Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630090, Russia.
Novosibirsk State University, Novosibirsk 630090, Russia.
Biomolecules. 2020 Nov 2;10(11):1509. doi: 10.3390/biom10111509.
The important role of miRNA in cell proliferation and differentiation has raised interest in exogenous ribonucleases (RNases) as tools to control tumour-associated intracellular and extracellular miRNAs. In this work, we evaluated the effects of the RNase binase from on small non-coding regulatory RNAs in the context of mouse RLS lymphosarcoma inhibition. In vitro binase exhibited cytotoxicity towards RLS cells via apoptosis induction through caspase-3/caspase-7 activation and decreased the levels of miR-21a, let-7g, miR-31 and miR-155. Intraperitoneal injections of binase in RLS-bearing mice resulted in the retardation of primary tumour growth by up to 60% and inhibition of metastasis in the liver by up to 86%, with a decrease in reactive inflammatory infiltration and mitosis in tumour tissue. In the blood serum of binase-treated mice, decreases in the levels of most studied miRNAs were observed, excluding let-7g, while in tumour tissue, the levels of oncomirs miR-21, miR-10b, miR-31 and miR-155, and the oncosuppressor let-7g, were upregulated. Analysis of binase-susceptible miRNAs and their regulatory networks showed that the main modulated events were transcription and translation control, the cell cycle, cell proliferation, adhesion and invasion, apoptosis and autophagy, as well as some other tumour-related cascades, with an impact on the observed antitumour effects.
miRNA 在细胞增殖和分化中的重要作用引起了人们对外源核糖核酸酶 (RNases) 的兴趣，将其作为控制与肿瘤相关的细胞内和细胞外 miRNA 的工具。在这项工作中，我们评估了来自 的核糖核酸酶 binase 在抑制小鼠 RLS 淋巴肉瘤过程中小非编码调控 RNA 的作用。体外 binase 通过 caspase-3/caspase-7 激活诱导细胞凋亡，对 RLS 细胞表现出细胞毒性，并降低了 miR-21a、let-7g、miR-31 和 miR-155 的水平。在 RLS 荷瘤小鼠中腹腔注射 binase 可使原发性肿瘤生长延迟高达 60%，并抑制肝脏转移高达 86%，同时减少肿瘤组织中的反应性炎症浸润和有丝分裂。在 binase 治疗小鼠的血清中，观察到大多数研究 miRNA 的水平下降，排除了 let-7g，而在肿瘤组织中，致癌 miRNA miR-21、miR-10b、miR-31 和 miR-155 以及肿瘤抑制因子 let-7g 的水平上调。对 binase 易感 miRNA 及其调控网络的分析表明，主要调节的事件是转录和翻译控制、细胞周期、细胞增殖、黏附和侵袭、凋亡和自噬，以及其他一些与肿瘤相关的级联反应，对观察到的抗肿瘤作用产生影响。
