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Molecular mechanisms of intrahepatic metastasis of hepatocellular carcinoma and application for diagnosis and treatment

肝细胞癌肝内转移的分子机制及其在诊疗中的应用

基本信息

批准号：
12470049
负责人：
SAKAMOTO Michiie
金额：
$ 3.65万
依托单位：
NATIONAL CANCER CENTER
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470049/
关键词：
hepatocellular carcinoma invasion and metastasis cell motility integrin c-Src Rho kinase gene expression analysis CO-029 DRH1 VDUP1 tetraspanin 転移カドヘリン Rho

项目摘要

Intrahepatic metastasis is one of the most important prognostic factors for patients with hepatocellular carcinoma (HCC). Cell motility mediated by Rho-and p160 Rho-associated coiled-coil forming protein kinase (p160ROCK) signaling pathways has recently been shown to play a critical role in intrahepatic metastasis in human HCC. One of such highly metastatic cell line, KYN-2 cells having a high level of c-Src kinase activity become scattered, extend lamellipodia, and exhibit high motility in adherent condition. Expression of a dominant-negative mutant form of c-Src caused formation of stress fibers and focal adhesions, and markedly reduced motility. it was suggested that c-Src activation is critically involved in carcinoma cell migration and metastasis. To investigate whether the specific p160ROCK inhibitor Y-27632 could also inhibit intrahepatic metastasis, the effect of Y-27632 on the cell motility and intrahepatic metastasis of Li7 was investigated. Y-27632 markedly blocked actin reo … More rganization and motility of Li7 cells mediated by lysophosphatidic acid. Y-27632 was administered continuously into the peritoneal cavity using a micro-osmotic pump, together with orthotopic implantation of Li7 cells into the liver of SCID mice. The incidence of mice with metastatic nodules decreased in the Y-27632-treated group. These findings confirm the importance of the Rho/p160ROCK signaling pathway in intrahepatic metastasis of human HCC, and indicate that Y-27632 may be useful for the prevention of intrahepatic metastasis of human HCC.Crucial genes involved in liver cancer metastasis were screened using differential display analysis. A novel gene, DRH1, which is frequently down-regulated in HCC was identified. CO-029 was found to be frequently and significantly overexpressed in HCC and in tumors with intrahepatic spreading. In contrast, mRNA expression of the other tetraspanins CD9 and CD82 was down-regulated in HCC, especially in tumors with intrahepatic spreading. It was suggested that CO-029 has some roles in the promotion of metastasis of HCC. Less

肝内转移是影响肝癌患者预后的重要因素之一。最近研究表明，由Rho和p160 Rho相关卷曲螺旋形成蛋白激酶（p160 ROCK）信号通路介导的细胞运动在人肝癌肝内转移中起关键作用。这种高转移性细胞系之一，具有高水平c-Src激酶活性的KYN-2细胞变得分散，延伸板状伪足，并在贴壁条件下表现出高运动性。显性负突变形式的c-Src的表达引起应力纤维和局灶性粘连的形成，并显着降低运动性。提示c-Src活化与癌细胞迁移和转移密切相关。为了研究特异性p160 ROCK抑制剂Y-27632是否也可以抑制肝内转移，研究了Y-27632对Li 7细胞运动性和肝内转移的影响。Y-27632显著阻断肌动蛋白还原酶， ...更多信息溶血磷脂酸介导的Li 7细胞的组织化和运动。使用微渗透泵将Y-27632连续施用到腹膜腔中，同时将Li 7细胞原位植入到SCID小鼠的肝脏中。在Y-27632治疗组中，具有转移性结节的小鼠的发生率降低。这些结果证实了Rho/p160 ROCK信号通路在人肝癌肝内转移中的重要性，提示Y-27632可能对人肝癌肝内转移有一定的预防作用。一个新的基因，DRH 1，这是经常下调肝癌被确定。发现CO-029在HCC和具有肝内扩散的肿瘤中频繁且显著地过表达。相反，其他四跨膜蛋白CD 9和CD 82的mRNA表达在HCC中下调，特别是在肝内扩散的肿瘤中。提示CO-029在促进肝癌转移中有一定作用。少