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Clinical Cancer Research 13, 3229, June 1, 2007. doi: 10.1158/1078-0432.CCR-07-0393
© 2007 American Association for Cancer Research
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Imaging, Diagnosis, Prognosis

KIF14 Messenger RNA Expression Is Independently Prognostic for Outcome in Lung Cancer

Timothy W. Corson1,4, Chang Qi Zhu1, Suzanne K. Lau1,5, Frances A. Shepherd2,3,6, Ming-Sound Tsao1,2,5,7 and Brenda L. Gallie1,4,5,8

Authors' Affiliations: 1 Division of Applied Molecular Oncology and 2 Clinical Studies Resource Centre, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network; 3 Division of Medical Oncology and Hematology, Department of Medicine, University Health Network; and Departments of 4 Molecular and Medical Genetics, 5 Medical Biophysics, 6 Medicine, 7 Laboratory Medicine and Pathobiology, and 8 Ophthalmology, University of Toronto, Toronto, Ontario, Canada

Requests for reprints: Brenda L. Gallie, Division of Applied Molecular Oncology, Room 8-415, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-2324; Fax: 416-946-4619; E-mail: gallie{at}attglobal.net.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
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Purpose: The mitotic kinesin KIF14 is overexpressed in multiple cancers including lung cancer. Therefore, we investigated KIF14 expression in association with clinical variables and the effect of KIF14 on in vitro colony formation in non–small-cell lung carcinoma.

Experimental Design: RNA was extracted from 129 untreated, resected tumors and KIF14 expression was quantified by real-time reverse transcription-PCR. Associations with clinical variables were determined by standard statistical methods. KIF14 expression was knocked down by small interfering RNA in H1299 and HeLa cells; proliferation and growth in soft agar were assayed.

Results: Squamous cell carcinoma had the highest KIF14 level, followed by large-cell undifferentiated carcinoma, then adenocarcinoma (P = 0.002). KIF14 level decreased with differentiation (P = 0.01) but was not associated with pathologic stage, T or N stage, or sex. When dichotomized about the median, KIF14 overexpression significantly decreased disease-free survival (Kaplan-Meier log-rank, P = 0.01) and trended toward decreasing overall survival (P = 0.08). In a univariate Cox proportional hazard regression, increasing KIF14 expression decreased disease-free survival [P = 0.01; hazard ratio, 1.44 (95% confidence interval, 1.09-1.91)]. In a multivariate Cox regression, including stage, differentiation, histology, and tumor purity as covariates, KIF14 overexpression remained an independent prognostic factor for disease-free survival [P = 0.01; hazard ratio, 1.45 (95% confidence interval, 1.09-1.94)]. Knockdown of KIF14 in non–small-cell lung carcinoma and cervical carcinoma cell lines decreased proliferation and colony formation in soft agar.

Conclusions: KIF14 expression is independently prognostic for disease-free survival in lung cancer and knockdown decreases tumorigenicity in vitro, showing that it is a clinically relevant oncogene and an exciting therapeutic target for further study.

Lung cancer remains the most common cancer mortality worldwide, with 5-year survival in the United States of only 15% (1). Although effective surgical and chemotherapeutic interventions exist, the high fatality rates emphasize the need for early detection, useful genetic diagnostic and prognostic tools, and molecular targets for next-generation therapeutics (2). Hence, we and others have endeavored to identify clinically significant gene expression signatures of lung tumors (3–8).

Cancer progression initiates with genomic change, secondarily reflected in gene expression changes. By searching for genes with altered genomic copy number in cancer, we recently identified the mitotic kinesin KIF14 as a candidate oncogene in multiple cancers, including lung tumors (9). We applied a DNA-based genomic approach in retinoblastoma and breast cancer to narrow the region of genomic gain at 1q31-q32 in these cancers. This region has also been reported to be gained or amplified in 22% of 430 lung tumors currently in the Progenetix cytogenetic abnormalities in human cancer database (10); a minimal region of gain at 1q32 containing KIF14 was recently defined in lung cancer (8). Gain of this region has also recently been shown to associate with the progression from premalignant to malignant lesions and with metastasis in squamous cell lung carcinoma (11). We found that KIF14 was a gene in the minimal region of gain that was dramatically overexpressed in breast cancer and medulloblastoma cell lines and primary retinoblastoma (9). The KIF14 locus itself also showed genomic gain or amplification in the majority of retinoblastoma, breast cancer cell lines, and hepatocellular carcinoma (12).

We showed that 10 of 22 primary lung tumors displayed 3- to 34-fold increased KIF14 mRNA expression over matched normal samples. The patients in this very small, preliminary cohort with increased KIF14 levels showed a trend (P = 0.08) toward decreased survival time (9). We have since shown that KIF14 mRNA expression increases with grade in breast cancer, seeming to be a novel proliferation marker, and in univariate analyses is prognostic for both disease-free and overall outcome in this cancer (13).

Despite its growing importance as a candidate oncogene, relatively little is known about the cellular function of KIF14. It was cloned in 1994 (14) and was readily identified as a member of the kinesin superfamily, which are molecular motors that use the hydrolysis of ATP to power movement along microtubules (15). Only recently has KIF14 been functionally analyzed. In a study knocking down mitotic kinesins in HeLa cells, decreased KIF14 expression caused misalignment of chromosomes at the metaphase plate, with a subsequent delay in mitosis (16). However, more recently, two studies have localized KIF14 to the central spindle in HeLa cells, where it is essential for the final phase of cytokinesis, rather than chromosome alignment (17, 18). KIF14 interacts with protein regulator of cytokinesis 1 and citron kinase, displaying a central organizing role at the midbody in cytokinesis (18). Knockdown of KIF14 leads to binucleate cells (17, 18), with consequent polyploidy and apoptosis (17). KIF14 thus seems to be an important, previously overlooked part of the machinery that allows efficient cell division. Moreover, as an ATPase, KIF14 is a very promising anticancer drug target.

We report here for the first time the clinical significance of KIF14 mRNA expression in a large cohort of non–small-cell lung carcinoma (NSCLC) patients and its effect on tumor cell colony formation in vitro. These results further implicate KIF14 as an oncogene that is potentially a powerful prognostic marker and attractive therapeutic target in lung cancer.


   Materials and Methods
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Results
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Clinical samples. Lung tumor samples were obtained from patients who had undergone lung cancer resection as their primary mode of therapy without preoperative radiation or chemotherapy, as previously described (3). Tissue specimens were banked with informed consent, and the University Health Network Research Ethics Board approved the study. Percentage tumor purity in sections adjacent to regions used for RNA extraction was estimated during routine histopathologic analysis.

RNA extraction, reverse transcription, and real-time reverse transcription-PCR. Total RNA was extracted from primary tumor material by the guanidinium isothiocyanate-phenol-chloroform method and 5-µg RNA was reverse transcribed using TaqMan reverse transcription reagents and random hexamer primers (Applied Biosystems, Inc.) as described (3).

First-strand reverse transcription products (5 µL) were added to 12.5-µL reactions with 1x TaqMan Universal PCR Master Mix including AmpErase UNG (Applied Biosystems) and 1x TaqMan Gene Expression Assay primer-probe mix (Applied Biosystems) for either KIF14 (Hs00978216_m1) or TBP (TATA-box binding protein), a housekeeping gene used as an endogenous control (Hs99999910_m1). These primers span exons. Triplicate reactions for each gene for each sample were prepared in 384-well plates and PCR was done using a PRISM 7900HT system (Applied Biosystems). Cycling conditions were 2 min at 50°C to activate UNG, 10 min at 95°C to activate the polymerase, and 40 cycles of 15 s at 95°C plus 1 min at 60°C. SDS 2.1 software (Applied Biosystems) was used to calculate {Delta}Ct relative expression values, normalized to TBP. Fold increase was calculated relative to a transformed lung epithelial cell line because matched normal tissue was not available for all samples; the choice of calibration sample does not influence statistical analyses of these data. Validation of equivalent amplification efficiency between KIF14 and TBP was confirmed in pilot experiments by amplification of a dilution series.

To validate the TaqMan results and assess the relationship between KIF14 and citron kinase (CIT) expression, a subset of samples (n = 94) was also analyzed by real-time quantitative PCR amplification using the SYBR Green assay in the PRISM 7900HT (Applied Biosystems). Each 10-µL reaction contained a 10-ng equivalent of cDNA. The reactions were activated at 95°C for 3 min followed by 40 cycles of 95°C (15 s), 65°C (15 s), and 72°C (20 s). The transcript number per nanogram of cDNA was obtained using standard curves generated with a pool of 10 nontumor lung genomic DNAs. Expression data were normalized to the geometric mean of four housekeeping genes (Table 1 ) to control for variability in expression levels. Primers were designed with Primer Express v 2.0 (Applied Biosystems) and sequences are provided in Table 1.


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  		Table 1. Primer sequences used in SYBR Green real-time quantitative reverse transcription-PCR, written 5' to 3'

 
RNA interference, proliferation, and soft-agar colony formation assays. H1299 NSCLC cells (a kind gift from the laboratory of Dr. Sam Benchimol, Ontario Cancer Institute, Totonto, Canada) and HeLa cervical carcinoma cells were grown in H21 minimal essential medium supplemented with penicillin-streptomycin and 10% fetal bovine serum at 37°C, 5% CO2. Cells in six-well plates were transfected with 100 pmol of small interfering RNA (siRNA) or buffer (mock) using 5 µL of Lipofectamine 2000 (Invitrogen) in OptiMEM (Invitrogen). Published siRNAs targeting KIF14 (18) and luciferase (GL2; ref. 19) were synthesized by Eurogentec, whereas two other siRNAs (SI00462336 and SI00462343) targeting different regions of the KIF14 transcript were obtained from Qiagen. After 24 h of growth, 100 cells were seeded in wells of a 96-well plate and counted at 24-h intervals using CyQUANT NF fluorescence (Invitrogen) on a Typhoon 9410 imaging system running ImageQuaNT TL software (version 2005, Amersham Biosciences). A further 250 cells were seeded in 3.5-cm dishes in 0.3% noble agar prepared in growth medium, atop a "plug" of 0.6% noble agar. After 2 weeks of growth, all colonies visible under the 0.8x objective of a dissecting microscope were scored. Efficacy of KIF14 knockdown was assessed by immunoblot with an anti-KIF14 antibody (K1760, U.S. Biological), normalized to ß-tubulin (T4026, Sigma) or ß-actin (AC-15, Sigma). Horseradish peroxidase–labeled secondary antibodies (H1299 experiments) were detected using ECL+ (Amersham) chemifluorescence on the Typhoon imager, whereas alkaline phosphatase–labeled secondary antibodies (HeLa experiments) were visualized with nitroblue tetrazolium/5-bromo-4-chloro-3-indolyl phosphate (Roche Applied Science). Relative KIF14 band intensity was calculated using ImageQuaNT TL software.

Statistical analyses. Relative KIF14 expression was treated as a continuous variable in all analyses. The associations between KIF14 expression and demographic and clinical data were analyzed by the Wilcoxon two-sample test or by the Kruskal-Wallis test (for more than two groups) where appropriate. Spearman's r was used to assess correlations. Disease-free survival (from the date of surgery to date of recurrence) and overall survival (from date of surgery to date of death) were used to describe the survival function and Cox proportional hazard regression was used for the univariate and multivariate analyses. In addition, for graphical display purposes, KIF14 expression was dichotomized at the median, which is the most conservative cutoff point for categorizing a continuous variable (20) and which also divides the bimodal distribution of KIF14 expression neatly (Fig. 1A ). Survival patterns of these two subgroups were compared using the Cox proportional hazards regression model and Kaplan-Meier log-rank test. These statistical analyses were done with SAS v.9.1 for Microsoft Windows. The Kruskal-Wallis test (SPSS v. 13 for MacOS) was used to test for differences in colony number between siRNA treatments. P ≤ 0.05 was considered significant in all tests.


Figure 1
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  		Fig. 1. KIF14 mRNA overexpression is prognostic for disease-free and overall survival in NSCLC. A, relative KIF14 expression distribution, showing dichotomization around the median. Some data points overlap and are not visible. B and C, survival plots for disease-free (B) and overall survival (C). P values shown are for Kaplan-Meier log-rank survival analyses. In univariate and multivariate Cox regressions, KIF14 expression was a significant predictor of disease-free survival (see text).

 

   Results
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Discussion
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To ascertain whether KIF14 expression is a prognostic factor in NSCLC, we examined its mRNA expression by real-time reverse transcription-PCR in 129 tumors (Fig. 1A). The results of this TaqMan-based analysis were highly correlated (r = 0.36, P = 0.004) to an independent analysis of absolute KIF14 mRNA levels in a subset of these tumors, validating this method.

The expression of KIF14 was highest in squamous cell carcinoma, followed by large-cell undifferentiated carcinoma and adenocarcinoma (Table 2 ; P = 0.002). KIF14 expression was inversely related to the pathologic differentiation of the tumor (P = 0.01). In contrast, KIF14 expression was not associated with pathologic stage (P = 0.29), T stage (P = 0.60) or N stage (P = 0.29), patient age (r = 0.097, P = 0.28), or gender (P = 0.84). There was a trend toward higher KIF14 expression in tumors with wild-type KRAS (P = 0.09). Because KIF14 interacts with citron kinase (18) and citron kinase mRNA expression is prognostic for disease-free survival in lung cancer (3), we examined the relationship between mRNA expression levels of these two genes in a subset (n = 94) of tumors. There was a weak negative correlation between KIF14 and CIT expression (r = –0.13, P = 0.2).


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  		Table 2. KIF14 expression stratified by demographic and clinical variables

 
When dichotomized at the median expression level (Fig. 1A), KIF14 overexpression was associated with significantly decreased disease-free survival (median survival time, 2.04 versus 3.70 years) in a Kaplan-Meier log-rank analysis (Fig. 1B; P = 0.01) and showed a trend toward decreasing overall survival (Fig. 1C; P = 0.08; median survival time, 3.09 versus 4.00 years). In univariate Cox proportional hazard regression survival analyses, increasing KIF14 expression was also associated with significantly decreased disease-free survival (Table 3 ; P = 0.01) and showed a trend toward decreased overall survival (Table 3; P = 0.10).


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  		Table 3. Effects of KIF14 expression and other prognostic variables on disease-free and overall survival in univariate and multivariate Cox proportional hazards regression analyses

 
In multivariate Cox regressions including stage, differentiation, histology, and tumor purity as covariates, KIF14 remained an independent prognostic factor for disease-free survival (Table 3) but not for overall survival (Table 3).

Because KIF14 overexpression is associated with poor prognosis in patients, we sought to evaluate if KIF14 is important for tumorigenicity in vitro, as a prelude to further investigations of this protein as a therapeutic target in NSCLC. Three different siRNA molecules targeting KIF14 transfected into H1299 NSCLC cells showed ~90% knockdown of KIF14 protein levels (Fig. 2A ). Two of the three siRNAs caused a subtle but reproducible decrease in proliferation (Fig. 2B), and all three markedly (P = 0.012) decreased the ability of these cells to form colonies in soft agar (Fig. 2C). Although the degree of knockdown was not quite as high in HeLa cells (Fig. 3A ), even more dramatic effects on proliferation (Fig. 3B) and colony formation (P = 0.016; Fig. 3C) were observed in this cell line.


Figure 2
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  		Fig. 2. Knockdown of KIF14 inhibits in vitro tumorigenicity in H1299 NSCLC cells. A, siRNAs decrease KIF14 compared with control (GL2) or mock transfection. Protein relative to mock, normalized to ß-tubulin. B, decreased KIF14 (filled symbols) decreases proliferation over GL2 (open squares) or mock (open diamonds). CyQUANT NF fluorescence relative to starting (points, mean of six wells; bars, SD). C, decreased KIF14 decreases soft agar colony formation ability. Left, colonies in soft agar. Right, colony counts (columns, mean of triplicate plates; bars, SD); P = 0.012. Representative results from three experiments.

 

Figure 3
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  		Fig. 3. Knockdown of KIF14 inhibits in vitro tumorigenicity in HeLa cervical carcinoma cells. A, siRNAs decrease KIF14 compared with control (GL2) or mock transfection. Protein relative to mock, normalized to ß-actin. B, decreased KIF14 (filled symbols) decreases proliferation over GL2 (open squares) or mock (open diamonds). CyQUANT NF fluorescence relative to starting (points, mean of three wells; bars, SD). C, decreased KIF14 decreases soft agar colony formation ability. Left, colonies in soft agar. Right, colony counts (columns, mean of triplicate plates; bars, SD); P = 0.016. Representative results from three experiments.

 

   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
To our knowledge, we present the first evidence that a kinesin is an independent prognostic factor in any cancer. Previously, KIF14 (initially known as KIAA0042) has been identified in high-throughput studies as an overexpressed gene in lung cancer cell lines (21) and was part of a 42-gene set indicating poor prognosis in a mixed population of lung tumors (22). It is also one of 91 genes that lie in a minimal region of genomic gain at 1q and are overexpressed in NSCLC (8). KIF14 was not represented on the microarrays used in our previous prognostic marker screening study (7). Our identification here of KIF14 mRNA expression as an independent prognostic factor for disease-free survival argues for the prognostic power of this gene alone in NSCLC. We note that our findings will require replication in larger, independent cohorts, but given our prior findings that KIF14 is a prognostic indicator in breast cancer (13), it is likely that this gene has wide-ranging prognostic power in cancer. That KIF14 expression is an independent prognostic factor for disease-free survival in NSCLC is particularly important and novel, given the paucity of useful prognostic indicators in this cancer.

How KIF14 acts as oncogene is unclear because the long-term cellular effects of KIF14 overexpression remain unknown. It is feasible, however, that high KIF14 levels contribute to uncontrolled proliferation and cancer cell aneuploidy, perhaps by stimulating premature cytokinesis and/or evasion of the spindle checkpoint (23). Overexpression may also enable cells to bypass apoptosis because KIF14 knockdown increases apoptosis at multiple stages of the cell cycle (17). However, no previous studies have examined the effects of KIF14 knockdown on anchorage-independent growth in colony formation assays—the best in vitro indicator of tumorigenesis in vivo (24).

We show here that reduction in KIF14 expression by siRNA moderately decreases proliferation but strongly decreases the ability of H1299 and HeLa cells to form colonies in soft agar. Together, these in vitro findings suggest that reduced KIF14 expression is not simply cytotoxic but specifically affects the tumorigenic cells capable of independent growth, perhaps the stem cells perpetuating the cell line. This makes KIF14 a very appealing target for cancer therapeutic development. It is interesting to note that HeLa cells (Fig. 3A) are more susceptible to colony formation inhibition when KIF14 is knocked down, yet do not display as high a degree of protein knockdown as H1299 cells (Fig. 2A). Both these phenomena may be attributable to the higher absolute KIF14 protein levels in untreated HeLa cells. Compared with H1299, HeLa cells may be more "addicted" to KIF14 overexpression and hence are more sensitive to its loss, even if incomplete. Extending this logic, the most rapidly fatal tumors with highest KIF14 levels might respond best to a future anti-KIF14 therapeutic.

KIF14 interacts with citron kinase, localizing this Rho effector kinase to the central spindle in HeLa cells (18). Intriguingly, citron kinase was one of three microarray-identified genes shown in our previous study to be prognostic for disease-free survival in univariate analyses of a subset of this same cohort of tumors (3). However, whereas KIF14 overexpression is associated with decreased disease-free survival (this work), for citron kinase, the converse is true (3). This inverse relationship is in keeping with the weak negative correlation we observed between the expression of these two genes, but also suggests that KIF14 has functional interactions in NSCLC cells with other proteins in addition to citron kinase. We speculate that the expressions of KIF14 and citron kinase are coordinately controlled to deregulate the central spindle and final phase of cytokinesis in lung cancer cells. It will be interesting to evaluate if KIF14 expression is predictive for response to treatment with spindle poisons such as Vinca alkaloids and taxanes.

There does not yet exist an anti-KIF14 antibody that will reliably stain formalin-fixed, paraffin-embedded tissues. Thus, we could not confirm KIF14 overexpression at the protein level in our cohort of tumors. Whereas it is possible that KIF14 is not overexpressed at the protein level, or that overexpression is not specific to the tumor cells, our previous findings of low to undetectable KIF14 mRNA in normal lung samples and in other normal adult tissues (9) suggest that overexpression is a tumor-specific phenomenon. In breast cancer cell lines, KIF14 mRNA expression agrees closely with protein expression by immunoblot (9). Moreover, in the present study, KIF14 remained an independent prognostic factor, even when the potential confounding variable of tumor purity was included in multivariate analyses (Table 3). By adopting a real-time reverse transcription-PCR approach, we were able to quickly obtain quantitative information on KIF14 mRNA level. As long as fresh or frozen tumor tissue is available, this technique lends itself to clinical deployment for providing prognostic information because it is rapid, rigorous, and highly specific.

We now identify for the first time that KIF14 is an independent prognostic factor for disease-free survival in any cancer; this is the largest clinical study of KIF14 expression to date. We also show that KIF14 is necessary for the transformed state in NSCLC and cervical cancer cell lines. We conclude that KIF14 is an important oncogene in NSCLC. Independent validation of these clinical findings, examination of KIF14 expression in other tumor types, and further investigation of the cell biology of KIF14 and its potential as a therapeutic target are clearly warranted.


   Acknowledgments
 
We thank Ni Liu and Davina Lau for technical assistance, the laboratory of Dr. Sam Benchimol for the gift of H1299 cells, and members of the Gallie laboratory for critical reading of the manuscript.


   Footnotes
 
Grant support: National Cancer Institute of Canada with funds from the Canadian Cancer Society (M-S. Tsao and B.L. Gallie) and the Terry Fox Run (B.L. Gallie), and a Canadian Institutes of Health Research Canada Graduate Scholarship (T.W. Corson).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: M-S. Tsao holds the Qasim M. Choksi Chair in Lung Cancer Translational Research at Princess Margaret Hospital. F.A. Shepherd holds the Scott Taylor Chair in Lung Cancer Research at Princess Margaret Hospital.

Received 2/15/07; accepted 3/ 9/07.


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