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Collagen type I-induced Smad-interacting protein 1 expression downregulates E-cadherin in pancreatic cancer

Abstract

Pancreatic cancer is a devastating disease with poor prognosis. Production of large quantities of extracellular matrix and early metastasis are characteristics of this disease. One important step in the development of various cancers is the loss of E-cadherin gene expression or inactivation of E-cadherin mediated cell–cell adhesion. It has been shown that collagen type I promotes downregulation of E-cadherin expression, which correlates with enhanced cell migration and invasiveness. In this context, we elucidated the role of Smad-interacting protein 1 (SIP1), which has been discussed as a negative regulator of E-cadherin gene expression. We demonstrate that SIP1 upregulation shows an inverse relationship with E-cadherin in advanced pancreatic tumour stages. In Panc-1 cells, SIP1 expression can be induced by exposure to collagen type I in a src-dependent manner. In addition, overexpression of SIP1 reduces E-cadherin mRNA and protein levels. Taken together, these results suggest that SIP1 is involved in the progression of pancreatic cancer and plays a role in mediating signal transduction from collagen type I to downregulate E-cadherin expression.

Main

Highly invasive growth and early onset of metastasis are responsible for the poor prognosis of pancreatic adenocarcinoma. One major prognostic parameter for invasive growth and metastasis is the loss of E-cadherin-based cell–cell adhesion, which often correlates with downregulation of E-cadherin on the protein and/or the mRNA level (Birchmeier and Behrens, 1994). Moreover, re-expression of E-cadherin in E-cadherin-negative carcinoma cells leads to reversal to a well-differentiated, non-invasive phenotype (Frixen et al., 1991; Vleminckx et al., 1991; Seidel et al., 2004). In pancreatic cancer, loss of membranous E-cadherin localization is correlated with lymph node metastasis and advanced tumour stage (Pignatelli et al., 1994). Various processes can lead to E-cadherin downregulation, for example, mutations in the E-cadherin gene (reviewed by Berx et al., 1998), silencing of the E-cadherin promoter through hypermethylation (Yoshiura et al., 1995), alterations in chromatin structure or transcription factor binding (Hennig et al., 1995), as well as increased turnover and diminished stability of the protein induced by phosphorylation or alterations in the association with catenins (reviewed by D’Souza-Schorey, 2005). While genomic mutations in the E-cadherin locus seem to be rather rare events, there are various studies that report a correlation between upregulation of transcription factors like snail (Cano et al., 2000), slug (Hajra et al., 2002) or twist (Yang et al., 2004), which repress E-cadherin promoter activity, and decline of E-cadherin concentration. Recently, SIP1 (ZFHX1B/ZEB2), a Smad-interacting protein (Verschueren et al., 1999), has been reported to bind to E-boxes in the E-cadherin promoter, where it acts as a transcriptional repressor (Comijn et al., 2001). SIP1 is a member of the small Zfh-1 family of multi-zinc-finger transcription factors containing a homeodomain. SIP1 binds with two clusters of zinc-fingers simultaneously to two defined DNA target sites (Remacle et al., 1999). SIP1 was identified in a large-scale screen for cancer-related genes, implicating a putative role in oncogenic transformation (Mikkers et al., 2002).

We addressed the question if SIP1 promotes the progression of pancreatic cancer and specifically if it is involved in the loss of E-cadherin-mediated cell–cell adhesion. We performed quantitative reverse transcription–PCR (RT–PCR) analysis to investigate SIP1 and E-cadherin expression levels in normal pancreatic tissue and pancreatic cancer tissue. Samples consisted of snap-frozen material gained in curative resections in accordance with ethical guidelines. The results are shown in Figure 1a. The six normal tissue samples showed high E-cadherin levels and low levels of SIP1. In contrast, five out of 12 tumour samples showed at least twofold elevated SIP1 levels and low E-cadherin levels, whereas tumour samples exhibiting low SIP1 levels generally showed high E-cadherin mRNA levels. An inverse correlation between amounts of SIP1 and E-cadherin mRNAs was observed in 10 out of 12 tumour samples. Additionally, we performed quantitative RT–PCR with microdissected material from normal pancreatic tissue, pancreatic intraepithelial neoplasia (PanIN3) and pancreatic carcinoma. As shown in Figure 1b, progressing stages of pancreatic cancer correspond to increasing amounts of SIP1. These findings strongly suggest that SIP1 is involved in the downregulation of E-cadherin in pancreatic cancer.

Figure 1
figure1

An inverse correlation between SIP1 and E-cadherin mRNA levels is observed in pancreatic cancer samples. (a) SIP1 and E-cadherin mRNA levels were analysed by quantitative RT–PCR in tissue samples from normal pancreas (N) and from pancreatic cancer (P). One microgram of total RNA was mixed with random hexamer primers and reverse transcribed using superscript reverse transcriptase (InvitrogenTM Life Technologies, Karlsrube, Germany). Quantitative PCRs were carried out with the ABI Prism 7700 Sequence detection system (Applied Biosystems, Darmstadt, Germany) using gene-specific primers and SYBR Green PCR Master Mix. SIP1 and E-cadherin expression were normalized to RPLP0 expression. Values are given in relation to the mean of all six control samples. (b) Microdissected material from at least three samples of normal pancreatic tissue, pancreatic intraepithelial neoplasia (PanIN3) and pancreatic cancer was analysed by quantitative RT–PCR (Heidenblut et al., 2004). SIP1 and E-cadherin mRNA levels were normalized to cyclophilinA and values are given in relation to the mean of the expression levels in normal pancreatic tissue.

Pancreatic carcinomas produce high amounts of extracellular matrix (ECM) consisting mainly of fibronectin, collagen type I and collagen type V (Mollenhauer et al., 1987). The microenvironment influences cell differentiation and behaviour and is considered as an important factor in cancer progression (reviewed by Erickson and Barcellos-Hoff, 2003). Our group has previously shown that pancreatic carcinoma cell lines grown on collagen type I show reduced E-cadherin expression compared to cells grown on tissue culture plastic (TCP) (Menke et al., 2001). We addressed the question if SIP1 plays a role in the mechanism of collagen type I-induced E-cadherin downregulation. Therefore, we analysed SIP1 and E-cadherin expression in Panc-1 cells grown on TCP, collagen type I or fibronectin for 3 days (Figure 2). We observed that cells grown on TCP or fibronectin had low levels of SIP1 mRNA, whereas E-cadherin mRNA was abundant (Figure 2a). In contrast, cells grown on collagen type I showed an obvious increase in SIP1 mRNA levels and a correspondingly lower concentration of E-cadherin mRNA. To investigate whether the observed increase of SIP1 and decrease of E-cadherin mRNA concentrations in cells grown on collagen type I resulted in altered protein concentrations, we analysed SIP1 and E-cadherin protein concentrations by Western blotting (Figure 2b). Cells grown on collagen type I exhibit a marked increase in SIP1 protein concentration in comparison to cells grown on TCP (Figure 2b, left panel). Conversely, E-cadherin protein concentrations are markedly decreased in cells grown on collagen type I compared to cells grown on TCP. Thus, we can demonstrate an inverse correlation between SIP1 and E-cadherin concentrations on the mRNA and protein levels in Panc-1 cells depending on the cell environment. We observed no changes in the mRNA levels of other transcription factors that have been reported to be able to downregulate E-cadherin in Panc-1 cells grown on TCP, collagen I or fibronectin. Figure 2c shows a representative RT–PCR experiment detecting snail, slug and twist. Densitometry analysis of at least three individual semiquantitative RT–PCRs confirmed that SIP1, but not snail, slug or twist, is upregulated in Panc-1 cells grown on collagen type I (Figure 2d).

Figure 2
figure2

(a) SIP1 mRNA is increased in cells grown on collagen type I. RT–PCR analysis was performed using RNA isolated from Panc-1 cells grown on TCP, collagen type I or fibronectin. Gene-specific primers were used for detection of SIP1 (top) or E-cadherin (middle). PCRs for β-actin (bottom) document the use of equal amounts of complementary DNA in each reaction. RNA was extracted from cells grown to confluence, using the RNeasy kit (Qiagen, Hilden, Germany). One microgram of RNA was reverse transcribed with superscript reverse transcriptase (InvitrogenTM Life Technologies). Complementary DNA corresponding to 20 ng RNA was used in each PCR reaction. (b) SIP1 protein concentration is enhanced in cells grown on collagen type I. Detection of SIP1 by immunoprecipitation (left) and E-cadherin by Western blotting (right) using lysates of Panc-1 cells grown on TCP or collagen type I: the amount of immunoprecipitated SIP1 using 1 mg of Panc-1 cell lysate with 5 μl SIP1 antibody (sc-18392, Santa Cruz, Heidelberg, Germany) was analysed by Western blotting. In parallel, aliquots of the lysates corresponding to 30 μg protein were analysed for E-cadherin and β-actin protein levels by Western blotting. (c) Snail, slug and twist mRNA levels are not influenced by collagen type I. RT–PCRs were performed as described in (a). PCRs using 5 ng of the appropriate plasmid were included as positive control. (d) Densitometric analysis of the data shown in (a) and (c) with Image Quant software (Molecular Dynamics, Krefeld, Germany). Relative values of SIP1 and E-cadherin mRNA concentrations (in relation to actin and normalized to cells grown on TCP) are shown for 3–5 individual experiments.

As it has been described that SIP1 downregulates the activity of the E-cadherin promoter in epithelial cells such as breast carcinoma cell lines (Comijn et al., 2001), we performed luciferase reporter assays in pancreatic carcinoma cells transfected with pGL3-Ecad178, a fragment of the E-cadherin promoter containing the SIP1-binding sequences (Remacle et al., 1999). SIP1 quenched the basal activity of the E-cadherin reporter construct in a dose-dependent manner (Figure 3a). To investigate if the observed downregulation of E-cadherin promoter activity leads to reduction of E-cadherin protein levels, we analysed E-cadherin protein concentrations in pEGFP- or pEGFP-SIP1-transfected Panc-1 cells. Forced EGFP-SIP1 expression in Panc-1 cells resulted in a marked decrease in E-cadherin protein levels as shown in Figure 3b. We obtained similar results with another pancreatic cell line, PaTu8902 (data not shown).

Figure 3
figure3

SIP1 diminishes the activity of an E-cadherin-luciferase reporter construct and leads to reduced E-cadherin levels. (a) Influence of SIP1 expression on murine E-cadherin promoter activity was demonstrated with luciferase reporter assays (Promega, Mannheim, Germany) in Panc-1 cells transfected with pGL3-Ecad178 and increasing amounts of an SIP1 expression construct. Means and ranges of one representative assay performed in duplicate out of three are shown. Panc-1 cells were transfected with 0.5 μg pGL3-Ecad178 and up to 0.5 μg SIP1-EGFP or pcDNA3.1 in 12-well plates. All transfections were normalized to Renilla luciferase activity by co-transfection of 50 ng of pRLTK (Promega, Mannheim, Germany). (b) E-cadherin protein levels were analysed by Western blotting using lysates of Panc-1 cells transfected with EGFP-SIP1. Left lane: mock-transfected cells; right lane: EGFP-SIP1-transfected cells. Top panel: probing with anti-E-cadherin antibody (610181, BD Pharmingen, Heidelberg, Germany); middle panel: probing with anti-GFP antibody (1814460, Roche, Mannheim, Germany) to demonstrate efficient transfection; bottom panel: the membrane was reprobed with anti-β-actin antibody (A5441, Sigma, Taufkirchen, Germany) to demonstrate equal amounts of protein in each lane.

We have reported before that E-cadherin downregulation induced by collagen type I in pancreatic cancer cells depends on src kinase activity (Menke et al., 2001). The non-receptor tyrosine kinase src is discussed as a mediator of ECM-derived signalling (reviewed by Avizienyte and Frame, 2005). Therefore, we asked if src activity may be necessary for collagen type I/SIP1 regulation of E-cadherin expression. To test this hypothesis, we incubated Panc-1 cells grown on collagen type I with 0.5 or 1 μ M of the src inhibitor SU6656 (Blake et al., 2000) for 24 h. Figure 4a and b show that treatment of cells with 0.5 μ M SU6656 diminished and treatment with 1 μ M SU6656 completely abolished the increase in SIP1 mRNA in response to collagen type I. To test if the collagen I-induced endogenous SIP1 influenced E-cadherin gene expression, we performed luciferase reporter assays from cells grown on TCP or collagen I with and without src inhibitor (Figure 4c). Apparently, the E-cadherin reporter construct is less active in cells grown on collagen type I than in cells grown on TCP. Addition of the src inhibitor SU6656 restores the activity of the E-cadherin reporter construct in cells grown on collagen type I in a dose-dependent manner.

Figure 4
figure4

Elevation of SIP1 mRNA levels in cells grown on collagen type I depends on src kinase activity. (a) RT–PCR analysis was performed to detect levels of SIP1 mRNA in Panc-1 cells grown on collagen type I and treated without or with 1 or 0.5 μ M of the src inhibitor SU6656 (Alexis Corp., Axxora, Gru"nberg, Germany) for 24 h. (b) Graphical representation of densitometrically evaluated RT–PCR results. Relative intensity of PCR signals compared to actin is shown in x-fold of cells grown on collagen type I treated with solvent. One representative experiment out of two independent experiments is shown. (c) Cells grown on TCP or collagen type I were transfected with 1 μg pGL3-Ecad178 and 100 ng pRLTK in 12-well plates. Treatment with 0.5 or 1 μ M SU6656 started 16 h before transfection. Relative luciferase activity is shown as x-fold luciferase activity of cells grown on TCP and transfected with pGL3-Ecad178. Means and standard deviations of three individual experiments performed in duplicate are shown.

Consistent with our findings that SIP1 mRNA is upregulated in pancreatic cancer samples, elevated levels of SIP1 have been shown in other cancers like intestinal type gastric cancer (Rosivatz et al., 2002) and oral squamous cell carcinoma (Maeda et al., 2005). Although SIP1 can bind to the E-boxes of the E-cadherin promoter, which has been suggested to downregulate E-cadherin, it has been observed that SIP1 overexpression does not always correlate with E-cadherin downregulation. Similar findings were observed for other transcription factors, for example, snail and slug, which like SIP1 are able to downregulate E-cadherin promoter activity (Batlle et al., 2000; Hajra et al., 2002; Rosivatz et al., 2002). These data mirror the complexity of E-cadherin regulation. The inconsistent effect of the presence of SIP1 on E-cadherin expression levels in different tumours may also be explained by the presence or absence of cofactors in these tumours. For instance, it has been shown that sumoylation of SIP1 by Pc2, although not affecting the half-life or the nuclear localization of the protein, has a negative effect on its ability to repress the activity of the E-cadherin promoter (Long et al., 2005). Postigo et al. (2003) have suggested that repression of Smad-mediated transcription by SIP1 depends on binding of the C-terminal binding protein (CtBP) to SIP1, leading to recruitment of this corepressor to the Smad complex. Indeed, SIP1 represses Smad-mediated transcription, whereas its close family member δEF1 synergizes with Smad-mediated transcription. In the case of δEF1, binding of the acetyltransferase P/CAF leads to acetylation of several lysine residues of δEF1, resulting in displacement of CtBP, whereas SIP1 is unable to interact with P/CAF (Postigo et al., 2003). On the other hand, it has been shown that SIP1 does not need to be associated with CtBP for repression of the E-cadherin promoter, as a SIP1 mutant that cannot bind CtBP reduced E-cadherin promoter activity as efficiently as wild-type SIP1 (Van Grunsven et al., 2003). Still, it cannot be excluded that there are other yet unidentified SIP1 binding partners that are necessary to induce E-cadherin transcriptional repression. Our data show that SIP1 is able to repress the transcription of E-cadherin in pancreatic epithelial cells and they suggest that the downregulation of E-cadherin expression in pancreatic carcinoma cells grown on collagen type I is mediated by SIP1 upregulation and subsequent downregulation of E-cadherin promoter activity. This view is supported by the findings in Sip1 knockout mouse embryos, which show upregulation of E-cadherin in tissues where Sip1 is usually expressed, such as the neuroepithelium and the neural tube (Van de Putte et al., 2003). There is also evidence that SIP1 might affect various aspects of cancer progression. Data from Sip1 knockout mice demonstrate that Sip1 is necessary for the migratory capacities of cranial neural crest cells (Van de Putte et al., 2003). Moreover, SIP1 promotes the expression of matrix metalloproteinases MMP-1, MMP-2 and MT1-MMP in hepatocellular carcinoma cell lines (Miyoshi et al., 2004).

In summary, we suggest that SIP1 may contribute to the high migratory activity of pancreatic cancer cells by downregulation of E-cadherin. Pancreatic carcinomas have an unusually high metastatic potential, and SIP1 expression is elevated in a substantial number of cancer samples tested. E-cadherin downregulation, as a prerequisite for migratory activity, would be the first step in the development of an invasive metastatic phenotype.

References

  1. Avizienyte E, Frame MC . (2005). Src and FAK signalling controls adhesion fate and the epithelial-to-mesenchymal transition. Curr Opin Cell Biol 17: 542–547.

    CAS  Article  Google Scholar 

  2. Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J 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.

    CAS  Article  Google Scholar 

  3. Berx G, Becker KF, Höfler H, van Roy F . (1998). Mutations of the human E-cadherin (CDH1) gene. Hum Mutat 12: 226–237.

    CAS  Article  Google Scholar 

  4. Birchmeier W, Behrens J . (1994). Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta 1198: 11–26.

    CAS  PubMed  Google Scholar 

  5. Blake RA, Broome MA, Liu X, Wu J, Gishizky M, Sun L et al. (2000). SU6656, a selective src family kinase inhibitor, used to probe growth factor signaling. Mol Cell Biol 20: 9018–9027.

    CAS  Article  Google Scholar 

  6. Cano A, Perez-Moreno M, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG et al. (2000). The transcription factor snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2: 76–83.

    CAS  Article  Google Scholar 

  7. Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E et al. (2001). The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell 7: 1267–1278.

    CAS  Article  Google Scholar 

  8. D’Souza-Schorey C . (2005). Disassembling adherens junctions: breaking up is hard to do. Trends Cell Biol 15: 19–26.

    Article  Google Scholar 

  9. Erickson AC, Barcellos-Hoff MH . (2003). The not-so innocent bystander: the microenvironment as a therapeutic target in cancer. Expert Opin Ther Targets 7: 71–88.

    CAS  Article  Google Scholar 

  10. Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A et al. (1991). E-cadherin-mediated cell–cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 113: 173–185.

    CAS  Article  Google Scholar 

  11. Hajra KM, Chen DYS, Fearon ER . (2002). The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res 62: 1613–1618.

    CAS  PubMed  Google Scholar 

  12. Heidenblut AM, Lüttges J, Buchholz M, Heinitz C, Emmersen J, Nielsen KL et al. (2004). aRNA-longSAGE: a new approach to generate SAGE libraries from microdissected cells. Nucleic Acids Res 32: e131.

    Article  Google Scholar 

  13. Hennig G, Behrens J, Truss M, Frisch S, Reichmann E, Birchmeier W . (1995). Progression of carcinoma cells is associated with alterations in chromatin structure and factor binding at the E-cadherin promoter in vivo. Oncogene 11: 475–484.

    CAS  PubMed  Google Scholar 

  14. Long J, Zuo D, Park M . (2005). Pc2-mediated sumoylation of Smad-interacting protein 1 attenuates transcriptional repression of E-cadherin. J Biol Chem 280: 35477–35489.

    CAS  Article  Google Scholar 

  15. Maeda G, Chiba T, Okazaki M, Satoh T, Taya Y, Aoba T et al. (2005). Expression of SIP1 in oral squamous cell carcinomas: implications for E-cadherin expression and tumor progression. Int J Oncol 27: 1535–1541.

    CAS  PubMed  Google Scholar 

  16. Menke A, Philippi C, Vogelmann R, Seidel B, Lutz MP, Adler G et al. (2001). Down-regulation of E-cadherin gene expression by collagen type I and type III in pancreatic cancer cell lines. Cancer Res 61: 3508–3517.

    CAS  PubMed  Google Scholar 

  17. Mikkers H, Allen J, Knipscheer P, Romeijn L, Hart A, Vink E et al. (2002). High-throughput retroviral tagging to identify components of specific signaling pathways in cancer. Nat Genet 32: 153–159.

    CAS  Article  Google Scholar 

  18. Miyoshi A, Kitajima Y, Sumi K, Sato K, Hagiwara A, Koga Y et al. (2004). Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma. Br J Cancer 90: 1265–1273.

    CAS  Article  Google Scholar 

  19. Mollenhauer J, Roether I, Kern HF . (1987). Distribution of extracellular matrix proteins in pancreatic ductal adenocarcinoma and its influence on tumor cell proliferation in vitro. Pancreas 2: 14–24.

    CAS  Article  Google Scholar 

  20. Pignatelli M, Ansari TW, Gunter P, Liu D, Hirano S, Takeichi M et al. (1994). Loss of membranous E-cadherin expression in pancreatic cancer: correlation with lymph node metastasis, high grade, and advanced stage. J Pathol 174: 243–248.

    CAS  Article  Google Scholar 

  21. Postigo AA, Depp JL, Taylor JJ, Kroll KL . (2003). Regulation of Smad signaling through a differential recruitment of coactivators and corepressors by ZEB proteins. EMBO J 22: 2453–2462.

    CAS  Article  Google Scholar 

  22. Remacle JE, Kraft H, Lerchner W, Wuytens G, Colart C, Verschueren K et al. (1999). New mode of DNA binding of multi-zinc finger transcription factors: deltaEF1 family members bind with two hands to two target sites. EMBO J 18: 5073–5084.

    CAS  Article  Google Scholar 

  23. Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R et al. (2002). Differential expression of the epithelial–mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am J Pathol 161: 1881–1891.

    CAS  Article  Google Scholar 

  24. Seidel B, Braeg S, Adler G, Wedlich D, Menke A . (2004). E- and N-cadherin differ with respect to their associated p120ctn isoforms and their ability to suppress invasive growth in pancreatic cancer cells. Oncogene 23: 5532–5542.

    CAS  Article  Google Scholar 

  25. Van de Putte T, Maruhashi M, Francis A, Nelles L, Kondoh H, Huylebroeck D et al. (2003). Mice lacking ZFHX1B, the gene that codes for Smad-interacting protein-1, reveal a role for multiple neural crest cell defects in the etiology of Hirschsprung disease–mental retardation syndrome. Am J Hum Genet 72: 465–470.

    CAS  Article  Google Scholar 

  26. Van Grunsven LA, Michiels C, Van de Putte T, Nelles L, Wuytens G, Verschueren K et al. (2003). Interaction between Smad-interacting protein-1 and the corepressor C-terminal binding protein is dispensable for transcriptional repression of E-cadherin. J Biol Chem 278: 26135–26145.

    CAS  Article  Google Scholar 

  27. Verschueren K, Remacle JE, Collart C, Kraft H, Baker BS, Tylzanowski P et al. (1999). SIP1, a novel zinc finger/homeodomain repressor, interacts with Smad proteins and binds to 5′-CACCT sequences in candidate target genes. J Biol Chem 274: 20489–20498.

    CAS  Article  Google Scholar 

  28. Vleminckx K, Vakaet Jr L, Mareel M, Fiers W, van Roy F . (1991). Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66: 107–119.

    CAS  Article  Google Scholar 

  29. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C et al. (2004). Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117: 927–939.

    CAS  Article  Google Scholar 

  30. Yoshiura K, Kanai Y, Ochiai A, Shimoyama Y, Sugimura T, Hirohashi S . (1995). Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. Proc Natl Acad Sci USA 92: 7416–7419.

    CAS  Article  Google Scholar 

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Acknowledgements

We thank Dr Walter Birchmeier (MDC, Berlin, Germany) for the gift of the pCat-Ecad178 plasmid. This work was funded by the DFG, SFB 518.

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Correspondence to Y Imamichi.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Imamichi, Y., König, A., Gress, T. et al. Collagen type I-induced Smad-interacting protein 1 expression downregulates E-cadherin in pancreatic cancer. Oncogene 26, 2381–2385 (2007). https://doi.org/10.1038/sj.onc.1210012

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Keywords

  • pancreatic cancer
  • Smad-interacting protein 1 (SIP1)
  • extracellular matrix (ECM)
  • E-cadherin

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