PDF(Pubmed)
Abstract：
Vasohihibin-2 (VASH2) is a homolog of vasohibin-1 (VASH1) and is overexpressed in various cancers. Vasohihibin-2 acts on both cancer cells and cancer microenvironmental cells. Previous analyses have shown that VASH2 promotes cancer progression and abrogation of VASH2 results in significant anticancer effects. We therefore propose VASH2 to be a practical molecular target for cancer treatment. Modifications of antisense oligonucleotide (ASO) such as bridged nucleic acids (BNA)-based modification increases the specificity and stability of ASO, and are now applied to the development of a number of oligonucleotide-based drugs. Here we designed human VASH2-ASOs, selected an optimal one, and developed 2\',4\'-BNA-based VASH2-ASO. When systemically administered, naked 2\',4\'-BNA-based VASH2-ASO accumulated in the liver and showed its gene-silencing activity. We then examined the effect of 2\',4\'-BNA-based VASH2-ASO in liver cancers. Intraperitoneal injection of naked 2\',4\'-BNA-based VASH2-ASO exerted a potent antitumor effect on orthotopically inoculated human hepatocellular carcinoma cells. The same manipulation also showed potent antitumor activity on the splenic inoculation of human colon cancer cells for liver metastasis. These results provide a novel strategy for the treatment of primary as well as metastatic liver cancers by using modified ASOs targeting VASH2.
摘要：
Vasohihibin-2（VASH2）是vasohibin-1（VASH1）的同源物，在各种癌症中过表达。Vasohihibin-2作用于癌细胞和癌症微环境细胞。先前的分析表明,VASH2促进癌症进展,并且VASH2的废除导致显著的抗癌作用。因此，我们建议VASH2成为癌症治疗的实用分子靶标。反义寡核苷酸(ASO)的修饰如基于桥接核酸(BNA)的修饰增加了ASO的特异性和稳定性,现在被应用于许多基于寡核苷酸的药物的开发。在这里，我们设计了人类VASH2-ASO，选择了一个最优的，并开发了2\'，4\'-基于BNA的VASH2-ASO。当全身给药时，裸体2\'，4'-基于BNA的VASH2-ASO在肝脏中积累并显示其基因沉默活性。然后我们检查了2\'的效果，4\'-基于BNA的VASH2-ASO在肝癌中的应用。腹膜内注射裸2'，基于4'-BNA的VASH2-ASO对原位接种的人肝细胞癌细胞具有有效的抗肿瘤作用。相同的操作还显示出对脾接种人结肠癌细胞进行肝转移的有效抗肿瘤活性。这些结果提供了通过使用靶向VASH2的修饰的ASO治疗原发性和转移性肝癌的新策略。
