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eEF1A2 promotes cell migration, invasion and metastasis in pancreatic cancer by upregulating MMP-9 expression through Akt activation

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Abstract

eEF1A2 is a protein translation factor involved in protein synthesis that is overexpressed in various cancers, with important functions in tumor genesis and progression. We have previously showed that the ectopic expression of eEF1A2 is correlated with lymph node metastasis and perineural invasion in pancreatic cancer. In this study, we investigated the functional role of eEF1A2 in the regulation of cell migration, invasion, and metastasis in pancreatic cancer. Furthermore, we investigated the potential molecular mechanisms involved. By evaluating the invasive ability of a panel of pancreatic cancer cell lines with different metastatic potentials, eEF1A2 expression in cells was positively associated with their invasive ability. The knockdown of eEF1A2 by siRNA decreased the migration and invasion of PANC-1 cells. By contrast, the ectopic expression of exogenous eEF1A2 significantly promoted the migration and invasion of SW1990 cells. Stable eEF1A2 overexpression in a nude mouse model of peritoneal metastasis likewise dramatically enhanced the intraperitoneal metastatic ability of SW1990 cells. In addition, eEF1A2 overexpression could upregulate MMP-9 expression and activity. A significant positive correlation between the overexpression of both eEF1A2 and MMP-9 was observed in pancreatic cancer tissues. The inhibition of MMP-9 activity reduced the promoting effect of eEF1A2 on cell migration and invasion. Furthermore, eEF1A2-mediated cell migration and invasion, as well as MMP-9 expression and upregulation, were largely dependent on the eEF1A2-induced Akt activation. The findings suggested the potentially important role of eEF1A2 in pancreatic cancer migration, invasion, and metastasis. Thus, the results provide evidence of eEF1A2 as a potential therapeutic target in the treatment of aggressive pancreatic cancer.

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Abbreviations

eEF1A2:

Eukaryotic elongation factor 1 alpha 2

MMP-9:

Matrix metalloproteinase-9

References

  1. Siegel R, Naishadham D, Jemal A et al (2012) Cancer statistics, 2012. CA Cancer J Clin 62(1):10–29

    Article  PubMed  Google Scholar 

  2. Hidalgo M (2010) Pancreatic cancer. N Engl J Med 362(17):1605–1617

    Article  PubMed  CAS  Google Scholar 

  3. Rhim AD, Mirek ET, Aiello NM et al (2012) EMT and dissemination even precede pancreatic tumor formation. Cell 148(1–2):349–361

    Article  PubMed  CAS  Google Scholar 

  4. Neoptolemos JP, Stocken DD, Friess H et al (2004) A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350(12):1200–1210

    Article  PubMed  CAS  Google Scholar 

  5. Browne GJ, Proud CG (2002) Regulation of peptide-chain elongation in mammalian cells. Eur J Biochem 269(22):5360–5368

    Article  PubMed  CAS  Google Scholar 

  6. Soares DC, Barlow PN, Newbery HJ et al (2009) Structural models of human eEF1A1 and eEF1A2 reveal two distinct surface clusters of sequence variation and potential differences in phosphorylation. PLoS One 4(7):e6315

    Article  PubMed  Google Scholar 

  7. Knudsen SM, Frydenberg J, Clark BF et al (1993) Tissue-dependent variation in the expression of elongation factor-1 alpha isoforms: isolation and characterisation of a cDNA encoding a novel variant of human elongation-factor 1 alpha. Eur J Biochem 215(3):549–554

    Article  PubMed  CAS  Google Scholar 

  8. Lee S, Francoeur AM, Liu S et al (1992) Tissue-specific expression in mammalian brain, heart, and muscle of S1, a member of the elongation factor-1 alpha gene family. J Biol Chem 267(33):24064–24068

    PubMed  CAS  Google Scholar 

  9. Bektas M, Nurten R, Gurel Z et al (1994) Interactions of eukaryotic elongation factor 2 with actin: a possible link between protein synthetic machinery and cytoskeleton. FEBS Lett 356(1):89–93

    Article  PubMed  CAS  Google Scholar 

  10. Gross SR, Kinzy TG (2005) Translation elongation factor 1A is essential for regulation of the actin cytoskeleton and cell morphology. Nat Struct Mol Biol 12(9):772–778

    Article  PubMed  CAS  Google Scholar 

  11. Chung CM, Man C, Jin Y et al (2005) Amplification and overexpression of aurora kinase A (AURKA) in immortalized human ovarian epithelial (HOSE) cells. Mol Carcinog 43(3):165–174

    Article  PubMed  CAS  Google Scholar 

  12. Shamovsky I, Ivannikov M, Kandel ES et al (2006) RNA-mediated response to heat shock in mammalian cells. Nature 440(7083):556–560

    Article  PubMed  CAS  Google Scholar 

  13. Chang R, Wang E (2007) Mouse translation elongation factor eEF1A-2 interacts with Prdx-I to protect cells against apoptotic death induced by oxidative stress. J Cell Biochem 100(2):267–278

    Article  PubMed  CAS  Google Scholar 

  14. Amiri A, Noei F, Jeganatham S et al (2007) eEF1A2 activates Akt and stimulates Akt-dependent actin remodelling, invasion and migration. Oncogene 26(21):3027–3040

    Article  PubMed  CAS  Google Scholar 

  15. Li Z, Qi CF, Shin DM et al (2010) Eef1a2 promotes cell growth, inhibits apoptosis and activates JAK/STAT and AKT signaling in mouse plasmacytomas. PLoS One 5(5):e10755

    Article  PubMed  Google Scholar 

  16. Anand N, Murthy S, Amann G et al (2002) Protein elongation factor EEF1A2 is a putative oncogene in ovarian cancer. Nat Genet 31(3):301–305

    PubMed  CAS  Google Scholar 

  17. Tomlinson VA, Newbery HJ, Wray NR et al (2005) Translation elongation factor eEF1A2 is a potential oncoprotein that is overexpressed in two-thirds of breast tumours. BMC Cancer 5:113

    Article  PubMed  Google Scholar 

  18. Li R, Wang H, Bekele BN et al (2006) Identification of putative oncogenes in lung adenocarcinoma by a comprehensive functional genomic approach. Oncogene 25(18):2628–2635

    Article  PubMed  CAS  Google Scholar 

  19. Scaggiante B, Dapas B, Bonin S et al (2012) Dissecting the expression of EEF1A1/2 genes in human prostate cancer cells: the potential of EEF1A2 as a hallmark for prostate transformation and progression. Br J Cancer 106(1):166–173

    Article  PubMed  CAS  Google Scholar 

  20. Grassi G, Scaggiante B, Farra R et al (2007) The expression levels of the translational factors eEF1A 1/2 correlate with cell growth but not apoptosis in hepatocellular carcinoma cell lines with different differentiation grade. Biochimie 89(12):1544–1552

    Article  PubMed  CAS  Google Scholar 

  21. Cao HX, Zhu Q, Huang J et al (2009) Regulation and functional role of eEF1A2 in pancreatic carcinoma. Biochem Biophys Res Commun 380(1):11–16

    Article  PubMed  CAS  Google Scholar 

  22. Hu DM, Xu C, Zhu Q (2013) eEF1A2 protein expression correlates with lymph node metastasis and decreased survival in pancreatic ductal adenocarcinoma. Hepatogastroenterology 60(124):222–227

    Google Scholar 

  23. Pencil SD, Toh Y, Nicolson GL (1993) Candidate metastasis-associated genes of the rat 13762NF mammary adenocarcinoma. Breast Cancer Res Treat 25(2):165–174

    Article  PubMed  CAS  Google Scholar 

  24. Edmonds BT, Wyckoff J, Yeung YG et al (1996) Elongation factor-1 alpha is an overexpressed actin binding protein in metastatic rat mammary adenocarcinoma. J Cell Sci 109(Pt 11):2705–2714

    PubMed  CAS  Google Scholar 

  25. Pecorari L, Marin O, Silvestri C et al (2009) Elongation factor 1 alpha interacts with phospho-Akt in breast cancer cells and regulates their proliferation, survival and motility. Mol Cancer 8:58

    Article  PubMed  Google Scholar 

  26. Li Y, Aoki T, Mori Y et al (2004) Cleavage of lumican by membrane-type matrix metalloproteinase-1 abrogates this proteoglycan-mediated suppression of tumor cell colony formation in soft agar. Cancer Res 64(19):7058–7064

    Article  PubMed  CAS  Google Scholar 

  27. Ozaki H, Matsuzaki H, Ando H et al (2012) Enhancement of metastatic ability by ectopic expression of ST6GalNAcI on a gastric cancer cell line in a mouse model. Clin Exp Metastasis 29(3):229–238

    Article  PubMed  CAS  Google Scholar 

  28. Pryczynicz A, Guzińska-Ustymowicz K, Dymicka-Piekarska V et al (2007) Expression of matrix metalloproteinase 9 in pancreatic ductal carcinoma is associated with tumor metastasis formation. Folia Histochem Cytobiol 45(1):37–40

    PubMed  CAS  Google Scholar 

  29. Itoh Y, Nagase H (2002) Matrix metalloproteinases in cancer. Essays Biochem 38:21–36

    PubMed  CAS  Google Scholar 

  30. Bernhard EJ, Gruber SB, Muschel RJ (1994) Direct evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cells. Proc Natl Acad Sci USA 91(10):4293–4297

    Article  PubMed  CAS  Google Scholar 

  31. Gress TM, Müller-Pillasch F, Lerch MM et al (1995) Expression and in situ localization of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in pancreatic cancer. Int J Cancer 62(4):407–413

    Article  PubMed  CAS  Google Scholar 

  32. Shi WD, Meng ZQ, Chen Z et al (2009) Identification of liver metastasis-related genes in a novel human pancreatic carcinoma cell model by microarray analysis. Cancer Lett 283(1):84–91

    Article  PubMed  CAS  Google Scholar 

  33. Chin YR, Toker A (2009) Function of Akt/PKB signaling to cell motility, invasion and the tumor stroma in cancer. Cell Signal 21(4):470–476

    Article  PubMed  CAS  Google Scholar 

  34. Meng Q, Xia C, Fang J et al (2006) Role of PI3 K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway. Cell Signal 18(12):2262–2271

    Article  PubMed  CAS  Google Scholar 

  35. Grille SJ, Bellacosa A, Upson J et al (2003) The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma line. Cancer Res 63(9):2172–2178

    PubMed  CAS  Google Scholar 

  36. Mohi MG, Neel BG (2007) The role of Shp2 (PTPN11) in cancer. Curr Opin Genet Dev 17(1):23–30

    Article  PubMed  CAS  Google Scholar 

  37. Panasyuk G, Nemazanyy I, Filonenko V et al (2008) A2 isoform of mammalian translation factor eEF1A displays increased tyrosine phosphorylation and ability to interact with different signalling molecules. Int J Biochem Cell Biol 40(1):63–71

    Article  PubMed  CAS  Google Scholar 

  38. Zhu X, Wang L, Zhang B et al (2011) TGF-beta 1-induced PI3 K/Akt/NF-kappa B/MMP9 signalling pathway is activated in Philadelphia chromosome-positive chronic myeloid leukaemia hemangioblasts. J Biochem 149(4):405–414

    Article  PubMed  CAS  Google Scholar 

  39. Kim D, Kim S, Koh H et al (2001) Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. FASEB J 15(11):1953–1962

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This research was supported by the Grant from National Natural Sciences Foundation of China (No. 30972921). The authors give thanks to Meifang Dai in KangChen Bio-tech Inc for her help in microarray experiment performs.

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The authors declare that they have no conflict of interest.

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Correspondence to Qi Zhu.

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Chao Xu and Duan-min Hu contributed equally to this study.

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Xu, C., Hu, Dm. & Zhu, Q. eEF1A2 promotes cell migration, invasion and metastasis in pancreatic cancer by upregulating MMP-9 expression through Akt activation. Clin Exp Metastasis 30, 933–944 (2013). https://doi.org/10.1007/s10585-013-9593-6

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  • DOI: https://doi.org/10.1007/s10585-013-9593-6

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