Molecular and Cellular Pathobiology MiR-155 Is a Liposarcoma Oncogene That Targets Casein Kinase-1a and Enhances b-Catenin Signaling

Liposarcoma can be an aggressive, debilitating, and fatal malignancy. In this study, we identifed 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 dedifferentiated 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 dedifferentiated 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 inmurine xenografts in vivo. We identified casein kinase 1a (CK1a) as a direct target of miR-155 control which enhanced b-catenin signaling and cyclin D1 expression, promoting tumor cell growth. In summary, our results point to important functions for miR-155 and b-catenin signaling in progression of liposarcoma, revealingmechanistic vulnerabilities thatmight be exploited for both prognostic and therapeutic purposes. Cancer Res; 72(7); 1751–62. 2012 AACR.