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Expressions of insulin-like growth factor receptor-1 and cezanne-1 in lung adenocarcinoma

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Abstract

IGF1R (insulin-like growth factor receptor-1) was confirmed to play a significant role in the development of cancer. Cezanne-1 overexpression was considered to be associated with enhancement of EGFR signaling pathway and reduced degeneration of EGFR. There was a close relationship between EGFR and IGFR as previous study showed. Dynamic balance between receptor ubiquitination and deubiquitination was critical in the process of termination of IGF signaling pathway. So we conducted an IHC staining to initially prove the correlation. Cezanne-1 and IGF1R expressions were evaluated in 103 patients with lung adenocarcinoma using immunohistochemical (IHC) analysis. The relationship between expressions of cezanne-1 and IGF1R were analyzed by χ2 test. Kaplan–Meier method was used to generate the survival curve, and the statistical difference was calculated by log-rank test. We also used data in R2 system to verify the relationship between IGF1R and cezanne-1. R2 system showed there was a close correlation between IGF1R and cezanne-1. Positive expression of cezanne-1 was detected in 64.1% patients. A significant association was shown between cezanne-1 and IGF1R expression (p < 0.001). Multivariate analysis confirmed that both cezanne-1 and IGF1R expressions were independent prognostic factors for OS. (HR 2.96, 95% CI 1.090–8.060, p = 0.033; HR 2.273, 95% CI 1.016–5.085, p = 0.046, respectively). Our findings indicated both cezanne-1 and IGF1R expressions were negative independent predictive factors for the prognosis of lung adenocarcinoma, respectively. There was a close positive interrelationship between cezanne-1 and IGF1R expression.

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References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. doi:10.3322/caac.21262.

    Article  PubMed  Google Scholar 

  2. Pardee AB. G1 events and regulation of cell proliferation. Science (New York, NY). 1989;246(4930):603–8.

    Article  CAS  Google Scholar 

  3. Cross M, Dexter TM. Growth factors in development, transformation, and tumorigenesis. Cell. 1991;64(2):271–80.

    Article  CAS  PubMed  Google Scholar 

  4. Iams WT, Lovly CM. Molecular pathways: clinical applications and future direction of insulin-like growth factor-1 receptor pathway blockade. Clin Cancer Res. 2015;21(19):4270–7. doi:10.1158/1078-0432.ccr-14-2518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gately K, Forde L, Cuffe S, Cummins R, Kay EW, Feuerhake F, et al. High coexpression of both EGFR and IGF1R correlates with poor patient prognosis in resected non-small-cell lung cancer. Clin Lung Cancer. 2014;15(1):58–66. doi:10.1016/j.cllc.2013.08.005.

    Article  CAS  PubMed  Google Scholar 

  6. Lee AV, Jackson JG, Gooch JL, Hilsenbeck SG, Coronado-Heinsohn E, Osborne CK et al. Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo. Molecular endocrinology (Baltimore, Md). 1999;13(5):787-96. doi:10.1210/mend.13.5.0274.

  7. Rowinsky EK, Youssoufian H, Tonra JR, Solomon P, Burtrum D, Ludwig DL. IMC-A12, a human IgG1 monoclonal antibody to the insulin-like growth factor I receptor. Clin Cancer Res. 2007;13(18 Pt 2):5549s–55s. doi:10.1158/1078-0432.ccr-07-1109.

    Article  CAS  PubMed  Google Scholar 

  8. Macaulay VM, Middleton MR, Protheroe AS, Tolcher A, Dieras V, Sessa C, et al. Phase I study of humanized monoclonal antibody AVE1642 directed against the type 1 insulin-like growth factor receptor (IGF-1R), administered in combination with anticancer therapies to patients with advanced solid tumors. Ann Oncol. 2013;24(3):784–91. doi:10.1093/annonc/mds511.

    Article  CAS  PubMed  Google Scholar 

  9. Naing A, Kurzrock R, Burger A, Gupta S, Lei X, Busaidy N, et al. Phase I trial of cixutumumab combined with temsirolimus in patients with advanced cancer. Clin Cancer Res. 2011;17(18):6052–60. doi:10.1158/1078-0432.ccr-10-2979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kim YH, Sumiyoshi S, Hashimoto S, Masago K, Togashi Y, Sakamori Y, et al. Expressions of insulin-like growth factor receptor-1 and insulin-like growth factor binding protein 3 in advanced non-small-cell lung cancer. Clin Lung Cancer. 2012;13(5):385–90. doi:10.1016/j.cllc.2011.11.009.

    Article  CAS  PubMed  Google Scholar 

  11. Gong Y, Yao E, Shen R, Goel A, Arcila M, Teruya-Feldstein J, et al. High expression levels of total IGF-1R and sensitivity of NSCLC cells in vitro to an anti-IGF-1R antibody (R1507). PLoS ONE. 2009;4(10):e7273. doi:10.1371/journal.pone.0007273.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Zhao S, Chen SS, Gu Y, Jiang EZ, Yu ZH. Expression and clinical significance of sushi domain- containing protein 3 (SUSD3) and Insulin-like growth factor-I receptor (IGF-IR) in breast cancer. Asian Pacific J Cancer Prev APJCP. 2015;16(18):8633–6.

    Article  Google Scholar 

  13. Evans PC, Smith TS, Lai MJ, Williams MG, Burke DF, Heyninck K, et al. A novel type of deubiquitinating enzyme. J Biol Chem. 2003;278(25):23180–6. doi:10.1074/jbc.M301863200.

    Article  CAS  PubMed  Google Scholar 

  14. Bremm A, Freund SM, Komander D. Lys11-linked ubiquitin chains adopt compact conformations and are preferentially hydrolyzed by the deubiquitinase Cezanne. Nat Struct Mol Biol. 2010;17(8):939–47. doi:10.1038/nsmb.1873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pareja F, Ferraro DA, Rubin C, Cohen-Dvashi H, Zhang F, Aulmann S, et al. Deubiquitination of EGFR by Cezanne-1 contributes to cancer progression. Oncogene. 2012;31(43):4599–608. doi:10.1038/onc.2011.587.

    Article  CAS  PubMed  Google Scholar 

  16. Worrall C, Nedelcu D, Serly J, Suleymanova N, Oprea I, Girnita A, et al. Novel mechanisms of regulation of IGF-1R action: functional and therapeutic implications. Pediatric Endocrinol Rev PER. 2013;10(4):473–84.

    Google Scholar 

  17. Mountain CF. Revisions in the international system for staging lung cancer. Chest. 1997;111(6):1710–7.

    Article  CAS  PubMed  Google Scholar 

  18. Yu J, Wang L, Zhang T, Shen H, Dong W, Ni Y, et al. Co-expression of beta-arrestin1 and NF-small ka, CyrillicB is associated with cancer progression and poor prognosis in lung adenocarcinoma. Tumour Biol. 2015;36(8):6551–8. doi:10.1007/s13277-015-3349-7.

    Article  CAS  PubMed  Google Scholar 

  19. Sehat B, Andersson S, Girnita L, Larsson O. Identification of c-Cbl as a new ligase for insulin-like growth factor-I receptor with distinct roles from Mdm2 in receptor ubiquitination and endocytosis. Cancer Res. 2008;68(14):5669–77. doi:10.1158/0008-5472.can-07-6364.

    Article  CAS  PubMed  Google Scholar 

  20. Vecchione A, Marchese A, Henry P, Rotin D, Morrione A. The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor. Mol Cell Biol. 2003;23(9):3363–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev. 2002;82(2):373–428. doi:10.1152/physrev.00027.2001.

    Article  CAS  PubMed  Google Scholar 

  22. Prager D, Li HL, Yamasaki H, Melmed S. Human insulin-like growth factor I receptor internalization. Role of the juxtamembrane domain. J Biol Chem. 1994;269(16):11934–7.

    CAS  PubMed  Google Scholar 

  23. Miura M, Baserga R. The tyrosine residue at 1250 of the insulin-like growth factor I receptor is required for ligand-mediated internalization. Biochem Biophys Res Commun. 1997;239(1):182–5. doi:10.1006/bbrc.1997.7449.

    Article  CAS  PubMed  Google Scholar 

  24. Komander D, Clague MJ, Urbe S. Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol. 2009;10(8):550–63. doi:10.1038/nrm2731.

    Article  CAS  PubMed  Google Scholar 

  25. Moniz S, Bandarra D, Biddlestone J, Campbell KJ, Komander D, Bremm A, et al. Cezanne regulates E2F1-dependent HIF2alpha expression. J Cell Sci. 2015;128(16):3082–93. doi:10.1242/jcs.168864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Enesa K, Zakkar M, Chaudhury H, le Luong A, Rawlinson L, Mason JC, et al. NF-kappaB suppression by the deubiquitinating enzyme Cezanne: a novel negative feedback loop in pro-inflammatory signaling. J Biol Chem. 2008;283(11):7036–45. doi:10.1074/jbc.M708690200.

    Article  CAS  PubMed  Google Scholar 

  27. Goetsch L, Gonzalez A, Leger O, Beck A, Pauwels PJ, Haeuw JF, et al. A recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti-epidermal growth factor receptor therapy against human cancer xenografts. Int J Cancer. 2005;113(2):316–28. doi:10.1002/ijc.20543.

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was funded by Chinese National Natural Science Foundation (81672288) and Shandong Provincial Natural Science Foundation (ZR2014HQ073) and Provincial science and technology development plan of Shandong (2015GSF118109).

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Author notes

  1. Zhaofei Pang and Lixuan Cui contributed equally to this work.

Authors and Affiliations

  1. Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, 250021, China

    Zhaofei Pang, Lixuan Cui, Nan Ding, Xiao Qu, Jiajun Du & Qi Liu

  2. Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, 250021, China

    Linhai Zhu, Wei Dong & Jiajun Du

Authors
  1. Zhaofei Pang
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  2. Lixuan Cui
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  3. Nan Ding
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  4. Linhai Zhu
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  5. Xiao Qu
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  6. Wei Dong
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  7. Jiajun Du
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  8. Qi Liu
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Correspondence to Jiajun Du or Qi Liu.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Pang, Z., Cui, L., Ding, N. et al. Expressions of insulin-like growth factor receptor-1 and cezanne-1 in lung adenocarcinoma. Med Oncol 34, 78 (2017). https://doi.org/10.1007/s12032-017-0934-1

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  • DOI: https://doi.org/10.1007/s12032-017-0934-1

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