Development of molecular- targeting therapy and prediction of mode of recurrence by analysis of molecular mechanism of invasion and metastasis of hepatocellular carcinoma

1)在前人研究的基础上，我们重点从DNA结合蛋白A （dbpA）研究HCC发生发展的候选基因。通过对82例肝癌切除标本的免疫染色分析，我们明确了dbpA与门静脉侵袭、癌细胞分化等级及血清α胎蛋白水平密切相关，并进一步表明启动子区T向G的转化可能与预后不良有关。这些发现提示dbpA可能不仅是HCC侵袭的生物标志物，而且是分子靶向治疗的候选基因。2)基于前期研究表明血管生成素-2是HCC中重要的血管生成因子，我们研究了该分子的诱导机制。因此，我们发现PGE2和COX-2是血管生成素-2的强诱导剂，COX-2抑制剂在体内通过抑制肿瘤血管生成来抑制肿瘤生长。我们还建议血管生成素-2及其受体Tie-2可能是靶向治疗的候选分子。3)我们发现在HCC缺氧环境下，除了VEGF外，无氧糖酵解相关酶己糖激酶- ii也增强，提示抗血管生成治疗的局限性。

1) Based on the previous studies, we focused on DNA binding protein A (dbpA) to investigate the candidate gene for occurrence and development of HCC. By the analyses of immunostaining of 82 resected specimen of HCC we clarified that dbpA was closely related to the portal invasion, venous invasion, differentiation grade of cancer cell and serum level of α fetoprotein, and further showed that transformation of T to G in the promoter region may be associated with poor prognosis. These findings suggested that dbpA might be not only a biomarker for invasion of HCC, but also a candidate gene of molecular-targeting therapy.2) Based on the previous studies showing that angiopoietin-2 is an important angiogenic factor in HCC, we studied the mechanism on the induction of this molecule. Consequently, we found that PGE2 and COX-2 is strong inducers for angiopoietin-2, and that COX-2 inhibitor suppressed the tumor growth in vivo through inhibiting the tumor angiogenesis. We also suggested that angiopoietin-2 and its receptor Tie-2 may be candidate molecules for targeting therapy.3) We found that not only VEGF but also anaerobic glycolysis- related enzyme of hexisokinase-II was enhanced under the hypoxic environment in HCC, suggesting the limitation of antiangiogenic therapy.