Asian Pacific Journal of Cancer Prevention

  • 제13권4호
  • /
  • Pages.1297-1303
  • /
  • 2012
  • /
  • 1513-7368(pISSN)
  • /
  • 2476-762X(eISSN)
아시아태평양암예방학회 (Asian Pacific Journal of Cancer Prevention)
권호 표지
DOI QR코드

DOI QR Code

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)
  • 발행 : 2012.04.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

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.

키워드

참고문헌

  1. 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. https://doi.org/10.1093/carcin/bgq137
  2. 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. https://doi.org/10.1002/1097-0142(20010401)91:7<1332::AID-CNCR1136>3.0.CO;2-4
  3. de Caestecker MP, Piek E, Roberts AB (2000). Role of transforming growth factor-beta signaling in cancer. J Natl Cancer Inst, 92, 1388-402. https://doi.org/10.1093/jnci/92.17.1388
  4. Feitelson MA, Lee J (2007). Hepatitis B virus integration, fragile sites, and hepatocarcinogenesis. Cancer Lett, 252, 157-70. https://doi.org/10.1016/j.canlet.2006.11.010
  5. 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.
  6. Hahn SA, Hoque AT, Moskaluk CA, et al (1996a). Homozygous deletion map at 18q21.1 in pancreatic cancer. Cancer Res, 56, 490-4.
  7. Hahn SA, Schutte M, Hoque AT, et al (1996b). DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science, 271, 350-3. https://doi.org/10.1126/science.271.5247.350
  8. 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. https://doi.org/10.1245/s10434-009-0614-2
  9. 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. https://doi.org/10.1002/1097-4652(2001)9999:9999<00::AID-JCP1059>3.0.CO;2-S
  10. 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.
  11. 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. https://doi.org/10.1128/JVI.02020-06
  12. Lai CL, Ratziu V, Yuen MF, Poynard T (2003). Viral hepatitis B. Lancet, 362, 2089-94. https://doi.org/10.1016/S0140-6736(03)15108-2
  13. 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. https://doi.org/10.1101/gad.856201
  14. 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.
  15. Lonn P, Moren A, Raja E, et al (2009). Regulating the stability of TGFbeta receptors and Smads. Cell Res, 19, 21-35. https://doi.org/10.1038/cr.2008.308
  16. 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.
  17. 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. https://doi.org/10.1016/S0002-9440(10)64625-1
  18. Massague J (2008). TGFbeta in Cancer. Cell, 134, 215-30. https://doi.org/10.1016/j.cell.2008.07.001
  19. 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. https://doi.org/10.1074/jbc.M105895200
  20. Miyaki M, Kuroki T (2003). Role of Smad4 (DPC4) inactivation in human cancer. Biochem Biophys Res Commun, 306, 799-804. https://doi.org/10.1016/S0006-291X(03)01066-0
  21. Ozturk M (1995). Biology of hepatocellular carcinoma. In 'Gastrointestinal Cancers: Biology, Diagnosis, and Therapy', Ed Rustgi A. Raven Press, New York pp 511-25.
  22. 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.
  23. 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.
  24. Rossmanith W, Schulte-Hermann R (2001). Biology of transforming growth factor beta in hepatocarcinogenesis. Microsc Res Tech, 52, 430-6. https://doi.org/10.1002/1097-0029(20010215)52:4<430::AID-JEMT1028>3.0.CO;2-3
  25. 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. https://doi.org/10.1016/j.ciresp.2010.10.011
  26. Schutte M, Hruban RH, Hedrick L, et al (1996). DPC4 gene in various tumor types. Cancer Res, 56, 2527-30.
  27. 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. https://doi.org/10.1016/j.virusres.2005.12.012
  28. 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. https://doi.org/10.1074/jbc.275.22.16709
  29. 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. https://doi.org/10.1053/hupa.2002.128061
  30. Vince A (2005). Hepatitis B and C: natural course of disease. Acta Med Croatica, 59, 389-92.
  31. 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. https://doi.org/10.1038/nrg1178
  32. Yakicier M, Irmak M, Romano A, et al (1999). Smad2 and Smad4 gene mutations in hepatocellular carcinoma. Oncogene, 18, 4879-83. https://doi.org/10.1038/sj.onc.1202866
  33. 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. https://doi.org/10.1159/000327560
  34. Yang G, Yang X (2010). Smad4-mediated TGF- signaling in tumorigenesis. Int J Biol Sci, 6, 1-8. https://doi.org/10.3923/ijb.2010.1.10

피인용 문헌

  1. Circulating MicroRNAs in Plasma of Hepatitis B e Antigen Positive Children Reveal Liver-Specific Target Genes vol.2014, pp.2090-3456, 2014, https://doi.org/10.1155/2014/791045
  2. SMAD4 exerts a tumor-promoting role in hepatocellular carcinoma vol.34, pp.39, 2015, https://doi.org/10.1038/onc.2014.425
  3. Significance of pSmad2/3 and Smad4 in hepatitis C virus-related liver fibrosis and hepatocellular carcinoma vol.126, pp.6, 2018, https://doi.org/10.1111/apm.12844