MiR-155 is a liposarcoma oncogene that targets casein kinase-1α and enhances β-catenin signaling.
MiR-155 is a liposarcoma oncogene that targets casein kinase-1α and enhances β-catenin signaling.
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DOI：
10.1158/0008-5472.can-11-3027
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发表时间：
2012-04-01
期刊：
影响因子：
11.2
通讯作者：
Lev D
中科院分区：
文献类型：
--
作者：
Zhang P;Bill K;Liu J;Young E;Peng T;Bolshakov S;Hoffman A;Song Y;Demicco EG;Terrada DL;Creighton CJ;Anderson ML;Lazar AJ;Calin GG;Pollock RE;Lev D
脂肪肉瘤可以是一种侵袭性的、使人衰弱的和致命的恶性肿瘤。在这项研究中，我们鉴定了与脂肪肉瘤分化状态相关的microRNAs（miRNAs），以了解其进展的基础。在人类肿瘤和正常脂肪标本中确定的miRNA表达谱鉴定了由35种miRNA组成的去分化肿瘤表达特征。在第二个独立样本队列中证实了miRNA表达失调。miR-155是过表达最多的miRNA，功能研究表明其在去分化脂肪肉瘤细胞系的生长中起重要作用。瞬时或稳定敲低miR-155在体外延缓肿瘤细胞生长，减少集落形成并诱导G1-S细胞周期停滞，在体内阻断小鼠异种移植物中的肿瘤生长。我们鉴定了酪蛋白激酶1α（CK 1 α）作为miR-155调控的直接靶点，其增强β-catenin信号传导和细胞周期蛋白D1表达，促进肿瘤细胞生长。总之，我们的结果指出了miR-155和β-catenin信号在脂肪肉瘤进展中的重要作用，揭示了可能用于预后和治疗目的的机制漏洞。
Liposarcoma can be an aggressive, debilitating and fatal malignancy. In this study, we identifed microRNAs (miRNAs) associated with the differentiation status of liposarcoma to gain insight into the basis for its progression. miRNA expression profiles determined in human tumors and normal fat specimens identified a de-differentiated tumor expression signature consisting of 35 miRNAs. Deregulated miRNA expression was confirmed in a second independent sample cohort. The miR-155 was the most overexpressed miRNA and functional investigations assigned an important role in the growth of de-differentiated liposarcoma cell lines. Transient or stable knockdown of miR-155 retarded tumor cell growth, decreased colony formation and induced G1-S cell cycle arrest in vitro and blocked tumor growth in murine xenografts in vivo. We identified casein kinase 1α (CK1α) as a direct target of miR-155 control which enhanced β-catenin signaling and cyclin D1 expression, promoting tumor cell growth. In summary, our results point to important functions for miR-155 and β-catenin signaling in progression of liposarcoma, revealing mechanistic vulnerabilities that might be exploited for both prognostic and therapeutic purposes.