Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Carcinogenesis. 2010 Apr;31(4):552-8. doi: 10.1093/carcin/bgp330. Epub 2009 Dec 30.
Osteosarcoma is the most common primary malignant bone tumor affecting children and adolescents. The majority of patients are treated by surgery and chemotherapy but have limited alternative therapeutic options. Kinases play an important role in the growth and survival of tumor cells. We aim to identify specific kinases to be vital in the survival of osteosarcoma cells and thus may be a key target in creating novel anticancer therapies. A lentiviral short hairpin RNA kinase library, screened osteosarcoma cells, identified kinase minibrain-related kinase (Mirk) (Dyrk1B) as a potential target. Knockdown Mirk expression could inhibit cell growth and induce apoptosis. Chemically synthetic small interfering RNA knockdown and complementary DNA rescue assay further confirmed the results from the decrease of Mirk gene expression. The relationship between Mirk gene expression and the clinical characteristics of patients with osteosarcoma was investigated using tissue microarray and immunohistochemistry analysis. The data indicate that the overall survival rate of patients with Mirk high staining (high levels of Mirk protein expression) is significantly shorter than those with Mirk low staining and moderate staining. This highlights Mirk's potential to serve as a promising target for molecular therapy in the treatment of osteosarcoma.
骨肉瘤是最常见的影响儿童和青少年的原发性恶性骨肿瘤。大多数患者通过手术和化疗治疗,但治疗选择有限。激酶在肿瘤细胞的生长和存活中起着重要作用。我们旨在确定在骨肉瘤细胞存活中至关重要的特定激酶,因此可能成为开发新型抗癌疗法的关键靶点。筛选骨肉瘤细胞的慢病毒短发夹 RNA 激酶文库鉴定激酶微脑相关激酶(Mirk)(Dyrk1B)为潜在靶标。敲低 Mirk 表达可抑制细胞生长并诱导细胞凋亡。化学合成小干扰 RNA 敲低和 cDNA 挽救实验进一步证实了降低 Mirk 基因表达的结果。使用组织微阵列和免疫组织化学分析研究了 Mirk 基因表达与骨肉瘤患者临床特征之间的关系。数据表明,Mirk 高染色(Mirk 蛋白表达水平高)患者的总生存率明显短于 Mirk 低染色和中度染色患者。这突出了 Mirk 作为骨肉瘤分子治疗有前途的靶点的潜力。