gms | German Medical Science

Objective: The kinesin superfamily (KIF) members are highly conserved motor proteins, which are classified into 14 families. Kinesins play an important role in cellular functions including transport of vesicles and mitosis. Overexpression of the motor protein KIF11 can induce premature sister chromatid separation, leading to unequal distributed genetic material and therefore may promote malignant progression. Kinesin proteins are involved in multiple cancer types including melanoma, retinoblastoma, and glioma. So far, kinesin family members have not been investigated in meningiomas yet. Hence, in this study we evaluated the role of kinesins in meningioma.

Methods: qRT-PCR of seventy-five meningioma tissues for KIFC1, KIF4A, KIF11, KIF14, and KIF20A was performed (WHO °I n= 24, °II n=20, °III n=31) and data was normalized to GAPDH and ACTB and to WHO °I meningiomas. For subgroup analysis, meningiomas were grouped into primary tumors without recurrence in given time interval (B), meningioma with malignant progression (M), recurrent (R), non-recurrent (NR) meningiomas and where data is not available (NA). Kinesin expression levels were divided into high and low-expressing groups by the median and correlated to progression-free survival. Only Simpson grade I-III° and primary tumors were included. For in vitro work, benign meningioma cell line Ben-Men-1 and malignant meningioma cell line NCH93 were used. NCH93 was derived from a patient with anaplastic meningioma. For proliferation assays, meningioma cells were transfected with two different siRNA (25 nM final concentration) or control-siRNA and relative cell growth was assessed by BrdU assay at indicated time points.

Results: As a first step, we selected kinesin family members from our initial gene expression array for further validation by quantitative real-time PCR. We evaluated the mRNA expression levels of kinesin family members KIFC1, KIF4A, KIF11, KIF14, and KIF20A in 24 meningioma tumor WHO grade °I, 20 grade °II and 31 grade °III meningiomas. The mRNA levels of all investigated kinesins showed a statistically significant increase with WHO grade. Subgroup analysis of benign meningioma as compared to recurrent and malignantly progressing meningioma revealed increased levels of all investigated kinesins. High expression of KIFC1 (p=.026), KIF11 (p=.048), and KIF14 (p=.017) was associated with a shorter progression-free survival of meningioma patients. Depletion of KIF11 via two different siRNAs inhibited cell proliferation by 91% and 95% on day 3 and 5 (p<.001) in the benign cell line Ben-Men-1 and by 56%, 72%, and 71% on day 1, 3 and 5 in the malignant cell line NCH93 (p<.001), respectively.

Conclusion: Taken together, KIF11 seems to play an important role in meningioma pathogenesis and thus may become a feasible target for meningioma therapy.