MiR-155 Is a Liposarcoma Oncogene That Targets Casein Kinase-1α and Enhances β-Catenin Signaling

Abstract

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.

miR200c Attenuates P-gp–Mediated MDR and Metastasis by Targeting JNK2/c-Jun Signaling Pathway in Colorectal Cancer

“…Recently, several lines of evidence have purported to study the drug resistance and invasion/metastasis as a single entity. It was reported that miRNAs can regulate the expression of certain proteins and genes, which function as tumor suppressors or oncogenes in the occurrence and development of tumor MDR and metastases (31)(32)(33). Our current study elucidated that miR200c was downregulated in MDR cells compared with the parent cells, and a similar phenomenon also occurred in clinical recurrent and metastatic tumors.…”

Casein kinase 1α–dependent feedback loop controls autophagy in RAS-driven cancers

“…Until recently, CK1α was considered to be a "rogue" kinase (36), as its catalytic activity appears to be unregulated. However, fresh perspectives on the regulation of CK1α were gained in two recent studies, one showing CK1α protein expression to be downregulated by miR-155 in liposarcoma (53) and the other identifying a subset of the DDX family of RNA helicase as essential kinase-stimulatory cofactors of multiple CK1 isoforms, including CK1α (36). We demonstrate that oncogenic RAS, via its PI3K/ AKT/mTOR effector pathway, can also increase CK1α protein abundance and function.…”

Demethylation of microRNA-142 induced by demethylation agents plays a suppressive role in osteosarcoma cells

“…The overexpression of miR-142 has been shown to inhibit the proliferation and colony-forming ability of primitive hematopoietic cells (31). Some of these functions appear to depend on the cellular type and context, since it was reported that miR-142 acts as an anti-migratory factor in hepatocellular carcinoma cells (32) and has also been reported to be deregulated in mesenchymal tumors (33). In the present study, demethylation agents induced Saos-2 and MG63 cell cycle arrest, thus inducing an increase in G 2 phase cells with a concomitant decrease in S phase cells.…”