miR-8 modulates cytoskeletal regulators to influence cell survival and epithelial organization in Drosophila wings.
miR-8 modulates cytoskeletal regulators to influence cell survival and epithelial organization in Drosophila wings.
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DOI：
10.1016/j.ydbio.2016.01.041
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发表时间：
2016-04-01
影响因子：
2.7
通讯作者：
Buttitta L
中科院分区：
文献类型：
--
作者：
Bolin K;Rachmaninoff N;Moncada K;Pula K;Kennell J;Buttitta L
MiR-200microRNA家族发挥着重要的肿瘤抑制作用。唯一的果蝇miR-200同源基因miR-8在与肿瘤发生相关的Wingless、Notch和Insulin信号通路中发挥着保守的作用，然而纯合子缺失的动物是存活的，并且通常看起来形态正常。我们观察到，由于遗传损失或功能获得而嵌合到miR-8水平的翅膀组织显示出与miR-8在体内调节细胞存活的作用相一致的细胞死亡模式。在这里，我们显示miR-8水平影响几个肌动蛋白细胞骨架调节因子，从而影响细胞存活和上皮组织。我们发现，miR-8的缺失可以独立于上皮细胞向间充质细胞的转变而产生对凋亡的抵抗，而高表达miR-8的细胞在翅上皮细胞中的持续表达导致JNK信号的增加，细胞外基质重塑蛋白的异常表达，并破坏正常的翅上皮组织。总而言之，我们的结果表明，非常低和非常高的miR-8水平都可能导致与癌症相关的特征，这表明在癌症治疗中增加miR-200 microRNAs的方法应该是适度的。
The miR-200 microRNA family plays important tumor suppressive roles. The sole Drosophila miR-200 ortholog, miR-8 plays conserved roles in Wingless, Notch and Insulin signaling pathways linked to tumorigenesis, yet homozygous null animals are viable and often appear morphologically normal. We observed that wing tissues mosaic for miR-8 levels by genetic loss or gain of function exhibited patterns of cell death consistent with a role for miR-8 in modulating cell survival in vivo. Here we show that miR-8 levels impact several actin cytoskeletal regulators that can affect cell survival and epithelial organization. We show that loss of miR-8 can confer resistance to apoptosis independent of an epithelial to mesenchymal transition while the persistence of cells expressing high levels of miR-8 in the wing epithelium leads to increased JNK signaling, aberrant expression of extracellular matrix remodeling proteins and disruption of proper wing epithelial organization. Altogether our results suggest that very low as well as very high levels of miR-8 can contribute to hallmarks associated with cancer, suggesting approaches to increase miR-200 microRNAs in cancer treatment should be moderate.