BACKGROUND: Oral squamous cell carcinoma (OSCC) severely affects the quality of life and the 5-year survival rate is low. Exploring the potential miRNA-mRNA regulatory network and analyzing hub genes and clinical data can provide a theoretical basis for further elucidating the pathogenesis of OSCC. METHODS: The miRNA expression datasets of GSE113956 and GSE124566 and mRNA expression datasets of GSE31056, GSE37991 and GSE13601 were obtained from the Gene Expression Omnibus databases. The differentially expressed miRNAs (DEMs) and mRNAs (DEGs) were screened using GEO2R. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by DAVID database. The PPI network was established through STRING database and the hub genes were preliminarily screened out by Cytoscape software. After identifying the hub genes in the TCGA database, we predicted the potential DEM transcription factors, constructed a miRNA-mRNA regulatory network, and analyzed the relationship between the hub genes and clinical data. RESULTS: A total of 28 DEMs and 764 DEGs were screened out, which were composed of 285 up-regulated genes and 479 down-regulated genes. Enrichment analysis showed that up-regulation of DEGs were mainly enriched in extracellular matrix organization and cancer-related pathway, while down-regulation of DEGs were mainly enriched in muscular system process and adrenaline signal transduction. After preliminary screening by PPI network and identification in TCGA, the up-regulated FN1, COL1A1, COL1A2, AURKA, CCNB1, CCNA2, SPP1, CDC6, and down-regulated ACTN2, TTN, IGF1, CAV3, MYL2, DMD, LDB3, CSRP3, ACTA1, PPARG were identified as hub genes. The miRNA-mRNA regulation network showed that hsa-miR-513b was the DEM with the most regulation, and COL1A1 was the DEG with the most regulation. In addition, CDC6, AURKA, CCNB1 and CCNA2 were related to overall survival and tumor differentiation. CONCLUSIONS: The regulatory relationship of hsa-miR-513b/ CDC6, CCNB1, CCNA2 and the regulatory relationship of hsa-miR-342-5p /AURKA were not only verified in the miRNA-mRNA regulatory network but also related to overall survival and tumor differentiation. These results indicated that they participated in the cellular regulatory process, and provided a molecular mechanism model for the study of pathogenesis.

• MeSH
• Epinephrine MeSH
• Aurora Kinase A genetics   metabolism   MeSH
• Squamous Cell Carcinoma of Head and Neck * genetics   MeSH
• Gene Regulatory Networks MeSH
• Quality of Life MeSH
• Humans MeSH
• RNA, Messenger genetics   metabolism   MeSH
• MicroRNAs * genetics   MeSH
• Mouth Neoplasms * genetics   MeSH
• PPAR gamma genetics   metabolism   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Gene Expression Profiling MeSH
• Transcription Factors genetics   MeSH
• Computational Biology methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

The Aurora protein kinases are well-established regulators of spindle building and chromosome segregation in mitotic and meiotic cells. In mouse oocytes, there is significant Aurora kinase A (AURKA) compensatory abilities when the other Aurora kinase homologs are deleted. Whether the other homologs, AURKB or AURKC can compensate for loss of AURKA is not known. Using a conditional mouse oocyte knockout model, we demonstrate that this compensation is not reciprocal because female oocyte-specific knockout mice are sterile, and their oocytes fail to complete meiosis I. In determining AURKA-specific functions, we demonstrate that its first meiotic requirement is to activate Polo-like kinase 1 at acentriolar microtubule organizing centers (aMTOCs; meiotic spindle poles). This activation induces fragmentation of the aMTOCs, a step essential for building a bipolar spindle. We also show that AURKA is required for regulating localization of TACC3, another protein required for spindle building. We conclude that AURKA has multiple functions essential to completing MI that are distinct from AURKB and AURKC.

• MeSH
• Spindle Apparatus genetics   MeSH
• Aurora Kinase A genetics   MeSH
• Aurora Kinase B genetics   MeSH
• Aurora Kinase C genetics   MeSH
• Cell Nucleus Division genetics   MeSH
• Fetal Proteins genetics   MeSH
• Humans MeSH
• Meiosis genetics   MeSH
• Mice MeSH
• Oocytes growth & development   metabolism   MeSH
• Microtubule-Organizing Center metabolism   MeSH
• Spindle Poles genetics   MeSH
• Protein Serine-Threonine Kinases genetics   MeSH
• Microtubule-Associated Proteins genetics   MeSH
• Cell Cycle Proteins genetics   MeSH
• Proto-Oncogene Proteins genetics   MeSH
• Chromosome Segregation genetics   MeSH
• Gene Expression Regulation, Developmental genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Primary cilia play critical roles in development and disease. Their assembly and disassembly are tightly coupled to cell cycle progression. Here, we present data identifying KIF14 as a regulator of cilia formation and Hedgehog (HH) signaling. We show that RNAi depletion of KIF14 specifically leads to defects in ciliogenesis and basal body (BB) biogenesis, as its absence hampers the efficiency of primary cilium formation and the dynamics of primary cilium elongation, and disrupts the localization of the distal appendage proteins SCLT1 and FBF1 and components of the IFT-B complex. We identify deregulated Aurora A activity as a mechanism contributing to the primary cilium and BB formation defects seen after KIF14 depletion. In addition, we show that primary cilia in KIF14-depleted cells are defective in response to HH pathway activation, independently of the effects of Aurora A. In sum, our data point to KIF14 as a critical node connecting cell cycle machinery, effective ciliogenesis, and HH signaling.

• MeSH
• Adaptor Proteins, Signal Transducing metabolism   MeSH
• Aurora Kinase A antagonists & inhibitors   genetics   metabolism   MeSH
• Basal Bodies metabolism   MeSH
• Cell Cycle genetics   MeSH
• Chromatography, Liquid MeSH
• Cilia genetics   metabolism   pathology   MeSH
• HEK293 Cells MeSH
• Interphase physiology   MeSH
• Intracellular Signaling Peptides and Proteins genetics   metabolism   MeSH
• Kinesins genetics   metabolism   MeSH
• Humans MeSH
• Mitosis genetics   MeSH
• Oncogene Proteins genetics   metabolism   MeSH
• Protein Serine-Threonine Kinases genetics   metabolism   MeSH
• Hedgehog Proteins metabolism   MeSH
• RNA Interference MeSH
• Signal Transduction genetics   MeSH
• Sodium Channels metabolism   MeSH
• Tandem Mass Spectrometry MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Errors in chromosome segregation during female meiosis I occur frequently, and aneuploid embryos account for 1/3 of all miscarriages in humans [1]. Unlike mitotic cells that require two Aurora kinase (AURK) homologs to help prevent aneuploidy (AURKA and AURKB), mammalian germ cells also require a third (AURKC) [2, 3]. AURKA is the spindle-pole-associated homolog, and AURKB/C are the chromosome-localized homologs. In mitosis, AURKB has essential roles as the catalytic subunit of the chromosomal passenger complex (CPC), regulating chromosome alignment, kinetochore-microtubule attachments, cohesion, the spindle assembly checkpoint, and cytokinesis [4, 5]. In mouse oocyte meiosis, AURKC takes over as the predominant CPC kinase [6], although the requirement for AURKB remains elusive [7]. In the absence of AURKC, AURKB compensates, making defining potential non-overlapping functions difficult [6, 8]. To investigate the role(s) of AURKB and AURKC in oocytes, we analyzed oocyte-specific Aurkb and Aurkc single- and double-knockout (KO) mice. Surprisingly, we find that double KO female mice are fertile. We demonstrate that, in the absence of AURKC, AURKA localizes to chromosomes in a CPC-dependent manner. These data suggest that AURKC prevents AURKA from localizing to chromosomes by competing for CPC binding. This competition is important for adequate spindle length to support meiosis I. We also describe a unique requirement for AURKB to negatively regulate AURKC to prevent aneuploidy. Together, our work reveals oocyte-specific roles for the AURKs in regulating each other's localization and activity. This inter-kinase regulation is critical to support wild-type levels of fecundity in female mice.

• MeSH
• Aneuploidy MeSH
• Aurora Kinase A genetics   metabolism   MeSH
• Aurora Kinase B genetics   metabolism   MeSH
• Aurora Kinase C genetics   metabolism   MeSH
• Fertility genetics   MeSH
• Meiosis * MeSH
• Mice MeSH
• Oocytes metabolism   MeSH
• Chromosome Segregation genetics   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

The mitotic kinase Aurora-A and its partner protein TPX2 (Targeting Protein for Xenopus kinesin-like protein 2) are overexpressed in cancers, and it has been proposed that they work together as an oncogenic holoenzyme. TPX2 is responsible for activating Aurora-A during mitosis, ensuring proper cell division. Disruption of the interface with TPX2 is therefore a potential target for novel anticancer drugs that exploit the increased sensitivity of cancer cells to mitotic stress. Here, we investigate the interface using coprecipitation assays and isothermal titration calorimetry to quantify the energetic contribution of individual residues of TPX2. Residues Tyr8, Tyr10, Phe16, and Trp34 of TPX2 are shown to be crucial for robust complex formation, suggesting that the interaction could be abrogated through blocking any of the three pockets on Aurora-A that complement these residues. Phosphorylation of Aurora-A on Thr288 is also necessary for high-affinity binding, and here we identify arginine residues that communicate the phosphorylation of Thr288 to the TPX2 binding site. With these findings in mind, we conducted a high-throughput X-ray crystallography-based screen of 1255 fragments against Aurora-A and identified 59 hits. Over three-quarters of these hits bound to the pockets described above, both validating our identification of hotspots and demonstrating the druggability of this protein-protein interaction. Our study exemplifies the potential of high-throughput crystallography facilities such as XChem to aid drug discovery. These results will accelerate the development of chemical inhibitors of the Aurora-A/TPX2 interaction.

• MeSH
• Aurora Kinase A chemistry   metabolism   MeSH
• Nuclear Proteins chemistry   metabolism   MeSH
• Crystallography, X-Ray MeSH
• Humans MeSH
• Ligands MeSH
• Protein Interaction Maps drug effects   MeSH
• Drug Discovery MeSH
• Microtubule-Associated Proteins chemistry   metabolism   MeSH
• Cell Cycle Proteins chemistry   metabolism   MeSH
• Molecular Docking Simulation MeSH
• Thiazolidines chemistry   pharmacology   MeSH
• Protein Binding drug effects   MeSH
• Binding Sites drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Alisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. Aurora A contains two functional single nucleotide polymorphisms (SNPs; codon 31 [F/I] and codon 57 [V/I]) that lead to functional changes. This study investigated the prognostic and predictive significance of these SNPs. METHODS: This study evaluated associations between Aurora A SNPs and overall survival (OS) in The Cancer Genome Atlas (TCGA) database. The Aurora A SNPs were also evaluated as predictive biomarkers for clinical outcomes to alisertib in two phase 2 studies (NCT01045421 and NCT01091428). Aurora A SNP genotyping was obtained from 85 patients with advanced solid tumors receiving single-agent alisertib and 122 patients with advanced recurrent ovarian cancer treated with alisertib plus weekly paclitaxel (n=62) or paclitaxel alone (n=60). Whole blood was collected prior to treatment and genotypes were analyzed by PCR. FINDINGS: TCGA data suggested prognostic significance for codon 57 SNP; solid tumor patients with VV and VI alleles had significantly reduced OS versus those with II alleles (HR 1.9 [VI] and 1.8 [VV]; p<0.0001). In NCT01045421, patients carrying the VV alleles at codon 57 (n=53, 62%) had significantly longer progression-free survival (PFS) than patients carrying IV or II alleles (n=32, 38%; HR 0.5; p=0.0195). In NCT01091428, patients with the VV alleles at codon 57 who received alisertib plus paclitaxel (n=47, 39%) had a trend towards improved PFS (7.5months) vs paclitaxel alone (n=32, 26%; 3.8months; HR 0.618; p=0.0593). In the paclitaxel alone arm, patients with the VV alleles had reduced PFS vs modified intent-to-treat (mITT) patients (3.8 vs 5.1months), consistent with the TCGA study identifying the VV alleles as a poor prognostic biomarker. No significant associations were identified for codon 31 SNP from the same data set. INTERPRETATION: These findings suggest that Aurora A SNP at codon 57 may predict disease outcome and response to alisertib in patients with solid tumors. Further investigation is warranted.

• MeSH
• Alleles MeSH
• Aurora Kinase A genetics   MeSH
• Azepines administration & dosage   adverse effects   MeSH
• Adult MeSH
• Protein Kinase Inhibitors administration & dosage   MeSH
• Polymorphism, Single Nucleotide MeSH
• Middle Aged MeSH
• Humans MeSH
• Biomarkers, Tumor genetics   MeSH
• Neoplasms drug therapy   genetics   pathology   MeSH
• Paclitaxel administration & dosage   adverse effects   MeSH
• Disease-Free Survival MeSH
• Pyrimidines administration & dosage   adverse effects   MeSH
• Aged MeSH
• Neoplasm Staging MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH
• Clinical Trial, Phase II MeSH
• Multicenter Study MeSH

Aurora-A kinase (AURKA), a member of the serine/threonine protein kinase family, is involved in multiple steps of mitotic progression. It regulates centrosome maturation, mitotic spindle formation, and cytokinesis. While studied extensively in somatic cells, little information is known about AURKA in the early cleavage mouse embryo with respect to acentrosomal spindle assembly. In vitro experiments in which AURKA was inactivated with specific inhibitor MLN8237 during the early stages of embryogenesis documented gradual arrest in the cleavage ability of the mouse embryo. In the AURKA-inhibited 1-cell embryos, spindle formation and anaphase onset were delayed and chromosome segregation was defective. AURKA inhibition increased apoptosis during early embryonic development. In conclusion these data suggest that AURKA is essential for the correct chromosome segregation in the first mitosis as a prerequisite for normal later development after first cleavage.

• MeSH
• Aurora Kinase A antagonists & inhibitors   metabolism   MeSH
• Azepines pharmacology   MeSH
• Time-Lapse Imaging MeSH
• Microscopy, Fluorescence MeSH
• Phosphorylation drug effects   MeSH
• Protein Kinase Inhibitors pharmacology   MeSH
• Microscopy, Confocal MeSH
• Embryo Culture Techniques MeSH
• Mitosis drug effects   physiology   MeSH
• Mice, Inbred BALB C MeSH
• Mice, Inbred C57BL MeSH
• Pyrimidines pharmacology   MeSH
• Chromosome Segregation drug effects   physiology   MeSH
• Animals MeSH
• Zygote drug effects   physiology   MeSH
• Check Tag
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

• Keywords
• daratumumab,
• MeSH
• Leukemia, Myeloid, Acute drug therapy   genetics   MeSH
• Aurora Kinase A antagonists & inhibitors   MeSH
• Azepines therapeutic use   MeSH
• Fusion Proteins, bcr-abl antagonists & inhibitors   MeSH
• Chimera MeSH
• Hematology * MeSH
• Congresses as Topic MeSH
• Humans MeSH
• Multiple Myeloma drug therapy   therapy   MeSH
• Antibodies, Monoclonal therapeutic use   MeSH
• Lymphoma, T-Cell, Peripheral drug therapy   MeSH
• Antineoplastic Agents therapeutic use   MeSH
• Pyrimidines therapeutic use   MeSH
• Societies, Medical MeSH
• Staurosporine analogs & derivatives   therapeutic use   MeSH
• T-Lymphocytes transplantation   MeSH
• Check Tag
• Humans MeSH
• Publication type
• News MeSH
• Geographicals
• United States MeSH

Aurora kinase A (AURKA) is a centrosomal protein that is overexpressed in a number of human malignancies and can contribute to tumor progression. As we used this protein as a target of DNA immunization, we increased its immunogenicity by the addition of the PADRE helper epitope and decreased its potential oncogenicity by mutagenesis of the kinase domain. For in vitro analysis of induced immune responses in mice, we identified the Aurka(220-228) nonapeptide representing an H-2Kb epitope. As DNA vaccination against the Aurka self-antigen by a gene gun did not show any antitumor effect, we combined DNA immunization with anti-CD25 treatment that depletes mainly regulatory T cells. Whereas 1 anti-CD25 dose injected before DNA vaccination did not enhance the activation of Aurka-specific splenocytes, 3 doses administered on days of immunizations augmented about 10-fold immunity against Aurka. However, an opposite effect was found for antitumor immunity-only 1 anti-CD25 dose combined with DNA vaccination reduced tumor growth. Moreover, the administration of 3 doses of anti-CD25 antibody alone accelerated tumor growth. Analysis of tumor-infiltrating cells showed that 3 anti-CD25 doses not only efficiently depleted regulatory T cells but also activated helper T cells and CD3(-)CD25(+) cells. Next, we found that blockade of the PD-1 receptor initiated 1 week after the first immunization was necessary for significant inhibition of tumor growth with therapeutic DNA vaccination against Aurka combined with depletion of CD25 cells. Our results suggest that combined cancer immunotherapy should be carefully evaluated to achieve the optimal antitumor effect.

• MeSH
• Lymphocyte Activation MeSH
• Programmed Cell Death 1 Receptor antagonists & inhibitors   MeSH
• Aurora Kinase A genetics   immunology   metabolism   MeSH
• Cell Growth Processes drug effects   MeSH
• CD8-Positive T-Lymphocytes immunology   MeSH
• Vaccines, DNA MeSH
• Epitopes, T-Lymphocyte genetics   immunology   metabolism   MeSH
• H-2 Antigens metabolism   MeSH
• HEK293 Cells MeSH
• Immunization MeSH
• Immunotherapy * MeSH
• Combined Modality Therapy MeSH
• Humans MeSH
• Antibodies, Monoclonal therapeutic use   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Cancer Vaccines immunology   MeSH
• Interleukin-2 Receptor alpha Subunit immunology   MeSH
• T-Lymphocytes, Regulatory immunology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Selective inhibitors of kinases that regulate the cell cycle, such as cyclin-dependent kinases (CDKs) and aurora kinases, could potentially become powerful tools for the treatment of cancer. We prepared and studied a series of 3,5,7-trisubstituted pyrazolo[4,3-d]pyrimidines, a new CDK inhibitor scaffold, to assess their CDK2 inhibitory and antiproliferative activities. A new compound, 2i, which preferentially inhibits CDK2, CDK5, and aurora A was identified. Both biochemical and cellular assays indicated that treatment with compound 2i caused the downregulation of cyclins A and B, the dephosphorylation of histone H3 at Ser10, and the induction of mitochondrial apoptosis in the HCT-116 colon cancer cell line. It also reduced migration as well as tube and lamellipodia formation in human endothelial cells. The kinase inhibitory profile of compound 2i suggests that its anti-angiogenic activity is linked to CDK5 inhibition. This dual mode of action involving apoptosis induction in cancer cells and the blocking of angiogenesis-like activity in endothelial cells offers possible therapeutic potential.

• MeSH
• Apoptosis drug effects   MeSH
• Aurora Kinase A antagonists & inhibitors   MeSH
• Cell Cycle drug effects   MeSH
• Cyclin-Dependent Kinase 2 antagonists & inhibitors   MeSH
• Cyclin-Dependent Kinase 5 antagonists & inhibitors   MeSH
• Human Umbilical Vein Endothelial Cells MeSH
• HCT116 Cells MeSH
• Cyclin-Dependent Kinase Inhibitor Proteins chemical synthesis   chemistry   pharmacology   MeSH
• Angiogenesis Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Protein Kinase Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Humans MeSH
• Antineoplastic Agents chemical synthesis   chemistry   pharmacology   MeSH
• Drug Design MeSH
• Drug Screening Assays, Antitumor MeSH
• Molecular Docking Simulation MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH