs. Q1 = 2.55, 95% CI: 1.41–4.61) and the higher CBS including MCP1, PAI1, and leptin (aORQ4 vs. Q1 = 1.82, 95% CI = 1.04–3.18) were also associated with increased pancreatic cancer risk among women with BMI <25 kg/m2 (P values for interaction <0.05). We found an inverse association between prediagnostic sRAGE concentrations and risk of incident pancreatic cancer in postmenopausal women. A proinflammatory CBS was associated with increased risk only in women with normal BMI. MCP1 was not modulated by sRAGE.

Anti-Hypertensive Medication Use, Soluble Receptor for Glycation End Products and Risk of Pancreatic Cancer in the Women’s Health Initiative Study

“…sRAGE could mitigate the inflammatory response by blocking RAGE-ligand binding [ 8 ]. Our previous study showed the significant inverse association between sRAGE and risk of pancreatic cancer [ 7 ]. It is unknown whether the antagonism of the calcium channel reduced sRAGE release to circulation.…”

“…In two previous nested case-control studies within the WHI, we measured baseline serum levels of sRAGE [ 7 , 18 ] using human sRAGE Quantikine ELISA kit (R&D System Inc., Minneapolis, MN, USA) at BCM. Our study included 489 pancreatic cancer cases that were ascertained until August 2014 and 977 controls that were individually matched to each case according to age at baseline (±3 years), ethnicity, baseline blood draw date (±6 months), OS enrollment (yes/no), HT trial arm (yes/no), calcium and vitamin D trial arm (yes/no), hysterectomy at baseline (yes/no) and study center [ 18 ].…”

“…Our study included 489 pancreatic cancer cases that were ascertained until August 2014 and 977 controls that were individually matched to each case according to age at baseline (±3 years), ethnicity, baseline blood draw date (±6 months), OS enrollment (yes/no), HT trial arm (yes/no), calcium and vitamin D trial arm (yes/no), hysterectomy at baseline (yes/no) and study center [ 18 ]. In the other study on colorectal cancer, we measured sRAGE levels of among 638 cancer-free controls [ 7 ]. Because the ELISA for sRAGE is a highly reproducible assay, we did not find the sRAGE measured in two studies to be systematically different.…”

“…We previously showed a significant inverse association between soluble receptor for advanced glycation end products (sRAGE) and risk of incident pancreatic cancer [ 6 , 7 ]. The anti-inflammatory sRAGE is thought to mitigate the inflammatory response induced by ligation of receptor for AGE (RAGE) and its ligands [ 8 ].…”

RAGE Signaling in Skeletal Biology

“…Numerous small molecule RAGE inhibitors have been developed over the last decade, and their research and clinical utility has been evaluated [3,8]. Further, the diagnostic potential of RAGE and its ligands as biomarkers for the progression and severity of various pathologies has also been demonstrated [2,[9][10][11][12].…”