Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
J Orthop Res. 2011 Aug;29(8):1259-66. doi: 10.1002/jor.21403. Epub 2011 Mar 8.
Osteosarcoma is the most common primary malignancy of bone. Patients with localized disease are routinely treated with surgery and chemotherapy. Unfortunately, many of these patients eventually relapse even after high-dose pre- and postoperative chemotherapy. Upon recurrence of the tumor locally or distantly, they have limited treatment options that are usually unsuccessful. Our prior studies screening lentiviral shRNA libraries, searching for kinases involved in osteosarcoma cell growth and proliferation have identified the Rho-associated coiled-coil containing protein kinase 1 (ROCK1) as a possible hit. We show in this study that ROCK1 is highly expressed in various tumor cell lines and tumor tissues from osteosarcoma patients. ROCK1 knockdown by synthetic siRNA decreases cell proliferation, viability and induces apoptosis in osteosarcoma cell lines KHOS and U-2OS. Finally, we established the relationship between expression levels of ROCK1 and clinical prognosis in osteosarcoma patients by using immunohistochemistry. There were significant differences in overall survival between cohorts of patients with ROCK1 levels categorized as high-staining, moderate-staining, and low-staining. High levels of ROCK1 were associated with poor outcomes in clinical osteosarcoma. These findings suggest that knockdown of ROCK1 inhibits proliferation and induces apoptosis in osteosarcoma cell lines. ROCK1 may be a promising therapeutic target for the treatment of osteosarcoma patients.
骨肉瘤是最常见的原发性骨恶性肿瘤。局部疾病患者通常采用手术和化疗进行治疗。不幸的是，许多患者即使在接受大剂量术前和术后化疗后最终仍会复发。当肿瘤局部或远处复发时，他们的治疗选择有限，而且通常无效。我们之前的研究通过筛选慢病毒 shRNA 文库，寻找参与骨肉瘤细胞生长和增殖的激酶，已经确定了 Rho 相关卷曲螺旋蛋白激酶 1（ROCK1）可能是一个潜在的靶点。在本研究中，我们表明 ROCK1 在各种肿瘤细胞系和骨肉瘤患者的肿瘤组织中高度表达。用合成 siRNA 敲低 ROCK1 可降低骨肉瘤细胞系 KHOS 和 U-2OS 的细胞增殖、活力，并诱导细胞凋亡。最后，我们通过免疫组织化学方法确定了 ROCK1 的表达水平与骨肉瘤患者临床预后之间的关系。ROCK1 水平高染色、中染色和低染色的患者总体生存率存在显著差异。高水平的 ROCK1 与骨肉瘤患者的不良预后相关。这些发现表明，敲低 ROCK1 可抑制骨肉瘤细胞系的增殖并诱导细胞凋亡。ROCK1 可能是治疗骨肉瘤患者的有前途的治疗靶点。
