Skip to main content
Top
Published in: BMC Cancer 1/2012

Open Access 01-12-2012 | Research article

Overexpression of Snail is associated with lymph node metastasis and poor prognosis in patients with gastric cancer

Authors: Na Ri Shin, Eun Hui Jeong, Chang In Choi, Hyun Jung Moon, Chae Hwa Kwon, In Sun Chu, Gwang Ha Kim, Tae Yong Jeon, Dae Hwan Kim, Jae Hyuk Lee, Do Youn Park

Published in: BMC Cancer | Issue 1/2012

Login to get access

Abstract

Background

Epithelial–mesenchymal transition (EMT) plays a significant role in tumor progression and invasion. Snail is a known regulator of EMT in various malignant tumors. This study investigated the role of Snail in gastric cancer.

Methods

We examined the effects of silenced or overexpressed Snail using lenti-viral constructs in gastric cancer cells. Immunohistochemical analysis of tissue microarrays from 314 patients with gastric adenocarcinoma (GC) was used to determine Snail’s clinicopathological and prognostic significance. Differential gene expression in 45 GC specimens with Snail overexpression was investigated using cDNA microarray analysis.

Results

Silencing of Snail by shRNA decreased invasion and migration in GC cell lines. Conversely, Snail overexpression increased invasion and migration of gastric cancer cells, in line with increased VEGF and MMP11. Snail overexpression (≥75% positive nuclear staining) was also significantly associated with tumor progression (P < 0.001), lymph node metastases (P = 0.002), lymphovascular invasion (P = 0.002), and perineural invasion (P = 0.002) in the 314 GC patients, and with shorter survival (P = 0.023). cDNA microarray analysis revealed 213 differentially expressed genes in GC tissues with Snail overexpression, including genes related to metastasis and invasion.

Conclusion

Snail significantly affects invasiveness/migratory ability of GCs, and may also be used as a predictive biomarker for prognosis or aggressiveness of GCs.
Appendix
Available only for authorised users
Literature
1.
go back to reference Polyak K, Weinberg RA: Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009, 9: 265-273. 10.1038/nrc2620.CrossRefPubMed Polyak K, Weinberg RA: Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009, 9: 265-273. 10.1038/nrc2620.CrossRefPubMed
2.
go back to reference Thompson EW, Newgreen DF, Tarin D: Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition?. Cancer Res. 2005, 65: 5991-5995.CrossRefPubMed Thompson EW, Newgreen DF, Tarin D: Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition?. Cancer Res. 2005, 65: 5991-5995.CrossRefPubMed
3.
go back to reference Thiery JP, Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006, 7: 131-142. 10.1038/nrm1835.CrossRefPubMed Thiery JP, Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006, 7: 131-142. 10.1038/nrm1835.CrossRefPubMed
4.
go back to reference Kang Y, Massagué J: Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 2004, 118: 277-279. 10.1016/j.cell.2004.07.011.CrossRefPubMed Kang Y, Massagué J: Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 2004, 118: 277-279. 10.1016/j.cell.2004.07.011.CrossRefPubMed
5.
go back to reference Yang J, Weinberg RA: Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008, 14: 818-829. 10.1016/j.devcel.2008.05.009.CrossRefPubMed Yang J, Weinberg RA: Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008, 14: 818-829. 10.1016/j.devcel.2008.05.009.CrossRefPubMed
6.
go back to reference Yook JI, Li XY, Ota I, Hu C, Kim HS, Kim NH, Cha SY, Ryu JK, Choi YJ, Kim J, Fearon ER, Weiss SJ: A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol. 2006, 8: 1398-1406. 10.1038/ncb1508.CrossRefPubMed Yook JI, Li XY, Ota I, Hu C, Kim HS, Kim NH, Cha SY, Ryu JK, Choi YJ, Kim J, Fearon ER, Weiss SJ: A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol. 2006, 8: 1398-1406. 10.1038/ncb1508.CrossRefPubMed
7.
go back to reference Nieto MA: The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol. 2002, 3: 155-166.CrossRefPubMed Nieto MA: The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol. 2002, 3: 155-166.CrossRefPubMed
8.
go back to reference Batlle E, Sancho E, Francí C, Domínguez D, Monfar M, Baulida J, García 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. 10.1038/35000034.CrossRefPubMed Batlle E, Sancho E, Francí C, Domínguez D, Monfar M, Baulida J, García 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. 10.1038/35000034.CrossRefPubMed
9.
go back to reference Cano A, Pérez-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. 10.1038/35000025.CrossRefPubMed Cano A, Pérez-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. 10.1038/35000025.CrossRefPubMed
10.
go back to reference Jin H, Yu Y, Zhang T, Zhou X, Zhou J, Jia L, Wu Y, Zhou BP, Feng Y: Snail is critical for tumor growth and metastasis of ovarian carcinoma. Int J Cancer. 2010, 126: 2102-2111.PubMed Jin H, Yu Y, Zhang T, Zhou X, Zhou J, Jia L, Wu Y, Zhou BP, Feng Y: Snail is critical for tumor growth and metastasis of ovarian carcinoma. Int J Cancer. 2010, 126: 2102-2111.PubMed
11.
go back to reference Yanagawa J, Walser TC, Zhu LX, Hong L, Fishbein MC, Mah V, Chia D, Goodglick L, Elashoff DA, Luo J, Magyar CE, Dohadwala M, Lee JM, St John MA, Strieter RM, Sharma S, Dubinett SM: Snail promotes CXCR2 ligand-dependent tumor progression in non-small cell lung carcinoma. Clin Cancer Res. 2009, 15: 6820-6829. 10.1158/1078-0432.CCR-09-1558.CrossRefPubMedPubMedCentral Yanagawa J, Walser TC, Zhu LX, Hong L, Fishbein MC, Mah V, Chia D, Goodglick L, Elashoff DA, Luo J, Magyar CE, Dohadwala M, Lee JM, St John MA, Strieter RM, Sharma S, Dubinett SM: Snail promotes CXCR2 ligand-dependent tumor progression in non-small cell lung carcinoma. Clin Cancer Res. 2009, 15: 6820-6829. 10.1158/1078-0432.CCR-09-1558.CrossRefPubMedPubMedCentral
12.
go back to reference Kosaka T, Kikuchi E, Mikami S, Miyajima A, Shirotake S, Ishida M, Okada Y, Oya M: Expression of snail in upper urinary tract urothelial carcinoma: prognostic significance and implications for tumor invasion. Clin Cancer Res. 2010, 16: 5814-5823. 10.1158/1078-0432.CCR-10-0230.CrossRefPubMed Kosaka T, Kikuchi E, Mikami S, Miyajima A, Shirotake S, Ishida M, Okada Y, Oya M: Expression of snail in upper urinary tract urothelial carcinoma: prognostic significance and implications for tumor invasion. Clin Cancer Res. 2010, 16: 5814-5823. 10.1158/1078-0432.CCR-10-0230.CrossRefPubMed
13.
go back to reference Yang MH, Chen CL, Chau GY, Chiou SH, Su CW, Chou TY, Peng WL, Wu JC: Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma. Hepatology. 2009, 50: 1464-1474. 10.1002/hep.23221.CrossRefPubMed Yang MH, Chen CL, Chau GY, Chiou SH, Su CW, Chou TY, Peng WL, Wu JC: Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma. Hepatology. 2009, 50: 1464-1474. 10.1002/hep.23221.CrossRefPubMed
14.
go back to reference Kim MA, Lee HS, Lee HE, Kim JH, Yang HK, Kim WH: Prognostic importance of epithelial-mesenchymal transition-related protein expression in gastric carcinoma. Histopathology. 2009, 54: 442-451. 10.1111/j.1365-2559.2009.03247.x.CrossRefPubMed Kim MA, Lee HS, Lee HE, Kim JH, Yang HK, Kim WH: Prognostic importance of epithelial-mesenchymal transition-related protein expression in gastric carcinoma. Histopathology. 2009, 54: 442-451. 10.1111/j.1365-2559.2009.03247.x.CrossRefPubMed
15.
go back to reference Ryu HS, do Park J, Kim HH, Kim WH, Lee HS: Combination of epithelial-mesenchymal transition and cancer stem cell-like phenotypes has independent prognostic value in gastric cancer. Hum Pathol. 2012, 43: 520-528. 10.1016/j.humpath.2011.07.003.CrossRefPubMed Ryu HS, do Park J, Kim HH, Kim WH, Lee HS: Combination of epithelial-mesenchymal transition and cancer stem cell-like phenotypes has independent prognostic value in gastric cancer. Hum Pathol. 2012, 43: 520-528. 10.1016/j.humpath.2011.07.003.CrossRefPubMed
16.
go back to reference Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta DeltaC(T)) Method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.CrossRefPubMed Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta DeltaC(T)) Method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.CrossRefPubMed
17.
go back to reference Kim WH, Park CK, Kim YB, et al: A standardized pathology report for gastric cancer. Korean J Pathol. 2005, 39: 106-113. Kim WH, Park CK, Kim YB, et al: A standardized pathology report for gastric cancer. Korean J Pathol. 2005, 39: 106-113.
18.
go back to reference Japanese Gastric Cancer Association: Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011, 14: 101-112.CrossRef Japanese Gastric Cancer Association: Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011, 14: 101-112.CrossRef
19.
go back to reference American Joint Committee on Cancer Staging Manual. Edited by: Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. 2009, New York: Springer, 7 American Joint Committee on Cancer Staging Manual. Edited by: Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. 2009, New York: Springer, 7
20.
go back to reference Eisen MB, Spellman PT, Brown PO, Botstein D: Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA. 1998, 95: 14863-14868. 10.1073/pnas.95.25.14863.CrossRefPubMedPubMedCentral Eisen MB, Spellman PT, Brown PO, Botstein D: Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA. 1998, 95: 14863-14868. 10.1073/pnas.95.25.14863.CrossRefPubMedPubMedCentral
21.
go back to reference Lehner F, Kulik U, Klempnauer J, Borlak J: The hepatocyte nuclear factor 6 (HNF6) and FOXA2 are key regulators in colorectal liver metastases. FASEB J. 2007, 21: 1445-1462. 10.1096/fj.06-6575com.CrossRefPubMed Lehner F, Kulik U, Klempnauer J, Borlak J: The hepatocyte nuclear factor 6 (HNF6) and FOXA2 are key regulators in colorectal liver metastases. FASEB J. 2007, 21: 1445-1462. 10.1096/fj.06-6575com.CrossRefPubMed
22.
go back to reference Wagstaff L, Kelwick R, Decock J, Edwards DR: The roles of ADAMTS metalloproteinases in tumorigenesis and metastasis. Front Biosci. 2011, 16: 1861-1872. 10.2741/3827.CrossRef Wagstaff L, Kelwick R, Decock J, Edwards DR: The roles of ADAMTS metalloproteinases in tumorigenesis and metastasis. Front Biosci. 2011, 16: 1861-1872. 10.2741/3827.CrossRef
23.
go back to reference Kamai T, Yanai Y, Arai K, Abe H, Yamanishi T, Kurimoto M, Yoshida K: Increased interferon alpha receptor 2 mRNA levels is associated with renal cell carcinoma metastasis. BMC Cancer. 2007, 7: 159-10.1186/1471-2407-7-159.CrossRefPubMedPubMedCentral Kamai T, Yanai Y, Arai K, Abe H, Yamanishi T, Kurimoto M, Yoshida K: Increased interferon alpha receptor 2 mRNA levels is associated with renal cell carcinoma metastasis. BMC Cancer. 2007, 7: 159-10.1186/1471-2407-7-159.CrossRefPubMedPubMedCentral
24.
go back to reference Ohtaki Y, Ishii G, Nagai K, Ashimine S, Kuwata T, Hishida T, Nishimura M, Yoshida J, Takeyoshi I, Ochiai A: Stromal macrophage expressing CD204 is associated with tumor aggressiveness in lung adenocarcinoma. J Thorac Oncol. 2010, 5: 1507-1515. 10.1097/JTO.0b013e3181eba692.CrossRefPubMed Ohtaki Y, Ishii G, Nagai K, Ashimine S, Kuwata T, Hishida T, Nishimura M, Yoshida J, Takeyoshi I, Ochiai A: Stromal macrophage expressing CD204 is associated with tumor aggressiveness in lung adenocarcinoma. J Thorac Oncol. 2010, 5: 1507-1515. 10.1097/JTO.0b013e3181eba692.CrossRefPubMed
25.
go back to reference Zhu Y, Bujo H, Yamazaki H, Ohwaki K, Jiang M, Hirayama S, Kanaki T, Shibasaki M, Takahashi K, Schneider WJ, Saito Y: LR11, an LDL receptor gene family member, is a novel regulator of smooth muscle cell migration. Circ Res. 2004, 94: 752-758. 10.1161/01.RES.0000120862.79154.0F.CrossRefPubMed Zhu Y, Bujo H, Yamazaki H, Ohwaki K, Jiang M, Hirayama S, Kanaki T, Shibasaki M, Takahashi K, Schneider WJ, Saito Y: LR11, an LDL receptor gene family member, is a novel regulator of smooth muscle cell migration. Circ Res. 2004, 94: 752-758. 10.1161/01.RES.0000120862.79154.0F.CrossRefPubMed
26.
go back to reference Guaita S, Puig I, Franci C, Garrido M, Dominguez D, Batlle E, Sancho E, Dedhar S, De Herreros AG, Baulida J: Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J Biol Chem. 2002, 277: 39209-39216. 10.1074/jbc.M206400200.CrossRefPubMed Guaita S, Puig I, Franci C, Garrido M, Dominguez D, Batlle E, Sancho E, Dedhar S, De Herreros AG, Baulida J: Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J Biol Chem. 2002, 277: 39209-39216. 10.1074/jbc.M206400200.CrossRefPubMed
27.
go back to reference Miyoshi A, Kitajima Y, Kido S, Shimonishi T, Matsuyama S, Kitahara K, Miyazaki K: Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma. Br J Cancer. 2005, 92: 252-258.PubMedPubMedCentral Miyoshi A, Kitajima Y, Kido S, Shimonishi T, Matsuyama S, Kitahara K, Miyazaki K: Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma. Br J Cancer. 2005, 92: 252-258.PubMedPubMedCentral
28.
go back to reference Peinado H, Marin F, Cubillo E, Stark HJ, Fusenig N, Nieto MA, Cano A: Snail and E47 repressors of E-cadherin induce distinct invasive and angiogenic properties in vivo. J Cell Sci. 2004, 117: 2827-2839. 10.1242/jcs.01145.CrossRefPubMed Peinado H, Marin F, Cubillo E, Stark HJ, Fusenig N, Nieto MA, Cano A: Snail and E47 repressors of E-cadherin induce distinct invasive and angiogenic properties in vivo. J Cell Sci. 2004, 117: 2827-2839. 10.1242/jcs.01145.CrossRefPubMed
29.
go back to reference Côme C, Magnino F, Bibeau F, De Santa Barbara P, Becker KF, Theillet C, Savagner P: Snail and slug play distinct roles during breast carcinoma progression. Clin Cancer Res. 2006, 12: 5395-5402. 10.1158/1078-0432.CCR-06-0478.CrossRefPubMed Côme C, Magnino F, Bibeau F, De Santa Barbara P, Becker KF, Theillet C, Savagner P: Snail and slug play distinct roles during breast carcinoma progression. Clin Cancer Res. 2006, 12: 5395-5402. 10.1158/1078-0432.CCR-06-0478.CrossRefPubMed
30.
go back to reference Rosivatz E, Becker KF, Kremmer E, Schott C, Blechschmidt K, Höfler H, Sarbia M: Expression and nuclear localization of Snail, an E-cadherin repressor, in adenocarcinomas of the upper gastrointestinal tract. Virchows Arch. 2006, 448: 277-287. 10.1007/s00428-005-0118-9.CrossRefPubMed Rosivatz E, Becker KF, Kremmer E, Schott C, Blechschmidt K, Höfler H, Sarbia M: Expression and nuclear localization of Snail, an E-cadherin repressor, in adenocarcinomas of the upper gastrointestinal tract. Virchows Arch. 2006, 448: 277-287. 10.1007/s00428-005-0118-9.CrossRefPubMed
31.
go back to reference He H, Chen W, Wang X, Wang C, Liu F, Shen Z, Xu J, Gu J, Sun Y: Snail is an independent prognostic predictor for progression and patient survival of gastric cancer. Cancer Sci. 2012, 103: 1296-1303. 10.1111/j.1349-7006.2012.02295.x.CrossRefPubMed He H, Chen W, Wang X, Wang C, Liu F, Shen Z, Xu J, Gu J, Sun Y: Snail is an independent prognostic predictor for progression and patient survival of gastric cancer. Cancer Sci. 2012, 103: 1296-1303. 10.1111/j.1349-7006.2012.02295.x.CrossRefPubMed
Metadata
Title
Overexpression of Snail is associated with lymph node metastasis and poor prognosis in patients with gastric cancer
Authors
Na Ri Shin
Eun Hui Jeong
Chang In Choi
Hyun Jung Moon
Chae Hwa Kwon
In Sun Chu
Gwang Ha Kim
Tae Yong Jeon
Dae Hwan Kim
Jae Hyuk Lee
Do Youn Park
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2012
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-12-521

Other articles of this Issue 1/2012

BMC Cancer 1/2012 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine