Department of Orthopedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM) (J.L.L., J.J.X., F.X., P.L.C., X.D.C., W.D.T., X.L.Z.); Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine (J.L.); Surgical Department, Kunshan Traditional Medicine Hospital (W.D.T.); and Shanghai Key Laboratory of Orthopedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (Z.G.Q.), Shanghai, People's Republic of China.
Department of Orthopedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM) (J.L.L., J.J.X., F.X., P.L.C., X.D.C., W.D.T., X.L.Z.); Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine (J.L.); Surgical Department, Kunshan Traditional Medicine Hospital (W.D.T.); and Shanghai Key Laboratory of Orthopedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (Z.G.Q.), Shanghai, People's Republic of China
Mol Pharmacol. 2019 Apr;95(4):451-461. doi: 10.1124/mol.118.114207. Epub 2019 Jan 23.
Several microRNAs (miRNAs) have been found expressed differentially in osteosarcoma (OS), so they may function in the onset and progression of OS. In this study, we found that miR-144 significantly suppresses osteosarcoma cell proliferation, migration, and invasion ability in vitro and inhibited tumor growth and metastasis in vivo. Mechanically, we demonstrated that Ras homolog family member A (RhoA) and its pivotal downstream effector Rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) were direct targets of miR-144. Moreover, the negative correlation between down-regulated miR-144 and up-regulated ROCK1/RhoA was verified in both OS cell lines and clinical patients' specimens. Functionally, RhoA with or without ROCK1 co-overexpression resulted a rescue phenotype on miR-144 inhibited cell growth, migration, and invasion abilities whereas individual overexpression of ROCK1 had no statistical significance compared with controls in miR-144-transfected SAOS2 and U2-OS cells. Taken together, this study demonstrates that miR-144 inhibited tumor growth and metastasis in OS via dual-suppressing of RhoA and ROCK1, which could be a new therapeutic approach for the treatment of OS.
几种 microRNAs（miRNAs）在骨肉瘤（OS）中表达差异，因此它们可能在 OS 的发生和进展中发挥作用。在本研究中，我们发现 miR-144 显著抑制骨肉瘤细胞在体外的增殖、迁移和侵袭能力，并抑制体内肿瘤生长和转移。从机制上讲，我们证明 Ras 同系物家族成员 A（RhoA）及其关键下游效应物 Rho 相关卷曲螺旋蛋白激酶 1（ROCK1）是 miR-144 的直接靶标。此外，在 OS 细胞系和临床患者标本中均验证了下调的 miR-144 和上调的 ROCK1/RhoA 之间的负相关关系。在功能上，用 RhoA 或 ROCK1 共过表达来挽救 miR-144 抑制的细胞生长、迁移和侵袭能力，而在 miR-144 转染的 SAOS2 和 U2-OS 细胞中，ROCK1 的单独过表达与对照组相比没有统计学意义。综上所述，本研究表明，miR-144 通过双重抑制 RhoA 和 ROCK1 抑制骨肉瘤的肿瘤生长和转移，这可能是骨肉瘤治疗的一种新方法。
