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http://dx.doi.org/10.7314/APJCP.2012.13.10.5161

Expression of Smad7 in Cholangiocarcinoma: Prognostic Significance and Implications for Tumor Metastasis  

Huang, Qiang (Department of General Surgery, the Affiliated Provincial Hospital of Anhui Medical University)
Liu, Lei (Department of General Surgery, the Affiliated Provincial Hospital of Anhui Medical University)
Liu, Chen-Hai (Department of General Surgery, the Affiliated Provincial Hospital of Anhui Medical University)
Shao, Feng (Department of General Surgery, the Affiliated Provincial Hospital of Anhui Medical University)
Xie, Fang (Department of General Surgery, the Affiliated Provincial Hospital of Anhui Medical University)
Zhang, Chuan-Hai (Department of General Surgery, the Affiliated Provincial Hospital of Anhui Medical University)
Hu, San-Yuan (Department of General Surgery, Qilu Hospital of Shandong University)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.13, no.10, 2012 , pp. 5161-5165 More about this Journal
Abstract
Background: There are few molecular markers known to predict cholangiocarcinoma (CCA) prognosis. Smad7 has a certain relationship with epithelial-mesenchymal transition (EMT), but its relevance to CCA in unclear. Therefore expression and clinical significance of Smad7 in CCA was the focus of this study. Methods: Expression of Smad7, E-cadherin and vimentin was assessed in 41 patients with CCA by immunohistochemistry and analyzed for associations with clinical parameters. Results: Smad7 and vimentin expression in the CCA tissue was dramatically higher than that in adjacent tissues. In addition, Smad7, vimentin and E-cadherin expression was significantly associated with CCA lymph node metastasis and perineural invasion($P{\leq}0.05$), but not other factors, such as gender, age, tumor location, tumor type and tumor differentiation degree (P>0.05). The overall survival and relapse-free survival rate was significantly higher in patients with negative Smad7 expression than those with positive Smad7 expression. Conclusion: EMT phenomena may occur in the process of CCA invasion and metastasis. Smad7, which was highly expressed in CCA, may be considered to be one feedback regulator in late stages and could have potential as a prognostic indicator for clinical assessment.
Keywords
Smad7; epithelial mesenchymal transition; cholangiocarcinoma; metastasis; prognostic indicator;
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1 Aljiffry M, Walsh M J, Molinari M (2009). Advance in diagnosis,treatment and palliation of cholangiocarcarcinoma: 1990-2009. World J Gastrointestinal, 15, 4240-62.   DOI
2 Chen YK, Huang AH, Cheng PH, et a1(2012). Overexpression of Smad proteins, especially Smad7, in oral epithelial dysplasias. Clin Oral Investig, 6, 6.
3 Dahler AL, Cavanagh LL, Saunders NA (2001). Suppression of keratinocyte growth and differentiation by transforming growth factor beta1 involves multiple signaling pathways. J Invest Dermatol, 116, 266-74.   DOI
4 Drabsch Y, Ten Dijke P (2012). TGF-${\beta}$ signalling and its role in cancer progression and metastasis. Cancer Metastasis Rev, 7, 20.
5 Gratchev A, Kzhyshkowska J, Kannookadan S, et a1 (2008). Activation of a TGF-beta-specific multistep gene expression program in mature macrophages requires glucocorticoidmediated surface expression of TGF-beta receptor II. J Immunol, 180, 6553-65.   DOI
6 Halder SK, Rachakonda G, Deane NG, et a1 (2008). Smad7 induces hepatic metastasis in colorectal cancer. Brit J Cancer, 4, 957-65.
7 Hayashi H, Abollah S, Qiu Y, et al (1997). The MAD-related protein Smad7 associates with the TGF-beta receptor and functions as an antagonist of TGF-beta signaling. Cell, 89, 1165-73.   DOI
8 Iiizumi M, Liu W, Pai SK, et al (2008). Drug development against metastasis-related genes and their pathways: a rationale for cancer therapy. Biochim Biophys Acta, 1786, 87-104.
9 Iwatsuki M, Mimori K, Yokobori T, et al (2010). Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Sci, 101, 293-9.   DOI
10 Kalluri R, Weinberg RA(2009). The basics of epithelial-mesenchymal transition. J Clin Invest, 119, 1420-8.   DOI
11 Kim YH, Lee HS, Lee HJ, et a1 (2004). Prognostic significance of the expression of Smad4 and Smad7 in human gastric carcinomas. Ann Oncol, 15, 574-80.   DOI   ScienceOn
12 Kleeff J, Ishiwata T, Maruyama H , et al(1999). The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Oncogene, 18, 5363-72.   DOI   ScienceOn
13 Kokkinos MA, wafai R, Wong MK, et al (2007). Vimentin and epithelial-mesenchymal transition in human breast cancer-observations in vitro and in vivo. Cells Tiss Organs, 185, 191-203.   DOI
14 Lan HY, Chung AC (2011). Transforming growth factor-${\beta}$ and Smads. Contrib Nephrol, 170, 75-82.   DOI
15 Leng A, Liu T, He Y, Li Q, Zhang G (2009). Smad4/Smad7 balance: A role of tumorigenesis in gastric cancer. Exp Mol Pathol, 87, 48-53.   DOI
16 Li H, Qin Y, Cui Y, et al (2011). Analysis of the surgical outcome and prognostic factors for hilar cholangiocarcinoma: a Chinese experience. Dig Surg, 28, 226-31.   DOI
17 Li Y, Wang JP, Santen RJ, et al (2010). Estrogen stimulation of cell migration involves multiple signaling pathway interactions. Endocrinology, 151, 5146-56.   DOI
18 Nakajima S, Doi R, Toyoda E, et al (2004). N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma. Clin Cancer Res, l0, 4125-33.
19 Liu Q, Zhang Y, Mao H, et a1 (2012). A crosstalk between the Smad and JNK signaling in the TGF-${\beta}$-induced epithelialmesenchymal transition in rat peritoneal mesothelial cells. PLoS One, 7, e32009.   DOI
20 Moustakas A, Heldin CH (2007). Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci, 98, 1512-20.   DOI   ScienceOn
21 Neilson EG (2006). Mechanisms of disease: Fibroblasts-a new look at an old problem. Nat Clin Pract Nephrol, 2, 101-8.   DOI
22 Park YN, Chae KJ, Oh B K, et al (2004). Expression of Smad7 in hepatocellular carcinoma and dysplastic nodules: resistance mechanism transforming growth factor-beta. Hepatogastroenterology, 51, 396-400.
23 Peinado H, Olmeda D, Cano A (2007). Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer, 7, 415-28.   DOI
24 Pittman AM, Naranjo S, Webb E, et al(2009). The colorectal cancer risk at 18q21 is caused by a novel variant altering SMAD7 expression. Genome Res, 19, 987-93.   DOI
25 Polette M, Mestdagt M, Bindels S, et al (2007). Beta-catenin and ZO-1: shuttle molecules involved in tumor invasionassociated epithelial-mesenchymal transition processes[J]. Cells Tiss Organs, 185, 61-5.   DOI
26 Sabe H (2011). Cancer early dissemination: cancerous epithelial-mesenchymal transdifferentiation and transforming growth factor ${\beta}$ signalling. J Biochem, 149, 633-9.   DOI
27 Zhu HJ, Iaria J, Sizeland AM(1999). Smad7 differentially regulates transforming growth factor beta-mediated signaling pathways. J Biol Chem, 274, 32258-64.   DOI
28 Sandusky G, Berg DT, Richardson MA, et al (2002). Modulation of thrombomodulin-dependent activation of human protein C through differential expression of endothelial Smads[J]. J Biol Chem, 277, 49815-9.   DOI
29 Sethi S, Sarkar FH, Ahmed Q, et al (2011). Molecular markers of epithelial-to-mesenchymal transition are associated with tumor aggressiveness in breast carcinoma. Transl Oncol, 4, 222-6.   DOI
30 Yu H, Zhao G, Li H, et al (2012). Candesartan antagonizes pressure overload-evoked cardiac remodeling through Smad7 gene-dependent MMP-9 suppression. Gene, 1, 3.
31 Zhu L, Wang L, Wang X, et al (2011). Hepatic deletion of Smad7 in mouse leads to spontaneous liver dysfunction and aggravates alcoholic liver injury. PLoS One, 6, e17415.   DOI