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SNAI1 Expression in Colon Cancer Related with CDH1 and VDR Downregulation in Normal Adjacent Tissue

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SNAI1 Expression in Colon Cancer Related with CDH1 and VDR Downregulation in Normal Adjacent Tissue Oncogene (2009) 28, 4375–4385 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc ORIGINAL ARTICLE SNAI1 expression in colon cancer related with CDH1 and VDR downregulation in normal adjacent tissue C Pen˜a1,7, JM Garcı´a1,7, MJ Larriba2, R Barderas3,IGo´mez1, M Herrera1, V Garcı´a1, J Silva1, GDomı´nguez1, R Rodrı´guez4, J Cuevas5, AG de Herreros6, JI Casal3, A Mun˜oz2 and F Bonilla1 1Department of Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain; 2Instituto de Investigaciones Biome´dicas ‘Alberto Sols’, Consejo Superior de Investigaciones Cientı´ficas-Universidad Auto´noma de Madrid, Madrid, Spain; 3Functional Proteomics Laboratory, Centro de Investigaciones Biolo´gicas (CIB-CSIC), Madrid, Spain; 4Department of Pathology, Hospital Virgen de la Salud, Toledo, Spain; 5Department of Pathology, Hospital General Universitario, Guadalajara, Spain and 6Unitat de Biologı´a Cellular i Molecular, Institut Municipal d’Investigacio´ Me`dica, Universitat Pompeu Fabra, Barcelona, Spain SNAI1, ZEB1, E-cadherin (CDH1), and vitamin D Introduction receptor (VDR) genes regulate the epithelial–mesen- chymal transition (EMT) that initiates the invasion Numerous studies have focused on the function of process of many tumor cells. We hypothesized that this genetic abnormalities in various cancers, but very few of process could also affect the behavior of normal cells these analyzed their importance in normal tissue adjacent to the tumor. To verify this hypothesis, the adjacent to tumors. Loss of heterozygosity (LOH) or expression level of these genes was determined by allele imbalances (AI) at various chromosomal loci have quantitative RT–PCR in tumor, normal adjacent, and been observed in normal tissue adjacent to tumor in normal distant tissues from 32 colorectal cancer (CC) breast and bladder cancer patients (Deng et al., 1996; patients. In addition, we extended the study to human Larson et al., 1998, 2002; Lakhani et al., 1999; Forsti HaCaT normal keratinocytes and SW480-ADH colon et al., 2001; Kurose et al., 2001; Li et al., 2002). cancer cells co-cultured with SW480-ADH cells over- Moreover, other studies have reported gene and expressing the mouse Snai1 gene. Of 18 CC cases with chromosome alterations in normal tissues, for example SNAI1 expression in tumor tissue, five also had SNAI1 TP53 mutations in normal epidermis of patients with in normal adjacent tissue (NAT). Expression of SNAI1 non-melanoma skin cancers (Ren et al., 1996) and in in tumor tissue correlated with downregulation of CDH1 histologically normal tissue from the upper aero- and VDR genes in both tumor (P ¼ 0.047 and P ¼ 0.014, digestive tract of cancer patients (Waridel et al., 1997), respectively) and NAT lacking SNAI1 expression or cytogenetic abnormalities and growth factor receptor (P ¼ 0.054 and P ¼ 0.003). ZEB1 expression was directly overexpression in normal bronchial epithelium of lung related to VDR expression in tumor tissue (r ¼ 0.39; cancer patients (Sozzi et al., 1991). Recently, the P ¼ 0.027) and inversely to CDH1 in NAT (r ¼À0.46; importance of normal myoepithelial cells in breast P ¼ 0.010). CDH1 and VDR were also downregulated in cancer progression has been shown (Hu et al., 2008). SW480-ADH and MaCaT cells, respectively, when they These studies proved the existence of alterations in were co-cultured with Snai1-expressing cells. Further- normal tissues of cancer patients and suggested that more, cytokine analysis showed differences in the condi- these alterations might predispose individuals to local tioned media obtained from the two cell types. These recurrence or may belong to the early stages of results indicate that histologically normal tissue adjacent pathogenesis, in which case, they may suffer further to tumor tissue expressing the EMT-inducing gene SNAI1 complex and multiple genetic changes during tumor shows alterations in the expression of epithelial differ- growth (Sozzi et al., 1991; Deng et al., 1996; Ren et al., entiation genes such as CDH1 and VDR. 1996; Larson et al., 1998, 2002; Lakhani et al., 1999; Oncogene (2009) 28, 4375–4385; doi:10.1038/onc.2009.285; Forsti et al., 2001; Li et al., 2002). published online 5 October 2009 SNAI1 is a zinc-finger transcription factor that induces epithelial–mesenchymal transition (EMT) (Nieto, 2002), Keywords: colorectal cancer; epithelial–mesenchymal a fundamental process in the early stages of carcinoma transition; SNAI1; CDH1; normal adjacent tissue invasion and metastasis (Vleminckx et al., 1991; Perl et al., 1998; Peinado et al., 2007). SNAI1 expression in epithelial cells promotes the acquisition of a fibro- Correspondence: Dr F Bonilla, Department of Medical Oncology, blastoid morphotype with invasive and migratory Hospital Universitario Puerta de Hierro Majadahonda, C/Joaquin properties and characteristic changes in gene expression Rodrigo, 2, Majadahonda, Madrid E-28222, Spain. (Cano et al., 2000; Guaita et al., 2002). Importantly, E-mail: [email protected] SNAI1 represses the CDH1 gene (Batlle et al., 2000), 7These authors contributed equally to this work. Received 25 January 2009; revised 30 June 2009; accepted 13 August which encodes E-cadherin, the main component of 2009; published online 5 October 2009 adherent junctions responsible for the maintenance of EMT genes in normal tissue adjacent to tumor CPen˜a et al 4376 the adhesive and polarized phenotype of epithelial cells Table 1 Minimum, maximum, and median of VDR, ZEB1, and (Perez-Moreno et al., 2003). CDH1 downregulation is CDH1 expression levels in tumor and normal adjacent tissue, as one of the hallmarks of EMT. The transcription factor against normal distant tissue ZEB1 also downregulates CDH1 in cultured cells and Tumor Normal adjacent cooperates with SNAI1 in inducing EMT (Grooteclaes and Frisch, 2000; Guaita et al., 2002; Peinado et al., VDR ZEB1 CDH1 VDR ZEB1 CDH1 2007). In contrast, vitamin D (1a,25-dihydroxyvitamin Minimum 0.03 0.01 0.03 0.17 0.05 0.01 D3) induces the expression of CDH1 and an epithelial Maximum 100 10 100 100 33.33 100 phenotype in human colon cells expressing vitamin D Median 0.72 0.52 1.16 1.45 1.30 1.03 receptor (VDR) (Palmer et al., 2001). In addition, we showed that SNAI1 represses VDR expression in tumor cell lines and that its gene expression in human tumors is associated with CDH1 and VDR downregulation tissues counterpart (Figure 1). Finally, SNAI1 protein (Palmer et al., 2004; Pena et al., 2005). was none detected in any of the normal tissues analyzed. As some genetic alterations occur before the devel- opment of histologically abnormal tissue in cancer Study of the relation between gene expression levels patients, and because of the interplay between SNAI1, A statistically significant association was observed ZEB1, CDH1 and VDR in the control of EMT, we between the presence of SNAI1 and the downregulation hypothesized that expression of EMT genes (SNAI1, of CDH1 and VDR in tumor tissues: geometric averages ZEB1) in tumors could affect expression of epithelial of the VDR and CDH1 expression levels in those cases genes (CDH1, VDR) in normal adjacent tissue (NAT). with SNAI1 presence in tumor tissue were, respectively, Paracrine regulation by the tumor or other mechanisms 0.52 and 0.83, compared with 2.04 and 3.57 when could drive changes in the overall structure of normal SNAI1 P P tissue surrounding the tumor and facilitate tumor was not detected ( ¼ 0.014 and ¼ 0.047, ANOVA) (Figure 2). growth or invasion. It should not be forgotten that Remarkably, presence of SNAI1 in tumor tissue but tissue remodeling occurs continuously during tumoro- genesis (Herzig and Christofori, 2002). To carry out this not in NAT was associated with downregulation of VDR and CDH1 in NAT (all of them SNAI1 negatives). study, we analyzed the expression of these four genes in Thus, of 13 cases with SNAI1 expression in tumor tissue the tumor tissue and in histologically normal tissue but not in NAT, the geometric averages of VDR and adjacent to carcinoma in a series of 32 colorectal cancer CDH1 in NAT tissue were 0.85 and 0.84, respectively, (CC) patients. Some patients with SNAI1 expression in against 4.75 and 3.38 in the 14 cases without SNAI1 tumors also had SNAI1 expression in NAT. In addition, expression in tumor tissue (P 0.003 and P 0.054, we found a correlation between expression of SNAI1 in ¼ ¼ the tumor and VDR and CDH1 downregulation in both ANOVA) (Figure 2). No association between the presence of SNAI1 in tumor and NAT (not expressing SNAI1). tumor tissue and the expression of ZEB1 in tumor or in NAT was observed (P ¼ 0.351 and P ¼ 0.273, respec- tively, ANOVA) (Figure 2). The study of the expression data of VDR, CDH1, and Results ZEB1 genes in tumor and NAT showed some correla- Gene expression analysis of patient samples tions. As expected, a correlation between expression levels of CDH1 and VDR was observed in both tumor Expression of SNAI1, CDH1, VDR, and ZEB1 genes (r 0.58; P 0.001) and NAT (r 0.54; P 0.001). In was studied in tumor (T) and histologically NAT in a ¼ o ¼ ¼ addition, direct correlation between VDR and ZEB1 series of 32 CC patients and related to expression found (r 0.39; P 0.027) was found in tumor tissue, but not in normal tissue distant from the tumor (N). ¼ ¼ in NAT. In contrast, when ZEB1 and CDH1 were SNAI1 was expressed in 18 out of 32 tumor samples (56.3%) and five of these patients also showed SNAI1 related, inverse correlation in the NAT was observed (r 0.46; P 0.010), but not in the tumor tissue expression in the NAT (15.6%). These patients were ¼À ¼ (Figure 3). excluded from the subsequent analysis to avoid mis- interpretations of the results obtained.
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