He Quan, Wang Fangfei, Honda Takashi, Lindquist Diana M, Dillman Jonathan R, Timchenko Nikolai A, Redington Andrew N
1 Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
2 Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Tumour Biol. 2017 Oct;39(10):1010428317737729. doi: 10.1177/1010428317737729.
Previous in vitro studies have demonstrated that miR-144 inhibits hepatocellular carcinoma cell proliferation, invasion, and migration. We have shown that miR-144, injected intravenously, is taken up by the liver and induces endogenous hepatic synthesis of miR-144. We hypothesized that administered miR-144 has tumor-suppressive effects on liver tumor development in vivo. The effects of miR-144 on tumorigenesis and tumor growth were tested in a diethylnitrosamine-induced hepatocellular carcinoma mouse model. MiR-144 injection had no effect on body weight but significantly reduced diethylnitrosamine-induced liver enlargement compared with scrambled microRNA. MiR-144 had no effect on diethylnitrosamine-induced liver tumor number but reduced the tumor size above 50%, as evaluated by magnetic resonance imaging (scrambled microRNA 23.07 ± 5.67 vs miR-144 10.38 ± 2.62, p < 0.05) and histological analysis (scrambled microRNA 30.75 ± 5.41 vs miR-144 15.20 ± 3.41, p < 0.05). The levels of miR-144 was suppressed in tumor tissue compared with non-tumor tissue in all treatment groups (diethylnitrosamine-phosphate-buffered saline non-tumor 1.05 ± 0.09 vs tumor 0.54 ± 0.08, p < 0.01; diethylnitrosamine-scrambled microRNA non-tumor 1.23 ± 0.33 vs tumor 0.44 ± 0.10, p < 0.05; diethylnitrosamine-miR-144 non-tumor 54.72 ± 11.80 vs tumor 11.66 ± 2.75, p < 0.01), but injection of miR-144 greatly increased miR-144 levels both in tumor and non-tumor tissues. Mechanistic studies showed that miR-144 targets epidermal growth factor receptor and inhibits the downstream Src/AKT signaling pathway which has previously been implicated in hepatocellular carcinoma tumorigenesis. Exogenously delivered miR-144 may be a therapeutic strategy to suppress tumor growth in hepatocellular carcinoma.
先前的体外研究表明，miR-144可抑制肝癌细胞的增殖、侵袭和迁移。我们已经证明，静脉注射的miR-144会被肝脏摄取，并诱导肝脏内源性合成miR-144。我们推测，给予的miR-144在体内对肝肿瘤的发生具有肿瘤抑制作用。在二乙基亚硝胺诱导的肝癌小鼠模型中测试了miR-144对肿瘤发生和肿瘤生长的影响。注射miR-144对体重没有影响，但与乱序微小RNA相比，显著减轻了二乙基亚硝胺诱导的肝脏肿大。miR-144对二乙基亚硝胺诱导的肝肿瘤数量没有影响，但通过磁共振成像评估（乱序微小RNA 23.07±5.67 vs miR-144 10.38±2.62，p< 0.05）和组织学分析（乱序微小RNA 30.75±5.41 vs miR-144 15.20±3.41，p< 0.05），肿瘤大小减少了50%以上。在所有治疗组中，与非肿瘤组织相比，肿瘤组织中miR-144的水平均受到抑制（二乙基亚硝胺-磷酸盐缓冲盐水非肿瘤组织1.05±0.09 vs肿瘤组织0.54±0.08，p< 0.01；二乙基亚硝胺-乱序微小RNA非肿瘤组织1.23±0.33 vs肿瘤组织0.44±0.10，p< 0.05；二乙基亚硝胺-miR-144非肿瘤组织54.72±11.80 vs肿瘤组织11.66±2.75，p< 0.01），但注射miR-144大大提高了肿瘤组织和非肿瘤组织中miR-144的水平。机制研究表明，miR-144靶向表皮生长因子受体并抑制下游Src/AKT信号通路，该信号通路先前与肝癌的发生有关。外源性递送的miR-144可能是一种抑制肝癌肿瘤生长的治疗策略。
