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Insulin-like growth factor-related components and the risk of liver cancer in a nested case-control study

  • Original Article
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Tumor Biology

Abstract

Insulin-like growth factor-1 (IGF1) is a potent mitogen. IGF-binding protein-3 (IGFBP3) binds and inhibits IGF1. High circulating IGF1 levels and low IGFBP3 levels are associated with increased risk of several cancers. We examined relationships between serum levels of these factors and hepatoma risk in a case-control study nested in a prospective cohort study (the Japan Collaborative Cohort Study (JACC Study)). A baseline survey was conducted from 1988 to 1990, and 39,242 subjects donated blood samples. Participants diagnosed with hepatoma by 1997 were considered cases for nested case-control studies. Ninety-one cases and 263 sex- and age-matched controls were analyzed. A conditional logistic model was used to estimate odds ratios (ORs) for the incidence of hepatoma associated with serum IGF1 and IGFBP3 levels. Neither IGF1 nor the molar ratio of IGF1/IGFBP3 was correlated with hepatoma risk. After adjustment for hepatitis viral infection, body mass index, smoking, and alcohol intake, a higher molar difference of (IGFBP3 − IGF1) was associated with a decreased hepatoma risk more than IGFBP3 alone (p for trend <0.001 and = 0.003, respectively). People in the highest quartile had a lower risk (OR = 0.098; 95 % confidence interval = 0.026–0.368). In subgroup analyses of males and females, the molar difference was associated with a decreased hepatoma risk (p for trend <0.05). In non-elderly individuals, the difference was inversely correlated with the incidence of hepatoma (p for trend <0.01). The molar difference of (IGFBP3 − IGF1) may be inversely associated with the incidence of hepatoma.

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Abbreviations

BMI:

Body mass index

CI:

Confidence intervals

HCC:

Hepatocellular carcinoma

IGF:

Insulin-like growth factor

IGFBP:

IGF-binding protein

IGF-1R:

IGF-1 receptor

JACC:

Japan Collaborative Cohort

OR:

Odds ratio

References

  1. Baserga R. Oncogenes and the strategy of growth factors. Cell. 1994;79:927–30.

    Article  CAS  PubMed  Google Scholar 

  2. Adachi Y, Yamamoto H, Imsumran A, Oka T, Oki M, Nosho K, Min Y, Shinomura Y, Lee CT, Carbone DP, Imai K. Insulin-like growth factor-I receptor as a candidate for a novel molecular target in the gastrointestinal cancers. Dig Endosc. 2006;18:245–51.

    Article  Google Scholar 

  3. Adachi Y, Yamamoto H, Ohashi H, Endo T, Carbone DP, Imai K, Shinomura Y. A candidate targeting molecule of insulin-like growth factor-I receptor for gastrointestinal cancers. World J Gastroenterol. 2010;16:5779–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Yee D. A tale of two receptors: insulin and insulin-like growth factor signaling in cancer. Clin Cancer Res. 2015;21:667–9.

    Article  CAS  PubMed  Google Scholar 

  5. Foulstone E, Prince S, Zaccheo O, Burns JL, Harper J, Jacobs C, Church D, Hassan AB. Insulin-like growth factor ligands, receptors, and binding proteins in cancer. J Pathol. 2005;205:145–53.

    Article  CAS  PubMed  Google Scholar 

  6. Caro JF, Poulos J, Ittoop O, Pories WJ, Flickinger EG, Sinha MK. Insulin-like growth factor I binding in hepatocytes from human liver, human hepatoma, and normal, regenerating, and fetal rat liver. J Clin Invest. 1988;81:976–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sedlaczek N, Hasilik A, Neuhaus P, Schuppan D, Herbst H. Focal overexpression of insulin-like growth factor 2 by hepatocytes and cholangiocytes in viral liver cirrhosis. Br J Cancer. 2003;88:733–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, LeRoith D. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci U S A. 1999;96:7324–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gu F, Schumacher FR, Canzian F, Allen NE, Albanes D, Berg CD, Berndt SI, Boeing H, Bueno-de-Mesquita HB, Buring JE, Chabbert-Buffet N, Chanock SJ, Clavel-Chapelon F, Dumeaux V, Gaziano JM, Giovannucci EL, Haiman CA, Hankinson SE, Hayes RB, Henderson BE, Hunter DJ, Hoover RN, Johansson M, Key TJ, Khaw KT, Kolonel LN, Lagiou P, Lee IM, LeMarchand L, Lund E, Ma J, Onland-Moret NC, Overvad K, Rodriguez L, Sacerdote C, Sanchez MJ, Stampfer MJ, Stattin P, Stram DO, Thomas G, Thun MJ, Tjonneland A, Trichopoulos D, Tumino R, Virtamo J, Weinstein SJ, Willett WC, Yeager M, Zhang SM, Kaaks R, Riboli E, Ziegler RG, Kraft P. Eighteen insulin-like growth factor pathway genes, circulating levels of IGF-I and its binding protein, and risk of prostate and breast cancer. Cancer Epidemiol Biomark Prev. 2010;19:2877–87.

    Article  CAS  Google Scholar 

  10. Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev. 2002;23:824–54.

    Article  CAS  PubMed  Google Scholar 

  11. Miyamoto S, Nakamura M, Yano K, Ishii G, Hasebe T, Endoh Y, Sangai T, Maeda H, Shi-Chuang Z, Chiba T, Ochiai A. Matrix metalloproteinase-7 triggers the matricrine action of insulin-like growth factor-II via proteinase activity on insulin-like growth factor binding protein 2 in the extracellular matrix. Cancer Sci. 2007;98:685–91.

    Article  CAS  PubMed  Google Scholar 

  12. Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH, Pollak M. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science. 1998;279:563–6.

    Article  CAS  PubMed  Google Scholar 

  13. Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE, Pollak M. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet. 1998;351:1393–6.

    Article  CAS  PubMed  Google Scholar 

  14. Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens CH, Stampfer MJ. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst. 1999;91:620–5.

    Article  CAS  PubMed  Google Scholar 

  15. Lin Y, Tamakoshi A, Kikuchi S, Yagyu K, Obata Y, Ishibashi T, Kawamura T, Inaba Y, Kurosawa M, Motohashi Y, Ohno Y. Serum insulin-like growth factor-I, insulin-like growth factor binding protein-3, and the risk of pancreatic cancer death. Int J Cancer. 2004;110:584–8.

    Article  CAS  PubMed  Google Scholar 

  16. Sakauchi F, Nojima M, Mori M, Wakai K, Suzuki S, Tamakoshi A, Ito Y, Watanabe Y, Inaba Y, Tajima K, Nakachi K. Serum insulin-like growth factors I and II, insulin-like growth factor binding protein-3 and risk of breast cancer in the Japan Collaborative Cohort Study. Asian Pac J Cancer Prev. 2009;10(Suppl):51–5.

    PubMed  Google Scholar 

  17. Ohno Y, Tamakoshi A, Group JS. Japan Collaborative Cohort Study for evaluation of cancer risk sponsored by monbusho (JACC study). J Epidemiol. 2001;11:144–50.

    Article  CAS  PubMed  Google Scholar 

  18. Tamakoshi A, Yoshimura T, Inaba Y, Ito Y, Watanabe Y, Fukuda K, Iso H, Group JS. Profile of the JACC study. J Epidemiol. 2005;15(Suppl 1):S4–8.

    Article  PubMed  Google Scholar 

  19. Tamakoshi A, Ozasa K, Fujino Y, Suzuki K, Sakata K, Mori M, Kikuchi S, Iso H, Group JS, Sakauchi F, Motohashi Y, Tsuji I, Nakamura Y, Mikami H, Kurosawa M, Hoshiyama Y, Tanabe N, Tamakoshi K, Wakai K, Tokudome S, Hashimoto S, Wada Y, Kawamura T, Watanabe Y, Miki T, Date C, Kurozawa Y, Yoshimura T, Shibata A, Okamoto N, Shio H. Cohort profile of the Japan Collaborative Cohort Study at final follow-up. J Epidemiol. 2013;23:227–32.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ito Y, Nakachi K, Imai K, Hashimoto S, Watanabe Y, Inaba Y, Tamakoshi A, Yoshimura T, Group JS. Stability of frozen serum levels of insulin-like growth factor-I, insulin-like growth factor-II, insulin-like growth factor binding protein-3, transforming growth factor beta, soluble Fas, and superoxide dismutase activity for the JACC study. J Epidemiol. 2005;15(Suppl 1):S67–73.

    Article  PubMed  Google Scholar 

  21. Wakai K, Kurozawa Y, Shibata A, Fujita Y, Kotani K, Ogimoto I, Naito M, Nishio K, Suzuki H, Yoshimura T, Tamakoshi A, Group JS. Liver cancer risk, coffee, and hepatitis C virus infection: a nested case-control study in Japan. Br J Cancer. 2007;97:426–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang YC, Wang XP, Zhang LY, Song AL, Kou ZM, Li XS. Effect of blocking IGF-I receptor on growth of human hepatocellular carcinoma cells. World J Gastroenterol. 2006;12:3977–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang Y, Adachi Y, Imsumran A, Yamamoto H, Piao W, Li H, Ii M, Arimura Y, Park MY, Kim D, Lee CT, Carbone DP, Imai K, Shinomura Y. Targeting for insulin-like growth factor-I receptor with short hairpin RNA for human digestive/gastrointestinal cancers. J Gastroenterol. 2010;45:159–70.

    Article  CAS  PubMed  Google Scholar 

  24. Ii M, Li H, Adachi Y, Yamamoto H, Ohashi H, Taniguchi H, Arimura Y, Carbone DP, Imai K, Shinomura Y. The efficacy of IGF-I receptor monoclonal antibody against human gastrointestinal carcinomas is independent of k-ras mutation status. Clin Cancer Res. 2011;17:5048–59.

    Article  CAS  PubMed  Google Scholar 

  25. Kasuga M, Ueki K, Tajima N, Noda M, Ohashi K, Noto H, Goto A, Ogawa W, Sakai R, Tsugane S, Hamajima N, Nakagama H, Tajima K, Miyazono K, Imai K. Report of the Japan Diabetes Society/Japanese Cancer Association Joint Committee on Diabetes and Cancer. Cancer Sci. 2013;104:965–76.

    Article  CAS  PubMed  Google Scholar 

  26. Sasazuki S, Charvat H, Hara A, Wakai K, Nagata C, Nakamura K, Tsuji I, Sugawara Y, Tamakoshi A, Matsuo K, Oze I, Mizoue T, Tanaka K, Inoue M, Tsugane S, Research Group for the D, Evaluation of Cancer Prevention Strategies in J. Diabetes mellitus and cancer risk: pooled analysis of eight cohort studies in Japan. Cancer Sci. 2013;104:1499–507.

    Article  CAS  PubMed  Google Scholar 

  27. Okan A, Comlekci A, Akpinar H, Okan I, Yesil S, Tankurt E, Simsek I. Serum concentrations of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in patients with chronic hepatitis. Scand J Gastroenterol. 2000;35:1212–5.

    Article  CAS  PubMed  Google Scholar 

  28. Nikolic JA, Todorovic V, Bozic M, Tosic L, Bulajic M, Alempijevic T, Nedic O, Masnikosa R. Serum insulin-like growth factor (IGF)-II is more closely associated with liver dysfunction than is IGF-I in patients with cirrhosis. Clin Chim Acta. 2000;294:169–77.

    Article  CAS  PubMed  Google Scholar 

  29. Adamek A, Kasprzak A, Mikos H, Przybyszewska W, Seraszek-Jaros A, Czajka A, Sterzynska K, Mozer-Lisewska I. The insulin-like growth factor-1 and expression of its binding protein-3 in chronic hepatitis C and hepatocellular carcinoma. Oncol Rep. 2013;30:1337–45.

    PubMed  Google Scholar 

  30. Colakoglu O, Taskiran B, Colakoglu G, Kizildag S, Ari Ozcan F, Unsal B. Serum insulin like growth factor-1 (IGF-1) and insulin like growth factor binding protein-3 (IGFBP-3) levels in liver cirrhosis. Turk J Gastroenterol. 2007;18:245–9.

    PubMed  Google Scholar 

  31. Mazziotti G, Sorvillo F, Morisco F, Carbone A, Rotondi M, Stornaiuolo G, Precone DF, Cioffi M, Gaeta GB, Caporaso N, Carella C. Serum insulin-like growth factor I evaluation as a useful tool for predicting the risk of developing hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis: a prospective study. Cancer. 2002;95:2539–45.

    Article  CAS  PubMed  Google Scholar 

  32. Mattera D, Capuano G, Colao A, Pivonello R, Manguso F, Puzziello A, D’Agostino L. Increased IGF-I: IGFBP-3 ratio in patients with hepatocellular carcinoma. Clin Endocrinol. 2003;59:699–706.

    Article  CAS  Google Scholar 

  33. Aleem E, Elshayeb A, Elhabachi N, Mansour AR, Gowily A, Hela A. Serum IGFBP-3 is a more effective predictor than IGF-1 and IGF-2 for the development of hepatocellular carcinoma in patients with chronic HCV infection. Oncol Lett. 2012;3:704–12.

    CAS  PubMed  Google Scholar 

  34. Stefano JT, Correa-Giannella ML, Ribeiro CM, Alves VA, Massarollo PC, Machado MC, Giannella-Neto D. Increased hepatic expression of insulin-like growth factor-I receptor in chronic hepatitis c. World J Gastroenterol. 2006;12:3821–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology and from the Ministry of Health, Labour and Welfare, Japan. This work was also supported in part by Daiwa Securities Health Foundation, Japan. The authors thank Prof. David P. Carbone, James Cancer Ctr, The Ohio State Univ Med Ctr, Columbus, OH, USA, for editorial assistance.

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba-dai Hospital, Sapporo, Japan

    Yasushi Adachi & Takao Endo

  2. Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan

    Yasushi Adachi, Yasutaka Matsunaga, Noriyuki Akutsu & Shigeru Sasaki

  3. The Institute of Medical Science Hospital, The University of Tokyo, Tokyo, Japan

    Masanori Nojima

  4. Department of Public Health, School of Medicine, Sapporo Medical University, Sapporo, Japan

    Mitsuru Mori

  5. Division of Health Administration and Promotion, Faculty of Medicine, Tottori University, Yonago, Japan

    Youichi Kurozawa

  6. Department of Preventive Medicine, Graduate School of Medicine, Nagoya University, Nagoya, Japan

    Kenji Wakai

  7. Department of Public Health, Hokkaido University School of Medicine, Sapporo, Japan

    Akiko Tamakoshi

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  1. Yasushi Adachi
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Correspondence to Yasushi Adachi.

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Adachi, Y., Nojima, M., Mori, M. et al. Insulin-like growth factor-related components and the risk of liver cancer in a nested case-control study. Tumor Biol. 37, 15125–15132 (2016). https://doi.org/10.1007/s13277-016-5360-z

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  • DOI: https://doi.org/10.1007/s13277-016-5360-z

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