Browse > Article
http://dx.doi.org/10.7314/APJCP.2012.13.4.1297

Smad4 Expression in Hepatocellular Carcinoma Differs by Hepatitis Status  

Yao, Lei (Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University)
Li, Fu-Jun (Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University)
Tang, Zhi-Qiang (Department of ICU, The Second Affiliated Hospital of Harbin Medical University)
Gao, Shuang (Heilongjiang Nursing College)
Wu, Qe-Quan (Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.13, no.4, 2012 , pp. 1297-1303 More about this Journal
Abstract
Aims: Primary hepatocellular carcinoma (HCC) is a common malignancy often related to hepatitis viral infection. Smad4 is known to mediate the TGF-${\beta}$ pathway to suppress tumorigenesis. However, the function of Smad4 in HCC is still controversial. In this study we compared levels of Smad4 in HCC tissues with or without hepatitis virus infection and adjacent normal-appearing liver. Methods: Samples from HCC patients were analyzed for Smad4 protein and mRNA expression by immunohistochemistry (IHC), RT-PCR and Western blotting. Results: We found that tumor tissues expressed less Smad4 mRNA and protein than the adjacent tissues. Most HCC tumor tissues were negative for Smad4 in IHC staining, while the majority of adjacent tissues were positively stained. Interestingly, protein levels were higher in HCC tissues with viral hepatitis than those without virus infection. Suppression of expression appeared closely related to HCC, so that Smad4 appears to function as a tumor suppressor gene (TSG). Conclusion: Patients with hepatitis viral infection, at higher risk for HCC, exhibited increased Smad4 protein expression suggesting hepatitis virus may modulate Smad4 expression, which is functionally distinct from its putative role as a TSG. Smad4 expression may thus be an applicable marker for diagnosis and/or a target to develop therapeutic agents for HCC.
Keywords
Liver neoplasms/genetics; SMAD4; liver cirrhosis/virology; tumor suppressor gene (TSG); viral/genetics;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Ji GZ, Wang XH, Miao L, et al (2006). Role of transforming growth factor-beta1-smad signal transduction pathway in patients with hepatocellular carcinoma. World J Gastroenterol, 12, 644-8.
2 Keasler VV, Hodgson AJ, Madden CR, Slagle BL (2007). Enhancement of hepatitis B virus replication by the regulatory X protein in vitro and in vivo. J Virol, 81, 2656-62.   DOI
3 Lai CL, Ratziu V, Yuen MF, Poynard T (2003). Viral hepatitis B. Lancet, 362, 2089-94.   DOI   ScienceOn
4 Lee DK, Park SH, Yi Y, et al (2001). The hepatitis B virus encoded oncoprotein pX amplifies TGF-$\beta$ family signaling through direct interaction with Smad4: potential mechanism of hepatitis B virus-induced liver fibrosis. Genes Dev, 15, 455-66.   DOI
5 Lei J, Zou TT, Shi YQ, et al (1996). Infrequent DPC4 gene mutation in esophageal cancer, gastric cancer and ulcerative colitis-associated neoplasms. Oncogene, 13, 2459-62.
6 Lonn P, Moren A, Raja E, et al (2009). Regulating the stability of TGFbeta receptors and Smads. Cell Res, 19, 21-35.   DOI
7 Lu Y, Wu LQ, Li CS, et al (2008). Expression of transforming growth factors in hepatocellular carcinoma and its relations with clinicopathological parameters and prognosis. Hepatobiliary Pancreat Dis Int, 7, 174-8.
8 Maitra A, Molberg K, Albores-Saavedra J, Lindberg G (2000). Loss of Dpc4 expression in colonic adenocarcinomas correlates with the presence of metastatic disease. Am J Pathol, 157, 1105-11.   DOI
9 Massague J (2008). TGFbeta in Cancer. Cell, 134, 215-30.   DOI   ScienceOn
10 Maurice D, Pierreux CE, Howell M, et al (2001). Loss of Smad4 function in pancreatic tumors: C-terminal truncation leads to decreased stability. J Biol Chem, 276, 43175-81.   DOI
11 Miyaki M, Kuroki T (2003). Role of Smad4 (DPC4) inactivation in human cancer. Biochem Biophys Res Commun, 306, 799-804.   DOI
12 Ozturk M (1995). Biology of hepatocellular carcinoma. In 'Gastrointestinal Cancers: Biology, Diagnosis, and Therapy', Ed Rustgi A. Raven Press, New York pp 511-25.
13 Pardali K, Moustakas A (2007). Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta, 1775, 21-62.
14 Remmele W, Stegner HE (1987). Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe, 8, 138-40.
15 Rossmanith W, Schulte-Hermann R (2001). Biology of transforming growth factor beta in hepatocarcinogenesis. Microsc Res Tech, 52, 430-6.   DOI   ScienceOn
16 Santiago JM, Sasako M, Osorio J (2011). TNM-7th edition 2009 (UICC/AJCC) and Japanese Classification 2010 in Gastric Cancer. Towards simplicity and standardisation in the management of gastric cancer. Cir Esp, 89, 275-81.   DOI
17 Schutte M, Hruban RH, Hedrick L, et al (1996). DPC4 gene in various tumor types. Cancer Res, 56, 2527-30.
18 Shin D, Kim SI, Kim M, Park M (2006). Efficient inhibition of hepatitis B virus replication by small interfering RNAs targeted to the viral X gene in mice. Virus Res, 119, 146-53.   DOI   ScienceOn
19 Taylor LM, Khachigian LM (2000). Induction of platelet-derived growth factor B-chain expression by transforming growth factor-$\beta$ involves transactivation by Smads. J Biol Chem, 275, 16709-16.   DOI
20 Torbenson M, Marinopoulos S, Dang DT, et al (2002). Smad4 overexpression in hepatocellular carcinoma is strongly associated with transforming growth factor beta II receptor immunolabeling. Hum Pathol, 33, 871-6.   DOI
21 Vince A (2005). Hepatitis B and C: natural course of disease. Acta Med Croatica, 59, 389-92.
22 Waite KA, Eng C (2003). From developmental disorder to heritable cancer: it's all in the BMP/TGF-beta family. Nat Rev Genet, 4, 763-73.   DOI
23 Yakicier M, Irmak M, Romano A, et al (1999). Smad2 and Smad4 gene mutations in hepatocellular carcinoma. Oncogene, 18, 4879-83.   DOI
24 Yamazaki K, Masugi Y, Sakamoto M (2011). Molecular pathogenesis of hepatocellular carcinoma: altering transforming growth factor-$\beta$ signaling in hepatocarcinogenesis. Dig Dis, 29, 284-8.   DOI   ScienceOn
25 Yang G, Yang X (2010). Smad4-mediated TGF- signaling in tumorigenesis. Int J Biol Sci, 6, 1-8.   DOI
26 Feitelson MA, Lee J (2007). Hepatitis B virus integration, fragile sites, and hepatocarcinogenesis. Cancer Lett, 252, 157-70.   DOI
27 Ang CW, Nedjadi T, Sheikh AA, et al (2010). Smad4 loss is associated with fewer S100A8-positive monocytes in colorectal tumors and attenuated response to S100A8 in colorectal and pancreatic cancer cells. Carcinogenesis, 31, 1541-51.   DOI
28 Argani P, Shaukat A, Kaushal M, et al (2001). Differing rates of loss of DPC4 expression and of p53 overexpression among carcinomas of the proximal and distal bile ducts. Cancer, 91, 1332-41.   DOI
29 de Caestecker MP, Piek E, Roberts AB (2000). Role of transforming growth factor-beta signaling in cancer. J Natl Cancer Inst, 92, 1388-402.   DOI   ScienceOn
30 Guo GH, Tan DM, Zhu PA, Liu F (2009). Hepatitis B virus X protein promotes proliferation and upregulates TGFbeta1 and CTGF in human hepatic stellate cell line, LX-2. Hepatobiliary Pancreat Dis Int, 8, 59-64.
31 Hahn SA, Hoque AT, Moskaluk CA, et al (1996a). Homozygous deletion map at 18q21.1 in pancreatic cancer. Cancer Res, 56, 490-4.
32 Hahn SA, Schutte M, Hoque AT, et al (1996b). DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science, 271, 350-3.   DOI
33 Hiwatashi K, Ueno S, Sakoda M, et al (2009). Strong Smad4 expression correlates with poor prognosis after surgery in patients with hepatocellular carcinoma. Ann Surg Oncol, 16, 3176-82.   DOI
34 Inagaki Y, Mamura M, Kanamaru Y, et al (2001). Constitutive phosphorylation and nuclear localization of Smad3 are correlated with increased collagen gene transcription in activated hepatic stellate cells. J Cell Physiol, 187, 117-23.   DOI