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Overexpression of integrin-linked kinase (ILK) promotes glioma cell invasion and migration and down-regulates E-cadherin via the NF-κB pathway

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Abstract

Integrin-linked kinase (ILK) is a ubiquitously expressed serine/threonine protein kinase that has been implicated in cancer development, progression and metastasis. The aim of the present study was to characterize the role of ILK in glioma cell invasion and migration. We generated a recombinant eukaryotic expression vector containing the human ILK gene and transfected it into human glioma SHG-44 cells. Real-time PCR and western blot analysis were used to identify the stable transformants. The wound healing and Transwell invasion assays showed that ectopic overexpression of ILK in SHG-44 cells significantly promoted their migration and invasion capabilities in culture. This was accompanied by a decrease in expression of E-cadherin and an increase in expression of Snail and Slug. Moreover, the decrease in E-cadherin expression induced by ILK overexpression was greatly restored by the nuclear factor-κB (NF-κB) inhibitor BAY 11-7028 or small interfering RNA targeting NF-κB p65, indicating an involvement of NF-κB in ILK-induced down-regulation of E-cadherin. In conclusion, our data underscore a novel role for ILK in glioma invasion and metastasis processes, implicating potential for therapeutic interference.

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References

  • Chan J, Ko FC, Yeung YS, Ng IO, Yam JW (2011) Integrin-linked kinase overexpression and its oncogenic role in promoting tumorigenicity of hepatocellular carcinoma. PLoS ONE 6(2):e16984. doi:10.1371/journal.pone.0016984

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen D, Zhang Y, Zhang X, Li J, Han B, Liu S, Wang L, Ling Y, Mao S, Wang X (2013) Overexpression of integrin-linked kinase correlates with malignant phenotype in non-small cell lung cancer and promotes lung cancer cell invasion and migration via regulating epithelial-mesenchymal transition (EMT)-related genes. Acta Histochem 115(2):128–136. doi:10.1016/j.acthis.2012.05.004

    Article  CAS  PubMed  Google Scholar 

  • Dai DL, Makretsov N, Campos EI, Huang C, Zhou Y, Huntsman D, Martinka M, Li G (2003) Increased expression of integrin-linked kinase is correlated with melanoma progression and poor patient survival. Clin Cancer Res 9(12):4409–4414

    CAS  PubMed  Google Scholar 

  • DeAngelis LM (2001) Brain tumors. N Engl J Med 344(2):114–123. doi:10.1056/NEJM200101113440207

    Article  CAS  PubMed  Google Scholar 

  • Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S (1998) Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci USA 95(19):11211–11216

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gao J, Zhu J, Li HY, Pan XY, Jiang R, Chen JX (2011) Small interfering RNA targeting integrin-linked kinase inhibited the growth and induced apoptosis in human bladder cancer cells. Int J Biochem Cell Biol 43(9):1294–1304. doi:10.1016/j.biocel.2011.05.003

    Article  CAS  PubMed  Google Scholar 

  • Giese A, Bjerkvig R, Berens ME, Westphal M (2003) Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol 21(8):1624–1636. doi:10.1200/JCO.2003.05.063

    Article  CAS  PubMed  Google Scholar 

  • Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L, Coppolino MG, Radeva G, Filmus J, Bell JC, Dedhar S (1996) Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase. Nature 379(6560):91–96. doi:10.1038/379091a0

    Article  CAS  PubMed  Google Scholar 

  • Hannigan G, Troussard AA, Dedhar S (2005) Integrin-linked kinase: a cancer therapeutic target unique among its ILK. Nat Rev Cancer 5(1):51–63. doi:10.1038/nrc1524

    Article  CAS  PubMed  Google Scholar 

  • Koul D, Shen R, Bergh S, Lu Y, de Groot JF, Liu TJ, Mills GB, Yung WK (2005) Targeting integrin-linked kinase inhibits Akt signaling pathways and decreases tumor progression of human glioblastoma. Mol Cancer Ther 4(11):1681–1688. doi:10.1158/1535-7163.MCT-05-0258

    Article  CAS  PubMed  Google Scholar 

  • Li J, Zhang H, Wu J, Guan H, Yuan J, Huang Z, Li M (2010) Prognostic significance of integrin-linked kinase1 overexpression in astrocytoma. Int J Cancer 126(6):1436–1444. doi:10.1002/ijc.24824

    CAS  PubMed  Google Scholar 

  • Li J, Yang ZL, Ren X, Zou Q, Yuan Y, Liang L, Chen M, Chen S (2013a) ILK and PRDX1 are prognostic markers in squamous cell/adenosquamous carcinomas and adenocarcinoma of gallbladder. Tumour Biol 34(1):359–368. doi:10.1007/s13277-012-0557-2

    Article  CAS  PubMed  Google Scholar 

  • Li R, Liu B, Yin H, Sun W, Yin J, Su Q (2013b) Overexpression of integrin-linked kinase (ILK) is associated with tumor progression and an unfavorable prognosis in patients with colorectal cancer. J Mol Histol 44(2):183–189. doi:10.1007/s10735-012-9463-6

    Article  CAS  PubMed  Google Scholar 

  • Liu Q, Xiao L, Yuan D, Shi X, Li P (2012) Silencing of the integrin-linked kinase gene induces the apoptosis in ovarian carcinoma. J Recept Signal Transduct Res 32(2):120–127. doi:10.3109/10799893.2012.660534

    Article  CAS  PubMed  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402–408. doi:10.1006/meth.2001.1262

    Article  CAS  PubMed  Google Scholar 

  • McDonald PC, Fielding AB, Dedhar S (2008) Integrin-linked kinase–essential roles in physiology and cancer biology. J Cell Sci 121(Pt 19):3121–3132. doi:10.1242/jcs.017996

    Article  CAS  PubMed  Google Scholar 

  • McPhee TR, McDonald PC, Oloumi A, Dedhar S (2008) Integrin-linked kinase regulates E-cadherin expression through PARP-1. Dev Dyn 237(10):2737–2747. doi:10.1002/dvdy.21685

    Article  CAS  PubMed  Google Scholar 

  • Min C, Eddy SF, Sherr DH, Sonenshein GE (2008) NF-kappaB and epithelial to mesenchymal transition of cancer. J Cell Biochem 104(3):733–744. doi:10.1002/jcb.21695

    Article  CAS  PubMed  Google Scholar 

  • Nakada M, Nakada S, Demuth T, Tran NL, Hoelzinger DB, Berens ME (2007) Molecular targets of glioma invasion. Cell Mol Life Sci 64(4):458–478. doi:10.1007/s00018-007-6342-5

    Article  CAS  PubMed  Google Scholar 

  • Oloumi A, McPhee T, Dedhar S (2004) Regulation of E-cadherin expression and beta-catenin/Tcf transcriptional activity by the integrin-linked kinase. Biochim Biophys Acta 1691(1):1–15. doi:10.1016/j.bbamcr.2003.12.002

    Article  CAS  PubMed  Google Scholar 

  • Sawai H, Okada Y, Funahashi H, Matsuo Y, Takahashi H, Takeyama H, Manabe T (2006) Integrin-linked kinase activity is associated with interleukin-1 alpha-induced progressive behavior of pancreatic cancer and poor patient survival. Oncogene 25(23):3237–3246. doi:10.1038/sj.onc.1209356

    Article  CAS  PubMed  Google Scholar 

  • Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10(5):459–466. doi:10.1016/S1470-2045(09)70025-7

    Article  CAS  PubMed  Google Scholar 

  • Talbot LJ, Bhattacharya SD, Kuo PC (2012) Epithelial-mesenchymal transition, the tumor microenvironment, and metastatic behavior of epithelial malignancies. Int J Biochem Mol Biol 3(2):117–136

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tan C, Costello P, Sanghera J, Dominguez D, Baulida J, de Herreros AG, Dedhar S (2001) Inhibition of integrin linked kinase (ILK) suppresses beta-catenin-Lef/Tcf-dependent transcription and expression of the E-cadherin repressor, snail, in APC −/− human colon carcinoma cells. Oncogene 20(1):133–140. doi:10.1038/sj.onc.1204052

    Article  CAS  PubMed  Google Scholar 

  • Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY, Olson JJ (2010) Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 60(3):166–193. doi:10.3322/caac.20069

    Article  PubMed Central  PubMed  Google Scholar 

  • van Roy F, Berx G (2008) The cell–cell adhesion molecule E-cadherin. Cell Mol Life Sci 65(23):3756–3788. doi:10.1007/s00018-008-8281-1

    Article  CAS  PubMed  Google Scholar 

  • Wani AA, Jafarnejad SM, Zhou J, Li G (2011) Integrin-linked kinase regulates melanoma angiogenesis by activating NF-kappaB/interleukin-6 signaling pathway. Oncogene 30(24):2778–2788. doi:10.1038/onc.2010.644

    Article  CAS  PubMed  Google Scholar 

  • Wijnhoven BP, Dinjens WN, Pignatelli M (2000) E-cadherin-catenin cell–cell adhesion complex and human cancer. Br J Surg 87(8):992–1005. doi:10.1046/j.1365-2168.2000.01513.x

    Article  CAS  PubMed  Google Scholar 

  • Wong RP, Ng P, Dedhar S, Li G (2007) The role of integrin-linked kinase in melanoma cell migration, invasion, and tumor growth. Mol Cancer Ther 6(6):1692–1700. doi:10.1158/1535-7163.MCT-07-0134

    Article  CAS  PubMed  Google Scholar 

  • Xing Y, Qi J, Deng S, Wang C, Zhang L, Chen J (2013) Small interfering RNA targeting ILK inhibits metastasis in human tongue cancer cells through repression of epithelial-to-mesenchymal transition. Exp Cell Res 319(13):2058–2072. doi:10.1016/j.yexcr.2013.05.014

    Article  CAS  PubMed  Google Scholar 

  • Yang L, Liu M, Deng C, Gu Z, Gao Y (2012) Expression of transforming growth factor-beta1 (TGF-beta1) and E-cadherin in glioma. Tumour Biol 33(5):1477–1484. doi:10.1007/s13277-012-0398-z

    Article  CAS  PubMed  Google Scholar 

  • Yu J, Shi R, Zhang D, Wang E, Qiu X (2011) Expression of integrin-linked kinase in lung squamous cell carcinoma and adenocarcinoma: correlation with E-cadherin expression, tumor microvessel density and clinical outcome. Virchows Arch 458(1):99–107. doi:10.1007/s00428-010-1016-3

    Article  CAS  PubMed  Google Scholar 

  • Zhao G, Guo LL, Xu JY, Yang H, Huang MX, Xiao G (2011) Integrin-linked kinase in gastric cancer cell attachment, invasion and tumor growth. World J Gastroenterol 17(30):3487–3496. doi:10.3748/wjg.v17.i30.3487

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhao D, Tang XF, Yang K, Liu JY, Ma XR (2012) Over-expression of integrin-linked kinase correlates with aberrant expression of Snail, E-cadherin and N-cadherin in oral squamous cell carcinoma: implications in tumor progression and metastasis. Clin Exp Metastasis 29(8):957–969. doi:10.1007/s10585-012-9485-1

    Article  CAS  PubMed  Google Scholar 

  • Zhao M, Gao Y, Wang L, Liu S, Han B, Ma L, Ling Y, Mao S, Wang X (2013) Overexpression of integrin-linked kinase promotes lung cancer cell migration and invasion via NF-kappaB-mediated upregulation of matrix metalloproteinase-9. Int J Med Sci 10(8):995–1002. doi:10.7150/ijms.5963

    Article  PubMed Central  PubMed  Google Scholar 

  • Zhu J, Pan X, Zhang Z, Gao J, Zhang L, Chen J (2012) Downregulation of integrin-linked kinase inhibits epithelial-to-mesenchymal transition and metastasis in bladder cancer cells. Cell Signal 24(6):1323–1332

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by a grant from the Science and Technology Startup Foundation of The First Affiliated Hospital of Liaoning Medical University (Grant No.: FYK201214).

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Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, Liaoning, People’s Republic of China

    Feng Liang & Yunjie Wang

  2. Department of Neurosurgery, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, 121001, Liaoning, People’s Republic of China

    Feng Liang, Bing Wang & Jianwu Qiu

  3. Department of Pediatrics, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, 121001, Liaoning, People’s Republic of China

    Shuqin Zhang

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  1. Feng Liang
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Correspondence to Yunjie Wang.

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Liang, F., Zhang, S., Wang, B. et al. Overexpression of integrin-linked kinase (ILK) promotes glioma cell invasion and migration and down-regulates E-cadherin via the NF-κB pathway. J Mol Hist 45, 141–151 (2014). https://doi.org/10.1007/s10735-013-9540-5

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