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The various cellular composition of the tumor microenvironment (TME) comprises the fundamental units of tumor tissue. The types of stromal cells in the TME are genetically stable, with reduced risk of tumor recurrence and drug resistance. More and more evidence shows their clinicopathological significance and therapeutic effect in predicting prognosis. Therefore, we performed an integrated analysis of the breast cancer TME, correlating it with genomic landscapes and clinical profiles. In this work, we first conducted unsupervised hierarchical clustering on 830 tumors in the breast cancer cohort. Then, we defined three TME phenotypes and applied principal component analysis to construct a TMEscore for quantifying TME. Analysis revealed that patients stratified into the high TMEscore cohort exhibited superior survival compared to the low‐scoring group. Additionally, a high TMEscore is associated with an improved response to immunotherapy. Through TME gene signature analysis, KIF15 was identified as a pivotal driver of the immunosuppressive microenvironment in breast cancer. KIF15 knockdown may promote dendritic cell infiltration and function, thereby inducing CD8+ T cell recruitment. In summary, the immune microenvironment‐derived TMEscore represents an independent prognostic biomarker in breast cancer, while KIF15 emerges as a crucial molecular determinant of its immunosuppressive niche.

Background: Pancreatic cancer is highly malignant and characterised by rapid and uncontrolled growth. While some of the important regulatory networks involved in pancreatic cancer have been determined, the cancer relevant genes have not been fully identified. Methods: We screened genes that may control proliferation in pancreatic cancer in seven pairs of matched pancreatic cancer and normal pancreatic tissue samples. We examined KIF15 expression in pancreatic cancer tissues and the effect of KIF15 on cell proliferation in vitro and in vivo . The mechanisms underlying KIF15 promotion of cell proliferation were investigated. Results: mRNA microarray and functional analysis identified 22 genes that potentially play an important role in the proliferation of pancreatic cancer. High-content siRNA screening evaluated whether silencing these 22 genes affected proliferation of pancreatic cancer. Notably, silencing KIF15 exhibited the most potent inhibition of proliferation compared with the rest of the 22 genes. KIF15 was upregulated in human pancreatic cancer tissues, and higher KIF15 expression levels correlated with shorter patient survival times. Upregulation KIF15 promoted pancreatic cancer growth. KIF15 upregulated cyclin D1, CDK2, and phospho-RB and also promoted G1/S transition in pancreatic cancer cells. KIF15 upregulation activated MEK–ERK signalling by increasing p-MEK and p-ERK levels. MEK–ERK inhibitors successfully inhibited cell cycle progression, and PD98059 blocked KIF15-mediated pancreatic cancer proliferation in vivo and in vitro . Conclusions: This study identified KIF15 as a critical regulator that promotes pancreatic cancer proliferation, broadening our understanding of KIF15 function in tumorigenesis.

Bladder cancer (BC) is the most common cancer of the urinary tract and invariably predicts a poor prognosis. In this study, we found a reliable gene signature and potential biomarker for predicting clinical prognosis. The gene expression profiles were obtained from the GEO database. By performing GEO2R analysis, numerous differentially expressed genes (DEGs) were found. Three different microarray datasets were integrated in order to more precisely identify up-expression genes. Functional analysis revealed that these genes were mainly involved in cell cycle, DNA replication and metabolic pathways. Based on protein-protein interactome (PPI) networks that were identified in the current study and previous studies, we focused on KIF15 for further study. The results showed that KIF15 promotes BC cell proliferation via the MEK -ERK pathway, and Kaplan-Meier survival analysis revealed that KIF15 expression was an independent prognostic risk factor in BC patients. KIF15 may represent a promising prognostic biomarker and a potential therapeutic option for BC.

Human Kinesin-12 (hKif15) plays a crucial role in assembly and maintenance of the mitotic spindle. These functions of hKif15 are partially redundant with Kinesin-5 (Eg5), which can cross-link and drive the extensile sliding of antiparallel microtubules. Although both motors are known to be tetramers, the functional properties of hKif15 are less well understood. Here we reveal how single or multiple Kif15 motors can cross-link, transport, and focus the plusends of intersecting microtubules. During transport, Kif15 motors step simultaneously along both microtubules with relative microtubule transport driven by a velocity differential between motor domain pairs. Remarkably, this differential is affected by the underlying intersection geometry: the differential is low on parallel and extreme on antiparallel microtubules where one motor domain pair becomes immobile. As a result, when intersecting microtubules are antiparallel, canonical transport of one microtubule along the other is allowed because one motor is firmly attached to one microtubule while it is stepping on the other. When intersecting microtubules are parallel, however, Kif15 motors can drive (biased) parallel sliding because the motor simultaneously steps on both microtubules that it cross-links. These microtubule rearrangements will focus microtubule plus-ends and finally lead to the formation of parallel bundles. At the same time, Kif15 motors cooperate to suppress catastrophe events at polymerizing microtubule plus-ends, raising the possibility that Kif15 motors may synchronize the dynamics of bundles that they have assembled. Thus, Kif15 is adapted to operate on parallel microtubule substrates, a property that clearly distinguishes it from the other tetrameric spindle motor, Eg5.

Cancer stem cells (CSCs) have the potential to self-renew and induce cancer, which may contribute to a poor prognosis by enabling metastasis, recurrence, and therapy resistance. Hence, this study was performed to identify the association between CSC-related genes and triple-negative breast cancer (TNBC) development. Stemness gene sets were downloaded from StemChecker. Based on the online databases, a consensus clustering algorithm was conducted for unsupervised classification of TNBC samples. The variations between subtypes were assessed with regard to prognosis, tumor immune microenvironment (TIME), and chemotherapeutic sensitivity. The stemness-related gene signature was established and random survival forest analysis was employed to identify the core gene for validation experiments and tumor sphere formation assays. 499 patients with TNBC were classified into three subgroups and the Cluster 1 had a better OS than others. After that, WGCNA study was performed to identify genes important for Cluster 1 subtype. Out of all 8 modules, the subtype of Cluster 1 and the yellow module with 103 genes demonstrated the largest positive association. After that, a four-gene stemness-related signature was established. Based on the yellow module, the 39 potential pivotal genes were subjected to the random forest survival analysis to find out the gene that was relatively important for OS. KIF15 was confirmed as the targeted gene by LASSO and random survival forest analyses. In vitro experiments, the downregulation of KIF15 promoted the stemness of TNBC cells. The expression levels of stem cell markers Nanog, SOX2, and OCT4 were found to be elevated in TNBC cell lines after KIF15 inhibition. A stemness-associated risk model was constructed to forecast the clinical outcomes of TNBC patients. The downregulation of KIF15 expression in a subpopulation of TNBC stem cells may promote stemness and possibly TNBC progression.

Glioblastoma (GBM) is highly invasive and lethal. The failure to cure GBM highlights the necessity of developing more effective targeted therapeutic strategies. KIF15 is a motor protein to be involved in cell mitosis promotion, cell structure assembly and cell signal transduction. The precise biological function and the potential upstream regulatory mechanisms of KIF15 in GBM remain elusive. Here, we demonstrated that KIF15 was abnormally up-regulated in GBM and predicted poor prognosis of GBM patients. KIF15 promotes GBM cell proliferation, metastasis and cell cycle progression. REST could bind to KIF15 promoter and transactivate KIF15. Furthermore, REST interacts with P300 and depends on its histone acetyltransferase (HAT) activity to co-regulate KIF15 expression. Both REST and P300 were highly expressed in GBM and predicted poor prognosis of GBM patients alone or in combination with KIF15. The tumorigenic function of KIF15 in GBM was regulated by REST and and the combinational treatment of cell cycle inhibitor Palbociclib with P300 HAT inhibitor inhibited GBM xenografts survival more significantly. Our findings indicate that KIF15 promotes GBM progression under the synergistic transactivation of REST and P300. P300/REST/KIF15 signaling axis is expected to be served as a cascade of candidate therapeutic targets in anti-GBM.

Breast cancer (BC) is one of the most common female cancers, and its incidence has been increasing in recent years. Although treatments are continuously improving, the prognosis of patients in the advanced stage is still unsatisfactory. Thus, an in-depth understanding of its molecular mechanisms is necessary for curing breast cancer. KIF15 is a tetrameric spindle motor which can regulate mitosis in cellular process and exert the crucial functions in several cancers. The purpose of our research was to investigate the functions of KIF15 in breast cancer. We tested the expression of KIF15 in breast cancer tissues and the survival rate of breast cancer patients with high or low level of KIF15 through TCGA data. What's more, western blot and immunohistochemistry assay were utilized to evaluate the protein level and mRNA level of KIF15 in breast cancer tissues. Then CCK-8, wound healing, transwell and flow cytometry experiments were adopted separately to test cell viability, migration, invasion and cell cycle distribution. We discovered that KIF15 was highly expressed in breast cancer tissues and high level KIF15 was associated with a low survival rate of breast cancer patients. Moreover, silence of KIF15 suppressed cell viability, migration, invasion and cell cycle distribution. Following, we discovered that ZNF367 was the upstream transcription factor of KIF15. In addition, silenced ZNF367 could also repress the growth of breast cancer cells. And rescue experiments indicated that overexpressed KIF15 could counteract the inhibition effect of silencing ZNF367 on the progression of breast cancer. Importantly, we discovered that KIF15 and ZNF367 were associated with the regulation of cell cycle. In short, ZNF367-activated KIF15 accelerated the progression of breast cancer by regulating cell cycle progress.

Objective This study aimed to systematically identify and validate KIF15 as a potential diagnostic and prognostic biomarker in colon cancer (CC) using integrated bioinformatics analyses. We further explored its role in the tumor immune microenvironment and its potential value in immunotherapy, and validated its expression and clinical significance through immunohistochemical analysis. Methods Gene expression profiles of CC were obtained from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs). A protein–protein interaction (PPI) network was constructed, and key genes were identified using the MCODE plugin in Cytoscape. External validation of candidate gene expression was performed using The Cancer Genome Atlas (TCGA) cohort. Kaplan–Meier survival analysis was conducted to evaluate prognostic significance. Receiver operating characteristic (ROC) and time-dependent ROC analyses were applied to assess diagnostic and prognostic performance. A nomogram model was established based on multivariate Cox regression, and its predictive accuracy and stability were evaluated using calibration curves and decision curve analysis (DCA). To investigate the role of KIF15 in the tumor microenvironment, single-cell RNA sequencing data from the TISCH database were analyzed to determine its expression distribution across immune cell subsets. Functional enrichment and immune correlation analyses were performed to elucidate the potential molecular mechanisms of KIF15 in CC progression and to identify downstream hub genes. Finally, immunohistochemistry (IHC) was conducted to validate the tissue expression pattern and clinical relevance of KIF15. Results A total of 611 DEGs were identified by integrating three GEO datasets (GSE24550, GSE21815, and GSE44076). Based on PPI network construction and MCODE analysis, 13 key genes, including KIF15, were identified. Combined univariate Cox regression and pan-cancer analysis ultimately determined KIF15 as the core gene of interest. TCGA analysis demonstrated that KIF15 was significantly upregulated in CC tissues ( P  < 0.0001), with a diagnostic ROC AUC of 0.874. Kaplan–Meier analysis showed that high KIF15 expression was significantly associated with poor prognosis ( P  = 0.004). Multivariate Cox regression confirmed that KIF15 was an independent prognostic factor. The nomogram model constructed based on KIF15 yielded a C-index of 0.783. Time-dependent ROCanalysis showed AUC values of 0.788, 0.777, and 0.712 for 1-, 3-, and 5-year survival, respectively. Calibrationcurves and DCA indicated good predictive consistency and clinical net benefit. Single-cell analysis revealedthat KIF15 was highly expressed in proliferating T cells (Tprolif). Functional enrichment analysis indicatedthat KIF15 was primarily involved in the cell cycle, DNA replication, mitosis, and the p53 signaling pathway.Immune correlation analysis showed significant associations between KIF15 expression and multipleimmune-infiltrating cells as well as immune checkpoint genes. Four downstream hub genes (TTK, CDK1,CHEK1, and KIF2C) were further identified and were all significantly upregulated in CC. IHC results confirmedthat KIF15 was highly expressed in CC tissues (P < 0.001) and was significantly associated with poorprognosis. Pearson correlation analysis demonstrated that KIF15 expression was positively correlated withimmune markers, including PD-1 and PD-L1. Conclusion KIF15 is significantly overexpressed in CC tissues and is strongly associated with unfavorable prognosis, suggesting its potential clinical value in the diagnosis and prognostic assessment of CC. Notably, KIF15 expression is closely correlated with immune cell infiltration and multiple immune checkpoint molecules, indicating a potential role in regulating the tumor immune microenvironment. Therefore, KIF15 may serve as a promising biomarker and potential therapeutic target for immunotherapy, as well as a candidate marker for diagnosis, prognosis evaluation, and individualized treatment in CC.

Background Idiopathic pulmonary fibrosis (IPF) has an unknown aetiology and limited treatment options. A recent meta-analysis identified three novel causal variants in the TERT , SPDL1 , and KIF15 genes. This observational study aimed to investigate whether the aforementioned variants cause clinical phenotypes in a well-characterised IPF cohort. Methods The study consisted of 138 patients with IPF who were diagnosed and treated at the Helsinki University Hospital and genotyped in the FinnGen FinnIPF study. Data on > 25 clinical parameters were collected by two pulmonologists who were blinded to the genetic data for patients with TERT loss of function and missense variants, SPDL1 and KIF15 missense variants, and a MUC5B variant commonly present in patients with IPF, or no variants were separately analysed. Results The KIF15 missense variant is associated with the early onset of the disease, leading to progression to early-age transplantation or death. In patients with the KIF15 variant, the median age at diagnosis was 54.0 years (36.5–69.5 years) compared with 72.0 years (65.8–75.3 years) in the other patients (P  = 0.023). The proportion of KIF15 variant carriers was 9- or 3.6-fold higher in patients aged < 55 or 65 years, respectively. The variants for TERT and MUC5B had similar effects on the patient’s clinical course, as previously described. No distinct phenotypes were observed in patients with the SPDL1 variant. Conclusions Our study indicated the potential of KIF15 to be used in the genetic diagnostics of IPF. Further studies are needed to elucidate the biological mechanisms of KIF15 in IPF.

Neuropsychiatric disorders have a high incidence worldwide. Kinesins, a family of microtubule-based molecular motor proteins, play essential roles in intracellular and axonal transport. Variants of kinesins have been found to be related to many diseases, including neurodevelopmental/neurodegenerative disorders. Kinesin-12 (also known as Kif15) was previously found to affect the frequency of both directional microtubule transports. However, whether Kif15 deficiency impacts mood in mice is yet to be investigated. In this study, we used the CRISPR/Cas9 method to obtain Kif15 −/− mice. In behavioral tests, Kif15 −/− female mice exhibited prominent depressive characteristics. Further studies showed that the expression of BDNF was significantly decreased in the frontal cortex, corpus callosum, and hippocampus of Kif15 −/− mice, along with the upregulation of Interleukin-6 and Interleukin-1β in the corpus callosum. In addition, the expression patterns of AnkG were notably changed in the developing brain of Kif15 −/− mice. Based on our previous studies, we suggested that this appearance of altered AnkG was due to the maladjustment of the microtubule patterns induced by Kif15 deficiency. The distribution of PSD95 in neurites notably decreased after cultured neurons treated with the Kif15 inhibitor, but total PSD95 protein level was not impacted, which revealed that Kif15 may contribute to PSD95 transportation. This study suggested that Kif15 may serve as a potential target for future depression studies.