SpringerLink
Log in

Phosphorylated 4E-binding protein 1 expression is associated with poor prognosis in small-cell lung cancer

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) binding protein (4E-BP1) results in release of eIF4E, which sequentially relieves translational repression and enhances oncogenic protein synthesis. We assessed the expression of phosphorylated 4E-BP1 (p-4E-BP1) in small-cell lung cancer (SCLC) and its correlation with clinicopathological factors and patient survival. This study included 117 SCLCs, which comprised 108 primary and 9 metastatic tumor tissues. We performed immunohistochemical staining for p-4E-BP1 in 117 tumors and found that 77 (66 %) were positive for p-4E-BP1 with cytoplasmic and/or nuclear immunostaining. The positive rate of p-4E-BP1 staining was significantly higher in never smokers (p = 0.034) and metastatic tumor tissues (p = 0.027). Patients with p-4E-BP1-positive SCLC tended to have poor performance status, although the difference was not statistically significant (p = 0.087). High p-4E-BP1 expression was significantly correlated with worse overall survival (OS) in all cohorts (p = 0.016). After stratification by clinical stage, p-4E-BP1 expression showed a stronger relationship with OS in patients with limited disease (p = 0.008). In addition, when stratified by treatment status, p-4E-BP1 expression was still significantly associated with worse OS in a subgroup of patients who completed treatment (p = 0.021). Our results indicate that p-4E-BP1 expression could represent oncogenic potential and contribute to the progression and aggressiveness of SCLC, suggesting it could be a candidate prognostic biomarker of SCLC, especially in limited disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Amini A, Byers LA, Welsh JW, Komaki RU (2014) Progress in the management of limited-stage small cell lung cancer. Cancer 120:790–798

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Argiris A, Murren JR (2001) Staging and clinical prognostic factors for small-cell lung cancer. Cancer J 7:437–447

    CAS  PubMed  Google Scholar 

  3. Kalemkerian GP (2014) Advances in pharmacotherapy of small cell lung cancer. Expert Opin Pharmacother 15:2385–2396

    Article  CAS  PubMed  Google Scholar 

  4. Rossi G, Bisagni A, Cavazza A (2014) High-grade neuroendocrine carcinoma. Curr Opin Pulm Med 20:332–339

    Article  CAS  PubMed  Google Scholar 

  5. Armengol G, Rojo F, Castellví J, Iglesias C, Cuatrecasas M, Pons B, Baselga J, Ramón y Cajal S (2007) 4E-binding protein 1: a key molecular “funnel factor” in human cancer with clinical implications. Cancer Res 67:7551–7555

    Article  CAS  PubMed  Google Scholar 

  6. Averous J, Proud CG (2006) When translation meets transformation: the mTOR story. Oncogene 25:6423–6435

    Article  CAS  PubMed  Google Scholar 

  7. Yeh CJ, Chuang WY, Chao YK, Liu YH, Chang YS, Kuo SY, Tseng CK, Chang HK, Hsueh C (2011) High expression of phosphorylated 4E-binding protein 1 is an adverse prognostic factor in esophageal squamous cell carcinoma. Virchows Arch 458:171–178

    Article  CAS  PubMed  Google Scholar 

  8. Korkolopoulou P, Levidou G, El-Habr EA, Piperi C, Adamopoulos C, Samaras V, Boviatsis E, Thymara I, Trigka EA, Sakellariou S, Kavantzas N, Patsouris E, Saetta AA (2012) Phosphorylated 4E-binding protein 1 (p-4E-BP1): a novel prognostic marker in human astrocytomas. Histopathology 61:293–305

    Article  PubMed  Google Scholar 

  9. Castellvi J, Garcia A, Ruiz-Marcellan C, Hernández-Losa J, Peg V, Salcedo M, Gil-Moreno A, Ramon Y, Cajal S (2009) Cell signaling in endometrial carcinoma: phosphorylated 4E-binding protein-1 expression in endometrial cancer correlates with aggressive tumors and prognosis. Hum Pathol 40:1418–1426

    Article  CAS  PubMed  Google Scholar 

  10. O’Reilly KE, Warycha M, Davies MA, Rodrik V, Zhou XK, Yee H, Polsky D, Pavlick AC, Rosen N, Bhardwaj N, Mills G, Osman I (2009) Phosphorylated 4E-BP1 is associated with poor survival in melanoma. Clin Cancer Res 15:2872–2878

    Article  PubMed Central  PubMed  Google Scholar 

  11. Castellvi J, Garcia A, Rojo F, Ruiz-Marcellan C, Gil A, Baselga J, Ramon y Cajal S (2006) Phosphorylated 4E binding protein 1: a hallmark of cell signaling that correlates with survival in ovarian cancer. Cancer 107:1801–1811

    Article  CAS  PubMed  Google Scholar 

  12. Trigka EA, Levidou G, Saetta AA, Chatziandreou I, Tomos P, Thalassinos N, Anastasiou N, Spartalis E, Kavantzas N, Patsouris E, Korkolopoulou P (2013) A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features. Oncol Rep 30:623–636

    CAS  PubMed  Google Scholar 

  13. Righi L, Volante M, Rapa I, Tavaglione V, Inzani F, Pelosi G, Papotti M (2010) Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung. Endocr Relat Cancer 17:977–987

    Article  CAS  PubMed  Google Scholar 

  14. Ou SH, Ziogas A, Zell JA (2009) Prognostic factors for survival in extensive stage small cell lung cancer (ED-SCLC): the importance of smoking history, socioeconomic and marital statuses, and ethnicity. J Thorac Oncol 4:37–43

    Article  PubMed  Google Scholar 

  15. Sun JM, Choi YL, Ji JH, Ahn JS, Kim KM, Han J, Ahn MJ, Park K (2015) Small-cell lung cancer detection in never-smokers: clinical characteristics and multigene mutation profiling using targeted next-generation sequencing. Ann Oncol 26:161–166

    Article  PubMed  Google Scholar 

  16. Lee C, Kang KH, Koh Y, Chang J, Chung HS, Park SK, Yoo K, Song JS (2000) Characteristics of lung cancer in Korea, 1997. Lung Cancer 30:15–22

    Article  CAS  PubMed  Google Scholar 

  17. Ahn MJ, Lee J, Park YH, Ahn JS, Ziogas A, Zell JA, Park K, Ou SH (2010) Korean ethnicity as compared with white ethnicity is an independent favorable prognostic factor for overall survival in non-small cell lung cancer before and after the oral epidermal growth factor receptor tyrosine kinase inhibitor era. J Thorac Oncol 5:1185–1196

    Article  PubMed  Google Scholar 

  18. Wakelee HA, Chang ET, Gomez SL, Keegan TH, Feskanich D, Clarke CA, Holmberg L, Yong LC, Kolonel LN, Gould MK, West DW (2007) Lung cancer incidence in never smokers. J Clin Oncol 25:472–478

    Article  PubMed Central  PubMed  Google Scholar 

  19. Lemaître V, Dabo AJ, D’Armiento J (2011) Cigarette smoke components induce matrix metalloproteinase-1 in aortic endothelial cells through inhibition of mTOR signaling. Toxicol Sci 123:542–549

    Article  PubMed Central  PubMed  Google Scholar 

  20. Yoshida T, Mett I, Bhunia AK, Bowman J, Perez M, Zhang L, Gandjeva A, Zhen L, Chukwueke U, Mao T, Richter A, Brown E, Ashush H, Notkin N, Gelfand A, Thimmulappa RK, Rangasamy T, Sussan T, Cosgrove G, Mouded M, Shapiro SD, Petrache I, Biswal S, Feinstein E, Tuder RM (2010) Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke-induced pulmonary injury and emphysema. Nat Med 16:767–773

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Memmott RM, Dennis PA (2010) The role of the Akt/mTOR pathway in tobacco-carcinogen induced lung tumorigenesis. Clin Cancer Res 16:4–10

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Pandya KJ, Dahlberg S, Hidalgo M, Cohen RB, Lee MW, Schiller JH, Johnson DH, Eastern Cooperative Oncology Group (E1500) (2007) A randomized, phase II trial of two dose levels of temsirolimus (CCI-779) in patients with extensive-stage small-cell lung cancer who have responding or stable disease after induction chemotherapy: a trial of the Eastern Cooperative Oncology Group (E1500). J Thorac Oncol 2:1036–1041

    Article  PubMed  Google Scholar 

  23. Zhang Y, He J (2013) The development of targeted therapy in small cell lung cancer. J Thorac Dis 5:538–548

    PubMed Central  PubMed  Google Scholar 

  24. Früh M, De Ruysscher D, Popat S, Crinò L, Peters S, Felip E, ESMO Guidelines Working Group (2013) Small-cell lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 24:vi99–v105

    Article  PubMed  Google Scholar 

  25. Nishi T, Iwasaki K, Ohashi N, Tanaka C, Kobayashi D, Nakayama G, Koike M, Fujiwara M, Kobayashi T, Kodera Y (2013) Phosphorylation of 4E-BP1 predicts sensitivity to everolimus in gastric cancer cells. Cancer Lett 331:220–229

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science, ICT & Future Planning) (grant number: 2013R1A1A3007362).

Author information

Authors and Affiliations

  1. Department of Pathology, Dong-A University College of Medicine, Busan, South Korea

    Mee Sook Roh

  2. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea

    Ji Hyun Lee & Kyung Woo Kang

  3. Department of Nuclear Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea

    Hyun-Yeol Nam

  4. Department of Clinical Laboratory Science, Dong-Eui Institute of Technology, Busan, South Korea

    Sang Bong Jung

  5. Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Kyungeun Kim

  6. Department of Pathology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, 50, Hapsung-dong, Masan Hoewon-gu, Changwon, 630-723, South Korea

    Eun Hee Lee, Moon-il Park, Mee-Seon Kim & Hyoun Wook Lee

Authors
  1. Mee Sook Roh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ji Hyun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kyung Woo Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hyun-Yeol Nam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sang Bong Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kyungeun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eun Hee Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Moon-il Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mee-Seon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hyoun Wook Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hyoun Wook Lee.

Ethics declarations

The study was approved by the institutional review board of our medical institution.

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Roh, M.S., Lee, J.H., Kang, K.W. et al. Phosphorylated 4E-binding protein 1 expression is associated with poor prognosis in small-cell lung cancer. Virchows Arch 467, 667–673 (2015). https://doi.org/10.1007/s00428-015-1860-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-015-1860-2

Keywords

Search

Navigation