Tumor Biology

, Volume 37, Issue 5, pp 6893–6904 | Cite as

Impact of IGF-1, IGF-1R, and IGFBP-3 promoter methylation on the risk and prognosis of esophageal carcinoma

Original Article

Abstract

The aim of this study is to investigate IGF-1, IGF-1R, and IGFBP-3 methylations in esophageal carcinoma (EC) patients and their relationship with the development and prognosis of EC. This study population consisted of 264 patients (case group) whom EC radical resection was performed and 283 healthy individuals (control group). Methylation-specific PCR (MSP) detected the methylation status of IGF-1, IGF-1R, and IGFBP-3 in the peripheral blood in both groups. The expressions of IGF-1, IGF-1R, and IGFBP-3 in EC and adjacent normal tissues were detected by immunohistochemistry (IHC). The methylation rates of IGF-1, IGF-1R, IGFBP3, and IGF-1 + IGF1R + IGFBP3 in the case group were higher than those in the control group (all P < 0.05). Additionally, there were statistical significances for the methylation rates of IGF-1, IGF-1R, IGFBP3, and IGF-1 + IGF1R + IGFBP3 IGF-1 among patients of different clinicopathological features (all P < 0.05). The positive expression rates of IGF-1 and IGF-1R in EC were significantly higher than those in adjacent normal tissues (both P < 0.001), and the rate of IGFBP-3 in EC was significantly lower than that in adjacent normal tissues (P < 0.05). Correlation analysis showed that IGF-1 and IGF1R gene promoter methylation was positively correlated with the positive expressions of IGF-1 (r = 0.139, P = 0.024) and IGF-1R (r = 0.135, P = 0.028), while the IGFBP3 methylation was negatively correlated with the positive expression of IGFBP3 (r = −0.133, P = 0.031). The positive expressions of IGF-1, IGF-1R, and IGFBP-3 were related to different clinicopathological features (all P < 0.05). Cox multivariate analysis results showed that methylation status of IGF-1, IGF-1R, and IGF-1 + IGF1R + IGFBP3 ; expressions of IGF-1 and IGF-1R protein; infiltration depth; and lymph node metastasis (LNM) were independent factors of EC prognosis. Our study demonstrated that methylation of IGF-1, IGF1R, IGFBP3, and IGF-1 + IGF1R + IGFBP3 was closely linked with the occurrence of EC and patients’ clinicopathological features. Besides, the methylation status of the target genes and the expressions of IGF-1 and IGF-1R protein were independent factors of EC prognosis, which could provide a direction for the prognosis and treatment of EC.

Keywords

Esophageal carcinoma IGF-1 IGF-1R IGFBP-3 Methylation Clinicopathological features Prognosis 

Notes

Acknowledgments

We would like to acknowledge the reviewers for their helpful comments on this paper.

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Dulak AM, Schumacher SE, van Lieshout J, Imamura Y, Fox C, Shim B, et al. Gastrointestinal adenocarcinomas of the esophagus, stomach, and colon exhibit distinct patterns of genome instability and oncogenesis. Cancer Res. 2012;72(17):4383–93.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Zheng RS, CWQ, Ceng HM. Analysis on China’s morbidity and mortality of malignant tumors in 2011. China Cancer. 2015;24(1).Google Scholar
  3. 3.
    Lao-Sirieix P, Caldas C, Fitzgerald RC. Genetic predisposition to gastro-oesophageal cancer. Curr Opin Genet Dev. 2010;20(3):210–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Zhou S, Chen L, Mashrah M, Zhu Y, He Z, Hu Y, et al. Expression and promoter methylation of Wnt inhibitory factor-1 in the development of oral submucous fibrosis. Oncol Rep. 2015;34(5):2636–42.PubMedGoogle Scholar
  5. 5.
    Liu JB, Qiang FL, Dong J, Cai J, Zhou SH, Shi MX, et al. Plasma DNA methylation of Wnt antagonists predicts recurrence of esophageal squamous cell carcinoma. World J Gastroenterol. 2011;17(44):4917–21.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Reboucas EL, Costa JJ, Passos MJ, Silva AW, Rossi RO, van den Hurk R, et al. Expression levels of mRNA for insulin-like growth factors 1 and 2, IGF receptors and IGF binding proteins in in vivo and in vitro grown bovine follicles. Zygote. 2014;22(4):521–32.CrossRefPubMedGoogle Scholar
  7. 7.
    Schedlich LJ, Yenson VM, Baxter RC. TGF-beta-induced expression of IGFBP-3 regulates IGF1R signaling in human osteosarcoma cells. Mol Cell Endocrinol. 2013;377(1–2):56–64.CrossRefPubMedGoogle Scholar
  8. 8.
    Dehan P, Kustermans G, Guenin S, Horion J, Boniver J, Delvenne P. DNA methylation and cancer diagnosis: new methods and applications. Expert Rev Mol Diagn. 2009;9(7):651–7.CrossRefPubMedGoogle Scholar
  9. 9.
    How Kit A, Nielsen HM, Tost J. DNA methylation based biomarkers: practical considerations and applications. Biochimie. 2012;94(11):2314–37.CrossRefPubMedGoogle Scholar
  10. 10.
    Zha J, Lackner MR. Targeting the insulin-like growth factor receptor-1R pathway for cancer therapy. Clin Cancer Res. 2010;16(9):2512–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Chang YS, Wang L, Suh YA, Mao L, Karpen SJ, Khuri FR, et al. Mechanisms underlying lack of insulin-like growth factor-binding protein-3 expression in non-small-cell lung cancer. Oncogene. 2004;23(39):6569–80.CrossRefPubMedGoogle Scholar
  12. 12.
    Xue Q, Zhou Y, Wan C, Lv L, Chen B, Cao X, et al. Epithelial membrane protein 3 is frequently shown as promoter methylation and functions as a tumor suppressor gene in non-small cell lung cancer. Exp Mol Pathol. 2013;95(3):313–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Pernia O, Belda-Iniesta C, Pulido V, Cortes-Sempere M, Rodriguez C, Vera O, et al. Methylation status of IGFBP-3 as a useful clinical tool for deciding on a concomitant radiotherapy. Epigenetics. 2014;9(11):1446–53.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Regel I, Eichenmuller M, Joppien S, Liebl J, Haberle B, Muller-Hocker J, et al. IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors. Mol Cancer. 2012;11:9.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Torng PL, Lin CW, Chan MW, Yang HW, Huang SC, Lin CT. Promoter methylation of IGFBP-3 and p53 expression in ovarian endometrioid carcinoma. Mol Cancer. 2009;8:120.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Oy GF, Slipicevic A, Davidson B, Solberg Faye R, Maelandsmo GM, Florenes VA. Biological effects induced by insulin-like growth factor binding protein 3 (IGFBP-3) in malignant melanoma. Int J Cancer. 2010;126(2):350–61.CrossRefPubMedGoogle Scholar
  17. 17.
    Ohashi H, Adachi Y, Yamamoto H, Taniguchi H, Nosho K, Suzuki H, et al. Insulin-like growth factor receptor expression is associated with aggressive phenotypes and has therapeutic activity in biliary tract cancers. Cancer Sci. 2012;103(2):252–61.CrossRefPubMedGoogle Scholar
  18. 18.
    Zeng L, Jarrett C, Brown K, Gillespie KM, Holly JM, Perks CM. Insulin-like growth factor binding protein-3 (IGFBP-3) plays a role in the anti-tumorigenic effects of 5-aza-2′-deoxycytidine (AZA) in breast cancer cells. Exp Cell Res. 2013;319(14):2282–95.CrossRefPubMedGoogle Scholar
  19. 19.
    Sobin LH, Fleming ID. TNM classification of malignant tumors, fifth edition (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer. 1997; 80 (9): 1803–4Google Scholar
  20. 20.
    Song C, Xing D, Tan W, Wei Q, Lin D. Methylenetetrahydrofolate reductase polymorphisms increase risk of esophageal squamous cell carcinoma in a Chinese population. Cancer Res. 2001;61(8):3272–5.PubMedGoogle Scholar
  21. 21.
    Dong XJ, Wang N, Guo W, Zhou RM, Zhang XJ, Li Y. Correlations of XRCC5 polymorphisms to genetic susceptibility to esophageal squamous cell carcinoma and gastric cardiac adenocarcinoma in a high incidence region. Ai Zheng. 2007;26(3):280–4.PubMedGoogle Scholar
  22. 22.
    Kaiser MF, Johnson DC, Wu P, Walker BA, Brioli A, Mirabella F, et al. Global methylation analysis identifies prognostically important epigenetically inactivated tumor suppressor genes in multiple myeloma. Blood. 2013;122(2):219–26.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Probst-Hensch NM, Yuan JM, Stanczyk FZ, Gao YT, Ross RK, Yu MC. IGF-1, IGF-2 and IGFBP-3 in prediagnostic serum: association with colorectal cancer in a cohort of Chinese men in Shanghai. Br J Cancer. 2001;85(11):1695–9.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    He H, Chang X, Gao J, Zhu L, Miao M, Yan T. Salidroside mitigates sepsis-induced myocarditis in rats by regulating IGF-1/PI3K/Akt/GSK-3beta signaling. Inflammation. 2015.Google Scholar
  25. 25.
    Elumalai P, Arunkumar R, Benson CS, Sharmila G, Arunakaran J. Nimbolide inhibits IGF-I-mediated PI3K/Akt and MAPK signalling in human breast cancer cell lines (MCF-7 and MDA-MB-231). Cell Biochem Funct. 2014;32(5):476–84.PubMedGoogle Scholar
  26. 26.
    Perks CM, Holly JM. Epigenetic regulation of insulin-like growth factor binding protein-3 (IGFBP-3) in cancer. J Cell Commun Signal. 2015;9(2):159–66.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    McIntosh J, Dennison G, Holly JM, Jarrett C, Frankow A, Foulstone EJ, et al. IGFBP-3 can either inhibit or enhance EGF-mediated growth of breast epithelial cells dependent upon the presence of fibronectin. J Biol Chem. 2010;285(50):38788–800.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Perez-Carbonell L, Balaguer F, Toiyama Y, Egoavil C, Rojas E, Guarinos C, et al. IGFBP3 methylation is a novel diagnostic and predictive biomarker in colorectal cancer. PLoS One. 2014;9(8):e104285.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Li Z, Guo X, Wu Y, Li S, Yan J, Peng L, et al. Methylation profiling of 48 candidate genes in tumor and matched normal tissues from breast cancer patients. Breast Cancer Res Treat. 2015;149(3):767–79.CrossRefPubMedGoogle Scholar
  30. 30.
    Gigek CO, Leal MF, Lisboa LC, Silva PN, Chen ES, Lima EM, et al. Insulin-like growth factor binding protein-3 gene methylation and protein expression in gastric adenocarcinoma. Growth Horm IGF Res. 2010;20(3):234–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Tang H, Liao Y, Chen G, Xu L, Zhang C, Ju S, et al. Estrogen upregulates the IGF-1 signaling pathway in lung cancer through estrogen receptor-beta. Med Oncol. 2012;29(4):2640–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Ozaki S, Kawahara E, Maenaka S, Hoang NV, Oyama T, Imai M, et al. Distinct allelic expression patterns of imprinted in adenocarcinoma and squamous cell carcinoma of the lung. Oncol Lett. 2014;8(6):2561–4.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Zanella ER, Galimi F, Sassi F, Migliardi G, Cottino F, Leto SM, et al. IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies. Sci Transl Med. 2015;7(272):272ra12.CrossRefPubMedGoogle Scholar
  34. 34.
    Geng YT, Qiu JR, Wang R, Su YT, Shu YQ, Yin YM. Expression of HER-2 and leptin in gastric cancer and their clinical significance. Zhonghua Zhong Liu Za Zhi. 2011;33(10):764–9.PubMedGoogle Scholar
  35. 35.
    Wang JF, Dai DQ. Difference in methylation of genomic DNA between gastric primary cancer and lymph nodes with metastatic gastric cancer. Zhonghua Yi Xue Za Zhi. 2006;86(8):536–9.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Thoracic Surgery, First Affiliated Hospital, College of MedicineZhejiang UniversityHangzhouChina
  2. 2.Department of Thoracic SurgeryCancer Hospital of Harbin Medical UniversityHarbinChina
  3. 3.Department of Thoracic SurgeryThe No. 1 People’s Hospital of ZhangjiagangZhangjiagangChina

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