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

肝细胞癌侵袭转移分子机制分析分子靶向治疗发展及复发模式预测

• 批准号: 16390375
• 负责人: ARII Shigeki
• 金额: $ 9.15万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390375/
• 关键词: hepatocellular carcinoma; invasion and metastasis; DNA binding protein; angiopoietin-2; hexisokinas-II; COX-2; VEGF; Skp-2; 浸潤・転移; dbpA; YB-1; Angiopioietin; Cox-2; 慢性肝障害; dbpa; 解糖系; 低酸素状態; 血管新生; 高癌化状態

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.

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。

项目成果

Induction of angiopoietin-2 gene expression by Cox-2.A novelrol for Cox-2 inhibitors during hepatocarcinogenesis.

Cox-2 诱导血管生成素 2 基因表达。肝癌发生过程中用于 Cox-2 抑制剂的novrol。

• 发表时间: 2006
• 期刊: Journal of Hepatology 44
• 作者: Tanaka S;Arii S;Wand J
• 通讯作者: Wand J

Current status and perspective of antiangiognic therapy for cancer : hepatocellular carcinoma.

癌症抗血管生成治疗的现状和前景：肝细胞癌。

• 发表时间: 2006
• 期刊: Int J Clin Oncol. 11
• 作者: Tanaka S;Arii S.
• 通讯作者: Arii S.

Predictive factors affecting early recurrence after hepatectomy for hepatocellular carcinoma in 5-year survivors.

影响肝细胞癌肝切除术后 5 年幸存者早期复发的预测因素。

• 发表时间: 2005
• 期刊: Hepatogastroenterology 52
• 作者: Kaido T;Arii S;Oe H;Mori A;Imamura M
• 通讯作者: Imamura M

肝細胞癌の血管新生 : HIF-1を機軸とした新たな視点 肝細胞癌 : 発癌・血管新生と血流イメージング(監修 松井修)

肝细胞癌的血管生成：以HIF-1为中心的新视角肝细胞癌：癌发生、血管生成和血流成像（指导老师：Osamu Matsui）

• 发表时间: 2004
• 作者: 有井滋樹;寺本研一;安田誠一;森章
• 通讯作者: 森章

Up-regulation of Y box binding proteins(dbpA and YB-1) as prognostic markers of hepatocellular carcinoma.

Y盒结合蛋白（dbpA和YB-1）的上调作为肝细胞癌的预后标志物。

• 发表时间: 2005
• 期刊: Clin Cancer Res. 11
• 作者: Yasen M;Kajino K;Kano S;Tobita H;Yamamoto J;Uchiumi T;Kon S;Maeda M;Obulhasim G;Arii S;Hino O
• 通讯作者: Hino O