Regulation of E‐cadherin expression by growth factor receptors in cancer cells

In a recent issue of the Journal of Surgical Oncology, Fang et al. [1] reported the expression of E-cadherin and other molecules of the cadherin-mediated cell adhesion system in patients with colorectal cancer (CRC). The authors found that reduced expression of E-cadherin was strongly associated with invasion and metastasis. In addition, there was a significant correlation between E-cadherin expression and 5-year survival in Duke’s stage B patients. The results support the view that cell adhesion molecules can be useful as biomarkers to predict response to adjuvant chemotherapy in CRC patients. The findings of Fang et al. [1] are consistent with most previous studies on the involvement of E-cadherin in cancer, which have focused on its role as a tumor suppressor, and in loss of E-cadherin as an event that induces epithelial–mesenchymal transition (EMT) and promotes tumor invasion and metastasis [2,3]. Other aspects of the involvement of E-cadherin in cancer progression and response to treatment are much less understood. For example, few studies have examined the role of E-cadherin in cell proliferation and survival, and the regulation of E-cadherin expression by membrane receptors that are targets for anticancer therapy. Given the critical role of E-cadherin in promoting tumor invasion and metastasis, it is important to understand how E-cadherin expression is altered in response to targeted antitumor agents that act on growth factor receptors and associated signaling pathways. A recent study by Hsu and Liou [4] has demonstrated that the inhibition of proliferation of MCF-7 human breast cancer cells induced by the antitumor catenin (-)-epigallocatechin-3-gallate (EGCg) was associated with a reduction in both mRNA and protein levels of E-cadherin, but not with changes in expression of N-cadherin. Because EGCg can act by altering the lipid composition of cell membranes, it affects the function of a wide range of membrane receptors. Evidence indicates that the antitumor effects of EGCg in cancer cells involves Fig. 1. GRPR blockade inhibits cell proliferation and reduces the expression of E-cadherin mRNA in human CRC cells. A: HT-29 cells were cultured and treated with the selective GRPR antagonist RC-3095 (1, 10 , and 10 6 mM) as previously described [9]. Cell proliferation was measured with the MTT assay as described in Ref. [9]. Data represent the mean SEM percentage of viable cells 24 hr after treatment. Control cells were treated with FBS alone. N1⁄4 4 experiments performed in triple wells each. The mean value for control cells was taken as 100%; *P1⁄4 0.05 and **P< 0.01 compared to control cells using one-way analysis of variance (ANOVA) followed by LSD post hoc tests. B: Semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) of mRNA for E-cadherin in CRC cells treated with RC-3095. HT-29 cells were cultured and treated as described above and E-cadherin mRNA expression was measured 24 h after treatment. The general methods for RT-PCR conditions were as previously described [9]. The relative abundance of each mRNAversus b-actin was determined by densitometry. Primers to E-cadherin (Genbank accession number Z13009) were F-CGTCTGTAGGAAGGCACAGCCTGTCG and R-GAGAATCATAAGGCGGGGCTGTGG. Primer specificity was confirmed by human genome search and identification of specific target sequences, ensuring no cross-amplification. Beta-actin (NM_001101) primers were F-GAGACCTTCAACACCCCAG and R-GTGGTGGTGAAGCTGTAGC. Data are shown as mean SEM percentage alteration in E-cadherin mRNA levels. N1⁄4 3 experiments; *P< 0.05 compared to control cells using ANOVA followed by LSD post hoc tests. Grant sponsor: National Council for Scientific and Technological Development (CNPq); Grant numbers: 312137/2006-0, 490753/2006-0, 303703/ 2009-1; Grant sponsor: National Institute for Translational Medicine (INCT-TM); Grant sponsor: South American Office for Anticancer Drug Development; Grant sponsor: Children’s Cancer Institute (ICI-RS). *Correspondence to: Mônica R.M. Vianna, PhD, Faculty of Biosciences, Pontifical Catholic University, Av. Ipiranga, 6681 Prédio 12D, Sala 340, 90619-900 Porto Alegre, RS, Brazil. Fax: þ55-51-3320-3612. E-mail: monica.vianna@pucrs.br **Correspondence to: Rafael Roesler, PhD, Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Rua Sarmento Leite, 500 (ICBS, Campus Centro/UFRGS), 90050-070 Porto Alegre, RS, Brazil. Fax: þ55-51-3308-3121. E-mail: rroesler@terra.com.br Received 22 January 2011; Accepted 25 January 2011 DOI 10.1002/jso.21898 Published online 28 February 2011 in Wiley Online Library (wileyonlinelibrary.com).