Nuclear Expression of Hepatitis B Virus X Protein Is Associated with Recurrence of Early-Stage Hepatocellular Carcinomas: Role of Viral Protein in Tumor Recurrence
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Background: Hepatitis B virus (HBV) plays well-known roles in tumorigenesis of hepatocellular carcinoma (HCC) in infected patients. However, HBV-associated protein status in tumor tissues and the relevance to tumor behavior has not been reported. Our study aimed to examine the expression of HBV-associated proteins in HCC and adjacent nontumorous tissue and their clinicopathologic implication in HCC patients. Methods: HBV surface antigen (HBsAg), HBV core antigen (HBcAg), and HBV X protein (HBx) were assessed in 328 HBV-associated HCCs and in 155 matched nontumorous tissues by immunohistochemistry staining. Results: The positive rates of HBsAg and cytoplasmic HBx staining in tumor tissue were lower than those in nontumorous tissue (7.3% vs. 57.4%, p < .001; 43.4% vs. 81.3%, p < .001). Conversely, nuclear HBx was detected more frequently in tumors than in nontumorous tissue (52.1% vs. 30.3%, p < .001). HCCs expressing HBsAg, HBcAg, or cytoplasmic HBx had smaller size; lower Edmondson-Steiner (ES) nuclear grade, pT stage, and serum alpha-fetoprotein, and less angioinvasion than HCCs not expressing HBV-associated proteins. Exceptionally, nuclear HBx-positive HCCs showed higher ES nuclear grade and more frequent large-vessel invasion than did nuclear HBx-negative HCCs. In survival analysis, only nuclear HBx-positive HCCs had shorter disease-free survival than nuclear HBx-negative HCCs in pT1 and ES nuclear grade 1–2 HCC subgroup (median, 126 months vs. 35 months; p = .015). Conclusions: Our data confirmed that expression of normal HBV-associated proteins generally decreases in tumor cells in comparison to nontumorous hepatocytes, with the exception of nuclear HBx, which suggests that nuclear HBx plays a role in recurrence of well-differentiated and early-stage HCCs.
Abstract
Background: Hepatitis B virus (HBV) plays well-known roles in tumorigenesis of hepatocellular carcinoma (HCC) in infected patients. However, HBV-associated protein status in tumor tissues and the relevance to tumor behavior has not been reported. Our study aimed to examine the expression of HBV-associated proteins in HCC and adjacent nontumorous tissue and their clinicopathologic implication in HCC patients. Methods: HBV surface antigen (HBsAg), HBV core antigen (HBcAg), and HBV X protein (HBx) were assessed in 328 HBV-associated HCCs and in 155 matched nontumorous tissues by immunohistochemistry staining. Results: The positive rates of HBsAg and cytoplasmic HBx staining in tumor tissue were lower than those in nontumorous tissue (7.3% vs. 57.4%, p < .001; 43.4% vs. 81.3%, p < .001). Conversely, nuclear HBx was detected more frequently in tumors than in nontumorous tissue (52.1% vs. 30.3%, p < .001). HCCs expressing HBsAg, HBcAg, or cytoplasmic HBx had smaller size; lower Edmondson-Steiner (ES) nuclear grade, pT stage, and serum alpha-fetoprotein, and less angioinvasion than HCCs not expressing HBV-associated proteins. Exceptionally, nuclear HBx-positive HCCs showed higher ES nuclear grade and more frequent large-vessel invasion than did nuclear HBx-negative HCCs. In survival analysis, only nuclear HBx-positive HCCs had shorter disease-free survival than nuclear HBx-negative HCCs in pT1 and ES nuclear grade 1–2 HCC subgroup (median, 126 months vs. 35 months; p = .015). Conclusions: Our data confirmed that expression of normal HBV-associated proteins generally decreases in tumor cells in comparison to nontumorous hepatocytes, with the exception of nuclear HBx, which suggests that nuclear HBx plays a role in recurrence of well-differentiated and early-stage HCCs.
참고문헌 (23)
- Ferlay J, "Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008", Int J Cancer, 127, pp.2893~2917 (2010)
- Nordenstedt H, "The changing pattern of epidemiology in hepatocellular carcinoma", Dig Liver Dis, 42(Suppl 3), pp.S206~S214 (2010)
- Brechot C, "Impact of HBV, HCV and GBV-C", HGV on hepatocellular carcinomas in Europe: results of a European concerted action, 1998, pp.29, 173~183
- Theise ND, "MacSween’s pathology of the liver", pp.361~401 (2012), Churchill Livingstone Elsevier
- Ng SA, "Hepatitis B virus X gene and hepatocarcinogenesis", J Gastroenterol, 46, pp.974~990 (2011)
- Goodman ZD, "Mac-Sween’s pathology of the live", pp.761~851 (2012), Churchill Livingstone Elsevier
- Xia F, "High serum hyaluronic acid and HBV viral load are main prognostic factors of local recurrence after complete radiofrequency ablation of hepatitis B-related small hepatocellular carcinoma", Ann Surg Oncol, 19, pp.1284~1291 (2012)
- Huang G, "Early viral suppression predicts good postoperative survivals in patients with hepatocellular carcinoma with a high baseline HBV-DNA load", Ann Surg Oncol, 20, pp.1482~1490 (2013)
- Yin J, "Association between the various mutations in viral core promoter region to different stages of hepatitis B, ranging of asymptomatic carrier state to hepatocellular carcinoma", Am J Gastroenterol, 106, pp.81~92 (2011)
- Tsai HW, "A clustered ground-glass hepatocyte pattern represents a new prognostic marker for the recurrence of hepatocellular carcinoma after surgery", Cancer, 117, pp.2951~2960 (2011)
- Kremsdorf D, "Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis", Oncogene, 25, pp.3823~3833 (2006)
- Zhu M, "The value of hepatitis B x antigen as a prognostic marker in the development of hepatocellular carcinoma", Int J Cancer, 55, pp.571~576 (1993)
- Edge SB, "The American Joint Committee on Cancer:the 7th edition of the AJCC cancer staging manual and the future of TNM", Ann Surg Oncol, 17, pp.1471~1474 (2010)
- Liver Cancer Study Group of Japan, "The general rules for the clinical and pathological study of primary liver cancer", Jpn J Surg, 19, pp.98~129 (1989)
- Shiota G, "Occult hepatitis B virus infection in HBs antigen-negative hepatocellular carcinoma in a Japanese population: involvement of HBx and p53", J Med Virol, 62, pp.151~158 (2000)
- Keasler VV, "Hepatitis B virus HBx protein localized to the nucleus restores HBx-deficient virus replication in HepG2 cells and in vivo in hydrodynamically-injected mice", Virology, 390, pp.122~129 (2009)
- Sung WK, "Deregulated direct targets of the hepatitis B virus (HBV) protein, HBx, identified through chromatin immunoprecipitation and expression microarray profiling", J Biol Chem, 284, pp.21941~21954 (2009)
- Ou DP, "The hepatitis B virus X protein promotes hepatocellular carcinoma metastasis by upregulation of matrix metalloproteinases", Int J Cancer, 120, pp.1208~1214 (2007)
- Xie H, "The expression of hypoxia-inducible factor-1alpha in hepatitis B virus-related hepatocellular carcinoma:correlation with patients’ prognosis and hepatitis B virus X protein", Dig Dis Sci, 53, pp.3225~3233 (2008)
- Xia L, "Upregulated FoxM1 expression induced by hepatitis B virus X protein promotes tumor metastasis and indicates poor prognosis in hepatitis B virus-related hepatocellular carcinoma", J Hepatol, 57, pp.600~612 (2012)
- Liu H, "Hepatitis B virus X protein promotes hepatoma cell invasion and metastasis by stabilizing Snail protein", Cancer Sci, 103, pp.2072~2081 (2012)
- Zhang X, "Effects of hepatitis B virus X protein on human telomerase reverse transcriptase expression and activity in hepatoma cells", J Lab Clin Med, 145, pp.98~104 (2005)
- Su CW, "The influence of hepatitis B viral load and pre-S deletion mutations on post-operative recurrence of hepatocellular carcinoma and the tertiary preventive effects by anti-viral therapy", PLoS One, 8, pp.E66457~ (2013)