β-Catenin Small Interfering RNA Successfully Suppressed Progression of Multiple Myeloma in a Mouse Model
β-Catenin Small Interfering RNA Successfully Suppressed Progression of Multiple Myeloma in a Mouse Model
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DOI：
10.1158/1078-0432.ccr-08-1350
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发表时间：
2009-04-15
影响因子：
11.5
通讯作者：
Maekawa, Taira
中科院分区：
文献类型：
--
作者：
Ashihara, Eishi;Kawata, Eri;Maekawa, Taira
目的：β-连环蛋白是Wnt信号通路的下游效应物，调节细胞增殖。在多种类型的恶性肿瘤中，β-连环蛋白的过度表达与预后呈正相关。在此，我们使用异种移植模型评估了其对多发性骨髓瘤细胞生长的影响。实验设计：我们首先研究了β-连环蛋白在多发性骨髓瘤细胞系和患者多发性骨髓瘤细胞中的表达。接下来，我们研究了β-连环蛋白小干扰RNA在体内对多发性骨髓瘤细胞生长的抑制作用。将6周龄雄性BALB/c nu/nu小鼠接种S.C.右侧有5 x 10(6)个RPM18226细胞，其次是S.C.每周两次注射β-连环蛋白小干扰RNA、干扰小干扰RNA或PBS/胶原复合体共8次。结果：在多发性骨髓瘤细胞系和多发性骨髓瘤患者标本中，β-连环蛋白的表达水平明显高于健康志愿者的单个核细胞。在体内实验中，干扰型小干扰RNA或PBS/胶原复合体对多发性骨髓瘤的生长无抑制作用，而β-连环素小干扰RNA/胶原复合体对多发性骨髓瘤的生长有明显的抑制作用(P<；0.05)。结论：β-连环素小干扰RNA对多发性骨髓瘤的生长有抑制作用。据我们所知，这是首次报道用β-连环素小干扰RNA治疗对体内恶性血液病的生长产生抑制作用。由于β-连环蛋白小干扰RNA可抑制多发性骨髓瘤细胞的生长，因此，β-连环蛋白成为治疗多发性骨髓瘤的新靶点。
Purpose: beta-catenin is the downstream effector of the Wnt signaling pathway, and it regulates cell proliferation. beta-catenin overexpression correlates positively with prognosis in several types of malignancies. We herein assessed its effects on growth of multiple myeloma cells using a xenograft model.Experimental Design: We first investigated the expression of beta-catenin in multiple myeloma cell lines and multiple myeloma cells obtained from patients. Next, we investigated the growth inhibitory effects of beta-catenin small interfering RNA on the growth of multiple myeloma cells in vivo. Six-week-old male BALB/c nu/nu mice were inoculated s.c. in the right flank with 5 x 10(6) RPM18226 cells, followed by s.c. injections of beta-catenin small interfering RNA, scramble small interfering RNA, or PBS/atelocollagen complex twice a week for a total of eight injections.Results: Significantly higher levels of beta-catenin expression were observed in multiple myeloma cell lines and in samples from patients with multiple myeloma than those found in mononuclear cells obtained from healthy volunteers. In in vivo experiments, no inhibitory effects were observed following treatment with scramble small interfering RNA or PBS/atelocollagen complexes, whereas treatment with beta-catenin small interfering RNA/atelocollagen complex significantly inhibited growth of multiple myeloma tumors (P < 0.05).Conclusions: beta-catenin small interfering RNA treatment inhibited the growth of multiple myeloma tumors in a xenograft model. To our knowledge, this is the first report showing that the treatment with beta-catenin small interfering RNA produces an inhibitory effects on growth of hematologic malignancies in vivo. Because treatment with beta-catenin small interfering RNA inhibited growth of multiple myeloma cells, beta-catenin is the attractive novel target for treating multiple myeloma.