The EMT (epithelial-mesenchymal-transition)-related protein expression indicates the metastatic status and prognosis in patients with ovarian cancer

Journal of Ovarian Research

Masahide Ohmichi¹  Akiko Tanabe¹  Masanori Kanemura¹  Hiroshi Sasaki¹  Yoshimichi Tanaka¹  Satoshi Tsunetoh¹  Tomohito Tanaka¹  Satoe Fujiwara¹  Keisuke Ashihara¹  Hiroshi Kawaguchi¹  Yoshito Terai¹  Masaaki Takai¹ 

[1] Department of Obstetrics and Gynecology, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan

关键词: Ovarian cancer;    E-cadherin;    Snail;    EMT;    Epithelial-mesenchymal-transition;   

Others  :  1151820
DOI  :  10.1186/1757-2215-7-76

 received in 2014-01-19, accepted in 2014-07-04,  发布年份 2014

【 摘 要 】

Objectives

The epithelial-mesenchymal-transition (EMT) is an important step in the invasion and metastasis of cancer. A critical molecular feature of this process is the downregulation of the E-cadherin expression, which is primarily controlled by Snail-related zinc-finger transcription factors. The aim of this study was to evaluate the prognostic impact of the expression of EMT-related proteins (E-cadherin and Snail) in patients with ovarian cancer.

Methods

An immunohistochemical analysis was conducted using tissue microarray samples of 174 primary tumors and 34 metastases of ovarian carcinoma, and the relationships between the protein expression, clinicopathological features and outcomes were investigated.

Results

A reduced E-cadherin expression was observed in 36.8% of the primary tumors and 30.4%, 35.7%, 37.7% and 52.7% of the stage I, II, III and IV tumors, respectively. The nuclear expression of Snail was positive in 33.9% of the primary tumors. The rate of an EMT-positive status, as represented by both a reduced E-cadherin expression and a nuclear expression of Snail, was significantly higher in the patients with peritoneal dissemination than in those without (p < 0.05). The EMT status was significantly associated with both the progression-free survival and overall survival (p <0.01). A multivariate analysis showed an EMT-positive status to be a significant predictor of both the progression-free survival (p < 0.05) and overall survival (P < 0.01).

Conclusions

These data indicate that the EMT status is significantly associated with peritoneal metastasis and both the progression-free survival and overall survival in patients with ovarian cancer. Therefore, clarifying and controlling EMT signaling is a promising approach to molecular targeted therapy for ovarian cancer.

【 授权许可】

   
2014 Takai et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Ozolos RF: Treatment goals in ovarian cancer. Int J Gynecol Cancer 2005, 15:3-11.
• [2]Thiery JP, Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 2006, 7:131-142.
• [3]Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED, Thompson EW: Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J Cell Physiol 2007, 213:374-383.
• [4]Yang J, Weinberg RA: Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 2008, 14:818-829.
• [5]Baum B, Settleman J, Quinlan MP: Transitions between epithelial and mesenchymal states in development and disease. Semin Cell Dev Biol 2008, 19:294-308.
• [6]Grunert S, Jechlinger M, Beug H: Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol 2003, 4:657-665.
• [7]Huber MA, Kraut N, Beug H: Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 2005, 17:548-558.
• [8]Nieto MA: The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 2002, 3:155-166.
• [9]Hemavathy K, Ashraf SI, Ip YT: Snail/slug family of repressors: slowly going into the fast lane of development and cancer. Gene 2000, 257:1-12.
• [10]Grau Y, Carteret C, Simpson P: Mutations and chromosomal rearrangements affecting the expression of snail, a gene involved in embryonic patterning in DROSOPHILA MELANOGASTER. Genetics 1984, 108:347-360.
• [11]Valdes F, Alvarez AM, Locascio A, Vega S, Herrera B, Fernandez M, Benito M, Nieto MA, Fabregat I: The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor Beta in fetal rat hepatocytes. Mol Cancer Res 2002, 1:68-78.
• [12]Perez-Losada J, Sanchez-Martin M, Perez-Caro M, Perez-Mancera PA, Sanchez-Garcia I: The radioresistance biological function of the SCF/kit signaling pathway is mediated by the zinc-finger transcription factor Slug. Oncogene 2003, 22:4205-4211.
• [13]Vega S, Morales AV, Ocana OH, Valdes F, Fabregat I, Nieto MA: Snail blocks the cell cycle and confers resistance to cell death. Genes Dev 2004, 18:1131-1143.
• [14]Takeichi M: Cadherins in cancer: implications for invasion and metastasis. Curr Opin Cell Biol 1993, 5:806-811.
• [15]Wijnhoven BP, Dinjens WN, Pignatelli M: E-cadherin-catenin cell-cell adhesion complex and human cancer. Br J Surg 2000, 87:992-1005.
• [16]Sakuragi N, Nishiya M, Ikeda K, Ohkouch T, Furth EE, Hareyama H, Satoh C, Fujimoto S: Decreased E-cadherin expression in endometrial carcinoma is associated with tumor dedifferentiation and deep myometrial invasion. Gynecol Oncol 1994, 53:183-189.
• [17]Cheng L, Nagabhushan M, Pretlow TP, Amini SB, Pretlow TG: Expression of E-cadherin in primary and metastatic prostate cancer. Am J Pathol 1996, 148:1375-1380.
• [18]Bremnes RM, Veve R, Gabrielson E, Hirsch FR, Baron A, Bemis L, Gemmill RM, Drabkin HA, Franklin WA: High-throughput tissue microarray analysis used to evaluate biology and prognostic significance of the E-cadherin pathway in non-small-cell lung cancer. J Clin Oncol 2002, 20:2417-2428.
• [19]Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R, Jarrard DF, Isaacs WB, Pitha PM, Davidson NE, Baylin SB: E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res 1995, 55:5195-5199.
• [20]Yoshiura K, Kanai Y, Ochiai A, Shimoyama Y, Sugimura T, Hirohashi S: Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. Proc Natl Acad Sci U S A 1995, 92:7416-7419.
• [21]Grooteclaes ML, Frisch SM: Evidence for a function of CtBP in epithelial gene regulation and anoikis. Oncogene 2000, 19:3823-3828.
• [22]Comijn J, Berx G, Vermassen P, Verschueren K, Van Grunsven L, Bruyneel E, Mareel M, Huylebroeck D, Van Roy F: The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell 2001, 7:1267-1278.
• [23]Blanco MJ, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J, Nieto MA: Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 2002, 21:3241-3246.
• [24]Grille SJ, Bellacosa A, Upson J, Klein-Szanto AJ, Van Roy F, Lee-Kwon W, Donowitz M, Tsichlis PN, Larue L: The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res 2003, 63:2172-2178.
• [25]Hajra KM, Chen DY, Fearon ER: The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res 2002, 62:1613-1618.
• [26]Sugimachi K, Tanaka S, Kameyama T, Taguchi K, Aishima S, Shimada M, Sugimachi K, Tsuneyoshi M: Transcriptional repressor snail and progression of human hepatocellular carcinoma. Clin Cancer Res 2003, 9:2657-2664.
• [27]Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, Garcia De Herreros A: The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2000, 2:84-89.
• [28]Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, Del Barrio MG, Portillo F, Nieto MA: The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2000, 2:76-83.
• [29]Blechschmidt K, Sassen S, Schmalfeldt B, Schuster T, Hofler H, Becker KF: The E-cadherin repressor Snail is associated with lower overall survival of ovarian cancer patients. Br J Cancer 2008, 98:489-495.
• [30]Tuhkanen H, Soini Y, Kosma VM, Anttila M, Sironen R, Hamalainen K, Mannermaa A: Nuclear expression of Snail1 in borderline and malignant epithelial ovarian tumours is associated with tumour progression. BMC Cancer 2009, 9:289. BioMed Central Full Text
• [31]Kurrey NK, K A , Bapat SA: Snail and Slug are major determinants of ovarian cancer invasiveness at the transcription level. Gynecol Oncol 2005, 97:155-165.
• [32]Elloul S, Elstrand MB, Nesland JM, Trope CG, Kvalheim G, Goldberg I, Reich R, Davidson B: Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer 2005, 103:1631-1643.
• [33]Tanaka Y, Terai Y, Kawaguchi H, Fujiwara S, Yoo S, Tsunetoh S, Takai M, Kanemura M, Tanabe A, Ohmichi M: Prognostic impact of EMT (epithelial-mesenchymal-transition)-related protein expression in endometrial cancer. Cancer Biol Ther 2013, 14:13-19.
• [34]Yilmaz M, Christofori G, Lehembre F: Distinct mechanisms of tumor invasion and metastasis. Trends Mol Med 2007, 13:535-541.
• [35]Imai T, Horiuchi A, Shiozawa T, Osada R, Kikuchi N, Ohira S, Oka K, Konishi I: Elevated expression of E-cadherin and alpha-, beta-, and gamma-catenins in metastatic lesions compared with primary epithelial ovarian carcinoma. Hum Pathol 2004, 35:1469-1476.
• [36]Voutilainen KA, Anttila MA, Sillanpaa SM, Ropponen KM, Saarikoski SV, Juhola MT, Kosma NM: Prognostic significance of E-cadherin-catenin complex in epithelial ovarian cancer. J Clin Pathol 2006, 59:460-467.
• [37]Thiery JP, Acloque H, Huang RY, Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell 2009, 139:871-890.
• [38]Iwatsuki M, Mimori K, Yokobori T, Ishi H, Beppu T, Nakamori S, Baba H, Mori M: Epithelial-mesenchymal trasition in cancer development and its clinical significance. Cancer Sci 2010, 101:293-299.
• [39]Yang AD, Fan F, Camp ER, Van Buren G, Liu W, Somcio R, Gray MJ, Cheng H, Hoff PM, Ellis LM: Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transistion in colorectal cancer cell lines. Clin Cancer Res 2006, 12:4147-4153.