Lei Pengfei, Xie Jie, Wang Long, Yang Xucheng, Dai Zixun, Hu Yihe
Department of Orthopedics, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China.
Mol Med Rep. 2014 Jul;10(1):155-60. doi: 10.3892/mmr.2014.2195. Epub 2014 Apr 28.
Osteosarcoma (OS), a malignant mesenchymal sarcoma, is the most frequent primary bone tumor, with a peak incidence in young children and adolescents. The downregulation of microRNA‑145 (miRNA/miR‑145) has previously been identified to be associated with the aggressiveness and metastasis of OS. However, the detailed regulatory mechanism by which miR‑145 inhibits OS remains largely unknown. The present study demonstrated that miR‑145 was significantly downregulated in OS tissues and KHOS and U2OS cell lines. Rho‑associated protein kinase 1 (ROCK1), a key regulator of actin cytoskeleton reorganization, was identified as a novel target of miR‑145. Ectopic expression of miR‑145 notably suppressed the protein expression of ROCK1 without affecting its mRNA level. Furthermore, the expression of ROCK1 was significantly increased in the OS tissues and in the KHOS and U2OS cells. It was further demonstrated that the overexpression of miR‑145 downregulated KHOS and U2OS cell proliferation and invasion, which was reversed by restoration of ROCK1. To the best of our knowledge, the present study demonstrates for the first time that, as a tumor suppressor, miRNA‑145 inhibits OS cell proliferation and invasion, at least in part by directly targeting ROCK1. These results indicate that miR‑145 may be a potential candidate for the diagnosis and treatment of OS.
骨肉瘤（OS）是一种恶性间充质肉瘤，是最常见的原发性骨肿瘤，在幼儿和青少年中发病率最高。先前已确定微小RNA-145（miRNA/miR-145）的下调与骨肉瘤的侵袭性和转移有关。然而，miR-145抑制骨肉瘤的详细调控机制仍不清楚。本研究表明，miR-145在骨肉瘤组织以及KHOS和U2OS细胞系中显著下调。Rho相关蛋白激酶1（ROCK1）是肌动蛋白细胞骨架重组的关键调节因子，被确定为miR-145的一个新靶点。miR-145的异位表达显著抑制了ROCK1的蛋白表达，而不影响其mRNA水平。此外，ROCK1在骨肉瘤组织以及KHOS和U2OS细胞中的表达显著增加。进一步证明，miR-145的过表达下调了KHOS和U2OS细胞的增殖和侵袭，而ROCK1的恢复则逆转了这种作用。据我们所知，本研究首次表明，作为一种肿瘤抑制因子，miRNA-145至少部分通过直接靶向ROCK1来抑制骨肉瘤细胞的增殖和侵袭。这些结果表明，miR-145可能是骨肉瘤诊断和治疗的潜在候选物。
