Abstract
BackgroundKinesin family member 4A (KIF4A), a microtubule-based motor protein, was implicated in regulation of chromosomal structure and kinetochore microtubule dynamics. Considering the functions of KIF4A, we assumed that KIF4A is involved in progression of oral squamous cell carcinomas (OSCCs) via activation of the spindle assembly checkpoint (SAC). However, little is known about the relevance of KIF4A in the behavior of OSCC. We investigated the KIF4A expression status and its functional mechanisms in OSCC.MethodsThe KIF4A expression levels in seven OSCC-derived cells were analyzed by quantitative reverse transcriptase-polymerase chain reaction and immunoblotting analyses. Using a KIF4A knockdown model, we assessed the expression of (SAC)-related molecules (BUB1, MAD2, CDC20, and cyclin B1), cell-cycle, and cellular proliferation. In addition to in vitro data, the clinical correlation between the KIF4A expression levels in primary OSCCs (n = 106 patients) and the clinicopathologic status by immunohistochemistry (IHC) also were evaluated. ResultsKIF4A mRNA and protein were up-regulated significantly (P < 0.05) in seven OSCC-derived cells compared with human normal oral keratinocytes. In the KIF4A knockdown cells, SAC activation was observed via increased BUB1 expression on the kinetochores, appropriate kinetochore localization of MAD2, down-regulation of CDC20, up-regulation of cyclin B1, and cell-cycle arrested at G2/M phase. The results showed that cellular proliferation of KIF4A knockdown cells decreased significantly (P < 0.05) compared with control cells. IHC showed that KIF4A expression in primary OSCCs was significantly (P < 0.05) greater than in the normal oral counterparts and that KIF4A-positive OSCCs were correlated closely (P < 0.05) with tumoral size. ConclusionsOur results proposed for the first time that KIF4A controls cellular proliferation via SAC activation. Therefore, KIF4A might be a key regulator for tumoral progression in OSCCs.
Highlights
The kinesin superfamily proteins (KIFs), classified into 14 subfamilies, are ATP-dependent motor proteins with microtubule-dependent plus-end motion ability [1,2]
Kinesin family member 4A (KIF4A) mRNA was up-regulated significantly in all oral squamous cell carcinomas (OSCCs)-derived cellular lines compared with the human normal oral keratinocytes (HNOKs) (Figure 1A)
In addition to the current data that KIF4A was significantly up-regulated in OSCCs, Castillo et al reported that overexpression of some motor kinesins, including KIF4A, which generate additional outward forces during mitosis, induces excessive spindle separation leading to unequal distribution of genetic material in anaphase and eventually development of daughter cells affected by aneuploidy [61]
Summary
The kinesin superfamily proteins (KIFs), classified into 14 subfamilies, are ATP-dependent motor proteins with microtubule-dependent plus-end motion ability [1,2]. Among the KIFs, KIF4A controls spindle organization, chromosome alignment, and kinetochore microtubule dynamics with a protein regulator of cytokinesis 1 [4,7,8,9,10,11,12,13]. Using a KIF4A knockdown model, we assessed the expression of (SAC)-related molecules (BUB1, MAD2, CDC20, and cyclin B1), cell-cycle, and cellular proliferation. Results: KIF4A mRNA and protein were up-regulated significantly (P < 0.05) in seven OSCC-derived cells compared with human normal oral keratinocytes. In the KIF4A knockdown cells, SAC activation was observed via increased BUB1 expression on the kinetochores, appropriate kinetochore localization of MAD2, down-regulation of CDC20, upregulation of cyclin B1, and cell-cycle arrested at G2/M phase. KIF4A might be a key regulator for tumoral progression in OSCCs
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