Four centrosome-related genes to predict the prognosis and drug sensitivity of patients with colon cancer

BACKGROUND As the primary microtubule organizing center in animal cells,centrosome abnormalities are involved in human colon cancer.AIM To explore the role of centrosome-related genes(CRGs)in colon cancer.METHODS CRGs were collected from public databases.Consensus clustering analysis was performed to separate the Cancer Genome Atlas cohort.Univariate Cox and least absolute shrinkage selection operator regression analyses were performed to identify candidate prognostic CRGs and construct a centrosome-related signature(CRS)to score colon cancer patients.A nomogram was developed to evaluate the CRS risk in colon cancer patients.An integrated bioinformatics analysis was conducted to explore the correlation between the CRS and tumor immune microenvironment and response to immunotherapy,chemotherapy,and targeted therapy.Single-cell transcriptome analysis was conducted to examine the immune cell landscape of core prognostic genes.RESULTS A total of 726 CRGs were collected from public databases.A CRS was constructed,which consisted of the following four genes:TSC1,AXIN2,COPS7A,and MTUS1.Colon cancer patients with a high-risk signature had poor survival.Patients with a high-risk signature exhibited decreased levels of plasma cells and activated memory CD4+T cells.Regarding treatment response,patients with a high-risk signature were resistant to immunotherapy,chemotherapy,and targeted therapy.COPS7A expression was relatively high in endothelial cells and fibroblasts.MTUS1 expression was high in endothelial cells,fibroblasts,and malignant cells.CONCLUSION We constructed a centrosome-related prognostic signature that can accurately predict the prognosis of colon cancer patients,contributing to the development of individualized treatment for colon cancer.

KIFC1 overexpression promotes prostate cancer cell survival and proliferation in vitro by clustering of amplified centrosomes via interaction with Centrin 2

Mitotic kinesin KIFC1 plays critical roles in mitosis by regulating the spindle length,pole formation,and known for clustering extra centrosomes in cancer cells.Centrosome clustering is associated with the survival of cancer cells,but this phenomenon remains obscure in prostate cancer(PCa).The present study demonstrated that PCa cells showed centrosome amplification and clustering during interphase and mitosis,respectively.KIFC1 is highly expressed in PCa cells and tumor tissues of prostatic adenocarcinoma(PAC)patients.Up-regulation of KIFC1 facilitated the PCa cell survival in vitro by ensuring bipolar mitosis through clustering the multiple centrosomes,suggesting centrosome clustering could be a leading cause of prostate carcinogenesis.Conversely,the silencing of KIFC1 resulted in normal centrosome number or multipolar mitosis by inhibiting the clustering of amplified centrosomes in PCa cells.Besides,knockdown of KIFC1 by RNAi in PCa cells reduced cancer cell survival,and proliferation.KIFC1 interacted with centrosome structural protein Centrin 2 in clustering of amplified centrosomes in PCa cells to ensure the bipolar mitotic spindle formation.Knockdown of Centrin 2 in PCa cells inhibited the centrosome amplification and clustering.Moreover,up-regulated KIFC1 promotes PCa cell proliferation via progression of cell cycle possibly through aberrant activation of cyclin dependent kinase 1(Cdk1).Therefore,KIFC1 can be a prognostic marker and therapeutic target of PCa for inhibiting the cancer cell proliferation.

The more the messier：centrosome amplification as a novel biomarker for personalized treatment of colorectal cancers

Colon cancer is currently the third most common cancer and second most fatal cancer in the United States,resulting in approximately 600,000 deaths annually.Though colorectal cancer death rates are decreasing by about 3%every year,disease outcomes could be substantially improved with more research into the drivers of colon carcinogenesis,the determinants of aggressiveness in colorectal cancer and the identification of biomarkers that could enable choice of more optimal treatments.Colon carcinogenesis is notably a slow process that can take decades.Known factors that contribute to the development of colon cancer are mutational,epigenetic and environmental,and risk factors include age,history of polyps and family history of colon cancer.Colorectal cancers exhibit heterogeneity in their features and are often characterized by the presence of chromosomal instability,microscopic satellite instability,or CpG island methylator phenotype.In this review,we propose that centrosome amplification may be a widespread occurrence in colorectal cancers and could potently influence tumor biology.Moreover,the quantitation of this cancer-specific anomaly could offer valuable prognostic information and pave the way for further customization of treatment based on the organellar profile of patients.Patient stratification models that take into account centrosomal status could thus potentially reduce adverse side effects and result in improved outcomes for colorectal cancer patients.

Stem cells' centrosomes: How can organelles identified 130 years ago contribute to the future of regenerative medicine?

At the core of regenerative medicine lies the expectation of repair or replacementof damaged tissues or whole organs. Donor scarcity and transplant rejection aremajor obstacles, and exactly the obstacles that stem cell􀀀based therapy promisesto overcome. These therapies demand a comprehensive understanding of theasymmetric division of stem cells, i.e. their ability to produce cells with identicalpotency or differentiated cells. It is believed that with better understanding,researchers will be able to direct stem cell differentiation. Here, we describeextraordinary advances in manipulating stem cell fate that show that we need tofocus on the centrosome and the centrosome-derived primary cilium. This beliefcomes from the fact that this organelle is the vehicle that coordinates theasymmetric division of stem cells. This is supported by studies that report thesignificant role of the centrosome/cilium in orchestrating signaling pathways thatdictate stem cell fate. We anticipate that there is sufficient evidence to place thisorganelle at the center of efforts that will shape the future of regenerativemedicine.

Centrosome Functions as a Molecular Dynamo in the Living Cell

Recent development in the field of quantum biology highlights that the intracellular electromagnetic field (EMF) of microtubules plays an important role in many fundamental cellular processes such as mitosis. Here I propose an intriguing hypothesis that centrosome functions as molecular dynamo to generate electric flow over the microtubules, leading to the electric excitation of microtubule EMF that is required for spindle body microtubule self-assembly. With the help of motors proteins within the centrosome, centrosome transforms the energy from ATP into intracellular EMF in the living cell that shapes the functions of microtubules. There will be a general impact for the cell biology field to understand the mechanistic function of centrosome for the first time in correlation with its structural features. This hypothesis can be tested with technics such as super resolution live cell microscope.

Chromosomes and Centrosomes—Team Players in Cell Division

This paper provides a mid-level description of cell division and duplication. The focus is on the roles by the chromosomes, centrosomes, microtubules and the kinetochores. The emphasis is on the mechanical activity and the resulting physical developments. The paper also provides, in its discussion, the harmful effects occurring when duplication procedures go awry. This often leads to unwanted duplication and possibly cancer.

Centrosome and vascular microenvironmental homeostasis

The homeostasis of vascular microenvironment is essential to maintain the normal vascular structure and function,while its disorder leads to vascular dysfunction,and cardiovascular and cerebrovascular diseases.Centrosome is an important organelle existing in mammalian cells as well as the microtubule organizing center,playing an important role in maintaining vascular structure and homeostasis.This study reviewed the role of centrosome in the regulation of vascular microenvironmental homeostasis.Centrosomal proteins intricately regulate microtubule dynamics and stabilization,and diverse microtubule-relatived cellular activities,including the division,polarization and directional migration of vascular endothelial cells,smooth muscle cells and other types of cells.In addition,primary cilia formed by centrosome are essential in vascular microenvironment.Tumor endothelial cells usually acquire excess centrosomes,and excess centrosomes are regulated by several angiogenic factors.Therefore,uncovering the detailed molecular mechanisms underlying centrosome affecting vascular microenvironmental homeostasis are needed for the treatment of cardiovascular and cerebrovascular diseases.

CNKSR2 interactome analysis indicates its association with the centrosome/microtubule system

The protein connector enhancer of kinase suppressor of Ras 2(CNKSR2),present in both the postsynaptic density and cytoplasm of neurons,is a scaffolding protein with several protein-binding domains.Variants of the CNKSR2 gene have been implicated in neurodevelopmental disorders,particularly intellectual disability,although the precise mechanism involved has not yet been fully understood.Research has demonstrated that CNKSR2 plays a role in facilitating the localization of postsynaptic density protein complexes to the membrane,thereby influencing synaptic signaling and the morphogenesis of dendritic spines.However,the function of CNKSR2 in the cytoplasm remains to be elucidated.In this study,we used immunoprecipitation and high-resolution liquid chromatography-mass spectrometry to identify the interactors of CNKSR2.Through a combination of bioinformatic analysis and cytological experiments,we found that the CNKSR2 interactors were significantly enriched in the proteome of the centrosome.We also showed that CNKSR2 interacted with the microtubule protein DYNC1H1 and with the centrosome marker CEP290.Subsequent colocalization analysis confirmed the centrosomal localization of CNKSR2.When we downregulated CNKSR2 expression in mouse neuroblastoma cells(Neuro 2A),we observed significant changes in the expression of numerous centrosomal genes.This manipulation also affected centrosome-related functions,including cell size and shape,cell proliferation,and motility.Furthermore,we found that CNKSR2 interactors were highly enriched in de novo variants associated with intellectual disability and autism spectrum disorder.Our findings establish a connection between CNKSR2 and the centrosome,and offer new insights into the underlying mechanisms of neurodevelopmental disorders.

Multifaceted roles of centrosomes in development,health,and disease

The centrosome is a membrane-less organelle consisting of a pair of barrel-shaped centrioles and pericentriolar material and functions as the major microtubule-organizing center and signaling hub in animal cells.The past decades have witnessed the functional complexity and importance of centrosomes in various cellular processes such as cell shaping,division,and migration.In addition,centrosome abnormalities are linked to a wide range of human diseases and pathological states,such as cancer,reproductive disorder,brain disease,and ciliopathies.Herein,we discuss various functions of centrosomes in development and health,with an emphasis on their roles in germ cells,stem cells,and immune responses.We also discuss how centrosome dysfunctions are involved in diseases.A better understanding of the mechanisms regulating centrosome functions may lead the way to potential therapeutic targeting of this organelle in disease treatment.

The cloning and expression characterization of the centrosome protein genes family (centrin genes) in rat testis

Centrins are members of the centrosome protein family, which is highly conserved during revolution. The homologous genes of centrin in many organisms had been cloned, but the sequences of the rat centrin genes were not reported yet in GenBank. We cloned the cDNA fragments of centrin-1, -2 and -3 from the rat testis by RT-PCR, and analyzed the homology of the deduced amino acid sequences. The expression characterization of centrin genes in rat spermatogenesis was carried out by semi-quantitative RT-PCR. The results show that the homology of the corresponding centrin proteins in human, mouse and rat is high. The expression of centrin-1 is testis-specific, spermatogenic cell-specific and developmental stage-related. Centrin-1 begins to be transcribed when the meiosis occurs, and its mRNA level reaches the peak in round spermatids. Centrin-2 and centrin-3 are highly expressed in spermatogonia and their mRNA level decreases markedly when meiosis occurs. These results suggest that centrin-1 may play roles in meiosis and spermiogenesis, and centrin-2 and centrin-3 may be related to mitosis.

Centrosome aberrations and chromosome instability contribute to tumorigenesis and intratumor heterogeneity

Centrosomes serve as the major microtubule organizing centers in cells and thereby contribute to cell shape,polarity,and motility.Also,centrosomes ensure equal chromosome segregation during mitosis.Centrosome aberrations arise when the centrosome cycle is deregulated,or as a result of cytokinesis failure.A long-standing postulate is that centrosome aberrations are involved in the initiation and progression of cancer.However,this notion has been a subject of controversy because until recently the relationship has been correlative.Recently,it was shown that numerical or structural centrosome aberrations can initiate tumors in certain tissues in mice,as well as invasion.Particularly,we will focus on centrosome amplification and chromosome instability as drivers of intra-tumor heterogeneity and their consequences in cancer.We will also discuss briefly the controversies surrounding this theory to highlight the fact that the role of both centrosome amplification and chromosome instability in cancer is highly context-dependent.Further,we will discuss single-cell sequencing as a novel technique to understand intra-tumor heterogeneity and some therapeutic approaches to target chromosome instability.

Overcome cancer drug resistance by targeting epigenetic modifications of centrosome

The centrosome is an organelle that serves as the microtubule-and actin-organizing center of human cells.Although the centrosome is small of size,it is great important on cellular function that regulates cytoskeletal organization and governs precise spindle orientation/positioning ensuring equal distribution of cellular components in cell division.Epigenetic modifications to centrosome proteins can lead to centrosome aberrations,such as disorganized spindles and centrosome amplification causing aneuploidy and genomic instability.Epigenetic disturbances are associated not only with carcinogenesis and cancer progression,but also with drug resistance to chemotherapy.In this review,we discuss mechanisms of epigenetic alteration during the centrosome biogenesis in cancer.We provide an update on the current status of clinical trials that aim to target epigenetic modifications in centrosome aberrations and to thwart drug resistance.

Identification of new centrosome proteins by autoimmune patient sera

Compared to other subcellular organelles, centrosome proteome can hardly be studied, due to the dif- ficulties in separation and purification of centrosome. Auto-antisera from 6 autoimmune patients, which recognized centrosome specifically in immunofluorescence, were used to identify the corresponding centrosomal proteins. The sera were first tested by Western blot on whole cell lysate, and all bound antibodies were then eluted from each single band in Western blot membrane to assure which antibody was responsible for the centrosome specific immunofluorescence staining. The corresponding pro- teins were obtained by immunoprecipitation and identified by mass spectrometry. Six centrosomal proteins, including 2 known centrosomal proteins and 4 proteins with unknown localization or report- edly non-centrosomal localization, were identified. These proteins apparently involve in cell cycle regulation, signal transduction pathways, molecular chaperons, and metabolism enzymes, which may reflect the expected functional diversity of centrosome.

Centrosome positioning and primary cilia assembly orchestrate neuronal development

Establishment of axon and dendrite polarity, migration to a desired location in the developing brain, and establishment of proper synaptic connections are essential processes during neuronal development. The cellular and molecular mechanisms that govern these processes are under intensive investigation. The function of the centrosome in neuronal development has been examined and discussed in few recent studies that underscore the fundamental role of the centrosome in brain development. Clusters of emerging studies have shown that centrosome positioning tightly regulates neuronal development, leading to the segregation of cell factors, directed neurite differentiation, neuronal migration, and synaptic integration. Furthermore, cilia, that arise from the axoneme, a modified centriole, are emerging as new regulatory modules in neuronal development in conjunction with the centrosome. In this review, we focus on summarizing and discussing recent studies on centrosome positioning during neuronal development and also highlight recent findings on the role of cilia in brain development. We further discuss shared molecular signaling pathways that might regulate both centrosome and cilia associated signaling in neuronal development. Furthermore, molecular determinants such as DISC1 and LKB1 have been recently demonstrated to be crucial regulators of various aspects of neuronal development. Strikingly, these determinants might exert their function, at least in part, via the regulation of centrosome and cilia associated signaling and serve as a link between these two signaling centers. We thus include an overview of these molecular determinants.

Centrosome Defects in Hematological Malignancies: Molecular Mechanisms and Therapeutic Insights

Defects in centrosomes are associated with a broad spectrum of hematological malignancies,such as leukemia and lymphoma.Centrosomes in these malignancies display both numerical and structural aberrations,including alterations in the number and size of centrioles,inappropriate post-translational modification of centrosomal proteins,and extra centrosome clustering.There is accumulating evidence that centrosome defects observed in hematological malignancies result from multiple factors,including dysregulation of the centrosome cycle and impairment of centriole biogenesis.In this review,we discuss the plausible mechanisms of centrosome defects and highlight their consequences in hematological malignancies.We also illustrate the latest therapeutic strategies against hematological malignancies by targeting centrosome anomalies.

Sequential Phosphorylation of Nedd1 by Cdk1 and Plk1 is required for γTuRC targeting to centrosome

Nedd1 (neural precursor cell expressed, developmentally down-regulated gene 1) is an evolutionarily conserved protein that has previously been characterized as a new member

CORRELATION ANALYSIS BETWEEN STK15 GENE AND LARYNGEAL CARCINOMA

To explore the relationship between STK15 gene abnormal expression and laryngeal carcinoma. Methods: Tumor tissues and matched normal tissues were taken from 55 LSCC patients. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to detect STK15 expression in 110 specimens. Results: In 38 of the 55 cases (69.1%), the STK15 expression at the mRNA levels was higher than that of the paired normal tissue. The ratio of ADV (average density value) of STK15 gene to ADV of b-actin gene was 1.220.49 in the cancer tissue, and 0.990.54 in the paired normal tissue with a significant difference (t=4.539, P<0.01). Conclusion: There was obvious association between the STK15 overexpression and laryngeal carcinoma. It may serve as an alternative mechanism of activating the pathogenesis of human laryngeal squamous cell carcinoma.

Genomic Instability in Cancer II: 4N-Skewed (90°) Reductive Division via Fragile Sites to Fitness Increase for Solid and Hematological Cancer Beginnings

The objective herein was to connect the ontogeny process of diplochromosomal, amitotic, 4n-skewed division-system, to cytogenetic deficiency lesions in satellite, repetitive DNAs, especially in the chromosomal fragile sites, some 100 distributed over the genome. These latter studies had shown that chemical induced replication-stress led to un-replicated lesions in these fragile sites, which from inaccurate repair processes caused genomic instability. In the chain of events of the ontogeny process to the special tetraploidy, it was proposed that primary damaged human cells could undergo replication stress from repair-process present during cell replication, a suggestion verified by X-ray damaged cells producing the unstable fragile sites (see text). The cancer-importance for therapy is recognition of cell cycle change for the 4n derivative fitness-gained, diploid progeny cells. An open question is whether RB controlling G1 to S-period is mutated at this suggested tumorigenesis initiating phase, and if so, with what consequences for therapy. The fragile site studies further showed that repair of repetitive DNAs could produce two types of genomic changes: single gene mutations and CNVs, which were here shown to be chromosomally located on “borders” to repairing satellite lesions. This genomic placement was found to correspond to mutations identified in tumor sequencing (p53, Rb, MYC), favoring a bad luck location for their cancer “mutational nature”. The CNVs in cancers, are here seen as molecular expressions of long-known cytogenetic HSRs and DMs also with demonstrated origin from amplifications of single genes. Over-expression of oncogenes was hinted of being from duplications, but Drosophila genetics demonstrated the opposite, gene inactivation. The reduced eye-size from dominant, BAR-Ultra-Bar-eye phenotypes, was caused by duplications, inactivating the genetic system for eye-size. The finding of CNVs showing “evasion” of the immune system suggests, inactivation of immune-determining genetics. Since mutated genes on borders to satellite DNAs are a fact in hematological cancers, the 4n-skewed division-system is suggested to replace debated leukemogenesis with fitness-gain from molecular mutations. For these cancers the question is how normal bone marrow cells attain genomic damage for special tetraploidy, which was referred to studies of cells moving in artificial marrow-like substrate, needing serious attention.

表观遗传性精子异常对早期胚胎发生的影响(英文)

Sperm are a highly specialized cell type derived to deliver the paternal haploid genome to the oocyte. The epigenetic, or gene regulatory, properties and mechanisms of the sperm assist in preparation of the paternal genome to contribute to embryogenesis and the genome of the zygote. Many recent studies have addressed the issue of altered epigenetic processes in the sperm. This review evaluates the current understanding of DNA damage, chromosome aneuploidy, reduced telomere length, malformations of the centrosome, genomic imprinting errors, altered mRNA profiles, and abnormal nuclear packaging in the sperm prior to fertilization and the observed effects on embryogenesis. Attention has also been given to understanding the underlying etiology of sperm with altered epigenetic mechanisms in humans. （Asian J Androl 2006 Mar; 8： 131-142）

A New Exposition on Cell Division

This paper provides summary description of the procedures by which human and animal cells (eucaryotic cells) divide into two identical parts. The focus is on the nucleus, with particular attention given to the centrosome and the chromosome. Within the centrosome is a pair of organelle known as centriole. When the cell is about to divide, the centrioles duplicate themselves. At the same time, the DNA within the chromosome duplicates itself. The centriole pair, now two pairs, then separate with one pair migrating about the nucleus to the diametrically opposite side. The original and migrated centriole then emit long strands known as microtubules across the nucleus. Similarly, the chromosome emits long strands known as kinetochores. The microtubules and the kinetochores are perpendicular to each other and they cover the nucleus with a checkered appearance. The diametrically opposed centriole then forms centrosomes which pull the nucleus apart. The two nuclear parts then separate with each part taking with its half of the remainder of the cell (the cytoplasm) and thus two virtually identical cells are attained. The significance of this paper is that it provides the reader with a condensed summary of the life-dependent process known as cell division.