Tumor Biology

, Volume 36, Issue 8, pp 6541–6550 | Cite as

Integrin β6 can be translationally regulated by eukaryotic initiation factor 4E: Contributing to colonic tumor malignancy

  • Liu Enyu
  • Niu Zhengchuan
  • Wang Jiayong
  • Liang Benjia
  • Sun Qi
  • Qin Ruixi
  • Peng Cheng
  • Abdul Qadir Khan
  • Song Wei
  • Niu Jun
Research Article


It is well known that both eukaryotic initiation factor 4E (eIF4E) and integrin αvβ6 can contribute to malignant behavior of colon cancer. We have found that integrin αvβ6 and eIF4E were co-expressed and positively correlated in colon cancer tissues. Recently, deregulation of the protein synthesis apparatus has begun to gain attention as a major participant in cancer development and progression. However, the regulation of integrin β6 expression at translational level has never been investigated before. In present study, gene-silencing technique for eIF4E by small interfering RNA (siRNA) was used in all the subsequent experiments, in order to investigate whether eIF4E could translationally regulate expression of integrin β6 in colon cancer SW480 and HT-29 cell lines. Additionally, the subsequent effects of eIF4E knockdown on cellular malignant behavior were observed. siRNA in SW480 and HT-29 transfectants. Subsequently, protein expression of β6 was markedly suppressed, while mRNA expression of β6 showed no significant variation before and after eIF4E RNA interfering. Therefore, it could be seen that eIF4E could upregulate the expression of β6, without effect on β6 mRNA expression. More importantly, after treated with eIF4E siRNA, cellular migratory capacity on fibronectin of HT-29 and β6-transfected SW480 as well as their survival to 5-FU was decreased distinctly. Expression of integrin β6 could be translationally regulated by eIF4E, which subsequently contributed to tumor malignancy through enhancing cellular migration, survival, anti-apoptosis, and chemoresistance of colon cancer in vitro. Thus, targeting eIF4E in integrin αvβ6 expressing tumors can be a potential therapeutic strategy for patients with colon cancer.


Integrin β6 eIF4E Translation initiation Protein synthesis 



This study was supported by the research grants from the National Natural Sciences Foundation of China (No. 81272653) and the Natural Sciences Foundation of Shandong Province (No. ZR2011HM003 and No. ZR2013HQ051).

Conflicts of interest



  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. doi: 10.3322/caac.20107.CrossRefPubMedGoogle Scholar
  2. 2.
    Parsyan A, Hernandez G, Meterissian S. Translation initiation in colorectal cancer. Cancer Metastasis Rev. 2012;31(1–2):387–95. doi: 10.1007/s10555-012-9349-9.CrossRefPubMedGoogle Scholar
  3. 3.
    Ramos DM, Dang D, Sadler S. The role of the integrin alpha v beta6 in regulating the epithelial to mesenchymal transition in oral cancer. Anticancer Res. 2009;29(1):125–30.PubMedGoogle Scholar
  4. 4.
    Bates RC, Bellovin DI, Brown C, Maynard E, Wu B, Kawakatsu H, et al. Transcriptional activation of integrin beta6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J Clin Invest. 2005;115(2):339–47. doi: 10.1172/JCI23183.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Zhang ZY, Xu KS, Wang JS, Yang GY, Wang W, Wang JY, et al. Integrin alphanvbeta6 acts as a prognostic indicator in gastric carcinoma. Clin Oncol (R Coll Radiol). 2008;20(1):61–6. doi: 10.1016/j.clon.2007.09.008.CrossRefGoogle Scholar
  6. 6.
    Niu J, Gu X, Turton J, Meldrum C, Howard EW, Agrez M. Integrin-mediated signalling of gelatinase B secretion in colon cancer cells. Biochem Biophys Res Commun. 1998;249(1):287–91. doi: 10.1006/bbrc.1998.9128.CrossRefPubMedGoogle Scholar
  7. 7.
    Yang GY, Xu KS, Pan ZQ, Zhang ZY, Mi YT, Wang JS, et al. Integrin alpha v beta 6 mediates the potential for colon cancer cells to colonize in and metastasize to the liver. Cancer Sci. 2008;99(5):879–87. doi: 10.1111/j.1349-7006.2008.00762.x.CrossRefPubMedGoogle Scholar
  8. 8.
    Zhao-Yang Z, Ke-Sen X, Qing-Si H, Wei-Bo N, Jia-Yong W, Yue-Tang M, et al. Signaling and regulatory mechanisms of integrin alphavbeta6 on the apoptosis of colon cancer cells. Cancer Lett. 2008;266(2):209–15. doi: 10.1016/j.canlet.2008.02.054.CrossRefPubMedGoogle Scholar
  9. 9.
    Peng C, Liu X, Liu E, Xu K, Niu W, Chen R, et al. Norcantharidin induces HT-29 colon cancer cell apoptosis through the alphavbeta6-extracellular signal-related kinase signaling pathway. Cancer Sci. 2009;100(12):2302–8. doi: 10.1111/j.1349-7006.2009.01320.x.CrossRefPubMedGoogle Scholar
  10. 10.
    Niu W, Liu X, Zhang Z, Xu K, Chen R, Liu E, et al. Effects of alphavbeta6 gene silencing by RNA interference in PANC-1 pancreatic carcinoma cells. Anticancer Res. 2010;30(1):135–42.PubMedGoogle Scholar
  11. 11.
    Liu S, Wang J, Niu W, Liu E, Peng C, Lin P, et al. The beta6-integrin-ERK/MAP kinase pathway contributes to chemo resistance in colon cancer. Cancer Lett. 2013;328(2):325–34. doi: 10.1016/j.canlet.2012.10.004.CrossRefPubMedGoogle Scholar
  12. 12.
    Niu Z, Wang J, Muhammad S, Niu W, Liu E, Peng C, et al. Protein expression of eIF4E and integrin alphavbeta6 in colon cancer can predict clinical significance, reveal their correlation and imply possible mechanism of interaction. Cell Biosci. 2014;4:23. doi: 10.1186/2045-3701-4-23.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Yang HY, Xue LY, Xing LX, Wang J, Wang JL, Yan X, et al. Putative role of the mTOR/4E-BP1 signaling pathway in the carcinogenesis and progression of gastric cardiac adenocarcinoma. Mol Med Rep. 2013;7(2):537–42. doi: 10.3892/mmr.2012.1208.PubMedGoogle Scholar
  14. 14.
    Joshi B, Cameron A, Jagus R. Characterization of mammalian eIF4E-family members. Eur J Biochem. 2004;271(11):2189–203. doi: 10.1111/j.1432-1033.2004.04149.x.CrossRefPubMedGoogle Scholar
  15. 15.
    Robalino J, Joshi B, Fahrenkrug SC, Jagus R. Two zebrafish eIF4E family members are differentially expressed and functionally divergent. J Biol Chem. 2004;279(11):10532–41. doi: 10.1074/jbc.M313688200.CrossRefPubMedGoogle Scholar
  16. 16.
    Carroll M, Borden KL. The oncogene eIF4E: using biochemical insights to target cancer. J Interferon Cytokine Res. 2013;33(5):227–38. doi: 10.1089/jir.2012.0142.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    De Benedetti A, Graff JR. eIF-4E expression and its role in malignancies and metastases. Oncogene. 2004;23(18):3189–99. doi: 10.1038/sj.onc.1207545.CrossRefPubMedGoogle Scholar
  18. 18.
    De Benedetti A, Harris AL. eIF4E expression in tumors: its possible role in progression of malignancies. Int J Biochem Cell Biol. 1999;31(1):59–72.CrossRefPubMedGoogle Scholar
  19. 19.
    Raught B, Gingras AC. eIF4E activity is regulated at multiple levels. Int J Biochem Cell Biol. 1999;31(1):43–57.CrossRefPubMedGoogle Scholar
  20. 20.
    Sun Q, Sun F, Wang B, Liu S, Niu W, Liu E, et al. Interleukin-8 promotes cell migration through integrin alphavbeta6 upregulation in colorectal cancer. Cancer Lett. 2014;354(2):245–53. doi: 10.1016/j.canlet.2014.08.021.CrossRefPubMedGoogle Scholar
  21. 21.
    Wang B, Wang W, Niu W, Liu E, Liu X, Wang J, et al. SDF-1/CXCR4 axis promotes directional migration of colorectal cancer cells through upregulation of integrin alphavbeta6. Carcinogenesis. 2014;35(2):282–91. doi: 10.1093/carcin/bgt331.CrossRefPubMedGoogle Scholar
  22. 22.
    Ahmed N, Niu J, Dorahy DJ, Gu X, Andrews S, Meldrum CJ, et al. Direct integrin alphavbeta6-ERK binding: implications for tumour growth. Oncogene. 2002;21(9):1370–80. doi: 10.1038/sj.onc.1205286.CrossRefPubMedGoogle Scholar
  23. 23.
    Soni A, Akcakanat A, Singh G, Luyimbazi D, Zheng Y, Kim D, et al. eIF4E knockdown decreases breast cancer cell growth without activating Akt signaling. Mol Cancer Ther. 2008;7(7):1782–8. doi: 10.1158/1535-7163.MCT-07-2357.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Agrez M, Chen A, Cone RI, Pytela R, Sheppard D. The alpha v beta 6 integrin promotes proliferation of colon carcinoma cells through a unique region of the beta 6 cytoplasmic domain. J Cell Biol. 1994;127(2):547–56.CrossRefPubMedGoogle Scholar
  25. 25.
    Chen BJ, Wu YL, Tanaka Y, Zhang W. Small molecules targeting c-Myc oncogene: promising anti-cancer therapeutics. Int J Biol Sci. 2014;10(10):1084–96. doi: 10.7150/ijbs.10190.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ito Y, Takeda T, Okada M, Matsuura N. Expression of ets-1 and ets-2 in colonic neoplasms. Anticancer Res. 2002;22(3):1581–4.PubMedGoogle Scholar
  27. 27.
    Silvera D, Formenti SC, Schneider RJ. Translational control in cancer. Nat Rev Cancer. 2010;10(4):254–66. doi: 10.1038/nrc2824.CrossRefPubMedGoogle Scholar
  28. 28.
    Lazaris-Karatzas A, Montine KS, Sonenberg N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5′ cap. Nature. 1990;345(6275):544–7. doi: 10.1038/345544a0.CrossRefPubMedGoogle Scholar
  29. 29.
    Zimmer SG, DeBenedetti A, Graff JR. Translational control of malignancy: the mRNA cap-binding protein, eIF-4E, as a central regulator of tumor formation, growth, invasion and metastasis. Anticancer Res. 2000;20(3A):1343–51.PubMedGoogle Scholar
  30. 30.
    Breuss JM, Gallo J, DeLisser HM, Klimanskaya IV, Folkesson HG, Pittet JF, et al. Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling. J Cell Sci. 1995;108(Pt 6):2241–51.PubMedGoogle Scholar
  31. 31.
    Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer. 2009;9(4):274–84. doi: 10.1038/nrc2622.CrossRefPubMedGoogle Scholar
  32. 32.
    Wang J, Wu J, Hong J, Chen R, Xu K, Niu W, et al. PKC promotes the migration of colon cancer cells by regulating the internalization and recycling of integrin alphavbeta6. Cancer Lett. 2011;311(1):38–47. doi: 10.1016/j.canlet.2011.06.025.CrossRefPubMedGoogle Scholar
  33. 33.
    Gao H, Peng C, Liang B, Shahbaz M, Liu S, Wang B, et al. beta6 integrin induces the expression of metalloproteinase-3 and metalloproteinase-9 in colon cancer cells via ERK-ETS1 pathway. Cancer Lett. 2014;354(2):427–37. doi: 10.1016/j.canlet.2014.08.017.CrossRefPubMedGoogle Scholar
  34. 34.
    Gu X, Niu J, Dorahy DJ, Scott R, Agrez MV. Integrin alpha(v)beta6-associated ERK2 mediates MMP-9 secretion in colon cancer cells. Br J Cancer. 2002;87(3):348–51. doi: 10.1038/sj.bjc.6600480.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Niu J, Dorahy DJ, Gu X, Scott RJ, Draganic B, Ahmed N, et al. Integrin expression in colon cancer cells is regulated by the cytoplasmic domain of the beta6 integrin subunit. Int J Cancer. 2002;99(4):529–37. doi: 10.1002/ijc.10397.CrossRefPubMedGoogle Scholar
  36. 36.
    Clark EA, Brugge JS. Integrins and signal transduction pathways: the road taken. Science. 1995;268(5208):233–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Howe A, Aplin AE, Alahari SK, Juliano RL. Integrin signaling and cell growth control. Curr Opin Cell Biol. 1998;10(2):220–31.CrossRefPubMedGoogle Scholar
  38. 38.
    Schwartz MA, Schaller MD, Ginsberg MH. Integrins: emerging paradigms of signal transduction. Annu Rev Cell Dev Biol. 1995;11:549–99. doi: 10.1146/annurev.cb.11.110195.003001.CrossRefPubMedGoogle Scholar
  39. 39.
    Chung J, Bachelder RE, Lipscomb EA, Shaw LM, Mercurio AM. Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells. J Cell Biol. 2002;158(1):165–74. doi: 10.1083/jcb.200112015.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Pabla R, Weyrich AS, Dixon DA, Bray PF, McIntyre TM, Prescott SM, et al. Integrin-dependent control of translation: engagement of integrin alphaIIbbeta3 regulates synthesis of proteins in activated human platelets. J Cell Biol. 1999;144(1):175–84.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Gorrini C, Loreni F, Gandin V, Sala LA, Sonenberg N, Marchisio PC, et al. Fibronectin controls cap-dependent translation through beta1 integrin and eukaryotic initiation factors 4 and 2 coordinated pathways. Proc Natl Acad Sci U S A. 2005;102(26):9200–5. doi: 10.1073/pnas.0409513102.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Chung J, Kim TH. Integrin-dependent translational control: implication in cancer progression. Microsc Res Tech. 2008;71(5):380–6. doi: 10.1002/jemt.20566.CrossRefPubMedGoogle Scholar
  43. 43.
    Populo H, Lopes JM, Soares P. The mTOR Signalling pathway in human cancer. Int J Mol Sci. 2012;13(2):1886–918. doi: 10.3390/ijms13021886.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Ye Q, Cai W, Zheng Y, Evers BM, She QB. ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer. Oncogene. 2014;33(14):1828–39. doi: 10.1038/onc.2013.122.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Liu Enyu
    • 1
  • Niu Zhengchuan
    • 1
    • 3
  • Wang Jiayong
    • 1
  • Liang Benjia
    • 1
    • 3
  • Sun Qi
    • 1
    • 3
  • Qin Ruixi
    • 2
  • Peng Cheng
    • 1
  • Abdul Qadir Khan
    • 1
  • Song Wei
    • 4
  • Niu Jun
    • 1
  1. 1.Department of General Surgery, Qilu HospitalShandong UniversityJinanPeople’s Republic of China
  2. 2.Department of Pathology, Qilu HospitalShandong UniversityJinanPeople’s Republic of China
  3. 3.Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of Education and Public HealthJinanPeople’s Republic of China
  4. 4.General Hospital of Yanzhou Mining GroupJiningPeople’s Republic of China

Personalised recommendations