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Интеллектуальная Система Тематического Исследования НАукометрических данных |
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Ubiquitin ligases: a new target for RNAi therapy of hepatocellular carcinomaстатья
Статья опубликована в высокорейтинговом журнале
Статья опубликована в журнале из списка Web of Science и/или ScopusДата последнего поиска статьи во внешних источниках: 26 декабря 2017 г.
- Авторы: Dominique Leboeuf, Timofei Zatsepin, Anderson Daniel G., Konstantin Piatkov
- Журнал: Cancer Research
- Том: 77
- Номер: 13S
- Год издания: 2017
- Издательство: American Association for Cancer Research
- Местоположение издательства: United States
- Первая страница: 3131
- Последняя страница: 3131
- DOI: 10.1158/1538-7445.AM2017-3131
- Аннотация: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer-related deaths in the world. HCC is a very aggressive cancer, resistant to all conventional chemotherapies and capable of acquiring resistance to Sorafenib, which is the only approved chemotherapeutic drug for HCC. This highlights the need to look for new therapeutic options and improve the survival of patients with advanced HCC. The N-end rule pathway is an emerging player in the field of cancer biology, because of its capacity to positively regulate many hallmarks of cancer including angiogenesis, cell proliferation, motility and survival. Therefore, the N-end rule pathway offers the potential to be a target for highly effective anti-tumor treatment. The aim of this study is to investigate the role of the N-end rule pathway in the context of hepatocellular carcinoma in vivo. We used siRNA-mediated RNA interference as the main approach for selective downregulation of the four N-end rule-dependent cognate ubiquitin ligases: UBR1, UBR2, UBR4 and UBR5. Initial screening of siRNAs was performed in Hepa 1-6 cells, followed by in vitro phenotyping using proliferation assays, migration assays, and TUNEL assays. The most potent siRNA against Ubr1, Ubr2, Ubr4 and Ubr5 were formulated into lipid nanoparticles (LNPs) and injected into mice in order to modulate the function of the N-end rule in vivo. We have confirmed that Ubr1, Ubr2, Ubr4 and Ubr5 are overexpressed in Hepa 1-6 cells and in mouse liver tumors, in comparison to normal liver. Upon transfection of siRNAs in Hepa 1-6 cells or injection of LNPs loaded with the same siRNAs into mice, we obtained successful down regulation of Ubr1, Ubr2, Ubr4 and Ubr5 both in vitro and in vivo (in the liver and in tumor tissue). We have also demonstrated that down regulation of these four Ubr proteins negatively affects cell migration and proliferation, and renders cells more susceptible to apoptosis. Bi-weekly injections of the LNPs in mice for a period up to 6 weeks efficiently downregulates the expression of Ubr1, Ubr2, Ubr4 and Ubr5 without any toxic effects. Indeed, we found no significant increase of ALT, AST or total bilirubin in the blood compared to controls. Considering that all four Ubrs are overexpressed in mouse liver tumors, and that the N-end rule plays a major role in many key pathways of cancer development, we expect that even a partial down regulation of this pathway will have prominent effects on tumor development and progression due to the suppression of tumor vascularization, cell proliferation and viability.
- Добавил в систему: Зацепин Тимофей Сергеевич