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1.
J Biochem Mol Toxicol ; 33(12): e22409, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31617652

RESUMEN

Melanoma is the most aggressive type of cutaneous tumor and the occurrence of metastasis makes it resistant to almost all available treatment and becomes incorrigible. Hence, identifying metastasis-related biomarkers and effective therapeutic targets will assist in preventing metastasis and ameliorating cutaneous melanoma. In our present study, we reported kinesin family member 18B (KIF18B) as a novel contributor in cutaneous melanoma proliferation and metastasis, and it was found to be of great significance in predicting the prognosis of cutaneous melanoma patients. Bioinformatics analysis based on ONCOMINE, The Cancer Genome Atlas, and Genotype-Tissue Expression database revealed that KIF18B was highly expressed in cutaneous melanoma and remarkably correlated with unfavorable clinical outcomes. Consistently, the results of the quantitative real-time polymerase chain reaction exhibited that the expression of KIF18B was significantly higher in cutaneous melanoma cell lines than that in normal cells. In vitro, biological assays found that knockdown of KIF18B in cutaneous melanoma cells noticeably repressed cell proliferation, migration, and invasion, while inducing cell apoptosis. Moreover, the protein expression of E-cadherin was enhanced while the expression of N-cadherin, vimentin, and Snail was decreased in M14 cells after knocking down KIF18B. In addition, the phosphorylation of phosphoinositide 3-kinase (PI3K) and extracellular-signal-regulated kinase (ERK) was significantly suppressed in M14 cells with silenced KIF18B. Above all, our results indicated that the repression of cutaneous melanoma cell migration and proliferation caused by KIF18B depletion suggested an oncogenic role of KIF18B in cutaneous melanoma, which acts through modulating epithelial-mesenchymal transition and ERK/PI3K pathway.


Asunto(s)
Proliferación Celular , Cinesina/metabolismo , Melanoma/enzimología , Melanoma/secundario , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/secundario , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Transición Epitelial-Mesenquimal , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Técnicas de Silenciamiento del Gen , Humanos , Estimación de Kaplan-Meier , Cinesina/genética , Invasividad Neoplásica , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Pronóstico , Factores de Transcripción de la Familia Snail/metabolismo , Vimentina/metabolismo
2.
Dev Genes Evol ; 229(5-6): 161-181, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31486889

RESUMEN

KIF3A and KIF3B are homologous motor subunits of the Kinesin II protein family. KIF3A, KIF3B, and KAP3 form a heterotrimeric complex and play a significant role in spermatogenesis. Here, we first cloned full-length kif3a/3b cDNAs from Larimichthys polyactis. Lp-kif3a/3b are highly related to their homologs in other animals. The proteins are composed of three domains, an N-terminal head domain, a central stalk domain, and a C-terminus tail domain. Lp-kif3a/3b mRNAs were found to be ubiquitously expressed in the examined tissues, with high expression in the testis. Fluorescence in situ hybridization (FISH) was used to analyze the expression of Lp-kif3a/3b mRNAs during spermiogenesis. The results showed that Lp-kif3a/3b mRNAs had similar expression pattern and were continuously expressed during spermiogenesis. From middle spermatid to mature sperm, Lp-kif3a/3b mRNAs gradually localized to the side of the spermatid where the midpiece and tail form. In addition, we used immunofluorescence (IF) to observe that Lp-KIF3A protein co-localizes with tubulin during spermiogenesis. In early spermatid, Lp-KIF3A protein and microtubule signals were randomly distributed in the cytoplasm. In middle spermatid, however, the protein was detected primarily around the nucleus. In late spermatid, the protein migrated primarily to one side of the nucleus where the tail forms. In mature sperm, Lp-KIF3A and microtubules accumulated in the midpiece. Moreover, Lp-KIF3A co-localized with the mitochondria. In mature sperm, Lp-KIF3A and mitochondria were present in the midpiece. Therefore, Lp-KIF3A/KIF3B may be involved in spermiogenesis in L. polyactis, particularly during nuclear reshaping and tail formation.


Asunto(s)
Proteínas de Peces/metabolismo , Peces/fisiología , Cinesina/metabolismo , Espermatogénesis , Espermatozoides/citología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Núcleo Celular/metabolismo , Clonación Molecular , Proteínas de Peces/química , Proteínas de Peces/genética , Humanos , Cinesina/química , Cinesina/genética , Masculino , Filogenia , Alineación de Secuencia , Espermatozoides/metabolismo
3.
Nat Cell Biol ; 21(9): 1138-1151, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31481795

RESUMEN

One of the first steps in mitotic spindle assembly is the dissolution of the centrosome linker followed by centrosome separation driven by EG5, a tetrameric plus-end-directed member of the kinesin-5 family. However, even in the absence of the centrosome linker, the two centrosomes are kept together by an ill-defined microtubule-dependent mechanism. Here we show that KIFC3, a minus-end-directed kinesin-14, provides microtubule-based centrosome cohesion. KIFC3 forms a homotetramer that pulls the two centrosomes together via a specific microtubule network. At mitotic onset, KIFC3 activity becomes the main driving force of centrosome cohesion to prevent premature spindle formation after linker dissolution as it counteracts the increasing EG5-driven pushing forces. KIFC3 is eventually inactivated by NEver in mitosis-related Kinase 2 (NEK2) to enable EG5-driven bipolar spindle assembly. We further show that persistent centrosome cohesion in mitosis leads to chromosome mis-segregation. Our findings reveal a mechanism of spindle assembly that is evolutionary conserved from yeast to humans.


Asunto(s)
Centrosoma/metabolismo , Cinesina/metabolismo , Microtúbulos/metabolismo , Huso Acromático/metabolismo , Segregación Cromosómica/fisiología , Células HeLa , Humanos , Cinesina/genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Mitosis , Quinasas Relacionadas con NIMA/metabolismo
4.
Artículo en Inglés | MEDLINE | ID: mdl-31413903

RESUMEN

Background: KIF1C (Kinesin Family Member 1C) variants have been associated with hereditary spastic paraplegia and spastic ataxia. Case report: We report fraternal twins presenting with cerebellar ataxia and dystonic tremor. Their brain MRI showed a hypomyelinating leukoencephalopathy. Whole exome sequencing identified a homozygous KIF1C variant in both patients. Discussion: KIF1C variants can manifest as a complex movement disorder with cerebellar ataxia and dystonic tremor. KIF1C variants may also cause a hypomyelinating leukoencephalopathy.


Asunto(s)
Ataxia Cerebelosa/genética , Cinesina/genética , Mutación/genética , Temblor/genética , Adolescente , Ataxia Cerebelosa/diagnóstico , Distonía/genética , Trastornos Distónicos , Femenino , Humanos , Masculino , Paraplejía Espástica Hereditaria/genética , Temblor/diagnóstico , Gemelos Dicigóticos
5.
Life Sci Alliance ; 2(4)2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31409625

RESUMEN

Eukaryotic flagella are conserved microtubule-based organelles that drive cell motility. Plasmodium, the causative agent of malaria, has a single flagellate stage: the male gamete in the mosquito. Three rounds of endomitotic division in male gametocyte together with an unusual mode of flagellum assembly rapidly produce eight motile gametes. These processes are tightly coordinated, but their regulation is poorly understood. To understand this important developmental stage, we studied the function and location of the microtubule-based motor kinesin-8B, using gene-targeting, electron microscopy, and live cell imaging. Deletion of the kinesin-8B gene showed no effect on mitosis but disrupted 9+2 axoneme assembly and flagellum formation during male gamete development and also completely ablated parasite transmission. Live cell imaging showed that kinesin-8B-GFP did not co-localise with kinetochores in the nucleus but instead revealed a dynamic, cytoplasmic localisation with the basal bodies and the assembling axoneme during flagellum formation. We, thus, uncovered an unexpected role for kinesin-8B in parasite flagellum formation that is vital for the parasite life cycle.


Asunto(s)
Cuerpos Basales/metabolismo , Flagelos/fisiología , Cinesina/metabolismo , Malaria/transmisión , Plasmodium malariae/fisiología , Animales , Axonema/metabolismo , Regulación del Desarrollo de la Expresión Génica , Marcación de Gen , Cinesina/genética , Cinetocoros/metabolismo , Microscopía Electrónica , Mitosis
6.
Med Sci Monit ; 25: 6418-6428, 2019 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-31451680

RESUMEN

BACKGROUND The role of KIF18A in tumorigenesis and tumor development has been well studied in several cancers, but not in prostate cancer. In this study, we investigated the potential prognostic utility of KIF18A and its role in prostate cancer progression. MATERIAL AND METHODS We collected prostate cancer and paracancerous tissue samples from the same patient. Immunohistochemical staining was performed to investigate the KIF18A expression levels in the clinical sample. The Cancer Genome Atlas (TCGA) database was analyzed via a bioinformatics approach to gain insight into the relationship between KIF18A expression and prognosis. We examined the effect of KIF18A knockdown on PC-3 cell proliferation via colony formation and MTT assays. Flow cytometry was used to assess the effect of KIF18A knockdown on PC-3 cell apoptosis. Transwell invasion assay was performed to assess whether KIF18A affects the invasion ability of PC-3 cells. RESULTS The KIF18A protein level was higher in PCa tissue than in paracancerous tissue. The In addition, upregulated KIF18A suggested a poor tumor stage and prognosis for prostate cancer patients. Our in vitro experiments demonstrated that KIF18A knockdown in PC-3 cells significantly inhibited proliferation and metastasis. CONCLUSIONS High KIF18A expression in prostate cancer patients predicts a poor prognosis. KIF18A knockdown inhibits prostate cell proliferation and metastasis. Therefore, this study confirms the usefulness of KIF18A as an oncological prognostic indicator and a potential therapeutic target for prostate cancer.


Asunto(s)
Cinesina/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Anciano , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Cinesina/metabolismo , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Pronóstico , Modelos de Riesgos Proporcionales , Prostatectomía , Neoplasias de la Próstata/cirugía , ARN Mensajero/genética , ARN Mensajero/metabolismo , Regulación hacia Arriba/genética
7.
Int J Mol Sci ; 20(17)2019 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-31466291

RESUMEN

Kinesin-12 family members are characterized by an N-terminal motor domain and the extensive presence of coiled-coil domains. Animal orthologs display microtubule plus-end directed motility, bundling of parallel and antiparallel microtubules, plus-end stabilization, and they play a crucial role in spindle assembly. In plants, kinesin-12 members mediate a number of developmental processes including male gametophyte, embryo, seedling, and seed development. At the cellular level, they participate in critical events during cell division. Several kinesin-12 members localize to the phragmoplast midzone, interact with isoforms of the conserved microtubule cross-linker MICROTUBULE-ASSOCIATED PROTEIN 65 (MAP65) family, and are required for phragmoplast stability and expansion, as well as for proper cell plate development. Throughout cell division, a subset of kinesin-12 reside, in addition or exclusively, at the cortical division zone and mediate the accurate guidance of the phragmoplast. This review aims to summarize the current knowledge on kinesin-12 in plants and shed some light onto the heterogeneous localization and domain architecture, which potentially conceals functional diversification.


Asunto(s)
División Celular , Cinesina/genética , Proteínas de Plantas/genética , Cromosomas de las Plantas/genética , Cinesina/metabolismo , Magnoliopsida/citología , Magnoliopsida/genética , Magnoliopsida/metabolismo , Proteínas de Plantas/metabolismo
8.
Cancer Sci ; 110(11): 3476-3485, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31454442

RESUMEN

Octamer transcription factor 1 (OCT1) is an androgen receptor (AR)-interacting partner and regulates the expression of target genes in prostate cancer cells. However, the function of OCT1 in castration-resistant prostate cancer (CRPC) is not fully understood. In the present study, we used 22Rv1 cells as AR-positive CRPC model cells to analyze the role of OCT1 in CRPC. We showed that OCT1 knockdown suppressed cell proliferation and migration of 22Rv1 cells. Using microarray analysis, we identified four AR and OCT1-target genes, disks large-associated protein 5 (DLGAP5), kinesin family member 15 (KIF15), non-SMC condensin I complex subunit G (NCAPG), and NDC80 kinetochore complex component (NUF2) in 22Rv1 cells. We observed that knockdown of DLGAP5 and NUF2 suppresses growth and migration of 22Rv1 cells. Furthermore, immunohistochemical analysis showed that positive expression of DLGAP5 in prostate cancer specimens is related to poor cancer-specific survival rates of patients. Notably, enhanced expression of DLGAP5 was observed in CRPC tissues of patients. Thus, our findings suggest that these four genes regulated by the AR/OCT1 complex could have an important role in CRPC progression.


Asunto(s)
Proteínas de Ciclo Celular/genética , Cinesina/genética , Proteínas de Neoplasias/genética , Factor 1 de Transcripción de Unión a Octámeros/fisiología , Neoplasias de la Próstata Resistentes a la Castración/genética , Receptores Androgénicos/genética , Anciano , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Proteínas del Citoesqueleto , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Humanos , Masculino , Análisis por Micromatrices , Proteínas Nucleares/genética , Factor 1 de Transcripción de Unión a Octámeros/genética , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Receptores Androgénicos/metabolismo , Tasa de Supervivencia , Regulación hacia Arriba
9.
Gene ; 719: 144074, 2019 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-31446094

RESUMEN

Kinesin-14 motor es-kifc1 is highly expressed in the male reproductive system of the Chinese mitten crab Eriocheir sinensis (E. sinensis). In addition to acrosomal formation, es-KIFC1 also tightly surrounds the nucleus and its specific mechanism remains unknown. During spermatogenesis, sperm nucleus dents into a cup-shaped structure with several radial arms and completed the nuclear decondensation. In this study, the spatial expression pattern of es-KIFC1 indicates a potential function in nuclear formation with the nuclear localization sequence (NLS) on N-terminal domain which is crucial for the translocation of es-KIFC1 into the nucleus. The Motor domain is associated with microtubule modulation and the Golgi vesicles positioning. Furthermore, the expression level of es-KIFC1 is not only related to the seasonal variation of crustacean development, but also associates with mature sperm storage. The double strand RNA (dsRNA) mediated RNA interference manifests that the cup-shaped sperm nucleus is remarkably malformed and even separates the chromatin throughout the nuclei at the last stage of spermiogenesis. Besides, the sperm nucleus almost disperses its structure and separates the chromatin into several segments throughout the nucleus showing an asymmetrical performance without cytoskeleton. In summary, these results indicate the importance of es-KIFC1 in microtubule positioning and the maintenance of the mature sperm nuclei.


Asunto(s)
Proteínas de Artrópodos/genética , Braquiuros/fisiología , Núcleo Celular/metabolismo , Cinesina/genética , Espermatogénesis/genética , Animales , Proteínas de Artrópodos/metabolismo , Núcleo Celular/ultraestructura , Citoesqueleto/metabolismo , Cinesina/metabolismo , Masculino , Microtúbulos/metabolismo , Transporte de Proteínas , ARN Bicatenario/genética , Espermatozoides/ultraestructura
10.
Invest Ophthalmol Vis Sci ; 60(10): 3636-3643, 2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31469403

RESUMEN

Purpose: CTG trinucleotide repeat (TNR) expansion in an intron of the TCF4 gene is the most common genetic variant associated with Fuchs' endothelial corneal dystrophy (FECD). Although several mechanisms have been implicated in the disease process, their exact pathophysiologic importance is unclear. To understand events leading from TCF4 TNR expansion to disease phenotype, we characterized splicing, gene expression, and exon sequence changes in a rare cohort of patients with TNR expansions but no phenotypic FECD (RE+/FECD-). Methods: Corneal endothelium and blood were collected from patients undergoing endothelial keratoplasty for non-FECD corneal edema. Total RNA was isolated from corneal endothelial tissue (n = 3) and used for RNASeq. Gene splicing and expression was assessed by Mixture of Isoforms (MISO) and MAP-RSeq software. Genomic DNA was isolated from blood mononuclear cells and used for whole genome exome sequencing. Base calling was performed using Illumina's Real-Time Analysis. Results: Three genes (MBNL1, KIF13A, AKAP13) that were previously identified as misspliced in patients with a CTG TNR expansion and FECD disease (RE+/FECD+) were found normally spliced in RE+/FECD- samples. Gene expression differences in pathways associated with the innate immune response, cell signaling (e.g., TGFß, WNT), and cell senescence markers were also identified between RE+/FECD- and RE+/FECD+ groups. No consistent genetic variants were identified in RE+/FECD- patient exomes. Conclusions: Identification of novel splicing patterns and differential gene expression in RE+/FECD- samples provides new insights and more relevant gene targets that may be protective against FECD disease in vulnerable patients with TCF4 CTG TNR expansions.


Asunto(s)
Proteínas de Anclaje a la Quinasa A/genética , Empalme Alternativo , Epitelio Posterior/metabolismo , Distrofia Endotelial de Fuchs/genética , Regulación de la Expresión Génica/fisiología , Cinesina/genética , Antígenos de Histocompatibilidad Menor/genética , Proteínas Proto-Oncogénicas/genética , Proteínas de Unión al ARN/genética , Factor de Transcripción 4/genética , Anciano , Anciano de 80 o más Años , Femenino , Genotipo , Humanos , Masculino , Expansión de Repetición de Trinucleótido/genética , Secuenciación del Exoma Completo
11.
Int J Pharm ; 569: 118570, 2019 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-31352048

RESUMEN

Small interfering RNA (siRNA) represents a new class of therapeutic agents. Its successful intracellular delivery is a major challenge. Lipo-oligomeric carriers can complex siRNA into lipopolyplexes and thus mediate its cellular uptake. In this study, siRNA against the kinesin related mRNA EG5 gene (siEG5) and the microtubule inhibitor pretubulysin (PT) were co-formulated into polyplexes using azide-containing lipo-oligomer 1198. Nanoparticles were further modified by click reaction using shielding agent DBCO-PEG or EGFR targeting peptide GE11 (DBCO-PEG-GE11). Polyplexes displayed efficient payload incorporation and homogenous particle sizes of 200 nm. The biological effects of the unmodified and surface-functionalized polyplexes were investigated. The successful GE11-mediated intracellular delivery of siRNA into the EGFR overexpressing KB and Huh7 cell lines facilitated potent silencing of an EGFP-luciferase reporter gene by GFP siRNA. Specific downregulation of EG5 mRNA by siEG5 resulted in the expected antitumoral activity. The combination formulation 1198 siEG5 + PT provided superior antitumoral activity over free PT and 1198 siEG5.


Asunto(s)
Cinesina/genética , Oligopéptidos/administración & dosificación , Péptidos/administración & dosificación , ARN Interferente Pequeño/administración & dosificación , Moduladores de Tubulina/administración & dosificación , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Receptores ErbB/genética , Proteínas Fluorescentes Verdes/genética , Humanos , Luciferasas/genética , Polietilenglicoles/administración & dosificación
12.
Cell Biochem Funct ; 37(6): 424-431, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31328811

RESUMEN

Nonsmall cell lung cancer (NSCLC) is one of the leading causes of cancer-related death worldwide. Kinesin family member 2C (KIF2C), a modulator in microtubule depolymerization, bipolar spindle formation, and chromosome segregation, has been reported to take roles in cancer biology, but its role in NSCLC remains unclear. This study was intended to investigate the expression and function of KIF2C in NSCLC. Our results demonstrated that KIF2C was up-regulated in NSCLC tissues and cell lines. The high expression of KIF2C in NSCLC tissues was significantly correlated with higher T stage (0.0078), worse differentiation status (0.0049), and lymph node metastasis (P < .0001). We also proved that the high expression level of KIF2C predicted worse prognosis of the patients. After knockdown of KIF2C, the proliferation and metastasis of NSCLC cells were inhibited. Luciferase reporter assay suggested that KIF2C was a target gene of miR-325-3p, which was reported to be a tumour suppressor in NSCLC. In conclusion, this study proved an oncogenic role of KIF2C in NSCLC and partly clarified the mechanism of its high expression. Our findings provided a useful insight into the mechanism of NSCLC progression and offered clues to novel therapy strategies.


Asunto(s)
Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Cinesina/metabolismo , MicroARNs/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Humanos , Cinesina/genética , MicroARNs/genética
13.
J Exp Clin Cancer Res ; 38(1): 329, 2019 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-31340839

RESUMEN

BACKGROUND: Kinesins play important roles in the development and progression of many human cancers. The functions and underlying mechanisms of kinesin family member C1 (KIFC1), a member of the kinesin-14 family, in the pathogenesis of hepatocellular carcinoma (HCC) have not been fully elucidated. METHODS: In this study, 168 HCC samples were first analyzed to examine the association between KIFC1 expression and patient clinicopathological features and prognosis. The role of KIFC1 in HCC cell proliferation and metastasis was investigated both in vivo and in vitro. The upstream regulation and downstream targets of KIFC1 were studied by qRT-PCR, western blotting, coimmunoprecipitation, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. RESULTS: KIFC1 was highly expressed in HCC tissues and positively associated with advanced stages and poor prognosis. KIFC1 knockdown suppressed HCC cell proliferation and invasion both in vitro and in vivo. Furthermore, KIFC1 knockdown decreased invadopodia formation and reduced epithelial-mesenchymal transition (EMT). HMGA1, an architectural transcriptional factor, was identified to interact with KIFC1. HMGA1 could bind to the promoters of Stat3, MMP2 and EMT-related genes and promote gene transcription. KIFC1 enhanced HMGA1 transcriptional activity and facilitated HCC proliferation and invasion. Moreover, KIFC1 was activated by TCF-4, and KIFC1 inhibition enhanced HCC cell sensitivity to paclitaxel. CONCLUSIONS: Our findings suggest that KIFC1, activated by TCF-4, functions as an oncogene and promotes HCC pathogenesis through regulating HMGA1 transcriptional activity and that KIFC1 is a potential therapeutic target to enhance the paclitaxel sensitivity of HCC.


Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Proteína HMGA1a/genética , Cinesina/genética , Neoplasias Hepáticas/tratamiento farmacológico , Proteína 2 Similar al Factor de Transcripción 7/genética , Anciano , Animales , Carcinogénesis/efectos de los fármacos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Supervivencia sin Enfermedad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Xenoinjertos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Ratones , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Pronóstico
14.
Oncol Rep ; 42(3): 1017-1034, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31322267

RESUMEN

The current study aimed to identify the potential clinical significance and molecular mechanisms of kinesin (KIF) family member genes in lung adenocarcinoma (LUAD) using genome­wide RNA sequencing (RNA­seq) datasets derived from The Cancer Genome Atlas (TCGA) database. Clinical parameters and RNA­seq data of patients with LUAD from the TCGA database enabled the assessment of the clinical significance of KIF genes, while the potential mechanisms of their interactions in LUAD were investigated by gene set enrichment analysis (GSEA). A gene signature with potential prognostic value was constructed via a stepwise multivariable Cox analysis. In total, 23 KIF genes were identified to be differentially expressed genes (DEGs) between the LUAD tumor and adjacent non­cancerous tissues. Of these, 8 differentially expressed KIF genes were strongly found to be strongly associated with the overall survival of patients with LUAD. Three of these genes were found to be able to be grouped as a potential prognostic gene signature. Patients with higher risk scores calculated using this gene signature were found to have a markedly higher risk of mortality (adjusted P=0.003; adjusted HR, 1.576; 95% CI, 1.166­2.129). Time­dependent receiver operating characteristic analysis indicated that this prognostic signature was able to accurately predict patient prognosis with an area under curve of 0.636, 0.643,0.665, 0.670 and 0.593 for the 1­, 2­, 3­, 4­ and 5­year survival, respectively. This prognostic gene signature was identified as an independent risk factor for LUAD and was able to more accurately predict prognosis in comparison to other known clinical parameters, as shown via comprehensive survival analysis. GSEA enrichment revealed that that KIF14, KIF18B and KIF20A mediated basic cell physiology through the regulation of the cell cycle, DNA replication, and DNA repair biological processes and pathways. On the whole, the findings of this study identified 23 KIF genes that were DEGs between LUAD tumor and adjacent non­cancerous tissues. In total, 8 of these genes had the potential to function as prognostic and diagnostic biomarkers in patients with LUAD.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Genoma Humano , Cinesina/genética , Neoplasias Pulmonares/genética , Adenocarcinoma del Pulmón/patología , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Humanos , Cinesina/clasificación , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia
15.
Dis Markers ; 2019: 4824902, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31354888

RESUMEN

Background: Bladder cancer is a common malignancy with uncontrolled and rapid growth. Although lots of the important regulatory networks in bladder cancer have been found, the cancer-relevant genes remain to be further identified. Methods: We examined the KIF5A expression levels in bladder cancer and normal bladder tissue samples via immunohistochemistry and observed the effect of KIF5A on bladder tumor cell proliferation in vitro and in vivo. Additionally, a coexpression between KIF5A and KIF20B in tumor tissues was explored. Results: KIF5A expression level was higher in the bladder cancer tissues than in the adjacent nontumor tissues. Patients with higher KIF5A expression displayed advanced clinical features and shorter survival time than those with lower KIF5A expression. Moreover, KIF5A knockdown inhibited bladder cancer cell proliferation, migration, and invasion demonstrated in vivo and in vitro. In addition, coexpression was found between KIF5A and KIF20B in tumor tissues. Conclusion: The results demonstrated that KIF5A is a critical regulator in bladder cancer development and progression, as well as a potential target in the treatment of bladder cancer.


Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma/metabolismo , Cinesina/genética , Neoplasias de la Vejiga Urinaria/metabolismo , Anciano , Animales , Biomarcadores de Tumor/metabolismo , Carcinoma/genética , Carcinoma/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Humanos , Cinesina/metabolismo , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología
16.
EBioMedicine ; 45: 92-107, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31204277

RESUMEN

BACKGROUND: Epithelial mesenchymal plasticity (EMP) is deemed vital in breast cancer progression, metastasis, stemness and resistance to therapy. Therefore, characterizing molecular mechanisms contributing to EMP are in need enabling the development of more advanced therapeutics against breast cancer. While kinesin superfamily proteins (KIFs) are well known for their role in intracellular cargo movement, our knowledge of their function in breast tumorigenesis is still limited. METHODS: Various breast cancer cell lines representing different molecular subtypes were used to determine the role of kinesine-1 subunits KIF5B/KLC1 in regulation of EMP. FINDINGS: In breast cancer, we show that kinesin family member 5B (KIF5B) and its partner protein kinesin light chain 1 (KLC1), subunits of kinesin-1, to play differential roles in regulating EMP and tumorigenesis. Indeed, we found KIF5B to be expressed in triple negative (TN)-basal-like/claudin low breast cancer subtype and to be an inducer of epithelial-mesenchymal transition (EMT), stemness, invasiveness, tumor formation and metastatic colonization. Whereas, we found KLC1 to be expressed in epithelial/luminal breast cancer subtypes and to be a suppressor of EMT, invasion, metastasis and stem cell markers expression as well as to be an inducer of epithelial/luminal phenotype. Interestingly, in TN-basal-like/claudin low cells we found a novel nuclear accumulation of KIF5B and its interaction with the EMT transcriptional regulator Snail1 independent of KLC1. In addition, TGF-ß mediated pro-invasive activity was found to be dependent on KIF5B expression. In contrast, the epithelial differentiation factor and EMT suppressor prolactin (PRL) was found to repress KIF5B gene expression and KIF5B-Snail1 nuclear accumulation, but enhanced KLC1 gene expression and KIF5B-KLC1 interaction. INTERPRETATION: Together, these results highlight a new paradigm for kinesin-1 function in breast tumorigenesis by regulating EMP programing and aggressiveness. FUND: This work was supported by the Canadian Institutes of Health Research (operating grants #233437 and 233438) granted to Suhad Ali.


Asunto(s)
Neoplasias de la Mama/genética , Carcinogénesis/genética , Transición Epitelial-Mesenquimal/genética , Cinesina/genética , Proteínas Asociadas a Microtúbulos/genética , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Xenoinjertos , Humanos , Ratones , Prolactina/genética , Factor de Crecimiento Transformador beta/genética
17.
Nat Commun ; 10(1): 2693, 2019 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-31217419

RESUMEN

The kinesin-3 KIF1C is a fast organelle transporter implicated in the transport of dense core vesicles in neurons and the delivery of integrins to cell adhesions. Here we report the mechanisms of autoinhibition and release that control the activity of KIF1C. We show that the microtubule binding surface of KIF1C motor domain interacts with its stalk and that these autoinhibitory interactions are released upon binding of protein tyrosine phosphatase PTPN21. The FERM domain of PTPN21 stimulates dense core vesicle transport in primary hippocampal neurons and rescues integrin trafficking in KIF1C-depleted cells. In vitro, human full-length KIF1C is a processive, plus-end directed motor. Its landing rate onto microtubules increases in the presence of either PTPN21 FERM domain or the cargo adapter Hook3 that binds the same region of KIF1C tail. This autoinhibition release mechanism allows cargo-activated transport and might enable motors to participate in bidirectional cargo transport without undertaking a tug-of-war.


Asunto(s)
Cinesina/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Animales , Transporte Biológico , Línea Celular , Vesículas Citoplasmáticas/metabolismo , Hipocampo/citología , Humanos , Integrinas/metabolismo , Microscopía Intravital/métodos , Cinesina/genética , Cinesina/aislamiento & purificación , Ratones , Proteínas Asociadas a Microtúbulos/aislamiento & purificación , Microtúbulos/metabolismo , Neuronas/citología , Cultivo Primario de Células , Unión Proteica , Dominios Proteicos , Proteínas Tirosina Fosfatasas no Receptoras/genética , Proteínas Tirosina Fosfatasas no Receptoras/aislamiento & purificación , ARN Interferente Pequeño/metabolismo , Ratas , Proteínas Recombinantes/genética , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/metabolismo , Imagen Individual de Molécula/métodos
18.
Cell Mol Life Sci ; 76(21): 4355-4368, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31041455

RESUMEN

Axons in the central nervous system (CNS) typically fail to regenerate after injury. This failure is multi-factorial and caused in part by disruption of the axonal cytoskeleton. The cytoskeleton, in particular microtubules (MT), plays a critical role in axonal transport and axon growth during development. In this regard, members of the kinesin superfamily of proteins (KIFs) regulate the extension of primary axons toward their targets and control the growth of collateral branches. KIF2A negatively regulates axon growth through MT depolymerization. Using three different injury models to induce SCI in adult rats, we examined the temporal and cellular expression of KIF2A in the injured spinal cord. We observed a progressive increase of KIF2A expression with maximal levels at 10 days to 8 weeks post-injury as determined by Western blot analysis. KIF2A immunoreactivity was present in axons, spinal neurons and mature oligodendrocytes adjacent to the injury site. Results from the present study suggest that KIF2A at the injured axonal tips may contribute to neurite outgrowth inhibition after injury, and that its increased expression in inhibitory spinal neurons adjacent to the injury site might contribute to an intrinsic wiring-control mechanism associated with neuropathic pain. Further studies will determine whether KIF2A may be a potential target for the development of regeneration-promoting or pain-preventing therapies.


Asunto(s)
Cinesina/análisis , Cinesina/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Animales , Axones/metabolismo , Axones/patología , Modelos Animales de Enfermedad , Cinesina/genética , Masculino , Regeneración Nerviosa/genética , Neuronas/metabolismo , Neuronas/patología , Ratas , Ratas Sprague-Dawley , Médula Espinal/metabolismo , Médula Espinal/patología , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/patología
19.
Mol Cell Biol ; 39(14)2019 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-31061095

RESUMEN

The Myc gene is a universal oncogene that promotes aggressive cancer, but its role in metastasis has remained elusive. Here, we show that Myc transcriptionally controls a gene network of subcellular mitochondrial trafficking that includes the atypical mitochondrial GTPases RHOT1 and RHOT2, the adapter protein TRAK2, the anterograde motor Kif5B, and an effector of mitochondrial fission, Drp1. Interference with this pathway deregulates mitochondrial dynamics, shuts off subcellular organelle movements, and prevents the recruitment of mitochondria to the cortical cytoskeleton of tumor cells. In turn, this inhibits tumor chemotaxis, blocks cell invasion, and prevents metastatic spreading in preclinical models. Therefore, Myc regulation of mitochondrial trafficking enables tumor cell motility and metastasis.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Neoplasias Hepáticas/metabolismo , Mitocondrias/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Animales , Línea Celular Tumoral , Dinaminas/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Cinesina/genética , Neoplasias Hepáticas/genética , Masculino , Ratones , Proteínas Mitocondriales/genética , Células 3T3 NIH , Invasividad Neoplásica , Trasplante de Neoplasias , Proteínas del Tejido Nervioso/genética , Proteínas de Unión al GTP rho/genética
20.
J Exp Clin Cancer Res ; 38(1): 188, 2019 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-31072351

RESUMEN

BACKGROUND: Forkhead box M1 (FOXM1) is a proliferation-associated transcription factor of the forkhead box proteins superfamily, which includes four isoforms FOXM1a, b, c, and d. FOXM1 has been implicated in hepatocellular carcinoma (HCC) progression, but the underlying molecular mechanism remains elusive. In this study, we aim to clarify the molecular basis for FOXM1-mediated HCC progression. METHODS: Bioinformatic analysis was used to explore the differentially expressed genes predicting HCC proliferation. The expression of FOXM1 and kinesin family member (KIF)4A was confirmed by western blotting and immunohistochemistry in HCC tissues. Kaplan-Meier survival analysis was conducted to analyze the clinical impact of FOXM1 and KIF4A on HCC. The effect of FOXM1 on the regulation of KIF4A expression was studied in cell biology experiments. The interaction between KIF4A and FOXM1 was analyzed by chromatin immunoprecipitation and luciferase experiments. A series of experiments was performed to explore the functions of FOXM1/KIF4A in HCC progression, such as cell proliferation, cell growth, cell viability, and cell cycle. A xenograft mouse model was used to explore the regulatory effect of FOXM1-KIF4A axis on HCC tumor growth. RESULTS: FOXM1 and KIF4A were overexpressed in human primary HCC tissues compared to that in matched adjacent normal liver tissue and are significant risk factors for HCC recurrence and shorter survival. We found that KIF4A was dominantly regulated by FOXM1c among the four isoforms, and further identified KIF4A as a direct downstream target of FOXM1c. Inhibiting FOXM1 decreased KIF4A expression in HCC cells, whereas its overexpression had the opposite effect. FOXM1-induced HCC cell proliferation was dependent on elevated KIF4A expression as KIF4A knockdown abolished FOXM1-induced proliferation of HCC cells both in vitro and in vivo. CONCLUSION: The FOXM1-KIF4A axis mediates human HCC progression and is a potential therapeutic target for HCC treatment.


Asunto(s)
Carcinoma Hepatocelular/genética , Proteína Forkhead Box M1/genética , Cinesina/genética , Neoplasias Hepáticas/genética , Adulto , Animales , Carcinoma Hepatocelular/patología , Movimiento Celular/genética , Proliferación Celular/genética , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células Hep G2 , Humanos , Estimación de Kaplan-Meier , Cinesina/antagonistas & inhibidores , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/patología , Masculino , Ratones , Persona de Mediana Edad , Transducción de Señal/genética , Ensayos Antitumor por Modelo de Xenoinjerto
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