The Motor Protein KIF14 Inhibits Tumor Growth and Cancer Metastasis in Lung Adenocarcinoma

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.

Kif14: A Clinically Relevant Kinesin and Potential Target for Cancer Therapy

“…The lung adenocarcinoma fi ndings [ 63 ] contrast with our earlier work showing KIF14 overexpression as prognostic for poor outcome in a mixed population of non-small cell lung carcinomas [ 44 ]. Aside from the possibility of inter-cohort variation explaining this difference, in our study, the squamous cell carcinomas had the highest KIF14 expression; perhaps KIF14 has an oncogenic role primarily in this histological subtype.…”

“…The authors confi rmed that approximately 30 % of lung adenocarcinomas exhibited a decrease in KIF14 protein expression compared to adjacent normal bronchial epithelial cells. In this same cohort, low KIF14 mRNA expression was associated with poor overall survival, while increased KIF14 expression was an independent factor associated with longer overall survival, and negatively correlated with lung metastasis [ 63 ]. Extending their analysis to a cohort of 122 patient samples, they confi rmed that low immunocytochemical KIF14 expression was independently prognostic for poor patient outcome.…”

“…A study in lung adenocarcinomas found a 30 % loss of chromosome 1q in a cohort of 53 patients [ 63 ]. The authors confi rmed that approximately 30 % of lung adenocarcinomas exhibited a decrease in KIF14 protein expression compared to adjacent normal bronchial epithelial cells.…”

“…Extending their analysis to a cohort of 122 patient samples, they confi rmed that low immunocytochemical KIF14 expression was independently prognostic for poor patient outcome. Overexpression of KIF14 in lung adenocarcinoma cell lines signifi cantly inhibited anchorageindependent growth in vitro, as well as xenograft formation in vivo, implying a tumor suppressive role for KIF14 in lung adenocarcinomas [ 63 ].…”

Inhibition of KIF14 Suppresses Tumor Cell Growth and Promotes Apoptosis in Human Glioblastoma

“…More than 45 KIFs have been described in mice and mammals and they are divided into 15 families that are grouped into three types depending on the position of the motor domain, namely N, M and C kinesins [7,8]. KIF14, an N-type kinesin belong to the kinesin-3 superfamily [9], is a cytoskeletal protein that plays a role in mitotic spindle formation [10], chromosome segregation [11] and cytokinesis completion [12,13].…”