Abstract
Integrin-linked kinase (ILK) is a key molecule involved in mediating several biological functions including cell-matrix interactions, angiogenesis, and invasion, as well as playing a role in epithelial to mesenchymal transition (EMT) in cancer cells. In ductal pancreatic adenocarcinoma, increased expression of ILK has been linked to tumor prognosis and correlated with increased chemoresistance to drugs, such as gemcitabine. However, the precise relationship between ILK, Snail, E-cadherin, and N-cadherin expression on the stepwise development of pancreatic cancer is unknown. Hence, the purpose of this work was to investigate levels of expression of ILK, Snail, and the cadherins in pancreatic intraepithelial neoplasia (PanIN), and cancer. Resection specimens of 25 randomly selected patients, who underwent a pyloric preserving pancreatoduodenectomy for ductal pancreatic adenocarcinoma, were utilized for this study. Formalin-fixed paraffin embedded pancreatic tissue was immunostained for ILK, E-cadherin, N-cadherin, and Snail by standard techniques. The extent of staining positivity was scored and the results correlated with clinicopathological parameters. In 23 of 25 cases, ILK expression showed extensive positivity (>50%), while two cases did not demonstrate any ILK staining. PanIN grades 1 (n = 16), 2 (n = 11), and 3 (n = 19) lesions demonstrated only focal positivity (<10%) for ILK. E-cadherin showed a reciprocal staining pattern to ILK in 21 of 25 cases, with only focal expression of the marker in pancreatic adenocarcinoma. Interestingly, 15 of 19 PanIN-3 lesions expressed extensive E-cadherin staining. N-cadherin, however, was moderately expressed in the majority of cases (n = 18). Snail expression (n = 22) correlated with ILK expression in ductal pancreatic adenocarcinoma (ρ = 0.8168, p = 0.02), but only minimal Snail staining activity was detected in PanIN lesions. The increase in expression of the E-cadherin repressor Snail, as well as the related increase in the ILK expression, may point towards an ILK-mediated induction, opening possible avenues for targeted drug therapy.
Similar content being viewed by others
References
Li D, Xie K, Wolff R et al (2004) Pancreatic cancer. Lancet 363:1049–1057
Chua YJ, Cunningham D (2005) Adjuvant treatment for resectable pancreatic cancer. J Clin Oncol 23:4532–4537
Giancotti FG, Ruoslahti E (1999) Integrin signaling. Science 285:1028–1032
Vogelmann R, Kreuser ED, Adler G et al (1999) Integrin alpha6beta1 role in metastatic behavior of human pancreatic carcinoma cells. Int J Cancer 80:791–795
Sawai H, Funahashi H, Matsuo Y et al (2003) Expression and prognostic roles of integrins and interleukin-1 receptor type I in patients with ductal adenocarcinoma of the pancreas. Dig Dis Sci 48:1241–1250
Mayoral R, Fernández-Martínez A, Boscá L et al (2005) Prostaglandin E2 promotes migration and adhesion in hepatocellular carcinoma cells. Carcinogenesis 26:753–761
Menendez JA, Vellon L, Mehmi I et al (2005) A novel CYR61-triggered ‘CYR61-alphavbeta3 integrin loop’ regulates breast cancer cell survival and chemosensitivity through activation of ERK1/ERK2 MAPK signaling pathway. Oncogene 24:761–779
Hannigan G, Troussard AA, Dedhar S (2005) Integrin-linked kinase: a cancer therapeutic target unique among its ILK. Nat Rev Cancer 5:51–63
Delcommenne M, Tan C, Gray V et al (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
Chen P, Shen WZ, Karnik P (2004) Suppression of malignant growth of human breast cancer cells by ectopic expression of integrin-linked kinase. Int J Cancer 111:881–891
Edwards LA, Thiessen B, Dragowska WH et al (2005) Inhibition of ILK in PTEN-mutant human glioblastomas inhibits PKB/Akt activation, induces apoptosis, and delays tumor growth. Oncogene 24:3596–3605
Filipenko NR, Attwell S, Roskelley C et al (2005) Integrin-linked kinase activity regulates Rac- and Cdc42-mediated actin cytoskeleton reorganization via alpha-PIX. Oncogene 24:5837–5849
Tan C, Cruet-Hennequart S, Troussard A et al (2004) Regulation of tumor angiogenesis by integrin-linked kinase (ILK). Cancer Cell 5:79–90
Janji B, Melchior C, Vallar L et al (2000) Cloning of an isoform of integrin-linked kinase (ILK) that is upregulated in HT-144 melanoma cells following TGF-beta1 stimulation. Oncogene 19:3069–3077
Wu C, Keightley SY, Leung-Hagesteijn C et al (1998) Integrin-linked protein kinase regulates fibronectin matrix assembly, E-cadherin expression, and tumorigenicity. J Biol Chem 273:528–536
Novak A, Hsu SC, Leung-Hagesteijn C et al (1998) Cell adhesion and the integrin-linked kinase regulate the LEF-1 and beta-catenin signaling pathways. Proc Natl Acad Sci USA 95:4374–4379
Janji B, Melchior C, Gouon V et al (1999) Autocrine TGF-beta-regulated expression of adhesion receptors and integrin-linked kinase in HT-144 melanoma cells correlates with their metastatic phenotype. Int J Cancer 83:255–262
Assi K, Mills J, Owen D et al (2008) ILK regulates cell proliferation and tumor growth in murine colitis associated carcinogenesis. Gut 57:931–940
Sawai H, Okada Y, Funahashi H et al (2006) Integrin-linked kinase activity is associated with interleukin-1 alpha-induced progressive behavior of pancreatic cancer and poor patient survival. Oncogene 25:3237–3246
Dai DL, Makretsov N, Campos EI et al (2003) Increased expression of integrin-linked kinase is correlated with melanoma progression and poor patient survival. Clin Cancer Res 9:4409–4414
Ahmed N, Oliva K, Rice GE et al (2004) Cell-free 59 kDa immunoreactive integrin-linked kinase: a novel marker for ovarian carcinoma. Clin Cancer Res 10:2415–2420
Duxbury MS, Ito H, Benoit E et al (2005) RNA interference demonstrates a novel role for integrin-linked kinase as a determinant of pancreatic adenocarcinoma cell gemcitabine chemoresistance. Clin Cancer Res 11:3433–3438
Birchmeier C, Birchmeier W, Brand-Saberi B (1996) Epithelial-mesenchymal transitions in cancer progression. Acta Anat (Basel) 156:217–226
Birchmeier W, Behrens J, Weidner KM et al (1996) Epithelial differentiation and the control of metastasis in carcinomas. Curr Top Microbiol Immunol 213:117–135
Batlle E, Sancho E, Francí C et al (2000) The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2:84–89
Tan C, Costello P, Sanghera J et al (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 20:133–140
Bates RC, Pursell BM, Mercurio AM (2007) Epithelial-mesenchymal transition and colorectal cancer: gaining insights into tumor progression using LIM 1863 cells. Cells Tissues Organs 185:29–39
Cheng GZ, Chan J, Wang Q et al (2007) Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res 67:1979–1987
Vasko V, Espinosa AV, Scouten W et al (2007) Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion. Proc Natl Acad Sci USA 104:2803–2808
Yang MH, Chang SY, Chiou SH et al (2007) Overexpression of NBS1 induces epithelial-mesenchymal transition and co-expression of NBS1 and Snail predicts metastasis of head and neck cancer. Oncogene 26:1459–1467
Nakajima S, Doi R, Toyoda E et al (2004) N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma. Clin Cancer Res 10:4125–4133
Javle MM, Gibbs JF, Iwata KK et al (2007) Epithelial-mesenchymal transition (EMT) and activated extracellular signal-regulated kinase (p-Erk) in surgically resected pancreatic cancer. Ann Surg Oncol 14:3527–3533
Conflicts of interest statement
We declare that we have no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
This paper was originally presented as a poster at the 97th Annual Meeting of the US and Canadian Academy of Pathology, March 1–7, 2008, Denver, Colorado.
Rights and permissions
About this article
Cite this article
Schaeffer, D.F., Assi, K., Chan, K. et al. Tumor expression of Integrin-linked kinase (ILK) correlates with the expression of the E-cadherin repressor Snail: an immunohistochemical study in ductal pancreatic adenocarcinoma. Virchows Arch 456, 261–268 (2010). https://doi.org/10.1007/s00428-009-0866-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00428-009-0866-z