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Induction of Angiopoietin-2 gene expression by COX-2: A novel role for COX-2 inhibitors during hepatocarcinogenesis

2005; Elsevier BV; Volume: 44; Issue: 1 Linguagem: Inglês

10.1016/j.jhep.2005.09.012

1600-0641

Shinji Tanaka, Jack R. Wands, Shigeki Arii,

Angiogenesis and VEGF in Cancer

The possibility of preventing hepatitis B and C related hepatocellular carcinoma (HCC) by anti-viral agents in high-risk patients has become increasingly important given the worldwide prevalence of this devastating disease [[1]Wands J.R. Prevention of hepatocellular carcinoma.N Engl J Med. 2004; 351: 1567-1570Crossref PubMed Scopus (93) Google Scholar]. In this regard reported by Márquez-Rosado et al. [[2]Marquez-Rosado L. Trejo-Solis M.C. Garcia-Cuellar C.M. Villa-Trevino S. Celecoxib, a cyclooxygenase-2 inhibitor, prevents induction of liver preneoplastic lesions in rats.J Hepatol. 2005; 43: 653-660Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar], there is also evidence that links cyclooxygenase-2 (COX-2) with hepatopathogenesis. Indeed, a more recent report demonstrates that hepatitis C virus replicons enhance COX-2 expression in human hepatocytes [[3]Waris G. Siddiqui A. Hepatitis C virus stimulates the expression of cyclooxygenase-2 via oxidative stress: role of prostaglandin E2 in RNA replication.J Virol. 2005; 79: 9725-9734Crossref PubMed Scopus (119) Google Scholar]. Although the precise role of COX-2 in the pathogenesis of HCC remains to be defined, there is accumulating evidence that 'angiogenesis' is one of the critical mechanisms important in the progression of HCC. We have previously identified Angiopoeitin-2 (Ang-2) as one of the angiogenic switch genes in the pathogenesis of HCC [4Tanaka S. Mori M. Sakamoto Y. Makuuchi M. Sugimachi K. Wands J.R. Biologic significance of angiopoietin-2 expression in human hepatocellular carcinoma.J Clin Invest. 1999; 103: 341-345Crossref PubMed Scopus (236) Google Scholar, 5Tanaka S. Sugimachi K. Yamashita Yi Y. Ohga T. Shirabe K. Shimada M. et al.Tie2 vascular endothelial receptor expression and function in hepatocellular carcinoma.Hepatology. 2002; 35: 861-867Crossref PubMed Scopus (79) Google Scholar, 6Sugimachi K. Tanaka S. Taguchi K. Aishima S. Shimada M. Tsuneyoshi M. Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinoma.J Clin Pathol. 2003; 56: 854-860Crossref PubMed Scopus (86) Google Scholar]. Ang-2 was extensively overexpressed in hypervascular HCCs, and resulted in rapid tumor growth and hemorrhage in an animal model system of HCC [4Tanaka S. Mori M. Sakamoto Y. Makuuchi M. Sugimachi K. Wands J.R. Biologic significance of angiopoietin-2 expression in human hepatocellular carcinoma.J Clin Invest. 1999; 103: 341-345Crossref PubMed Scopus (236) Google Scholar, 6Sugimachi K. Tanaka S. Taguchi K. Aishima S. Shimada M. Tsuneyoshi M. Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinoma.J Clin Pathol. 2003; 56: 854-860Crossref PubMed Scopus (86) Google Scholar]. Furthermore, inhibition of Ang-2 signaling induced vascular endothelial apoptosis, leading to in vivo anti-angiogenic effects and suppression of HCC tumor formation [[5]Tanaka S. Sugimachi K. Yamashita Yi Y. Ohga T. Shirabe K. Shimada M. et al.Tie2 vascular endothelial receptor expression and function in hepatocellular carcinoma.Hepatology. 2002; 35: 861-867Crossref PubMed Scopus (79) Google Scholar]. Although Ang-2 has a crucial role in hepatocarcinogenesis [7Mitsuhashi N. Shimizu H. Ohtsuka M. Wakabayashi Y. Ito H. Kimura F. et al.Angiopoietins and Tie-2 expression in angiogenesis and proliferation of human hepatocellular carcinoma.Hepatology. 2003; 37: 1105-1113Crossref PubMed Scopus (160) Google Scholar, 8Ogawa M. Yamamoto H. Nagano H. Miyake Y. Sugita Y. Hata T. et al.Hepatic expression of ANG2 RNA in metastatic colorectal cancer.Hepatology. 2004; 39: 528-539Crossref PubMed Scopus (47) Google Scholar], the effect of COX-2 on Ang-2 expression in HCC cells has not been determined. As shown in Fig. 1A, transient transfection of a COX-2 expressing cDNA enhanced Ang-2 expression in human HCC cells; gene induction was dose-dependent. Next, the effect of several inflammatory cytokines on Ang-2 gene expression was analyzed as demonstrated by the RT-PCR panel depicted in Fig. 1B. Prostaglandin E2 known to be involved in COX-2 synthesis induced expression of the Ang-2 gene. In contrast, Ang-2 expression was not induced by stimulation with several inflammatory cytokines such as interleukin-1β, interferon-γ, tumor necrosis factor-α, or tumor growth factor-β as controls. Finally, a specific inhibitor of COX-2, namely NS-398, was used in the murine model to study its effect of HCC tumor growth. Administration of NS-398 attenuated gene expression of Ang-2 (Fig. 1C), resulting in inhibition of tumor angiogenesis and growth in an animal model system of HCC (Fig. 1D and E). Thus, COX-2 inhibitors might be considered as a therapeutic agent to suppress Ang-2 expression and prevent or reduce HCC progression by targeting this pathway. The angiogenic switch mechanism involves sprouting of new blood vessels from pre-existing ones and appears essential for HCC development and progression [4Tanaka S. Mori M. Sakamoto Y. Makuuchi M. Sugimachi K. Wands J.R. Biologic significance of angiopoietin-2 expression in human hepatocellular carcinoma.J Clin Invest. 1999; 103: 341-345Crossref PubMed Scopus (236) Google Scholar, 9Tanaka S. Sugimachi K. Yamashita Yi Y. Shirabe K. Shimada M. Wands J.R. et al.Angiogenic switch as a molecular target of malignant tumors.J Gastroenterol. 2003; 38: 93-97PubMed Google Scholar]. The evidence presented here suggest that COX-2 regulates Ang-2 expression in HCC cells in vitro and in vivo, and COX-2 inhibitors may serve as anti-tumor agents [3Waris G. Siddiqui A. Hepatitis C virus stimulates the expression of cyclooxygenase-2 via oxidative stress: role of prostaglandin E2 in RNA replication.J Virol. 2005; 79: 9725-9734Crossref PubMed Scopus (119) Google Scholar, 10Koga H. Hepatocellular carcinoma: is there a potential for chemoprevention using cyclooxygenase-2 inhibitors?.Cancer. 2003; 98: 661-667Crossref PubMed Scopus (35) Google Scholar]. Finally, a better understanding of the relationship between COX-2 and Ang-2 gene expression will likely increase our knowledge of the role of angiogenic activity during hepatic oncogenesis as well as lead to new drug candidates for the treatment of HCC.