Expression of Cyclooxygenase-2 and Transforming Growth Factor-Beta 1 in Patients with the Early Recurrence of Hepatocellular Carcinoma Following Hepatectomy

DOI: 10.4236/ss.2012.36064   PDF   HTML   XML   3,191 Downloads   4,987 Views   Citations

Abstract

Background: Cyclooxygenase-2 (COX-2) and transforming growth factor-beta1 (TGF-β1) are modulated in variety cancers including Hepatocellular carcinoma (HCC). However, there is a paucity of data concerning their role in the pathologic process of recurrence of HCC following hepatectomy. We herein assessed the role of the hepatic expression of COX-2 and TGF-β as predictors for patients with early recurrence within 2 years of HCC diagnosis. Methods: Sixty patients with HCC who underwent curative hepatectomy between 2000 and 2003 were entered in the present study. The immunoreactivity and distribution patterns of COX-2 and TGF-β1 were examined in both the HCC and the adjacent nonHCC tissues of the liver. Risk factors of tumor recurrence within 2 years, including COX-2 and TGF-β1 expression, were investigated by univariate and multivariate analyses. Results: Among 60 patients, 31 patients had early recurrences within 2 years and 14 patients recurred after 2 years following surgery. Patients with low COX-2 expression in the HCC tissues and adjacent nonHCC tissues had favorable disease-free survival (p = 0.002 and p < 0.001, respectively) and patients with positive TGF-β1 expression in the nonHCC tissues had also longer disease-free survival (p = 0.045). Based on the expression patterns of COX-2 and TGF-β1, patients with low COX-2 and positive TGF-β1 expression in the nonHCC tissues had favorable overall and disease-free survival (p < 0.001, respectively). Conclusions: Increased COX-2 expression and decreased TGF-β1 signaling in nontumor tissues suggested high risk of recurrence and poor survival to the HCC patients following hepatectomy.

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T. Nakase, M. Ueno, K. Uchiyama, N. Matsuura and H. Yamaue, "Expression of Cyclooxygenase-2 and Transforming Growth Factor-Beta 1 in Patients with the Early Recurrence of Hepatocellular Carcinoma Following Hepatectomy," Surgical Science, Vol. 3 No. 6, 2012, pp. 322-331. doi: 10.4236/ss.2012.36064.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] K. Uchiyama, K. Mori, K. Tabuse, M. Ueno, S. Ozawa, T. Nakase, M. Kawai, M. Tani, H. Tanimura and H. Yamaue, “Assessment of Liver Function for Successful Hepatectomy in Patients with Hepatocellular Carcinoma with Impaired Hepatic Function,” Journal of Hepato-Biliary-Pancreatic Surgery, Vol. 15, No. 6, 2008, pp. 596-602. doi:10.1007/s00534-007-1326-2
[2] M. Ueno, K. Uchiyama, S. Ozawa, S. Hayami, S. Kiriyama and H. Yamaue, “A New Prediction Model of Postoperative Complications after Major Hepatectomy for Hepatocellular Carcinoma,” Digestive Surgery, Vol. 26, No. 5, 2009, pp. 392-399. doi:10.1159/000229973
[3] S. A. Shah, S. P. Cleary, A. C. Wei, I. Yang, B. R. Taylor, A. W. Hemming, B. Langer, D. R. Grant, P. D. Greig and S. Gallinger, “Recurrence after Liver Resection for Hepatocellular Carcinoma: Risk Factors, Treatment, and Outcomes,” Surgery, Vol. 141, No. 3, 2007, pp. 330-339. doi:10.1016/j.surg.2006.06.028
[4] M. Ueno, K. Uchiyama, S. Ozawa, T. Nakase, N. Togo, S. Hayami and H. Yamaue, “Prognostic Impact of Treatment Modalities on Patients with Single Nodular Recurrence of Hepatocellular Carcinoma,” Surgery Today, Vol. 39, No. 8, 2009, pp. 675-681. doi:10.1007/s00595-008-3942-0
[5] S. Yoshioka, I. Takemasa, H. Nagano, N. Kittaka, T. Noda, H. Wada, S. Kobayashi, S. Marubashi, Y. Takeda, K. Umeshita, K. Dono, K. Matsubara and M. Monden, “Molecular Prediction of Early Recurrence after Resection of Hepatocellular Carcinoma,” European Journal of Cancer, Vol. 45, No. 5, 2009, pp. 881-889. doi:10.1016/j.ejca.2008.12.019
[6] M. E. Herceg, A. C. Tsiatis, J. L. Halpern, G. E. Holt, H. S. Schwartz, V. L. Keedy and J. M. Cates, “Cyclooxygenase 2 Expression in Soft Tissue Leiomyosarcoma,” Anticancer Research, Vol. 29, No. 8, 2009, pp. 2913-2917.
[7] C. J. Liu, T. C. Hsia, R. F. Wang, C. W. Tsai, C. C. Chu, L. W. Hang, C. H. Wang, H. Z. Lee, R. Y. Tsai and D. T. Bau, “Interaction of Cyclooxygenase 2 Genotype and Smoking Habit in Taiwanese Lung Cancer Patients,” Anticancer Research, Vol. 30, No. 4, 2010, pp. 1195-1199.
[8] J. G. Kim, Y. S. Chae, S. K. Sohn, J. H. Moon, H. M. Ryoo, S. H. Bae, Y. Kum, S. W. Jeon, K. H. Lim, B. M. Kang, I. J. Park, G. S. Choi and S. H. Jun, “Prostaglandin Synthase 2/Cyclooxygenase 2 (PTGS2/COX2) 8473T>C Polymorphism Associated with Prognosis for Patients with Colorectal Cancer Treated with Capecitabine and Oxaliplatin,” Cancer Chemotherapy and Pharmacology, Vol. 64, No. 5, 2009, pp. 953-960. doi:10.1007/s00280-009-0947-3
[9] A. T. Panagopoulos, C. L. Lancellotti, J. C. Veiga, P. H. de Aguiar and A. Colquhoun, “Expression of Cell Adhesion Proteins and Proteins Related to Angiogenesis and Fatty Acid Metabolism in Benign, Atypical, and Anaplastic Meningiomas,” Journal of Neuro-Oncology, Vol. 89, No. 1, 2008, pp. 73-87. doi:10.1007/s11060-008-9588-3
[10] M. G. Alexandrow and H. L. Moses, “Transforming Growth Factor Beta and Cell Cycle Regulation,” Cancer Research, Vol. 55, No. 7, 1995, pp. 1452-1457.
[11] H. You, W. Ding and C. B. Rountree, “Epigenetic Regulation of Cancer Stem Cell Marker CD133 by Transforming Growth Factor-Beta,” Hepatology, Vol. 51, No. 5, 2010, pp. 1635-1644. doi:10.1002/hep.23544
[12] Y. S. Guo, Z. Chen, X. D. Wen, T. C. Ko, C. M. Townsend Jr. and M. R. Hellmich, “Synergistic Regulation of COX-2 Expression by Bombesin and Transforming Growth Factor-Beta,” Digestive Diseases and Sciences, Vol. 53, No. 8, 2008, pp.2045-2052. doi:10.1007/s10620-007-0122-9
[13] D. Saha, P. K. Datta, H. Sheng, J. D. Morrow, M. Wada, H. L. Moses and R. D. Beauchamp, “Synergistic Induction of cyclooxygenase-2 by Transforming Growth Factor-Beta1 and Epidermal Growth Factor Inhibits Apoptosis in Epithelial Cells,” Neoplasia, Vol. 1, No. 6, 1999, pp. 508-517. doi:10.1038/sj.neo.7900051
[14] H. Koga, S. Sakisaka, M. Ohishi, T. Kawaguchi, E. Taniguchi, K. Sasatomi, M. Harada, T. Kusaba, M. Tanaka, R. Kimura, Y. Nakashima, O. Nakashima, M. Kojiro, T. Kurohiji and M. Sata, “Expression of Cyclooxygenase-2 in Human Hepatocellular Carcinoma: Relevance to Tumor Dedifferentiation,” Hepatology, Vol. 29, No. 3, 1999, pp. 688-696 doi:10.1002/hep.510290355
[15] A. S. Cheng, H. L. Chan, W. K. Leung, K. F. To, M. Y. Go, J. Y. Chan, C. T. Liew and J. J. Sung, “Expression of HBx and COX-2 in Chronic Hepatitis B, Cirrhosis and Hepatocellular Carcinoma: Implication of HBx in Upregulation of COX-2,” Modern Pathology, Vol. 17, 2004, pp. 1169-1179. doi:10.1038/modpathol.3800196
[16] N. Nishida, T. Nagasaka, T. Nishimura, I. Ikai, C. R. Boland and A. Goel, “Aberrant Methylation of Multiple Tumor Suppressor Genes in Aging Liver, Chronic Hepatitis, and Hepatocellular Carcinoma,” Hepatology, Vol. 47, No. 3, 2008, pp. 908-918. doi:10.1002/hep.22110
[17] A. J. Dannenberg and K. Subbaramaiah, “Targeting Cyclooxygenase-2 in Human Neoplasia: Rationale and Promise,” Cancer Cell, Vol. 4, No. 6, 2003, pp. 431-436. doi:10.1016/S1535-6108(03)00310-6
[18] M. Kondo, H. Yamamoto, H. Nagano, J. Okami, Y. Ito, J. Shimizu, H. Eguchi, A. Miyamoto, K. Dono, K. Umeshita, N. Matsuura, K. Wakasa, S. Nakamori, M. Sakon and M. Monden, “Increased Expression of COX-2 in Nontumor Liver Tissue Is Associated with Shorter Disease-Free Survival in Patients with Hepatocellular Carcinoma,” Clinical Cancer Research, Vol. 5, No. 12, 1999, pp. 4005-4012.
[19] Y. F. He, J. Jin, W. Wei, Y. Chang, B. Hu, C. S. Ji, W. D. Jia, X. Q. Wang, K. Chen and J. Chen, “Overexpression of Cyclooxygenase-2 in Noncancerous Liver Tissue Increases the Postoperative Recurrence of Hepatocellular Carcinoma in Patients with Hepatitis B Virus-Related Cirrhosis,” Canadian Journal of Gastroenterology, Vol. 24, No. 7, 2010, pp. 435-440.
[20] S. Morinaga, K. Tarao, Y. Yamamoto, Y. Nakamura, Y. Rino, K. Miyakawa, S. Ohkawa, M. Akaike, Y. Sugimasa and S. Takemiya, “Overexpressed Cyclo-oxygenase-2 in the Background Liver Is Associated with the Clinical Course of Hepatitis C Virus-Related Cirrhosis Patients after Curative Surgery for Hepatocellular Carcinoma,” Journal of Gastroenterology and Hepatology, Vol. 22, No. 8, 2007, pp. 1249-1255. doi:10.1111/j.1440-1746.2006.04367.x
[21] S. Ozawa, K. Uchiyama, M. Nakamori, K. Ueda, M. Iwahashi, H. Ueno, Y. Muragaki, A. Ooshima and H. Yamaue, “Combination Gene Therapy of HGF and Truncated Type II TGF-beta Receptor for Rat Liver Cirrhosis after Partial Hepatectomy,” Surgery, Vol. 139, No. 4, 2006, pp.563-573. doi:10.1016/j.surg.2005.10.003
[22] J. Shao, H. Sheng, R. Aramandla, M. A. Pereira, R. A. Lubet, E. Hawk, L. Grogan, I. R. Kirsch, M. K. Washington, R. D. Beauchamp and R. N. DuBois, “Coordinate Regulation of Cyclooxygenase-2 and TGF-beta1 in Replication Error-Positive Colon Cancer and Azoxymethane-Induced Rat Colonic Tumors,” Carcinogenesis, Vol. 20, No. 2, 1999, pp. 185-191. doi:10.1093/carcin/20.2.185
[23] C. Han, A. J. Demetris, Y. Liu, J. H. Shelhamer and T. Wu, “Transforming Growth Factor-Beta (TGF-beta) Activates Cytosolic Phospholipase A2alpha (cPLA2alpha)-Mediated Prostaglandin E2 (PGE)2/EP1 and Peroxisome Proliferator-Activated Receptor-Gamma (PPAR-gamma)/ Smad Signaling Pathways in Human Liver Cancer Cells. A Novel Mechanism for Subversion of TGF-beta-induced Mitoinhibition,” Journal of Biological Chemistry, Vol. 279, No. 43, 2004, pp. 44344-44354. doi:10.1074/jbc.M404852200

  
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