Human Mitotic Centromere-Associated Kinesin Is Targeted by MicroRNA 485-5p/181c and Prognosticates Poor Survivability of Breast Cancer.

Huajun Lu,Frank Luh,Chaoqun Wang,Jianghai Wang,Qi Zhang,Yun Yen,Tiffany G Lin,Lijun Xue,Xiyong Liu

doi:10.1155/2019/2316237

Abstract

Purpose This study aims to evaluate the prognostic value of human Mitotic Centromere-Associated Kinesin (MCAK), a microtubule-dependent molecular motor, in breast cancers. The posttranscriptional regulation of MCAK by microRNAs will also be explored. Methods The large-scale gene expression datasets of breast cancer (total n=4,677) were obtained from GEO, NKI, and TCGA database. Kaplan-Meier and Cox analyses were used for survival analysis. MicroRNAs targeting MCAK were predicted by bioinformatic analysis and validated by a dual-luciferase reporter assay. Results The expression of MCAK was significantly associated with aggressive features of breast cancer, including tumor stage, Elston grade, and molecular subtypes, for global gene expression datasets of breast cancer (p<0.05). Overexpression of MCAK was significantly associated with poor outcome in a dose-dependent manner for either ER-positive or ER-negative breast cancer. Evidence from bioinformatic prediction, coexpression assays, and gene set enrichment analyses suggested that miR-485-5p and miR-181c might target MCAK and suppress its expression. A 3'UTR dual-luciferase target reporter assay demonstrated that miR-485-5p and miR-181c mimics specifically inhibited relative Firefly/Renilla luciferase activity by about 50% in corresponding reporter plasmids. Further survival analysis also revealed that miR-485-5p (HR=0.59, 95% CI 0.37-0.92) and miR-181c (HR=0.54, 95% CI 0.34-0.84) played opposite roles of MCAK (HR=2.80, 95% CI 1.77-4.57) and were significantly associated with better outcome in breast cancers. Conclusion MCAK could serve as a prognostic biomarker for breast cancers. miR-485-5p and miR-181c could specifically target and suppress the MCAK gene expression in breast cancer cells.

Highlights

Microtubules (MTs) are essential biological polymers of fundamental importance for mitosis in eukaryotic cells
The clinical relevance of Mitotic Centromere-Associated Kinesin (MCAK) mRNA expression levels was examined on Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) datasets
Analysis results from GEO dataset suggest that MCAK expression significantly and positively associated with factors including younger than 50 years of age, tumor equal to or larger than 2 cm, ER-negative status, and higher Elston histology grade (Figure 1(a) and Suppl

Summary

Introduction

Microtubules (MTs) are essential biological polymers of fundamental importance for mitosis in eukaryotic cells. The human Mitotic Centromere-Associated Kinesin (MCAK) gene, recognized as Kinesin Family Member 2C (KIF2C), encodes a kinesin-like protein that can depolymerize microtubules at the plus end, thereby promoting mitotic chromosome segregation during mitosis [1]. KIF18B to form an MCAK-KIF18B complex, which is negatively regulated by Aurora kinases through phosphorylation of MCAK [2]. Aurora kinases regulate MT plus-end stability through control of MCAK-KIF18B complex formation to constitute the major microtubule plus-end depolymerizing activity in mitotic cells. MCAK and KIF2B stimulate kinetochore-microtubule dynamics during distinct phases of mitosis to correct malorientations [3]. MCAK plays a role in chromosome congression and is required for the lateral

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