Pancreatic Cancer Risk Associated with Prediagnostic Plasma Levels of Leptin and Leptin Receptor Genetic Polymorphisms

Abstract

Leptin is an adipokine involved in regulating energy balance which has been identified as a potential biological link in development of obesity-associated cancers, such as pancreatic cancer. In this prospective, nested case-control study of 470 cases and 1094 controls from five U.S. cohorts, we used conditional logistic regression to evaluate pancreatic cancer risk by prediagnostic plasma leptin, adjusting for race/ethnicity, diabetes, body-mass index, physical activity, plasma C-peptide, adiponectin and 25-hydroxyvitamin D. Due to known differences in leptin levels by gender, analyses were conducted separately for men and women. We also evaluated associations between 32 tagging single nucleotide polymorphisms (SNPs) in the leptin receptor (LEPR) gene and pancreatic cancer risk. Leptin levels were higher in female versus male control participants (median, 20.8 vs. 6.7µg/mL; P<0.0001). Among men, plasma leptin was positively associated with pancreatic cancer risk, and those in the top quintile had a multivariable-adjusted odds ratio (OR) of 3.02 (95% CI, 1.27–7.16; Ptrend=0.02) compared to men in the bottom quintile. Among women, circulating leptin was not associated with pancreatic cancer risk (Ptrend=0.21). Results were similar across cohorts (Pheterogeneity=0.88 for two male cohorts and 0.35 for three female cohorts). In genetic analyses, rs10493380 in LEPR was associated with increased pancreatic cancer risk among women, with an OR per minor allele of 1.54 (95% CI, 1.18–2.02; multiple hypothesis-corrected P=0.03). No SNPs were significantly associated with risk in men. In conclusion, higher prediagnostic levels of plasma leptin were associated with an elevated risk of pancreatic cancer among men, but not among women.

Adiponectin, Leptin, IGF-1, and Tumor Necrosis Factor Alpha As Potential Serum Biomarkers for Non-Invasive Diagnosis of Colorectal Adenoma in African Americans

“…Leptin, a 167 amino acid peptide, plays a vital role in the hypothalamus in relation to mammalian feeding behavior and energy expenditure and is a useful serum biomarker that reflects total body fat over a wide range of body mass indexes (BMIs) ( 23 – 25 ). Leptin was shown to promote colonic cell growth in in vitro and in human studies independently of insulin ( 26 – 28 ).…”

MicroRNA‐212 promotes the recovery function and vascular regeneration of endothelial progenitor cells in mice with ischemic stroke through inactivation of the notch signaling pathway via downregulating MMP9 expression

“…MMP9 exhibited the highest degree value among these major genes after further analysis (MMP = 19, FCRG3B = 15, HLA‐DQB1 = 9), suggesting MMP9 as the core among these 25 differentially expressed genes. Moreover, previous evidence has demonstrated the association of the Notch signaling pathway with the progression of ischemic stroke (Babic et al, ; Ren et al, ), and studies have revealed that MMP9 connects with the Notch signaling pathway (Funahashi et al, ; L. Li et al, ). To further explore the potential mechanisms of MMP9 in ischemic stroke, the regulating miRNAs of MMP9 were predicted.…”

Endocrine-exocrine signaling drives obesity-associated pancreatic ductal adenocarcinoma

“…3) steroid sex hormones (Murphy et al, 2018;Ulrich et al, 2018). Of these mechanisms, epidemiologic studies support a role for both insulin/IGF1 and adipokines in pancreatic cancer development, as elevated levels of insulin, proinsulin, and leptin and low levels of IGF binding protein-1 and adiponectin are associated with increased PDAC risk (Babic et al, 2016;Bao et al, 2013a;Bao et al, 2013b;Wolpin et al, 2013;Wolpin et al, 2007). Though previous studies in cell lines and xenografts have demonstrated that leptin can promote PDAC proliferation (Harbuzariu et al, 2017;Mendonsa et al, 2015), our observation that obese mice deficient in leptin signaling (ob/ob and db/db) exhibit enhanced Kras-driven pancreatic tumor progression supports a leptin-independent mechanism for obesity in tumor promotion.…”