MicroRNA-224 is implicated in lung cancer pathogenesis through targeting caspase-3 and caspase-7.
MicroRNA-224 is implicated in lung cancer pathogenesis through targeting caspase-3 and caspase-7.
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DOI：
10.18632/oncotarget.5224
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发表时间：
2015-09-08
期刊：
影响因子：
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通讯作者：
Croce CM
中科院分区：
文献类型：
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作者：
Cui R;Kim T;Fassan M;Meng W;Sun HL;Jeon YJ;Vicentini C;Tili E;Peng Y;Scarpa A;Liang G;Zhang YK;Chakravarti A;Croce CM
我们最近报道了miR-224在非小细胞肺癌（NSCLC）组织中显著上调，特别是在切除的NSCLC转移灶中。我们进一步证明了miR-224通过直接靶向TNFAIP 1和SMAD 4在NSCLC中作为癌基因发挥作用。然而，miR-224在NSCLC中的生物学功能存在争议，miR-224在肺癌进展和转移中的潜在机制仍有待进一步探讨。在这里，我们报告了caspase 3（CASP 3）和caspase 7（CASP 7）是以前未确定的miR-224在NSCLC中的靶点，并且miR-224部分通过直接靶向CASP 7并下调其表达来促进肺癌细胞增殖和迁移。此外，miR-224通过直接靶向CASP 3减弱TNF-α诱导的细胞凋亡，导致肺癌细胞中切割的PARP 1表达减少。此外，在肺癌患者的组织样本中，miR-224的表达与CASP 7和CASP 3的表达呈负相关。最后，我们发现活化的NF-κB信号通路参与了肺癌中miR-224表达的调控。我们的研究为深入了解miR-224在肺癌发病机制中的作用提供了新的视角，并提示NF-κB/miR-224/CASP 3，7通路可能成为肺癌治疗的潜在靶点。
We recently reported that miR-224 was significantly up-regulated in non-small cell lung cancer (NSCLC) tissues, in particular in resected NSCLC metastasis. We further demonstrated that miR-224 functions as an oncogene in NSCLC by directly targeting TNFAIP1 and SMAD4. However, the biological functions of miR-224 in NSCLC are controversial and underlying mechanisms of miR-224 in the progression and metastasis of lung cancer remain to be further explored. Here we report that caspase3 (CASP3) and caspase7 (CASP7) are previously unidentified targets of miR-224 in NSCLC, and that miR-224 promotes lung cancer cells proliferation and migration in part by directly targeting CASP7 and down-regulating its expression. In addition, miR-224 attenuated TNF-α induced apoptosis by direct targeting of CASP3 resulting in reduction of cleaved PARP1 expression in lung cancer cells. Furthermore, the expression of miR-224 negatively correlates with the expression of CASP7 and CASP3 in tissue samples from patients with lung cancer. Finally, we found that activated NF-κB signaling is involved in the regulation of miR-224 expression in lung cancer. Our study provides new insight in understanding of oncogenic role of miR-224 in the lung cancer pathogenesis and suggests that NF-κB/miR-224/CASP3, 7 pathway could be a putative therapeutic target in lung cancer.