Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development.
Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development.
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DOI：
10.1158/2159-8290.cd-15-0854
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发表时间：
2016-02
期刊：
影响因子：
28.2
通讯作者：
Jacks T
中科院分区：
文献类型：
--
作者：
Dimitrova N;Gocheva V;Bhutkar A;Resnick R;Jong RM;Miller KM;Bendor J;Jacks T
已经提出了从miR-143/145簇共表达的两种不相关的miRNA，miR-143和miR-145，在人类癌症中充当肿瘤抑制剂，并且已经报道了将miR-143和miR-145递送至肿瘤的治疗益处。相反，我们发现在肺腺癌的本地小鼠模型中肿瘤特异性缺失miR-143/145并不影响肿瘤的发展。这与正常和转化肺上皮中缺乏内源性miR-143/145表达一致。令人惊讶的是，肿瘤微环境中的miR-143/145通过刺激内皮细胞的增殖显著促进肿瘤生长。体内miR-143/145的缺失导致miR-145靶点Camk 1d的去抑制，Camk 1d是一种抑制性激酶，当其过度表达时会阻止内皮细胞的有丝分裂进入。因此，miR-143/145缺陷动物中的肿瘤表现出减少的新血管生成、增加的细胞凋亡，并且它们的扩张受到肿瘤吸收肺泡脉管系统的能力的限制。这些发现表明，基质miR-143/145促进肿瘤发生，并警告不要使用这些miRNA作为癌症治疗剂。
The two unrelated miRNAs, miR-143 and miR-145, co-expressed from the miR-143/145 cluster have been proposed to act as tumor suppressors in human cancer and therapeutic benefits of delivering miR-143 and miR-145 to tumors have been reported. In contrast, we found that tumor-specific deletion of miR-143/145 in an autochthonous mouse model of lung adenocarcinoma did not affect tumor development. This was consistent with the lack of endogenous miR-143/145 expression in normal and transformed lung epithelium. Surprisingly, miR-143/145 in the tumor microenvironment dramatically promoted tumor growth by stimulating the proliferation of endothelial cells. Loss of miR-143/145 in vivo led to derepression of the miR-145 target Camk1d, an inhibitory kinase, which when overexpressed prevents mitotic entry of endothelial cells. As a consequence, tumors in miR-143/145-deficient animals exhibited diminished neoangiogenesis, increased apoptosis and their expansion was limited by the tumor’s ability to co-opt the alveolar vasculature. These findings demonstrate that stromal miR-143/145 promotes tumorigenesis and cautions against the use of these miRNAs as agents in cancer therapeutics.