Abstract
SNAI1, ZEB1, E-cadherin (CDH1), and vitamin D receptor (VDR) genes regulate the epithelial–mesenchymal transition (EMT) that initiates the invasion process of many tumor cells. We hypothesized that this process could also affect the behavior of normal cells adjacent to the tumor. To verify this hypothesis, the expression level of these genes was determined by quantitative RT–PCR in tumor, normal adjacent, and normal distant tissues from 32 colorectal cancer (CC) patients. In addition, we extended the study to human HaCaT normal keratinocytes and SW480-ADH colon cancer cells co-cultured with SW480-ADH cells overexpressing the mouse Snai1 gene. Of 18 CC cases with SNAI1 expression in tumor tissue, five also had SNAI1 in normal adjacent tissue (NAT). Expression of SNAI1 in tumor tissue correlated with downregulation of CDH1 and VDR genes in both tumor (P=0.047 and P=0.014, respectively) and NAT lacking SNAI1 expression (P=0.054 and P=0.003). ZEB1 expression was directly related to VDR expression in tumor tissue (r=0.39; P=0.027) and inversely to CDH1 in NAT (r=−0.46; P=0.010). CDH1 and VDR were also downregulated in SW480-ADH and MaCaT cells, respectively, when they were co-cultured with Snai1-expressing cells. Furthermore, cytokine analysis showed differences in the conditioned media obtained from the two cell types. These results indicate that histologically normal tissue adjacent to tumor tissue expressing the EMT-inducing gene SNAI1 shows alterations in the expression of epithelial differentiation genes such as CDH1 and VDR.
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Abbreviations
- AI:
-
allele imbalance
- CC:
-
colorectal cancer
- EMT:
-
epithelial–mesenchymal transition
- LOH:
-
loss of heterozygosity
- N:
-
normal
- NAT:
-
normal adjacent tissue
- T:
-
tumor
- VDR:
-
vitamin D receptor
References
Aboseif S, El-Sakka A, Young P, Cunha G . (1999). Mesenchymal reprogramming of adult human epithelial differentiation. Differentiation 65: 113–118.
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.
Baulida J, Batlle E, Garcia De HA . (1999). Adenomatous polyposis coli protein (APC)-independent regulation of beta-catenin/Tcf-4 mediated transcription in intestinal cells. Biochem J 344 (Pt 2): 565–570.
Blanco MJ, Barrallo-Gimeno A, Acloque H, Reyes AE, Tada M, Allende ML et al. (2007). Snail1a and Snail1b cooperate in the anterior migration of the axial mesendoderm in the zebrafish embryo. Development 134: 4073–4081.
Brabletz T, Jung A, Reu S, Porzner M, Hlubek F, Kunz-Schughart LA et al. (2001). Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci USA 98: 10356–10361.
Brown LF, Guidi AJ, Schnitt SJ, Van De WL, Iruela-Arispe ML, Yeo TK et al. (1999). Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast. Clin Cancer Res 5: 1041–1056.
Cano A, Perez-Moreno MA, 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.
Condeelis J, Segall JE . (2003). Intravital imaging of cell movement in tumours. Nat Rev Cancer 3: 921–930.
Deng G, Lu Y, Zlotnikov G, Thor AD, Smith HS . (1996). Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 274: 2057–2059.
Forsti A, Louhelainen J, Soderberg M, Wijkstrom H, Hemminki K . (2001). Loss of heterozygosity in tumour-adjacent normal tissue of breast and bladder cancer. Eur J Cancer 37: 1372–1380.
Franci C, Takkunen M, Dave N, Alameda F, Gomez S, Rodriguez R et al. (2006). Expression of Snail protein in tumor-stroma interface. Oncogene 25: 5134–5144.
Grooteclaes ML, Frisch SM . (2000). Evidence for a function of CtBP in epithelial gene regulation and anoikis. Oncogene 19: 3823–3828.
Guaita S, Puig I, Franci C, Garrido M, Dominguez D, Batlle E et al. (2002). Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J Biol Chem 277: 39209–39216.
Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.
Herzig M, Christofori G . (2002). Recent advances in cancer research: mouse models of tumorigenesis. Biochim Biophys Acta 1602: 97–113.
Hu M, Yao J, Carroll DK, Weremowicz S, Chen H, Carrasco D et al. (2008). Regulation of in situ to invasive breast carcinoma transition. Cancer Cell 13: 394–406.
Kurose K, Hoshaw-Woodard S, Adeyinka A, Lemeshow S, Watson PH, Eng C . (2001). Genetic model of multi-step breast carcinogenesis involving the epithelium and stroma: clues to tumour-microenvironment interactions. Hum Mol Genet 10: 1907–1913.
Lakhani SR, Chaggar R, Davies S, Jones C, Collins N, Odel C et al. (1999). Genetic alterations in ‘normal’ luminal and myoepithelial cells of the breast. J Pathol 189: 496–503.
Larson PS, de las MA, Bennett SR, Cupples LA, Rosenberg CL . (2002). Loss of heterozygosity or allele imbalance in histologically normal breast epithelium is distinct from loss of heterozygosity or allele imbalance in co-existing carcinomas. Am J Pathol 161: 283–290.
Larson PS, de las MA, Cupples LA, Huang K, Rosenberg CL . (1998). Genetically abnormal clones in histologically normal breast tissue. Am J Pathol 152: 1591–1598.
Lazarova DL, Bordonaro M, Sartorelli AC . (2001). Transcriptional regulation of the vitamin D(3) receptor gene by ZEB. Cell Growth Differ 12: 319–326.
Li Y, Liu W, Hayward SW, Cunha GR, Baskin LS . (2000). Plasticity of the urothelial phenotype: effects of gastro-intestinal mesenchyme/stroma and implications for urinary tract reconstruction. Differentiation 66: 126–135.
Li Z, Moore DH, Meng ZH, Ljung BM, Gray JW, Dairkee SH . (2002). Increased risk of local recurrence is associated with allelic loss in normal lobules of breast cancer patients. Cancer Res 62: 1000–1003.
Liotta LA, Steeg PS, Stetler-Stevenson WG . (1991). Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64: 327–336.
Locascio A, Vega S, de Frutos CA, Manzanares M, Nieto MA . (2002). Biological potential of a functional human SNAIL retrogene. J Biol Chem 277: 38803–38809.
Lochter A, Galosy S, Muschler J, Freedman N, Werb Z, Bissell MJ . (1997). Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J Cell Biol 139: 1861–1872.
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.
Nieto MA . (2002). The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 3: 155–166.
Nilsson E, Skinner MK . (2001). Cellular interactions that control primordial follicle development and folliculogenesis. J Soc Gynecol Investig 8: S17–S20.
Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR . (1999). Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 59: 5002–5011.
Oto M, Miyake S, Yuasa Y . (1993). Optimization of nonradioisotopic single strand conformation polymorphism analysis with a conventional minislab gel electrophoresis apparatus. Anal Biochem 213: 19–22.
Palmer HG, Gonzalez-Sancho JM, Espada J, Berciano MT, Puig I, Baulida J et al. (2001). Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol 154: 369–387.
Palmer HG, Larriba MJ, Garcia JM, Ordonez-Moran P, Pena C, Peiro S et al. (2004). The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer. Nat Med 10: 917–919.
Park CC, Bissell MJ, Barcellos-Hoff MH . (2000). The influence of the microenvironment on the malignant phenotype. Mol Med Today 6: 324–329.
Peinado H, Olmeda D, Cano A . (2007). Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7: 415–428.
Pena C, Garcia JM, Garcia V, Silva J, Dominguez G, Rodriguez R et al. (2006). The expression levels of the transcriptional regulators p300 and CtBP modulate the correlations between SNAIL, ZEB1, E-cadherin and vitamin D receptor in human colon carcinomas. Int J Cancer 119: 2098–2104.
Pena C, Garcia JM, Silva J, Garcia V, Rodriguez R, Alonso I et al. (2005). E-cadherin and vitamin D receptor regulation by SNAIL and ZEB1 in colon cancer: clinicopathological correlations. Hum Mol Genet 14: 3361–3370.
Perez-Moreno M, Jamora C, Fuchs E . (2003). Sticky business: orchestrating cellular signals at adherens junctions. Cell 112: 535–548.
Perl AK, Wilgenbus P, Dahl U, Semb H, Christofori G . (1998). A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 392: 190–193.
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.
Ren ZP, Hedrum A, Ponten F, Nister M, Ahmadian A, Lundeberg J et al. (1996). Human epidermal cancer and accompanying precursors have identical p53 mutations different from p53 mutations in adjacent areas of clonally expanded non-neoplastic keratinocytes. Oncogene 12: 765–773.
Sahai E, Marshall CJ . (2003). Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis. Nat Cell Biol 5: 711–719.
Sozzi G, Miozzo M, Tagliabue E, Calderone C, Lombardi L, Pilotti S et al. (1991). Cytogenetic abnormalities and overexpression of receptors for growth factors in normal bronchial epithelium and tumor samples of lung cancer patients. Cancer Res 51: 400–404.
Tan C, Costello P, Sanghera J, Dominguez D, Baulida J, De Herreros AG 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.
Tomita N, Jiang W, Hibshoosh H, Warburton D, Kahn SM, Weinstein IB . (1992). Isolation and characterization of a highly malignant variant of the SW480 human colon cancer cell line. Cancer Res 52: 6840–6847.
Vleminckx K, Vakaet Jr L, Mareel M, Fiers W, van RF . (1991). Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66: 107–119.
Waridel F, Estreicher A, Bron L, Flaman JM, Fontolliet C, Monnier P et al. (1997). Field cancerisation and polyclonal p53 mutation in the upper aero-digestive tract. Oncogene 14: 163–169.
Werb Z . (1997). ECM and cell surface proteolysis: regulating cellular ecology. Cell 91: 439–442.
Wolf K, Mazo I, Leung H, Engelke K, von Andrian UH, Deryugina EI et al. (2003). Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J Cell Biol 160: 267–277.
Wu C, Keightley SY, Leung-Hagesteijn C, Radeva G, Coppolino M, Goicoechea S et al. (1998). Integrin-linked protein kinase regulates fibronectin matrix assembly, E-cadherin expression, and tumorigenicity. J Biol Chem 273: 528–536.
Acknowledgements
We thank M Eaude for help with the English paper. This study was supported by the grants SAF2007-60431, CAM: S-GEN/0266/2006, ISCIII-RETIC RD06/0020 and /0009, and a grant from the Accion Transversal del Cancer (ISCIII).
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Peña, C., García, J., Larriba, M. et al. SNAI1 expression in colon cancer related with CDH1 and VDR downregulation in normal adjacent tissue. Oncogene 28, 4375–4385 (2009). https://doi.org/10.1038/onc.2009.285
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DOI: https://doi.org/10.1038/onc.2009.285
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