Research Progress of Epithelial-Mesenchymal-Transition in Gastrointestinal Cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

CAI Cheng , YU Jiwei , JIANG Bojian

Department of General Surgery， No.3 People’s Hospital， Shanghai Jiao-Tong University School of Medicine， Shanghai 201900， China;

Corresponding author：

Keywords：

Epithelial-mesenchymal transition; E-cadherin; Gastrointestinal; Carcinoma; Cancer stem cell; Transcriptional repressor

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ObjectiveTo summarize the role of epithelial-mesenchymal-transition （EMT） in occurrence and development of gastrointestinal cancer. MethodsDomestic and international publications online involving EMT of gastrointestinal cancer in recent years were collected and reviewed. ResultsEMT was a highly conserved process that has been well characterised in embryogenesis. Studies had shown that the aberrant activation of EMT in adult epithelia could promote tumour metastasis by repressing cell adhesion molecules. E-cadherin， one of the epithelial cell markers, maybe involved in the process of the EMT, especially of the Ecadherin transcriptional repressors， these transcriptional repressors significantly increased in the gastrointestinal cancer. Further more， EMT might involve in the process of gastrointestinal cancer stem cells formation. ConclusionsEMT and it’s regulators play a very important role in gastrointestinal cancer， and may provide a newsight into the gastrointestinal cancer. It also can provide a novel clinical targets to treat the gastrointestinal cancer.

Citation： CAI Cheng,YU Jiwei,JIANG Bojian,.. Research Progress of Epithelial-Mesenchymal-Transition in Gastrointestinal Cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2011, 18(11): 1234-F3. doi: Copy

1.	Thiery JP, Sleeman JP. Complex networks orchestrate epithelialmesenchymal transitions [J]. Nat Rev Mol Cell Biol, 2006, 7(2): 131142.
2.	Kong D, Li Y, Wang Z, et al. Cancer stem cells and epithelialtomesenchymal transition (EMT)phenotypic cells: are they cousins or twins? [J]. Cancers, 2011, 3(1): 716729.
3.	Pasqua Ferrara A, Scalera I, Rotelli MT, et al. Stem cells and colorectal cancerogenesis: new insight [J]. Minerva Chir, 2010, 65(2): 235242.
4.	Wellner U, Schubert J, Burk UC, et al. The EMTactivator ZEB1 promotes tumorigenicity by repressing stemnessinhibiting microRNAs [J]. Nat Cell Biol, 2009, 11(12): 14871495.
5.	Kalluri R, Weinberg RA. The basics of epithelialmesenchymal transition [J]. J Clin Invest, 2009, 119(6): 14201428.
6.	Kang H, Min BS, Lee KY, et al. Loss of Ecadherin and MUC2 expressions correlated with poor survival in patients with stages Ⅱ and Ⅲ colorectal carcinoma [J]. Ann Surg Oncol, 2011, 18(3): 711719.
7.	Mimata A, Fukamachi H, Eishi Y, et al. Loss of Ecadherin in mouse gastric epithelial cells induces signet ringlike cells, a possible precursor lesion of diffuse gastric cancer [J]. Cancer Sci, 2011, 102(5): 942950.
8.	Pryczynicz A, GuzińskaUstymowicz K, Kemona A, et al. Expression of the Ecadherincatenin complex in patients with pancreatic ductal adenocarcinoma [J]. Folia Histochem Cytobiol, 2010, 48(1): 128133.
9.	Huang WY, Yang PM, Chang YF, et al. Methotrexate induces apoptosis through p53/p21dependent pathway and increases Ecadherin expression through downregulation of HDAC/EZH2 [J]. Biochem Pharmacol, 2011, 81(4): 510517.
10.	Natalwala A, Spychal R, Tselepis C. Epithelialmesenchymal transition mediated tumourigenesis in the gastrointestinal tract [J]. World J Gastroenterol， 2008， 14(24): 37923797.
11.	Lee MY, Chou CY, Tang MJ, et al. Epithelialmesenchymal transition in cervical cancer: correlation with tumor progression, epidermal growth factor receptor overexpression, and snail upregulation [J]. Clin Cancer Res, 2008, 14(15): 47434750.
12.	Zeisberg M, Neilson EG. Biomarkers for epithelialmesenchymal transitions [J]. J Clin Invest, 2009, 119(6): 14291437.
13.	Yang J, Eddy JA, Pan Y, et al. Integrated proteomics and genomics analysis reveals a novel mesenchymal to epithelial reverting transition in leiomyosarcoma through regulation of slug [J]. Mol Cell Proteomics, 2010, 9(11): 24052413.
14.	PérezMancera PA, GonzálezHerrero I, Maclean K, et al. SLUG (SNAI2) overexpression in embryonic development [J]. Cytogenet Genome Res, 2006, 114(1): 2429.
15.	Clarhaut J, Gemmill RM, Potiron VA, et al. ZEB1, a repressor of the semaphorin 3F tumor suppressor gene in lung cancer cells [J]. Neoplasia, 2009, 11(2): 157166.
16.	Oztas E, Avci ME, Ozcan A, et al. Novel monoclonal antibodies detect Smadinteracting protein 1 (SIP1) in the cytoplasm of human cells from multiple tumor tissue arrays [J]. Exp Mol Pathol, 2010, 89(2): 182189.
17.	Xia M, Hu M, Wang J, et al. Identification of the role of Smad interacting protein 1 (SIP1) in glioma [J]. J Neurooncol, 2010, 97(2): 225232.
18.	Luo GQ, Li JH, Wen JF, et al. Effect and mechanism of the Twist gene on invasion and metastasis of gastric carcinoma cells [J]. World J Gastroenterol, 2008, 14(16): 24872493.
19.	Du C, Zhang C, Hassan S, et al. Protein kinase D1 suppresses epithelialtomesenchymal transition through phosphorylation of snail [J]. Cancer Res， 2010, 70(20): 78107819.
20.	唐志锋, 周永宁, 苏晓娟, 等. Snail与Ecadherin在胃癌中的表达及临床意义 [J]. 中国急救复苏与灾害医学杂志， 2010, 5(8): 696699.
21.	Castro Alves C, Rosivatz E, Schott C, et al. Slug is overexpressed in gastric carcinomas and may act synergistically with SIP1 and Snail in the downregulation of Ecadherin [J]. J Pathol, 2007, 211(5): 507515.
22.	Feng MY, Wang K, Song HT, et al. Metastasisinduction and apoptosisprotection by TWIST in gastric cancer cells [J]. Clin Exp Metastasis, 2009, 26(8): 10131023.
23.	Yang Z, Zhang X, Gang H, et al. Upregulation of gastric cancer cell invasion by Twist is accompanied by Ncadherin and fibronectin expression [J]. Biochem Biophys Res Commun， 2007， 358(3): 925930.
24.	Lee S, Bang S, Song K, et al. Differential expression in normaladenomacarcinoma sequence suggests complex molecular carcinogenesis in colon [J]. Oncol Rep, 2006, 16(4): 747754.
25.	Bottomly D, Kyler SL, McWeeney SK, et al. Identification of (beta)catenin binding regions in colon cancer cells using ChIPSeq [J]. Nucleic Acids Res， 2010, 38(17): 57355745.
26.	Kuphal F, Behrens J. Ecadherin modulates Wntdependent transcription in colorectal cancer cells but does not alter Wntindependent gene expression in fibroblasts [J]. Exp Cell Res, 2006, 312(4): 457467.
27.	郑伯安, 邓高里, 董全进, 等. 表皮钙黏附素和Snail蛋白的表达与大肠癌侵袭转移及预后的关系 [J]. 中华肿瘤杂志， 2010， 2010, 32(2): 111116.
28.	Shioiri M, Shida T, Koda K, et al. Slug expression is an independent prognostic parameter for poor survival in colorectalcarcinoma patients [J]. Br J Cancer, 2006, 94(12): 18161822.
29.	ValdésMora F, Gómez del Pulgar T, Bandrés E, et al. TWIST1 overexpression is associated with nodal invasion and male sex in primary colorectal cancer [J]. Ann Surg Oncol, 2009, 16(1): 7887.
30.	Anderson EC, Hessman C, Levin TG, et al. The role of colorectal cancer stem cells in metastatic disease and therapeutic response [J]. Cancer， 2011, 3(1): 319339.
31.	May CD, Sphyris N, Evans KW, et al. Epithelialmesenchymal transition and cancer stem cells: a dangerously dynamic duo in breast cancer progression [J]. Breast Cancer Res, 2011, 13(1): 202.
32.	Hollier BG, Evans K, Mani SA. The epithelialtomesenchymal transition and cancer stem cells: a coalition against cancer therapies [J]. J Mammary Gland Biol Neoplasia, 2009, 14(1): 2943.
33.	Mani SA, Guo W, Liao MJ, et al. The epithelialmesenchymal transition generates cells with properties of stem cells [J]. Cell, 2008, 133(4): 704715.
34.	Hermann PC, Huber SL, Herrler T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer [J]. Cell Stem Cell, 2007, 1(3): 313323.
35.	Na DC, Lee JE, Yoo JE, et al. Invasion and EMTassociated genes are upregulated in B viral hepatocellular carcinoma with high expression of CD133human and cell culture study [J]. Exp Mol Pathol, 2011, 90(1): 6673.

1. Thiery JP, Sleeman JP. Complex networks orchestrate epithelialmesenchymal transitions [J]. Nat Rev Mol Cell Biol, 2006, 7(2): 131142.
2. Kong D, Li Y, Wang Z, et al. Cancer stem cells and epithelialtomesenchymal transition (EMT)phenotypic cells: are they cousins or twins? [J]. Cancers, 2011, 3(1): 716729.
3. Pasqua Ferrara A, Scalera I, Rotelli MT, et al. Stem cells and colorectal cancerogenesis: new insight [J]. Minerva Chir, 2010, 65(2): 235242.
4. Wellner U, Schubert J, Burk UC, et al. The EMTactivator ZEB1 promotes tumorigenicity by repressing stemnessinhibiting microRNAs [J]. Nat Cell Biol, 2009, 11(12): 14871495.
5. Kalluri R, Weinberg RA. The basics of epithelialmesenchymal transition [J]. J Clin Invest, 2009, 119(6): 14201428.
6. Kang H, Min BS, Lee KY, et al. Loss of Ecadherin and MUC2 expressions correlated with poor survival in patients with stages Ⅱ and Ⅲ colorectal carcinoma [J]. Ann Surg Oncol, 2011, 18(3): 711719.
7. Mimata A, Fukamachi H, Eishi Y, et al. Loss of Ecadherin in mouse gastric epithelial cells induces signet ringlike cells, a possible precursor lesion of diffuse gastric cancer [J]. Cancer Sci, 2011, 102(5): 942950.
8. Pryczynicz A, GuzińskaUstymowicz K, Kemona A, et al. Expression of the Ecadherincatenin complex in patients with pancreatic ductal adenocarcinoma [J]. Folia Histochem Cytobiol, 2010, 48(1): 128133.
9. Huang WY, Yang PM, Chang YF, et al. Methotrexate induces apoptosis through p53/p21dependent pathway and increases Ecadherin expression through downregulation of HDAC/EZH2 [J]. Biochem Pharmacol, 2011, 81(4): 510517.
10. Natalwala A, Spychal R, Tselepis C. Epithelialmesenchymal transition mediated tumourigenesis in the gastrointestinal tract [J]. World J Gastroenterol， 2008， 14(24): 37923797.
11. Lee MY, Chou CY, Tang MJ, et al. Epithelialmesenchymal transition in cervical cancer: correlation with tumor progression, epidermal growth factor receptor overexpression, and snail upregulation [J]. Clin Cancer Res, 2008, 14(15): 47434750.
12. Zeisberg M, Neilson EG. Biomarkers for epithelialmesenchymal transitions [J]. J Clin Invest, 2009, 119(6): 14291437.
13. Yang J, Eddy JA, Pan Y, et al. Integrated proteomics and genomics analysis reveals a novel mesenchymal to epithelial reverting transition in leiomyosarcoma through regulation of slug [J]. Mol Cell Proteomics, 2010, 9(11): 24052413.
14. PérezMancera PA, GonzálezHerrero I, Maclean K, et al. SLUG (SNAI2) overexpression in embryonic development [J]. Cytogenet Genome Res, 2006, 114(1): 2429.
15. Clarhaut J, Gemmill RM, Potiron VA, et al. ZEB1, a repressor of the semaphorin 3F tumor suppressor gene in lung cancer cells [J]. Neoplasia, 2009, 11(2): 157166.
16. Oztas E, Avci ME, Ozcan A, et al. Novel monoclonal antibodies detect Smadinteracting protein 1 (SIP1) in the cytoplasm of human cells from multiple tumor tissue arrays [J]. Exp Mol Pathol, 2010, 89(2): 182189.
17. Xia M, Hu M, Wang J, et al. Identification of the role of Smad interacting protein 1 (SIP1) in glioma [J]. J Neurooncol, 2010, 97(2): 225232.
18. Luo GQ, Li JH, Wen JF, et al. Effect and mechanism of the Twist gene on invasion and metastasis of gastric carcinoma cells [J]. World J Gastroenterol, 2008, 14(16): 24872493.
19. Du C, Zhang C, Hassan S, et al. Protein kinase D1 suppresses epithelialtomesenchymal transition through phosphorylation of snail [J]. Cancer Res， 2010, 70(20): 78107819.
20. 唐志锋, 周永宁, 苏晓娟, 等. Snail与Ecadherin在胃癌中的表达及临床意义 [J]. 中国急救复苏与灾害医学杂志， 2010, 5(8): 696699.
21. Castro Alves C, Rosivatz E, Schott C, et al. Slug is overexpressed in gastric carcinomas and may act synergistically with SIP1 and Snail in the downregulation of Ecadherin [J]. J Pathol, 2007, 211(5): 507515.
22. Feng MY, Wang K, Song HT, et al. Metastasisinduction and apoptosisprotection by TWIST in gastric cancer cells [J]. Clin Exp Metastasis, 2009, 26(8): 10131023.
23. Yang Z, Zhang X, Gang H, et al. Upregulation of gastric cancer cell invasion by Twist is accompanied by Ncadherin and fibronectin expression [J]. Biochem Biophys Res Commun， 2007， 358(3): 925930.
24. Lee S, Bang S, Song K, et al. Differential expression in normaladenomacarcinoma sequence suggests complex molecular carcinogenesis in colon [J]. Oncol Rep, 2006, 16(4): 747754.
25. Bottomly D, Kyler SL, McWeeney SK, et al. Identification of (beta)catenin binding regions in colon cancer cells using ChIPSeq [J]. Nucleic Acids Res， 2010, 38(17): 57355745.
26. Kuphal F, Behrens J. Ecadherin modulates Wntdependent transcription in colorectal cancer cells but does not alter Wntindependent gene expression in fibroblasts [J]. Exp Cell Res, 2006, 312(4): 457467.
27. 郑伯安, 邓高里, 董全进, 等. 表皮钙黏附素和Snail蛋白的表达与大肠癌侵袭转移及预后的关系 [J]. 中华肿瘤杂志， 2010， 2010, 32(2): 111116.
28. Shioiri M, Shida T, Koda K, et al. Slug expression is an independent prognostic parameter for poor survival in colorectalcarcinoma patients [J]. Br J Cancer, 2006, 94(12): 18161822.
29. ValdésMora F, Gómez del Pulgar T, Bandrés E, et al. TWIST1 overexpression is associated with nodal invasion and male sex in primary colorectal cancer [J]. Ann Surg Oncol, 2009, 16(1): 7887.
30. Anderson EC, Hessman C, Levin TG, et al. The role of colorectal cancer stem cells in metastatic disease and therapeutic response [J]. Cancer， 2011, 3(1): 319339.
31. May CD, Sphyris N, Evans KW, et al. Epithelialmesenchymal transition and cancer stem cells: a dangerously dynamic duo in breast cancer progression [J]. Breast Cancer Res, 2011, 13(1): 202.
32. Hollier BG, Evans K, Mani SA. The epithelialtomesenchymal transition and cancer stem cells: a coalition against cancer therapies [J]. J Mammary Gland Biol Neoplasia, 2009, 14(1): 2943.
33. Mani SA, Guo W, Liao MJ, et al. The epithelialmesenchymal transition generates cells with properties of stem cells [J]. Cell, 2008, 133(4): 704715.
34. Hermann PC, Huber SL, Herrler T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer [J]. Cell Stem Cell, 2007, 1(3): 313323.
35. Na DC, Lee JE, Yoo JE, et al. Invasion and EMTassociated genes are upregulated in B viral hepatocellular carcinoma with high expression of CD133human and cell culture study [J]. Exp Mol Pathol, 2011, 90(1): 6673.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research Progress of Epithelial-Mesenchymal-Transition in Gastrointestinal Cancer

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