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Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 11/2009

01-11-2009 | Translational Research and Biomarkers

Strong Smad4 Expression Correlates with Poor Prognosis After Surgery in Patients with Hepatocellular Carcinoma

Authors: Kiyokazu Hiwatashi, MD, PhD, Shinichi Ueno, MD, PhD, Masahiko Sakoda, MD, PhD, Fumitake Kubo, MD, PhD, Taro Tateno, MD, PhD, Hiroshi Kurahara, MD, PhD, Yuko Mataki, MD, PhD, Kosei Maemura, MD, PhD, Sumiya Ishigami, MD, PhD, Hiroyuki Shinchi, MD, PhD, Shoji Natsugoe, MD, PhD

Published in: Annals of Surgical Oncology | Issue 11/2009

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Abstract

Background

As a pleiotropic cytokine, transforming growth factor-β (TGF-β) controls the functions of proliferation, adhesion, and differentiation, and contributes to cancer promotion and suppression. Moreover, it is related to the epithelial–mesenchymal transition process and T cell differentiation associated with inflammation. The Smad4 protein is the downstream mediator of TGF-β. In this study, we examined the relationship between Smad4 expression and clinicopathological features in patients with hepatocellular carcinoma (HCC).

Methods

Expression of Smad4 was assessed in five HCC cell lines and in paired cancerous and noncancerous tissues in three patients with HCC, using Western blotting analysis. Moreover, Smad4 expression in 121 HCC patients was evaluated by using immunohistochemistry.

Results

Only the Li7 and HT17 cell lines expressed the Smad4 protein. All human samples expressed the protein. Immunohistochemistry showed that Smad4 expression tended to be strong in small HCC nodules less than 45 mm in diameter (P = 0.06) and in the infiltrated part of the tumor capsule. Postoperative survival analysis indicated that HCC patients with strong Smad4 expression had shorter disease-specific survival than those with weak expression (P = 0.04). Multivariate analysis also showed that Smad4 expression could be one predictor of prognosis, but the correlation was not significant (P = 0.07).

Conclusions

Although TGF-β/Smad4 signaling may have various biological effects on human malignancies, strong Smad4 expression in HCC is likely to suggest poor prognosis. The information has implications for predicting HCC prognosis and developing targeted therapeutics.
Literature
1.
2.
3.
Wakefield LM, Roberts AB. TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev. 2002;12:22–9.CrossRefPubMed
4.
Akhurst RJ, Derynck R. TGF-beta signaling in cancer—a double-edged sword. Trends Cell Biol. 2001;11:S44–51.PubMed
5.
Baek HJ, Lim SC, Kitisin K, Jogunoori W, Tang Y, Marshall MB, et al. Hepatocellular cancer arises from loss of transforming growth factor beta signaling adaptor protein embryonic liver fodrin through abnormal angiogenesis. Hepatology. 2008;48:1128–37.CrossRefPubMed
6.
Seoane J, Le HV, Shen L, Anderson SA, Massague J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell. 2004;117:211–23.CrossRefPubMed
7.
Wu Y, Zhou BP. New insights of epithelial-mesenchymal transition in cancer metastasis. Acta Biochim Biophys Sin (Shanghai). 2008;40:643–50.CrossRef
8.
Nitta T, Kim JS, Mohuczy D, Behrns KE. Murine cirrhosis induces hepatocyte epithelial mesenchymal transition and alterations in survival signaling pathways. Hepatology. 2008;48:909–19.CrossRefPubMed
9.
Kaimori A, Potter J, Kaimori JY, Wang C, Mezey E, Koteish A. Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro. J Biol Chem. 2007;282:22089–101.CrossRefPubMed
10.
Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–8.CrossRefPubMed
11.
Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, et al. IL-23 promotes tumour incidence and growth. Nature. 2006;442:461–5.CrossRefPubMed
12.
Zhang B, Rong G, Wei H, Zhang M, Bi J, Ma L, et al. The prevalence of Th17 cells in patients with gastric cancer. Biochem Biophys Res Commun. 2008;374:533–7.CrossRefPubMed
13.
Coulouarn C, Factor VM, Thorgeirsson SS. Transforming growth factor-beta gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer. Hepatology. 2008;47:2059–67.CrossRefPubMed
14.
Leivonen SK, Kahari VM. Transforming growth factor-beta signaling in cancer invasion and metastasis. Int J Cancer. 2007;121:2119–24.CrossRefPubMed
15.
Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996;271:350–3.CrossRefPubMed
16.
Natsugoe S, Xiangming C, Matsumoto M, Okumura H, Nakashima S, Sakita H, et al. Smad4 and transforming growth factor beta1 expression in patients with squamous cell carcinoma of the esophagus. Clin Cancer Res. 2002;8:1838–42.PubMed
17.
Alhopuro P, Alazzouzi H, Sammalkorpi H, Davalos V, Salovaara R, Hemminki A, et al. SMAD4 levels and response to 5-fluorouracil in colorectal cancer. Clin Cancer Res. 2005;11:6311–6.CrossRefPubMed
18.
Stuelten CH, Buck MB, Dippon J, Roberts AB, Fritz P, Knabbe C. Smad4-expression is decreased in breast cancer tissues: a retrospective study. BMC Cancer. 2006;6:25.CrossRefPubMed
19.
Torbenson M, Marinopoulos S, Dang D, Choti M, Ashfaq R, Maitra A, et al. Smad4 over expression in hepatocellular carcinoma is strongly associated with transforming growth factor beta II receptor immunolabeling. Hum Pathol. 2002;9:871–6.CrossRef
Metadata
Title
Strong Smad4 Expression Correlates with Poor Prognosis After Surgery in Patients with Hepatocellular Carcinoma
Authors
Kiyokazu Hiwatashi, MD, PhD
Shinichi Ueno, MD, PhD
Masahiko Sakoda, MD, PhD
Fumitake Kubo, MD, PhD
Taro Tateno, MD, PhD
Hiroshi Kurahara, MD, PhD
Yuko Mataki, MD, PhD
Kosei Maemura, MD, PhD
Sumiya Ishigami, MD, PhD
Hiroyuki Shinchi, MD, PhD
Shoji Natsugoe, MD, PhD
Publication date
01-11-2009
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 11/2009
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-009-0614-2

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