Soluble Receptor for Advanced Glycation End Products
and Risk of Liver Cancer
Kristin A. Moy,1Li Jiao,2Neal D. Freedman,1Stephanie J. Weinstein,1Rashmi Sinha,1Jarmo Virtamo,3
Demetrius Albanes,1and Rachael Z. Stolzenberg-Solomon1
Binding of advanced glycation end products (AGEs) to their receptor (RAGE) increases oxi-
dative stress and inflammation and may be involved in liver injury and subsequent carcino-
genesis. Soluble RAGE (sRAGE) may neutralize the effects mediated by the AGE/RAGE
complex. Epidemiologic studies examining sRAGE or AGEs in association with liver cancer
are lacking. We examined the associations between prediagnostic serum concentrations of
sRAGE or N?-(carboxymethyl)-lysine (CML)-AGE and hepatocellular carcinoma in a case-
cohort study within a cohort of 29,133 Finnish male smokers who completed questionnaires
and provided a fasting blood sample between 1985 and 1988. During follow-up beginning
5 years after enrollment through April 2006, 145 liver cancers occurred. Serum concentra-
tions of sRAGE, CML-AGE, glucose, and insulin were measured in case subjects and 485
randomly sampled cohort participants. Chronic hepatitis B virus (HBV) and hepatitis C vi-
rus (HCV) were available in most cases and in a subset of the study population. Weighted
Cox proportional hazards regression was used to calculate relative risks (RR) and 95% confi-
dence intervals (CI) adjusted for age, years of smoking, and body mass index. sRAGE and
CML-AGE concentrations were inversely associated with liver cancer. Further adjustment
for glucose and insulin or exclusion of case subjects with chronic HBV or HCV did not
change the associations. Conclusion: Our results support the hypothesis that sRAGE is inver-
sely associated with liver cancer. The findings need confirmation, particularly in populations
that include women and nonsmokers. (HEPATOLOGY 2013;57:2338-2345)
deaths.1,2Established risk factors for hepatocellular
carcinoma or HCC, the most common type, include
aflatoxin B exposure, chronic infection with hepatitis
B virus (HBV) or hepatitis C virus (HCV), excessive
alcohol consumption, and obesity and diabetes, which
increasethe riskof nonalcoholic
(NASH).3,4These risk factors are typified by their
ability to cause chronic inflammation in the liver,
which is associated with subsequent carcinogenesis.5
Advanced glycation end products (AGE) and their re-
ceptor (RAGE) are implicated in both inflammation
and cancer (reviewed by Riehl et al.,6Singh et al.,7
orldwide, primary liver cancer is the sixth
most commonly occurring cancer and the
third most common cause of cancer-related
and Sparvero et al.8). However, the potential role of
the AGE-RAGE axis in the development of HCC is
AGEs are heterogeneous irreversible adducts formed
by the nonenzymatic glycation of proteins, lipids, and
nucleic acids.7The two major sources of AGEs are en-
dogenous AGEs that form during normal metabolism
and exogenous AGEs derived from tobacco smoke or
food.7,9Dietary AGEs are formed when food is proc-
essed at high temperatures using methods such as deep
frying, broiling, and grilling.10AGEs accumulate in tis-
sues, and the rate of accumulation increases with aging
and under hyperglycemic conditions.7Of the approxi-
mately 20 different AGEs identified, N?-(carboxy-
methyl)-lysine (CML)-AGE is the best characterized.11,12
Abbreviations: AGE, advanced glycation end product; anti-HBc, antibody to hepatitis B core antigen; anti-HBV, antibody to hepatitis B virus; ATBC, Alpha-
Tocopherol, Beta-Carotene Cancer Prevention Study; BMI, body mass index; CI, confidence interval; CML, N?-(carboxymethyl)-lysine; HBsAg, hepatitis B surface
antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; RAGE, receptor for advanced glycation end product; RR, relative risks;
sRAGE, soluble receptor for advanced glycation end product; NASH, nonalcoholic steatohepatitis.
From the1Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda,
Prevention, National Institute for Health and Welfare, Helsinki, Finland.
Received August 27, 2012; accepted December 27, 2012.
Supported by the Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute,
National Institutes of Health, Department of Health and Human Services, Bethesda, MD.
2Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX; and
3Department of Chronic Disease
33. Jiao L, Taylor PR, Weinstein SJ, Graubard BI, Virtamo J, Albanes D,
et al. Advanced glycation end products, soluble receptor for advanced
glycation end products, and risk of colorectal cancer. Cancer Epidemiol
Biomarkers Prev 2011;20:1430-1438.
34. The alpha-tocopherol, beta-carotene lung cancer prevention study,:
designmethods participant characteristics, and compliance. The ATBC
Cancer Prevention Study Group. Ann Epidemiol 1994;4:1-10.
35. Korhonen P, Malila N, Pukkala E, Teppo L, Albanes D, Virtamo J.
The Finnish Cancer Registry as follow-up source of a large trial
cohort—accuracy and delay. Acta Oncol 2002;41:381-388.
36. Boehm BO, Schilling S, Rosinger S, Lang GE, Lang GK, Kientsch-
Engel R, et al. Elevated serum levels of N(epsilon)-carboxymethyl-
lysine, an advanced glycation end product, are associated with prolifera-
tive diabetic retinopathy and macular oedema. Diabetologia 2004;47:
37. Limburg PJ, Stolzenberg-Solomon RZ, Vierkant RA, Roberts K, Sellers
TA, Taylor PR, et al. Insulin, glucose, insulin resistance, and incident
colorectal cancer in male smokers. Clin Gastroenterol Hepatol 2006;4:
38. Hu FB, Stampfer MJ, Rimm E, Ascherio A, Rosner BA, Spiegelman
D, et al. Dietary fat and coronary heart disease: a comparison of
approaches for adjusting for total energy intake and modeling repeated
dietary measurements. Am J Epidemiol 1999;149:531-540.
39. Kulathinal S, Karvanen J, Saarela O, Kuulasmaa K. Case-cohort design
in practice—experiences from the MORGAM Project. Epidemiol Per-
spect Innov 2007;4:15.
40. D’Adamo E, Giannini C, Chiavaroli V, de Giorgis T, Verrotti A,
Chiarelli F, et al. What is the significance of soluble and endogenous
secretory receptor for advanced glycation end products in liver steatosis
in obese prepubertal children? Antioxid Redox Signal 2011;14:
41. Albayrak A, Uyanik MH, Cerrah S, Altas S, Dursun H, Demir M,
et al. Is HMGB1 a new indirect marker for revealing fibrosis in chronic
hepatitis and a new therapeutic target in treatment? Viral Immunol
42. Semba RD, Arab L, Sun K, Nicklett EJ, Ferrucci L. Fat mass is inver-
sely associated with serum carboxymethyl-lysine, an advanced glycation
end product, in adults. J Nutr 2011;141:1726-1730.
43. Stolzenberg-Solomon RZ, Pietinen P, Taylor PR, Virtamo J, Albanes
D. Prospective study of diet and pancreatic cancer in male smokers.
Am J Epidemiol 2002;155:783-792.
44. Thiebaut AC, Jiao L, Silverman DT, Cross AJ, Thompson FE, Subar
AF, et al. Dietary fatty acids and pancreatic cancer in the NIH-AARP
diet and health study. J Natl Cancer Inst 2009;101:1001-1011.
45. Global surveillance and control of hepatitis C. Report of a WHO Con-
sultation organized in collaboration with the Viral Hepatitis Prevention
Board, Antwerp, Belgium. J Viral Hepat 1999;6:35-47.
HEPATOLOGY, Vol. 57, No. 6, 2013MOY ET AL.2345