Cytokinesis overexpression of kinesin motor kif14 in recurrent head and neck cancer: significance of microRNA regulation
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https://www.eduzhai.net Clinical Medicine and Diagnostics 2014, 4(1A): 1-7 DOI: 10.5923/s.cmd.201401.01 Overexpression of Cytokinesis Mediating Kinesin Motor KIF14 in Recurring Head and Neck Cancer: Implications for Regulation by MicroRNAs Shahid S. Siddiqui1,2,*, Sivakumar Loganathan1, Fathy M. El-Faskhany2,3, Faisal A. Allaf 4, Zeba K. Siddiqui5, Hanadi Lamfon2, Mohammad Beyari2 1Department of Medicine, University of Chicago, Chicago, IL 60637, USA 2Department of Basic and Clinical Oral Sciences, Faculty of Dentistry, Umm Al Qura University, Makkah, Saudi Arabia 3Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt 4Department of Medical Genetics, Faculty of Medicine, Umm Al Qura University, Makkah, Saudi Arabia 5Department of Medicine, University of Illinois, Chicago, IL 602012, USA Abstract Biomarkers that identify cancer risk provide early diagnosis, determine prognosis, or help in determining treatment choices for individual cancer patients, could dramatically improve cancer outcome. Head and neck cancer is the sixth most common cancer worldwide that continues to be a daunting challenge as many of these cancers recur, metastasize, or develop resistance to therapy. We have identified KF14 kinesin motor protein involved in cytokinesis and chromosome segregation to be highly expressed at both protein and mRNA levels in the cell lines derived from tumors in head and neck cancer, suggesting KIF14 as predictive biomarker for head and neck cancer. Interestingly, a number of microRNAs that potentially target the 3’UTR of KIF14 are also deregulated in the serum of recurring head and neck cancer subjects, providing a combinatory prediction paradigm for recurring head and neck cancer. Thus combining KIF14 over-expression and identification of signature miRNAs associated with recurring HNC may be an important approach for early diagnosis of recurring head and neck cancer, and may provide novel therapeutic reagents. Keywords Kinesin Motor Protein KIF14, Head and Neck Cancer, Cytokinesis, MicroRNAs 1. Introduction The cell cycle culminates in cytokinesis resulting in the separation of two daughter cells. Consequently interruption of normal cytokinesis may generate tetraploid cells, which gives rise to aneuploidy and may promote tumorigenesis [1-4]. Among the molecular components that govern cytokinesis, Kinesin motor proteins have been shown to play important role in cytokinesis[5-10]. Kinesins are ATP dependent family of molecular motor proteins that travel uni-directionally along microtubule tracks to transport diverse cellular cargo into intracellular compartments or facilitate cell division by segregating chromosomes during cell cycle. Many members of the kinesin superfamily of motor proteins have been shown to be involved in carcinogenesis, e.g. in breast cancer KIF2, and KIF15 are designated as tumor antigen and KIF20A expression is induced in * Corresponding author: firstname.lastname@example.org (Shahid S. Siddiqui) Published online at https://www.eduzhai.net Copyright © 2014 Scientific & Academic Publishing. All Rights Reserved pancreatic cancer. Member of the Kinesin-II family, the KIF3 kinesin, act as tumor suppressor genes in gastric cancer, whereas KIF13A is highly expressed in retinoblastomas. In hepatocellular carcinoma KIF10 expression is inhibited, and several other members of kinesin superfamily have intriguing expression patterns in carcinogenesis[12-20]. Since mitotic spindle formation is critical for cell cycle and essential for chromosome segregation; KIF14 motor contributes in the timing, formation and maintenance of spindle assembly; members of the KIF14 family organize microtubule organizing center (MTOC) to regulate bipolarity and as such is involved in the process of mitotic cell division, and are highly expressed in cancer cells[21, 22]. In lung adenocarcinoma cases, Hung et al have found that KIF14 expression inhibits tumor growth and cancer metastasis, and the authors have identified adhesion molecule cadherin 11 (CDH11) and melanoma adhesion molecule CDH11 as a cellular cargo of KIF14. In lung cancer, KIF14 mRNA is independently prognostic for outcome, as KIF14 knockdown decreases tumorigenicity in vitro, suggesting its clinical relevance. In breast cancer, KIF14 has been reported to negatively regulate Rap1a-RadiI 2 Shahid S. Siddiqui et al.: Overexpression of Cytokinesis Mediating Kinesin Motor KIF14 in Recurring Head and Neck Cancer: Implications for Regulation by MicroRNAs signaling, integrin activation, and cell matrix adhesiveness for tumorigenesis. Similarly, KIF14 has been shown to be an independent prognostic marker and essential for cell proliferation and in vitro colony formation in ovarian cancer. KIF14 and TLN1 were also identified in a targeted RNAi screen of the breast cancer genome, as genes that affect docetaxel chemosensitivity in triple negative breast cancer tissues. In retinoblastoma, KIF14 is over-expressed in a large cohort of retinoblastoma tumors, and KIF14’s location in the 1q minimal region has been implicated as a region of genomic gain in multiple cancers . These combined data suggest that KIF14 may play important role in oncongenesis, and may serve as a prognostic marker, and a therapeutic target. Here we have examined the expression of KIF14 protein expression using immunocytochemical techniques, and measurement of KIF14 transcripts using quantitative PCR on head and neck cancer derived cell lines and compared KIF14 expression in normal not transformed epithelial BAES cells, and discovered induction of KIF14 expression in several HNC cell lines. We have investigated the possibility of posttranscriptional regulation of KIF14 by microRNAs, and have profiled serum miRNAs from the peripheral blood of healthy controls and patients suffering from recurring head and neck cancer. MicroRNAs are small (about 22 nucleotide long) highly conserved non coding RNA that were originally discovered in C. elegans, that regulate about a third of all human protein coding transcripts by binding to the 3’UTR and inhibiting its translation into protein[27, 28]. Specific miRNAs have been associated with cancer and tumorigenesis. We have explored how serum miRNA profile can help in distinguishing recurrent and non-recurrent HNC patients using novel combinatory approach. Combining information on microRNAs with independent types of biomarkers can improve cancer risk assessment, detection, and prognosis. In breast cancer, for example mutations in BRCA1 and BRCA2 together with genetic variants in PTEN, p53, CHEK2 and ATM are associated with higher risk of the disease[30, 31], and polymorphisms in FGFR, XRCC1 and CCND1 have been associated with HNC and survival. Thus, adding miRNA information with other genomic markers associated with oncogenesis such as KIF14 could allow diagnostic markers that could be more accurate in cancer risk assessment, detection and diagnosis. 2. Material and Methods 2.1. Head and Neck Cancer Cell Lines Cell lines from head and neck cancer patients were obtained from University of Chicago and ATCC ( e.g. SSC25, Hep-2 human laryngeal cell line, or SSC15 from human tongue cancer). Cells were grown in medium recommended by ATCC (USA), and all cell culture reagents (purchased from Lonza USA), essentially in DMEM supplemented with 5-10% Fetal Bovine Serum (FBS), 100 units of streptomycin, 50 units of ampicillin. Cells were grown in 5% CO2 humid chamber at 37 C, as described[33, 34]. 2.2. Immunocytochemical Staining The staining was as described previously, Briefly cells were washed with Phosphate buffered Saline (PBS), and fixed with freshly prepared 4% formaldehyde for 10m minutes, washed and treated with chilled methanol for 5 min, washed with PBS and triton X-100 (0.1% in PBS). Affinity purified primary rabbit polyclonal antibodies against human KIF14 (Bethyl, USA), were used at a dilution of 1:500 in PBS, and incubated for one hr at 4 C. cells were washed with chilled PBS and incubated with Goat anti-rabbit IgG, conjugated with Alexa 480 for 30 minutes. Cells were washed again with PBS, and mounted in sodium n-propyl gallate to prevent photo-bleaching. DAPI stain was used to counterstain nuclei by DNA staining. In controls we used pre-immune rabbit serum that gave negative staining. 2.3. Head and Neck Cancer Study Samples The miRNA profiling studies were performed on peripheral serum sample resources at the University of Chicago, Chicago, Illinois. Briefly, samples from HNC patients were collected at diagnosis prior to any therapy. These patients were treated at the University of Chicago using a standard chemo radiotherapy regimen (FHX-based). The HNC sample group consists of two cohorts: ones who eventually developed disease recurrence and ones who are disease-free with at least 2 years follow-up. About 1 ml serum samples was used to purify total RNA using Trizol method, labeled, and profiled on Exiqon human miRNA microarray slides by hybridization [Siddiqui SS, Cohen E, and Vokes, E., unpublished data]. 2.4. Serum Samples from Peripheral Blood Serum samples from HNC patients were collected at diagnosis prior to any therapy. These patients were treated at the University of Chicago using a standard chemo-radiotherapy regimen (FHX-based). The HNC sample group consists of two cohorts: ones who eventually developed disease recurrence and ones who are disease-free with at least 2 years follow-up. For the proposed studies we randomly selected 14 HNC recurring cases and matched healthy controls from the tissue bank. The inclusion criteria were 1) male or female; 2) age above 18 years; 3) have donated serum and 4) without diagnosis of any cancers or inflammatory conditions. The healthy controls were selected to match the HNC cases. About 1 ml serum samples was used to purify total RNA using Trizol method, labeled, and profiled on latest version of Exiqon (Denmark), human miRNA microarray slides by hybridization. 2.5. Clustering and Statistical Analysis Clinical Medicine and Diagnostics 2014, 4(1A): 1-7 3 The expression level of signature miRNAs from serum in patients with HNC has been compared to the expression level in serum of patients with HNC recurrence using a two-sample t test or nonparametric Wilcoxon rank-sum test, as appropriate. We are following these results with 50 Saudi patients per group, there will be 80% power to detect an approximately 0.6 standard deviation difference in the means of the two groups using a two-sided significance level of 0.05. MicroRNA expression levels across groups will be assessed using ANOVA or the nonparametric Kruskal-Wallis test. Secondary analyses will examine the association between expression levels and disease characteristics (HNC non-recurring and HNC recurring types) using correlation analysis or ANOVA. 3. Results 3.1. Induction of KIF14 Expression in Recurring HNC Cell Lines Figure 1. KIF14 Kinesin Expression is induced in HNC cell line: Monolayer of control cells[BEAS, epithelial cells, panel a, and c] and transformed HNC cancer cell line SSC15,[panel b, and d]. Monolayer of cells was fixed with 4% formaldehyde; followed by cold methanol treatment and permeabilized with Triton[0.1%] Phosphate Buffered Saline. Primary polyclonal rabbit antibody against human KIF14 kinesin [Cell Signaling] was used at 1:500 dilutions. Cells were washed and incubated with Goat anti-rabbit-IgG-antibodies conjugated with Alexa-488 [Invitrogen] antibodies, used at 1:1000 dilution. Nuclei were stained with DAPI nuclear stain. Confocal images were taken on a Leica 2-photon microscope. There is a clear induction of KIF14 expression in transformed cells (SSC15) as seen in panel b, as compared to the control non-transformed cells in panel a Since several cancers have been associated with gain in the 1q region harboring KIF14 gene, we have investigated if KIF14 expression is altered in head and neck cancer cell lines. To study investigate the expression of KIF kinesin in cell lines from head and neck cancer subjects, we have used affinity purified Hunan anti-KIF14 polyclonal antibodies on cell monolayers stained as described in Methods section. As shown in Figure 1, KIF14 is significantly up-regulated in HNC cell lines as compared to the control epithelial cell line have used affinity purified Hunan anti-KIF14 polyclonal antibodies on cell monolayers stained as described in Methods section. As shown in Figure 1, KIF14 is significantly up-regulated in HNC cell lines as compared to the control epithelial cell line Image quantification using Metamorph (Imaging Software) suggest an increase from 2 fold to 24 fold KIF14 expression in the HNC samples, suggesting both variability and consistent higher expression in the HNC tissues. We also observed that KIF14 expression was mainly nuclear, but in 10% cases (11 of the110) the antibody also stained non-nuclear cytoplasm regions as shown in Figure 1, suggesting some additional transport role for KIF14 in addition to the chromosomal segregation and cytokinesis. The low intensity staining in control cells is mostly nuclear, and it co-localized with nuclear stain DAPI, panel a, and c. 3.2. Profiling miRNAs in HNC Serum Samples Systematic profiling of miRNAs from serum in patients with recurring HNC and in normal controls was done as follows: The serum miRNA profiling data was obtained using an miRCURY miRNA array platform[Exiqon, Denmark] that contains probes for all human miRNAs annotated in miRBase, show a distinct set of miRNAs whose expression is specifically altered in the samples from recurring HNC when compared with matched non-recurring cases and matched normal control cases. Among dysregulated microRNAs are, let-7c, let-7g, miR-423, miR-513, miR-551, miR-585, and miR-1280 and miR-1826 [Figure 2]. Interestingly these signature miRNAs target several transcripts that are associated with tumorigenesis, such as p53, BRCA1, BRCA2, FGF, FGFR, KRAS, HGF, and PTEN, and regulate conserved pathways in cell cycling, inflammation, angiogenesis, apoptosis, cell proliferation and cell survival based on gene ontology pathways. 3.3. Clustering and Statistical Analysis has been performed to obtain the signature profile of normal versus HNC patient serum samples i.e. disease-free versus recurrent HNC patients. Results obtained by hybridization profile have been used to validate miRNA signature using Exiqon (Denmark) probes for each miRNA, using RT-PCR in the serum samples. For validation we have used 12 human samples that include serum from four normal controls, 8 HNC recurring cases. 3.4. The 3’UTR of the Human Kinesin KIF14 The human KIF14 transcripts include a 3’UTR of 1.8 kb that contains target site of several miRNAs [Table 1]. Among 30 SNPs reported in the 3’UTR of KIF14 at the NCBI (NIH, USA) website, two SNPs rs16846879 and rs78301187 will affect seed region binding of the let-7g, miR-17, miR-18a, b; miR20a, b; mIR-93, miR-106, thereby affecting the expression of KIF14 in patients carrying these two SNPs. [Figure: 3]. 4 Shahid S. Siddiqui et al.: Overexpression of Cytokinesis Mediating Kinesin Motor KIF14 in Recurring Head and Neck Cancer: Implications for Regulation by MicroRNAs Figure 2. Heat Map, Serum miRNA expression profile in Recurring and Non-Recurring HNC subjects Figure 3. SNPs in the 3’UTR of human KIF14 that may affect predicted binding of miRNAs A reduced binding of the targeting miRNA to the 3’UTR of KIF14 may result in an increased protein expression of KIF14, which is consistent with data on higher KIF14 expression in cancer cell lines, compared to the normal control cell lines. Other SNPs exist in the 3’UTR of human KIF14 that may potentially alter binding of several target miRNAs, namely rs4304619, rs71797608, rs72400996, rs113846989, rs71936128, rs71782993, rs10529683, rs61535508, rs7412927, rs6667775, rs112727234, rs61827012, rs113754726, rs10800708, rs16846879. A risk variant in a miR-125b binding site in BMPR1B has been recently reported is that associated with breast cancer pathogenesis. Therefore, it will be useful to determine whether 3’UTR SNPs of KIF14 may affect KIF14 expression, thereby resulting in alterations in cell proliferation and tumorigenesis in HNC. For example the single SNP, rs16846879 may potentially affect seed region binding of several miRNA to the 3’UTR of KIF14. 4. Discussion Interestingly a significant number of the miRNAs that show altered expression in the serum of recurring HNC patients can potentially bind the 3’UTR of KIF14, suggesting that KIF14 expression may also be regulated by changes in miRNA expression in the recurring HNC cases. Clinical Medicine and Diagnostics 2014, 4(1A): 1-7 5 Table 1. The human KIF14 transcripts include a 3’UTR of 1.8 kb that contains target site of several miRNAs 3'UTR Position 7204 7104 6771 6700 6640 6618 6617 6615 6610 6608 6605 6605 6605 6593 6525 6490 6460 6202 5864 5863 5858 5854 5847 5826 5819 5812 5812 5682 5633 5617 5558 5557 5551 5407 5397 KIF14 3'UTR SNPs db SNP Heterozygosity rs114339113 rs112171695 rs10737572 rs76170059 rs75458976 rs80258132 rs78024886 rs78976496 rs67546421 rs10919974 rs71135368 rs72745039 rs77196694 rs78704393 rs75074050 rs12060793 rs74319334 rs76252675 rs59952024 rs4304619 rs71797608 rs72400996 rs113846989 rs71936128 rs71782993 rs10529683 rs61535508 rs7412927 rs6667775 rs112727234 rs61827012 rs113754726 rs10800708 rs16846879 rs78301187 N.D. N.D. 0.257 0.5 0.044 0.5 0.5 0.105 0.5 0.312 N.D. 0.369 N.D. 0.5 0.5 0.494 0.296 0.297 N.D. 0.278 N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. 0.18 N.D. 0.5 N.D. 0.219 0.014 0.022 3'UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR 3' UTR Allele C/T C/T C/T A/G C/T C/T C/T C/T -/TTC C/T -/AAG C/T (>6bp) A/T C/G A/G A/T A/C -/A G/T (>6bp) (>6bp) (>6bp) (>6bp) (>6bp) (>6bp) (>6bp) C/T A/G C/T A/G C/T A/T A/G C/G for non-invasive biomarkers with a potential for developing pre-clinical therapeutic targets. Furthermore, SNPs in KIF14 transcript 3’UTR may alter binding of specific miRNAs, altering KIF14 protein expression, thereby may contribute to cancer development. We will test whether SNPs in KIF14 are associated individually and most often collectively with miRNAs deregulated in HNC with the increased risk of HNC. Statistical Requirements for validation in larger samples: The expression level of microRNAs in our study in progress (Siddiqui SS, Cohen E, and Vokes E, unpublished data) from 50 paired samples of normal controls (no cancer), HNC non-recurring and recurring HNC patient groups will be compared using paired t tests or nonparametric Wilcoxon signed-rank tests, as appropriate. With 50 samples, there will be 80% power to detect an approximately 0.45 standard deviation difference in the mean expression levels of any two types of samples using a two-sided significance level of 0.017 to account for multiple comparisons. In addition, the agreement between miRNA expressions levels obtained from HNC non-recurring patients versus HNC recurring patients will be assessed using Bland-Altman plots. For statistical robustness we need to validate the preliminary data shown in Figure 1, on statistically robust sample size and we are planning about 100 samples to screen in future studies in Saudi subjects. 5. Conclusions We have shown that KIF14 kinesin expression is consistently increased in head and neck cancer cell lines as compared to the non-transformed control cell lines, and that these observations confirm the role of KIF14 in carcinogenesis as it has been shown in several other types of cancers. Serum profile of miRNAs from recurring HNC and non-recurring clearly suggest specific miRNAs that are dysregulated in recurring HNC, and some of these miRNAs target the 3’UTR of KIF14 kinesin gene. A number of SNPs exist in the NCBI database that can potentially affect predicted binding of specific miRNAs to the KIF14 3’UTR, and affect the KIF14 expression in HNC. Our sample size is small but we are undertaking these studies on a large cohort of HNC cases in Saudi Arabia to validate these markers as statistically significant. Characterization of serum miRNAs in HNC as biomarkers and its combined use with KIF14 genetic variants will be important for early diagnosis, managing risk assessment for developing pre-clinical therapeutic targets. Two single nucleotide polymorphisms (SNPs) in the 3’UTR of KIF14, namely rs16846879 and rs78301187 will affect binding of the let-7g, miR-17, miR-18a, b; miR20a, b; mIR-93, miR-106, thereby affecting the expression of KIF14 kinesin in patients harboring these SNPs. Discovery of serum miRNAs as HNC prognostic, diagnostic, and predictive biomarkers in patients will be an important step ACKNOWLEDGEMENTS We thank Prof. Joe Skip Garcia, former Chairman Department of Medicine, and Prof. Everett Vokes, Chairman of the Department of Medicine, University of Chicago, Chicago Illinois for encouragement and support; and Dr. Ezra Cohen, Dr. Ravi Salgia, Dr. Julian Solway for sharing 6 Shahid S. Siddiqui et al.: Overexpression of Cytokinesis Mediating Kinesin Motor KIF14 in Recurring Head and Neck Cancer: Implications for Regulation by MicroRNAs resources, and providing invaluable discussions. We are also grateful to Dr. Douglas Yau and Azam Farooqui for technical assistance with experiments. We thank Dr. S. Bajammal, Dr. S. Shahabuddin for the facilities at the Central Research Lab at College of Dentistry UQUDENT, Dr. A. Abdullah, Dr. A. Sakher, Dr. A. Herabi and Dr. T. 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