Abstract
The motor protein kinesin superfamily proteins (KIFs) are involved in cancer progression. The depletion of one of the KIFs, KIF14, might delay the metaphase-to-anaphase transition, resulting in a binucleated status, which enhances tumor progression; however, the exact correlation between KIF14 and cancer progression remains ambiguous. In this study, using loss of heterozygosity and array comparative genomic hybridization analyses, we observed a 30% loss in the regions surrounding KIF14 on chromosome 1q in lung adenocarcinomas. In addition, the protein expression levels of KIF14 in 122 lung adenocarcinomas also indicated that approximately 30% of adenocarcinomas showed KIF14 down-regulation compared with the expression in the bronchial epithelial cells of adjacent normal counterparts. In addition, the reduced expression of KIF14 mRNA or proteins was correlated with poor overall survival (P = 0.0158 and <0.0001, respectively), and the protein levels were also inversely correlated with metastasis (P<0.0001). The overexpression of KIF14 in lung adenocarcinoma cells inhibited anchorage-independent growth in vitro and xenograft tumor growth in vivo. The overexpression and silencing of KIF14 also inhibited or enhanced cancer cell migration, invasion and adhesion to the extracellular matrix proteins laminin and collagen IV. Furthermore, we detected the adhesion molecules cadherin 11 (CDH11) and melanoma cell adhesion molecule (MCAM) as cargo on KIF14. The overexpression and silencing of KIF14 enhanced or reduced the recruitment of CDH11 in the membrane fraction, suggesting that KIF14 might act through recruiting adhesion molecules to the cell membrane and modulating cell adhesive, migratory and invasive properties. Thus, KIF14 might inhibit tumor growth and cancer metastasis in lung adenocarcinomas.
Highlights
The kinesin (KIF) superfamily consists of motor proteins that transport organelles, proteins and mRNA in an adenosine-59triphosphate (ATP)- and microtubule-dependent manner [1,2]
KIF2 and KIF15 have been identified as tumor antigens in breast cancer [12,13]; KIF13A is overexpressed in some retinoblastomas [14]; KIF20A is up-regulated in pancreatic cancer [15]; KIF3 and KIF4 have been identified as tumor suppresser genes in gastric cancer [16,17]; and the expression of KIF10 is reduced in hepatocellular carcinoma [18]
KIF14 Expression in Lung Cancer Patients To evaluate the potential role of kinesin in lung adenocarcinoma, we first examined the frequency of loss of heterozygosity (LOH) in chromosomes using microsatellite markers, and observed that LOH occurred between markers D1S1660 (40.0% LOH and 86.7% microsatellite instability (MI)) and D1S213 (31.6% LOH and 60.5% MI), which are located near KIF14 on chromosome 1q (Figure 1A)
Summary
The kinesin (KIF) superfamily consists of motor proteins that transport organelles, proteins and mRNA in an adenosine-59triphosphate (ATP)- and microtubule-dependent manner [1,2]. There are more than 45 members of the KIF superfamily, which are divided into 13 subfamilies according to their orientation, domain and function [3]. KIF14, a member of the kinesin-3 family, contains a motor and a forkhead-associated domain, and this protein plays an important role in cytokinesis and in the segregation, congression and alignment of chromosomes [4,5,6]. Further studies have shown that KIF14 might promote efficient cytokinesis through interactions with citron kinase (CIK) and the protein regulator of cytokinesis 1 (PRC1) [7]. Many components that regulate cytokinesis have been identified, and some molecules, including KIFs, have been clearly associated with cancer. It has been reported that some KIF family members, including KIF3, KIF4 and KIF22, have conflicting roles in tumorigenesis [16,17,19,20,21,22,23]
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