MicroRNA-874-mediated inhibition of the major G1/S phase cyclin, CCNE1, is lost in osteosarcomas
MicroRNA-874-mediated inhibition of the major G1/S phase cyclin, CCNE1, is lost in osteosarcomas
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DOI：
10.1074/jbc.m117.808287
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发表时间：
2017-12-29
影响因子：
4.8
通讯作者：
Saxena, Sandeep
中科院分区：
文献类型：
--
作者：
Ghosh, Tanushree;Varshney, Akhil;Saxena, Sandeep
肿瘤微环境的特征是缺乏营养的条件，癌细胞必须适应生存。血清饥饿类似于血管化不良的肿瘤微环境的生长因子剥夺特征，并有助于发现在致癌转化中起作用的关键生长调节基因和microRNA（miRNAs）。我们在此报道，在血清饥饿过程中，miR-874下调主要的G（1）/S期细胞周期蛋白，细胞周期蛋白E1（CCNE 1）。由于癌细胞对肿瘤微环境的适应对于随后的肿瘤发生至关重要，我们测试了骨肉瘤细胞中miR-874和CCNE 1的相互依赖性。我们观察到，miR-874抑制CCNE 1在原代成骨细胞中的表达，但在侵袭性骨肉瘤中，miR-874下调，导致CCNE 1表达升高和癌症相关表型的出现。我们确定miR-874介导的细胞周期蛋白E1控制的丧失是骨肉瘤的一个普遍特征。miR-874对CCNE 1的下调不依赖于E2 F转录因子。在裸鼠中，miR-874表达的恢复阻碍S期进展，抑制侵袭性生长表型，例如细胞侵袭、迁移和异种移植肿瘤。总之，我们报道了miR-874在生长因子剥夺过程中抑制CCNE 1表达，并且在骨肉瘤中miR-874下调导致CCNE 1上调和更具侵袭性的生长表型。
The tumor microenvironment is characterized by nutrient-deprived conditions in which the cancer cells have to adapt for survival. Serum starvation resembles the growth factor deprivation characteristic of the poorly vascularized tumor microenvironment and has aided in the discovery of key growth regulatory genes and microRNAs (miRNAs) that have a role in the oncogenic transformation. We report here that miR-874 down-regulates the major G(1)/S phase cyclin, cyclin E1 (CCNE1), during serum starvation. Because the adaptation of cancer cells to the tumor microenvironment is vital for subsequent oncogenesis, we tested for miR-874 and CCNE1 interdependence in osteosarcoma cells. We observed that miR-874 inhibits CCNE1 expression in primary osteoblasts, but in aggressive osteosarcomas, miR-874 is down-regulated, leading to elevated CCNE1 expression and appearance of cancer-associated phenotypes. We established that loss of miR-874-mediated control of cyclin E1 is a general feature of osteosarcomas. The down-regulation of CCNE1 by miR-874 is independent of E2F transcription factors. Restoration of miR-874 expression impeded S phase progression, suppressing aggressive growth phenotypes, such as cell invasion, migration, and xenograft tumors, in nude mice. In summary, we report that miR-874 inhibits CCNE1 expression during growth factor deprivation and that miR-874 down-regulation in osteosarcomas leads to CCNE1 up-regulation and more aggressive growth phenotypes.