Autotaxin exacerbates tumor progression by enhancing MEK1 and overriding the function of miR-489-3p.
Autotaxin exacerbates tumor progression by enhancing MEK1 and overriding the function of miR-489-3p.
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DOI：
10.1016/j.canlet.2018.05.037
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发表时间：
2018-09-28
期刊：
影响因子：
9.7
通讯作者：
Murph MM
中科院分区：
文献类型：
--
作者：
Kuppa SS;Jia W;Liu S;Nguyen H;Smyth SS;Mills GB;Dobbin KK;Hardman WJ;Murph MM
自分泌运动因子是一种分泌型磷脂酶和磷酸二酯酶，在恶性疾病中表达上调。循环中miRNA特征的鉴定应该区分自分泌运动因子介导的疾病，并阐明使其恶性潜力合理化的未知分子机制。使用雌性转基因“AT-ATX”小鼠，其中人野生型自分泌运动因子在α-1抗胰蛋白酶启动子的控制下在肝脏中表达，转基因动物在循环中表达增强的自分泌运动因子，并且有一定百分比的动物发展肿瘤。在尸检时收集的血清具有分析统计学显著性的循环miRNA。随后的自分泌运动因子介导的miRNome在组之间区分：健康的FVB/N小鼠与具有和不具有肿瘤的AT-ATX小鼠。有趣的是，miR-489- 3 p在携带AT-ATX肿瘤的小鼠中急剧增加。组织分析显示肿瘤和周围环境中的miR-489- 3 p表达与循环中的自分泌运动因子浓度之间的相关性。序列比对表明miR-489- 3 p靶向MEK 1，这通过体外研究得到证实。外源性添加的miR-489- 3 p降低了正常细胞中的MEK 1，显著增加了稳定表达自分泌运动因子的细胞中的MEK 1表达。综上所述，这表明自分泌运动因子通过协同增加血清中出现的miR-489- 3 p来超越miR-489 - 3 p抑制MEK 1的正常调节功能。
Upregulated expression of autotaxin, a secreted phospholipase and phosphodiesterase enzyme, appears in malignant disease. The identification of a circulating miRNA signature should distinguish autotaxin-mediated disease and also elucidate unknown molecular mechanisms that rationalize its malignant potential. Using female transgenic ‘AT-ATX’ mice, whereby human wild-type autotaxin is expressed in liver under the control of the alpha-1 antitrypsin promoter, transgenic animals express augmented autotaxin in circulation and a percentage develop tumors. Serum collected at necropsy had circulating miRNAs analyzed for statistical significance. The ensuing autotaxin-mediated miRNome differentiated between groups: healthy FVB/N mice versus AT-ATX mice with and without tumors. Intriguingly, miR-489-3p was sharply increased in AT-ATX tumor-bearing mice. Tissue analysis showed a correlation between miR-489-3p expression in tumors and surrounding milieu with autotaxin concentration in circulation. Sequence alignment suggested miR-489-3p targets MEK1, which was confirmed through in vitro studies. Exogenously added miR-489-3p, which decreases MEK1 in normal cells, dramatically increased MEK1 expression in cells stably expressing autotaxin. Taken together, this suggests that autotaxin overrides the normal regulatory function of miR-489-3p to inhibit MEK1 via coordinately increased miR-489-3p appearing in serum.
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