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Original Article

Free Access

Increased Expression of the Receptor for Advanced Glycation End-Products (RAGE) Is Associated with Advanced Breast Cancer Stage

Nankali M.a · Karimi J.a · Goodarzi M.T.a · Saidijam M.b · Khodadadi I.a · Razavi A.N.E.c · Rahimi F.a

Author affiliations

a Department of Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; b Department of Genetics and Molecular Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; c Iran National Tumor Bank, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran

Corresponding Author

Dr. Jamshid Karimi

Department of Biochemistry, School of Medicine

Hamadan University of Medical Sciences

Fahmideh Blvd., 6517838736 Hamadan, Iran

jamshidkarimi2013@gmail.com

Related Articles for ""

Oncol Res Treat 2016;39:622-628

Abstract

Background: The receptor for advanced glycation end-products (RAGE) is a multiligand transmembrane receptor that is overexpressed in various pathological conditions including cancers. However, the expression pattern of RAGE in breast cancer tumors is still not completely clear. Methods: In this study, we investigated the expression levels of RAGE in 25 fresh-frozen breast cancer samples and corresponding noncancerous tissue samples collected from breast cancer patients, by real-time polymerase chain reaction (PCR). Additionally, we performed immunohistochemistry on breast cancer specimens. Results: The results indicate a high expression of the RAGE-encoding gene in the cancerous tissues. RAGE expression at the mRNA and protein levels was statistically significantly up-regulated in advanced-stage and triple-negative breast tumors and node-positive tissues compared with other tissues (p < 0.001). A significant association between RAGE expression and tumor size was observed (p = 0.029). Conclusions: Overexpression of RAGE in advanced-stage tumors may be a useful biomarker for diagnosis and the prediction of breast cancer progression.

© 2016 S. Karger GmbH, Freiburg


Introduction

Breast cancer is the only malignancy that is common in the female populations of the majority of countries worldwide and it is one of the leading causes of cancer mortality. The about 1.7 million new breast cancer cases diagnosed in 2012 accounted for 25% of the total new cases of cancer; 53% of these cases occurred in developing countries, and the incidence of this cancer has been increasing [1].

A widely available, cheap, and rapid tool, mammography is used as the acceptable standard screening examination for the diagnosis of breast cancer [2]. However, the utility of the mammography method as a screening test is not complete [3]. For example, the sensitivity of mammography examination in younger women is low because of the high density of the breast tissue in this age group [4]. For this reason, other markers are required in addition to mammography in order to improve the screening methods. Some markers, e.g., carcinoembryonic antigen (CEA) and the carbohydrate antigens (CAs), are being evaluated for helping diagnosis in the metastatic condition, but they are not yet in clinical use [5].

The receptor for advanced glycation end-products (RAGE) is a member of the immunoglobulin superfamily receptors; it is expressed in a range of cell types such as endothelium, smooth muscle cells, cardiac myocytes, neural tissue, and mononuclear cells [6]. RAGE expression during the adult period is very low, but there are high expression levels of this receptor in the lung tissue and in embryonic stages [7].

RAGE is a multiligand receptor that recognizes the 3-dimensional molecular conformation of ligands. There are several types of structures that are able to bind to RAGE, such as advanced glycation end-products (AGEs), high-mobility group box 1 (HMGB1), S100 proteins, β-sheets, or fibril structures [8,9]. Because of the diversity of the ligands, the RAGE-ligand interaction has been involved in many pathological conditions, including inflammation, diabetes, and neuronal degeneration [10].

Recent studies have shown that activation of the RAGE-ligand axis signaling pathway plays a key role in tumor invasion and metastasis [11,12,13]. Some genetic polymorphisms of RAGE have also been associated with an increased risk of cancer [14]. Data on RAGE expression levels in breast cancer tissues are limited. Thus, for an evaluation of the expression patterns of RAGE in breast cancer to identify molecular mechanisms of tumorigenicity, we analyzed the RAGE expression levels in breast cancer tissues by using real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) techniques.

Materials and Methods

Ethics Statement

This study was approved by the Hamadan University Medical Sciences and the institutional ethics committee, and informed consent was obtained from all individual participants included in the study.

Patients and Tissue Specimens

From breast cancer patients, 25 fresh-frozen breast cancer samples and corresponding noncancerous tissue samples were collected within 30 min after resection and immediately stored in liquid nitrogen until they were used for RNA extraction. 25 paraffin-embedded breast cancer tissue blocks were obtained from the above samples. None of these patients had been treated with radiotherapy or chemotherapy prior to surgery. The patients were diagnosed with breast cancer based on histopathological examination. All patients under study underwent surgical operation and their histopathological information, including the clinical tumor/node/metastasis (TNM) staging, was recorded. Other information, e.g. regarding the smoking status, was also provided through interviewing. Subjects with chronic or acute inflammatory diseases or any other malignancies were excluded from the study.

RNA Extraction and Real-Time qRT-PCR

RNA was extracted using the GeneAll® Hybrid-R™ kit (GeneAll Biotechnology, Seoul, Korea) following the manufacturer's instructions. The RNA was reverse transcribed into single-stranded cDNA using the RevertAid™ First-Strand cDNA Synthesis kit (Thermo Scientific) according to the manufacturer's instructions and the products were analyzed by the CFX96 real-time PCR detection system (BioRad, USA) using the RealQ Plus 2× Master Mix Green (Ampliqon). The amplification protocol consisted of 1 cycle at 95 °C for 10 min followed by 40 cycles at 95 °C for 30 s, 58 °C for 30 s, and then 72 °C for 30 s. Primer sequences were designed and they were synthesized by Takapou Zist Company. The primer sequences were as follows: RAGE (forward: 5'-CAGTAGCTCCTGGTGGAACCGTAAC-3'; reverse: 5'-CCTATCTCAGGGAGGATCAGCACAG-3') and 18S rRNA (forward: 5'-GTAACCCGTTGAACCCCATT-3'; reverse: 5'-CCATCCAATCGGTAGTAGCG-3'). Relative copy numbers were obtained from standard curve values and normalized to values obtained for the 18S rRNA used as internal control. The relative expression of the studied genes was calculated by measuring the Delta threshold cycle value (ΔCt) for each sample. The fold change in expression was then calculated by the formula 2-ΔΔCT[15].

Immunohistochemical Assay

Paraffin-embedded sections of formalin-fixed breast tissue were deparaffinized by xylene and rehydrated through an ethanol gradient in water (100%, 95%, 90%, and 80% ethanol). After washing with phosphate-buffered saline (PBS) for 3 times, the slides were boiled in antigen retrieval buffer, 0.01 M sodium citrate-hydrochloric acid (pH = 6.0), for 30 min in a microwave oven, and then rinsed in PBS. Thereafter, the specimens were treated with 1% H2O2 (10 min) to quench any endogenous peroxidase activity and subsequently treated with 1.5% bovine serum albumin (BSA) in PBS buffer (pH 7.4) to block nonspecific antibody binding. The sections were then incubated at room temperature with the mouse polyclonal RAGE antibody (sc-80652; Santa Cruz Biotechnology, USA) at 1:100 dilution as primary antibody. The signals were detected using the Immuno Cruz™ ABC Staining Systems kit (sc-2017; Santa Cruz Biotechnology, USA) according to the manufacturer's instructions. Peroxidase activity was visualized with 3,3'-diaminobenzadine (DAB) before the slides were counterstained with Gill's hematoxylin. The extent of staining was evaluated by 2 investigators blinded to the identities of the experimental groups according to the following scores. The score for the percentage of positive cells was assigned using the following scale: 0 (< 1%), 1 (1-9%), 2 (10-33%), 3 (34-66%), 4 (67-99%), and 5 (100%). The intensity of staining was scored using the following scales: 0 (negative), 1 (weak), 2 (moderate), and 3 (strong). The final total score was obtained by the sum of the score for the percentage of positive cells and the score of the staining intensity [16]. Immunoblotting was used to demonstrate that the primary antibody binds only to the RAGE. Additionally, appropriate positive and negative control slides were stained along with the experiments. Human lung tissues were taken as positive control because of their high expression levels of the RAGE protein. The primary antibody was deleted in negative controls.

Statistical Analysis

Data analysis was performed using the Statistical Package for Social Sciences version 13 (SPSS; Chicago, IL, USA). Data were expressed as mean ± standard deviation (SD) and the differences were considered statistically significant if p < 0.05. The Kolmogorov-Smirnov test of normality was applied. Statistical significance was tested with Student's t-test. The Mann-Whitney U test was used to evaluate non-normal distribution variables.

Results

Clinical Cases and Surgical Samples

The RAGE mRNA levels in the breast cancer tissues and adjacent noncancerous tissues of all samples were determined by real‐time PCR. It is important to notice that higher ΔCt values mean lower gene expression. The results indicate higher expression of the RAGE gene in the cancerous compared to the adjacent noncancerous tissues (table 1).

Table 1

Clinicopathological characteristics of the participants

http://www.karger.com/WebMaterial/ShowPic/521980

The histopathological characteristics of the participants and samples are shown in table 1. The final staging of the disease was determined on the basis of a combination of surgical and pathological findings in accordance with the American Joint Committee on Cancer guidelines [17]. RAGE expression is significantly increased in node-positive cancer, human epidermal growth factor receptor 2 (HER2)-positive and advanced-stage tissues. The tumor tissues were classified into 2 size groups: less than 3 cm and more than 3 cm in diameter. 32% of the samples were of high and 68% were of low TNM stage.

RAGE Expression in the TNBC and nTNBC Samples

The RAGE mRNA levels were statistically significantly increased in triple negative breast cancer (TNBC) tissues compared with non-TNBC (nTNBC) tissues, with an average increase of 3.48-fold (p < 0.001; fig. 1).

Fig. 1

Expression of RAGE in TNBC and nTNBC as detected by qRT-PCR. The difference in expression of RAGE between the 2 groups was statistically significant (p < 0.001).

http://www.karger.com/WebMaterial/ShowPic/521979

RAGE Expression in the High-Stage and Low-Stage Tissues

RAGE expression was statistically significantly up-regulated in the high-stage breast tumor tissues compared with the low-stage tumor tissues, with an average increase of 2.82-fold (fig. 2).

Fig. 2

RAGE gene expression in low-stage and high-stage cancerous tissues. *p < 0.001 versus low stage.

http://www.karger.com/WebMaterial/ShowPic/521978

Immunohistochemical Evaluation of RAGE Expression in Breast Cancer

RAGE protein expression was immunohistochemically detected in the cancer and non-cancer samples. RAGE immunoreactivity was heterogeneous among the tumor cells, and the staining intensity of individual cells varied from absent in the non-cancerous cells to intense in the high-stage cancerous cells. The expression of RAGE in the cancer samples is illustrated in figure 3. RAGE expression was significantly higher in the high-stage cancer tissues compared with the low-stage tissues (p < 0.001). Representative examples of the staining of negative, low-stage, high-stage, and control samples (micrographs with 200 × magnification) are shown in figure 3.

Fig. 3

Immunochemistry analysis of RAGE expression in breast carcinoma tissues; × 200. (a) Negative sample tissue showing no immunoreactivity to RAGE. (b) Low-stage sample with weak cytoplasmic and membrane positivity for RAGE staining. (c) High-stage sample with moderate positivity for RAGE staining. (d) The expression of RAGE based on the total score was statistically higher in high-stage breast cancer tissues than in low-stage cancerous tissues (p < 0.001). (e) Negative control. (f) Positive control.

http://www.karger.com/WebMaterial/ShowPic/521977

Correlation Study

A significant association between RAGE expression and tumor size was observed (r = -0.50, p = 0.029). A representative curve is shown in figure 4.

Fig. 4

Association between tumor size and RAGE expression in cancerous tissues of breast cancer. Regression analysis showed significant correlation, as indicated by the p value.

http://www.karger.com/WebMaterial/ShowPic/521976

Discussion

Breast cancer is one of the most prevalent cancers among all women in developed and developing countries [18]. Based on the molecular mechanisms, genetic alterations, and experimental and clinical data, breast cancer is a heterogeneous malignancy [19]. Breast cancer subtypes can be distinguished by IHC into: HER2 positive, estrogen receptor (ER) positive, and triple negative. The majority of breast cancer cases are ER positive [20,21].

Overexpression of RAGE has been reported in some pathological conditions including neuronal degeneration, diabetes, inflammation, and Alzheimer's disease [7,22]. Recent reports have indicated that RAGE also plays a key role in cancer. Indeed cancer is considered as a wound that has a disrupted healing pathway, with angiogenesis and inflammation processes [23,24].

Based on the results of this study, the RAGE mRNA levels in the cancerous samples were higher compared with the normal samples. Our results also showed differences in the RAGE protein levels in immunohistochemical experiments in the cancerous and adjacent noncancerous samples. When we compared low-stage samples with high-stage cancerous tissues, our results demonstrated that the expression levels of RAGE, at the mRNA and protein levels, were significantly increased in the high-stage samples compared to the low-stage samples.

Recently, several reports have revealed an association between the expression of RAGE and the malignancy of cancers. Wang et al. [25] found that RAGE expression was up-regulated in human gastric cancer compared with normal tissues. They also showed that high levels of RAGE were associated with the histological grade and the metastasis status. Sasahira et al. [26] have demonstrated by IHC experiments that RAGE expression was higher in colorectal adenomas with severe atypia and large-sized tumors. Zhao et al. [27] found RAGE overexpression in prostate cancer and the expression of RAGE was associated with the progression of this cancer.

Metastasis plays a major role in the mortality of many cancer patients, such as breast cancer patients, in part due to the lack of clinical therapies. Among the different types of breast cancer, TNBC (ER-, progesterone receptor (PR)-, HER2-) has been associated with the poorest prognosis and shortest survival. In this study, we demonstrated that RAGE is expressed in a set of aggressive breast cancer samples, TNBC and metastatic and node-positive cancerous tissues. This is consistent with a recent report that revealed that high RAGE expression was observed in node-positive and metastatic breast cancer [28]. A notable difference between our study and the previous study is the evaluation of RAGE expression based on more clinicopathological characteristics, e.g., tumor size, nodal status, hormone receptor status, HER2 status, lymphovascular invasion, and correlation studies. Additionally, our study was performed on a different racial population in a different country. There is some evidence on the role of RAGE in the stimulation of cell proliferation and migration, including the mitogen-activated protein kinase (MAPK) and Cdc42/Rac pathways [29]. Stimulation of RAGE activates the transcription of nuclear factor κB (NF-κB), and this RAGE-dependent pathway promotes cell survival by the activation of anti-apoptotic genes such as those encoding for inhibitors of apoptosis proteins (IAPs) and Bcl2 and related proteins [30,31].

In the present study, we demonstrated a statistically significant correlation between tumor size and RAGE expression. Michealson et al. [32] reported that, for women with equivalent lymph node status, the tumor size was associated with increased lethality. The tumor size is strongly related to prognosis. In general, the smaller the tumor, the higher is the chance of long-term survival. Other studies also revealed a correlation between tumor size and malignancy potential [33,34]. Based on our results, the up-regulation of RAGE with increased tumor size can be considered as a sign for the role of RAGE in the proliferation and malignancy of tumors.

RAGE can be considered as a potential target for cancer therapy by different approaches, such as the application of blocking antibodies, ligand binding molecules and NF-κB blockers [12,35,36]. Another study showed that the targeting of RAGE by specific small interfering RNAs (siRNAs) in different breast cancer cell lines decreased the proliferation of all subtypes of breast cancer [37].

In summary, our results show that RAGE expression was up-regulated in high-stage, metastatic, and aggressive breast cancer tumors, suggesting that it may contribute to the malignant potential of tumors. Therefore, RAGE could serve as an important novel marker for the diagnosis and prediction of advanced-stage tumors and it can be considered as a therapeutic target for breast cancer in the future. However, more studies are needed to reveal the mechanisms of RAGE up-regulation, for a better understanding of its potential.

Acknowledgements

This study is part of M.N.'s M.Sc. Thesis and is supported by the Hamadan University of Medical Science (No. 9312126511). We would like to thank N. Shabab and T. Ghiasvand for their assistance in the laboratory.

Disclosure Statement

There are no conflicts of interest.


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Author Contacts

Dr. Jamshid Karimi

Department of Biochemistry, School of Medicine

Hamadan University of Medical Sciences

Fahmideh Blvd., 6517838736 Hamadan, Iran

jamshidkarimi2013@gmail.com


Article / Publication Details

First-Page Preview
Abstract of Original Article

Received: May 31, 2016
Accepted: August 17, 2016
Published online: September 15, 2016
Issue release date: October 2016

Number of Print Pages: 7
Number of Figures: 4
Number of Tables: 1

ISSN: 2296-5270 (Print)
eISSN: 2296-5262 (Online)

For additional information: https://www.karger.com/ORT


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References

  1. American Cancer Society: Global Cancer Facts & Figures, ed 3. Atlanta, American Cancer Society, 2015.
  2. Li J, Shao Z: Mammography screening in less developed countries. Springerplus 2015;4:615.
  3. Bleyer A, Welch HG: Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med 2012;367:1998-2005.
  4. Checka CM, Chun JE, Schnabel FR, Lee J, Toth H: The relationship of mammographic density and age: implications for breast cancer screening. AJR Am J Roentgenol 2012;198:W292-W295.
  5. Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast RC Jr: American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 2007;25:5287-5312.
  6. Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, Stern DM, Nawroth PP: Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl) 2005;83:876-886.
  7. Han SH, Kim YH, Mook-Jung I: RAGE: the beneficial and deleterious effects by diverse mechanisms of actions. Mol Cells 2011;31:91-97.
  8. Bierhaus A, Stern DM, Nawroth PP: RAGE in inflammation: a new therapeutic target? Curr Opin Investig Drugs 2006;7:985-991.
    External Resources
  9. Moridi H, Karimi J, Sheikh N, Goodarzi MT, Saidijam M, Yadegarazari R, Khazaei M, Khodadadi I, Tavilani H, Piri H, Asadi S, Zarei S, Rezaei A: Resveratrol-dependent down-regulation of receptor for advanced glycation end-products and oxidative stress in kidney of rats with diabetes. Int J Endocrinol Metab 2015;13: e23542.
  10. Schmidt AM, Yan SD, Yan SF, Stern DM: The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. J Clin Invest 2001;108:949-955.
  11. Dougan M, Dranoff G: Inciting inflammation: the RAGE about tumor promotion. J Exp Med 2008;205:267-270.
  12. Abe R, Shimizu T, Sugawara H, Watanabe H, Nakamura H, Choei H, Sasaki N, Yamagishi S, Takeuchi M, Shimizu H: Regulation of human melanoma growth and metastasis by AGE-AGE receptor interactions. J Invest Dermatol 2004;122:461-467.
  13. Kuniyasu H, Chihara Y, Takahashi T: Co-expression of receptor for advanced glycation end products and the ligand amphoterin associates closely with metastasis of colorectal cancer. Oncol Rep 2003;10:445-448.
  14. Qian F, Sun BL, Zhang WY, Ke J, Zhu J: Gly82Ser polymorphism of the receptor for advanced glycation end-product (RAGE) potential high risk in patients with colorectal cancer. Tumour Biol 2014;35:3171-3175.
  15. Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 2001;25:402-408.
  16. Zhu X, Jin L, Zou S, Shen Q, Jiang W, Lin W, Zhu X: Immunohistochemical expression of RAGE and its ligand (S100A9) in cervical lesions. Cell Biochem Biophys 2013;66:843-850.
  17. Edge SB, Compton CC: The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010;17:1471-1474.
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