Abstract
Abstract Background; Epithelial-to-mesenchymal transition (EMT) is thought to play an important role in cancer invasion and metastasis and could be a critical target to improve survival. Recently, EMT has been actively studied in various cancers. In this study, we explored the impact of EMT on clinical prognosis of gastric cancer. Methods; Eleven gastric cancer cell lines (N87, NUGC2, MKN45, NUGC4, KATOIII, MKN74, SC-6-JCK, GCIY, MKN28, AZ521 and MKN1) and one hundred sixteen patients who underwent surgery for gastric cancer in our hospital were investigated in this study. The mRNA expression level of an epithelial marker (E-cadherin), a mesenchymal marker (vimentin) and several transcription factors known to induce EMT were measured by quantitative real-time PCR. EMT status of each gastric cancer patient was determined by calculating the V/E ratio (vimentin mRNA expression divided by E-cadherin expression in cancerous tissues) and the correlation between EMT status and clinicopathological factors and prognosis were analyzed. Results; 86 patients were classified as having epithelial tumors and 30 patients as having mesenchymal tumors. Mesenchymal tumor type was significantly associated with pathological diffuse type cancer (P = 0.0002) and stage IV (P = 0.046). On multivariate analysis, tumor size (≧ 65mm) (P = 0.013), T classification (T3/4) (P = 0.020), positive peritoneal washing cytology or peritoneal metastasis (P = 0.0002) and EMT status (mesenchymal phenotype) (P = 0.043) were independent prognostic factors for gastric cancer patients. Seven of the gastric cancer cell lines were classified as epithelial and four were classified as mesenchymal. Among the five transcription factors (Twist, Slug, Snail, Zeb-1 and Zeb-2) analyzed, Zeb-1 mRNA expression was significantly correlated with mesenchymal phenotype and the V/E ratio (r = 0.708, P = 0.015). These results indicated that Zeb-1 could play a key role in EMT for gastric cancer cell lines. Zeb-1 mRNA expression was therefore measured by real-time PCR in cancerous tissues from patients, and the patients were divided into low (n =84) and high (n = 32) expression groups. Not surprisingly, we found a significant correlation between V/E ratio and Zeb-1 mRNA expression (r = 0.727, P < 0.0001). High Zeb-1 expression was also significantly associated with age ( 63), pathological diffuse type and number of lymph node metastasis (n ≧ 16), (P = 0.036, P = 0.035, P = 0.018, respectively). Finally, patients in the high-expression group had significantly poorer survival than those in the low-expression group (P = 0.0071). Conclusion; EMT is a critical prognostic factor for gastric cancer. Zeb-1 is an important EMT-inducing transcription factor and might be a therapeutic target for patients with gastric cancer. Citation Format: Toshifumi Murai, Suguru Yamada, Bryan C. Fuchs, Tutomu Fujii, Michitaka Fujiwara, Kenneth K. Tanabe, Yasuhiro Kodera. Epithelial to mesenchymal transition predicts prognosis In clinical gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1473. doi:10.1158/1538-7445.AM2013-1473
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