Soluble receptor for advanced glycation end-products (sRAGE) and polymorphisms of RAGE and glyoxalase I genes in patients with pancreas cancer

https://doi.org/10.1016/j.clinbiochem.2010.04.004Get rights and content

Abstract

Objectives

The receptor for advanced glycation end-products (RAGE) takes part in the pathogenesis of many diseases, including diabetes mellitus and cancer. AGE-precursors are detoxified by glyoxalase (GLO). sRAGE, soluble RAGE, is an inhibitor of pathological effects mediated via RAGE. The aim was to study sRAGE and polymorphisms of RAGE (AGER) and GLO genes in patients with pancreas cancer (PC).

Design and Methods

The studied group consisted of 51 patients with PC (34 with impaired glucose tolerance—IGT, 17 without IGT), 34 type 2 DM and 154 controls. For genetic analysis, the number of patients was increased to 170. Serum sRAGE was measured by ELISA and all polymorphisms (RAGE −429T/C, −374T/A, 2184A/G, Gly82Ser and GLO A419C) were determined by PCR-RFLP and confirmed by sequencing.

Results

Soluble RAGE is decreased in patients with PC compared to patients with DM and controls (975 ± 532 vs. 1416 ± 868 vs. 1723 ± 643 pg/mL, p < 0.001). Patients with PC and IGT have lower sRAGE levels compared to patients with PC without IGT (886 ± 470 vs. 1153 ± 616 pg/mL, p < 0.05). No relationship of sRAGE to the stage was found. We did not show any difference in allelic and genotype frequencies in all RAGE and GLO polymorphisms among the studied groups.

Conclusion

This is the first study demonstrating decreased sRAGE in patients with pancreas cancer. Its levels are even lower than in diabetics and are lowest in patients with PC and IGT. Our study supports the role of glucose metabolism disorder in cancerogenesis. Further studies are clearly warranted, especially with respect to potential preventive and therapeutic implications.

Introduction

The receptor for advanced glycation end-products (RAGE), a member of the immunoglobulin super-family, takes part in the pathogenesis of many diseases, among them diabetes mellitus and cancer. RAGE is a multi-ligand receptor, first described as receptor for advanced glycation end products [1], however, binding mediators like proinflammatory S100 proteins/calgranulins (EN-RAGE), High Mobility Group proteins including HMGB1/amphoterin and amyloid β peptide [2]. RAGE–ligand interaction is followed by generation of oxidative stress and triggering of inflammatory and proliferative processes which critically contributes to tissue injury [3].

Advanced glycation end products have many pathological effects and may contribute to malignancies [4], [5]. They modify biological structures and change their physical and chemical properties and metabolism. Some of them might cause changes in DNA—glycation of DNA gives rise to characteristic nucleotide adducts, which are associated with mutagenesis and carcinogenesis [6], [7]. Stimulation of RAGE probably potentiates the process of growth, infiltration and metastases of tumor via activating nuclear factor κB. Precursors of advanced glycation end products, methylglyxal and glyoxal, are metabolized predominantly by a metalloenzyme glyoxalase I (GLO I). Decreased glyoxalase I activity due to the aging process and oxidative stress results in increased glycation and tissue damage [8]. There is recent evidence that activation of RAGE by S100A12 protein decreases the expression of glyoxalase I and so impairs the enzymatic defence against glycation [9], [10].

Another RAGE ligand, HMGB1 is highly expressed in pancreas. In pancreas cancer, enhanced expression of RAGE and HMGB1 was observed for the setting of metastases [2].

sRAGE, soluble RAGE, the extracellular domain of RAGE, is a naturally occurring inhibitor of pathological effects mediated via RAGE. It is a valuable biomarker in many pathological states—it increases in patients with decreased renal function [11], but decreases in diabetic complications [12], [14], coronary artery disease [14]. Recently, it was demonstrated as a new biomarker for lung cancer [15].

The RAGE gene (AGER—gene encoding RAGE) [16] as well as that for GLO I [17] are located on chromosome 6, close to the major histocompatibility complex. Several studies have focused on the genetic background of RAGE and have demonstrated that some gene polymorphisms are implicated in various pathological states, e.g. diabetic complications [18], [19], amplification of the inflammatory response [20], non small cell lung cancer [21], gastric cancer [22] or breast cancer [23]. Additionally, the A419C (E111A) polymorphisms of the GLO I gene was studied in patients with breast cancer and the higher presence of the C allele was found in patients with worse prognosis [24].

The aim was to study sRAGE and polymorphisms of RAGE (AGER) and GLO genes in patients with pancreas cancer (PC).

Section snippets

Study population and design

Fifty one patients with pancreas cancer (34 with impaired glucose tolerance—IGT, 17 without IGT) and thirty four patients with type 2 diabetes mellitus were enrolled in this cross-sectional study. For genetic analysis, the number of patients was increased to 170 (99 patients with PC and 71 patients with type 2 diabetes mellitus).

All patients with pancreas cancer had newly diagnosed tumor. The diagnosis for PC was based on recommended guidelines [25] and all the PC patients had the tumor

sRAGE

sRAGE is decreased in patients with PC compared to patients with DM and controls (p < 0.001, Fig. 1). Patients with PC and IGT have lower sRAGE levels compared to patients with PC without IGT (886 ± 470 vs. 1153 ± 616 pg/mL, p < 0.05, Fig. 2).

In patients with pancreas cancer, sRAGE correlated significantly negatively with erythrocyte count, hemoglobin and hematocrit (r = −0.325, r = −0.355, r = −0.374, respectively, p < 0.05) and significantly positively with HDL cholesterol (r = 0.358, p < 0.05). We did not find

Discussion

This is the first study demonstrating decreased sRAGE in patients with pancreas cancer. Its levels are even lower than in diabetics and are lowest in patients with PC and IGT.

Expression of RAGE on differentiated adult cells is low except for the lung. High expression is typical for embryonic cells [29] and postnatally is associated with pathological states like inflammation, diabetes or cancer [2], [30], [31]. In lung tumors it is vice versa—RAGE expression decreases [32].

RAGE is implicated in

Acknowledgments

The study was supported by grant IGA MH CZ NR9528-3. The authors are thankful to Mrs. Hana Řeháková, Mrs. Ludmila Pourová, Mrs. Eva Němcová, Mrs. Helena Miškovská and Mrs. Dita Hudcová for technical assistance.

References (43)

  • Y. Yamamoto et al.

    Advanced glycation endproducts–receptor interactions stimulate the growth of human pancreatic cancer cells through the induction of platelet-derived growth factor-B

    Biochem Biophys Res Commun

    (1996)
  • L.J. Sparvero et al.

    RAGE (Receptor for Advanced Glycation Endproducts), RAGE ligands, and their role in cancer and inflammation

    J Transl Med

    (2009)
  • A.M. Schmidt et al.

    The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory response

    J Clin Invest

    (2001)
  • E.U. Allmen et al.

    V domain of RAGE interacts with Agens on prostate carcinoma cells

    Prostate

    (2008)
  • A.M. Schmidt et al.

    Receptor for advanced glycation end products (AGEs) has a central role in vesel wall interactions and gene activation in response to circulating AGE proteins

    Proc Natl Acad Sci U S A

    (1994)
  • P.J. Thornalley

    Glyoxalase I—structure, function and a critical role in the enzymatic defence against glycation

    Biochem Soc Trans

    (2003)
  • P.J. Thornalley

    Dietary AGEs and ALEs and risk to human health by their interaction with the receptor for advanced glycation endproducts (RAGE)—an introduction

    Mol Nutr Food Res

    (2007)
  • P.J. Thornalley et al.

    Highlights and hotspots of protein glycation in end-stage renal disease

    Semin Dial

    (2009)
  • N. Katakami et al.

    Decreased endogenous secretory advanced glycation end product receptor in type 1 diabetic patients: its possible association with diabetic vascular complications

    Diabetes Care

    (2005)
  • B.I. Hudson et al.

    Soluble levels of receptor for advanced glycation endproducts (sRAGE) and coronary artery disease: the next C-reactive protein

    Arterioscler Tromb Vasc Biol

    (2005)
  • R. Jing et al.

    Receptor for advanced glycation end products (RAGE) soluble form (sRAGE): anew biomarker for lung cancer

    Neoplasma

    (2010)
  • Cited by (54)

    • Identification of novel advanced glycation end products receptor gene variants associated with colorectal cancer in Tunisians: A case-control study

      2020, Gene
      Citation Excerpt :

      Multiple splice transcripts, ranging from 15 to 19 (Sterenczak et al., 2013; Sterenczak et al., 2009) were reported, of which the 55 kDa variant is the predominant form. AGER is highly polymorphic, and several functional variants were reported to be associated with disease states (Serveaux-Dancer et al., 2019), including cancer (Krechler et al., 2010; Li et al., 2017; Pan et al., 2014). Heightened RAGE expression was reported for many cancers (Krechler et al., 2010; Sakellariou et al., 2016; Zhao et al., 2014), including CRC (Jiao et al., 2011; Jiao et al., 2012).

    • Serum levels of advanced glycation end products and their receptors sRAGE and Galectin-3 in chronic pancreatitis

      2020, Pancreatology
      Citation Excerpt :

      RAGE and sRAGE share the same ligand binding specificity with sRAGE appearing to act as an extracellular decoy receptor and antagonist that counteracts RAGE function [20–22]. In two prospective cohort studies sRAGE serum levels were inversely associated with pancreatic cancer risk indicating the relevance of aging molecules in pancreatic diseases [23,24], whereas in a further study this observation was not confirmed [25]. Of note, in a community-based study sRAGE levels measured twice within three years showed stable results, which implies that single measurements are reliable [26].

    • Association analysis between genomic variants within advanced glycation end product specific receptor (AGER) gene and risk of breast cancer in Iranian women

      2019, Heliyon
      Citation Excerpt :

      However, we could not find any association between mentioned SNPs and risk of breast cancer. The rs1800625 has not been associated with risk of pancreatic cancer in Czech population [13] or breast cancer in Iranian population [6]. Based on the relative small sample size, we could not assess associations between genotypes and patients' characteristics.

    • RAGE may act as a tumour suppressor to regulate lung cancer development

      2018, Gene
      Citation Excerpt :

      The primary reasons for study exclusion were as follows: (1) the studies did not involve RAGE; (2) they did not study the rs2070600 polymorphism; (3) they were not related to cancer research; and (4) no relevant genotype data were reported. Ultimately, this meta-analysis included 17 case-control studies comprising 5937 cases and 6181 controls (Tesarova et al., 2007; Gu et al., 2008; Krechler et al., 2010; Wang et al., 2012; Xu et al., 2012; Pan et al., 2013; Zhang et al., 2013; Duan et al., 2014; Pan et al., 2014; Qian et al., 2014; Chocholaty et al., 2015; Su et al., 2015a; Su et al., 2015b; Wang et al., 2015; Yue et al., 2016; Li et al., 2017; Wang et al., 2017). Two investigators (S.W. and M.C.) independently extracted the data and reached a consensus on all the items.

    View all citing articles on Scopus
    View full text