Insufficient KIF15 during porcine oocyte ageing induces HDAC6-based microtubule instability.

During aging, oocytes display cytoskeleton dynamics defects and aneuploidy, leading to embryonic aneuploidy, which in turn causes miscarriages, implantation failures, and birth defects. KIF15 (also known as Hklp2), a member of the kinesin-12 superfamily, is a cytoplasmic motor protein reported to be involved in Golgi and vesicle-related transport during mitosis in somatic cells. However, the regulatory mechanisms of KIF15 during meiosis in porcine oocytes and the connection with postovulatory aging remain unclear. In present study, we found that KIF15 is expressed during porcine oocyte maturation, and its localization is dependent on microtubule dynamics. Furthermore, the level of KIF15 expression decreased in postovulatory aged oocytes. The decrease in KIF15 blocked polar body extrusion, thereby hindering oocyte maturation. We demonstrated that KIF15 defects contributed to abnormal spindle morphologies and chromosome misalignment, possibly due to microtubule instability, as evidenced by microtubule depolymerization after cold treatment. Additionally, our data indicated that KIF15 modulates HDAC6 to affect tubulin acetylation in oocytes. Taken together, these results suggest that KIF15 regulates HDAC6-related microtubule stability for spindle organization in porcine oocytes during meiosis, which may contribute to the decline in maturation competence in aged porcine oocytes.

KIF15 promotes the development and progression of chordoma via activating PI3K-AKT signalling pathway.

Aims: Despite its implication in various human cancers, the expression and functional significance of Kinesin family member 15 (KIF15) in chordomas remain unexplored. Main methods: The evaluation of KIF15 protein levels was conducted through immunohistochemistry (IHC) staining and Western blot analysis. Cell proliferation was quantified using MTT and CCK8 assays, whereas cell migration was examined using wound healing and Transwell assays. Furthermore, flow cytometric analysis was utilized to assess cell apoptosis and the cell cycle. Additionally, in vivo experiments were performed using a mouse xenograft model. Key findings: Our study revealed significantly higher expression of KIF15 in stage III chordoma tissues compared to stage II tissues. Knockdown of KIF15 led to notable inhibition of cell proliferation and migration, along with enhanced apoptosis and cell cycle arrest. In vivo studies further confirmed the inhibitory effects of KIF15 knockdown on chordoma tumour growth. In terms of mechanism, we identified the involvement of the PI3K-AKT signalling pathway mediated by KIF15 in chordomas. Notably, the anti-tumour effects of KIF15 deficiency on chordomas were partially reversed by the addition of an AKT activator. Significance: KIF15 promotes chordoma development and progression through the activation of the PI3K-AKT signalling pathway. Thus, targeting KIF15 might be a promising therapeutic strategy for treating chordomas.

KIF15 knockdown inhibits colorectal cancer proliferation and migration through affecting the ubiquitination modification of NRAS.

As one of the most common malignancies, colorectal cancer (CRC) requires a thorough understanding of the mechanisms that promote its development and the discovery of new therapeutic targets. In this study, immunohistochemical staining confirmed significantly higher expression levels of KIF15 in CRC. qPCR and western blot results demonstrated the effective suppression of KIF15 mRNA and protein expression by shKIF15. Downregulation of KIF15 inhibited the proliferation and migration of CRC cells while promoting apoptosis. In addition, evidence from the xenograft experiments in nude mice demonstrated that KIF15 knockdown also suppressed tumor growth. Through bioinformatics analysis, the downstream molecular NRAS and Rac signaling pathway associated with KIF15 were identified. KIF15 knockdown was found to inhibit NRAS expression and disrupt Rac signaling pathway. Moreover, WB and Co-IP assays revealed that KIF15 reduced the ubiquitination modification of NRAS protein by interacting with the E3 ligase MDM2, thereby enhancing NRAS protein stability. Functionally, NRAS knockdown was shown to inhibit cell proliferation and migration. In conclusion, KIF15 promoted CRC progression by regulating NRAS expression and Rac signaling pathway.

Forkhead box O6 (FoxO6) promotes cardiac pathological remodeling and dysfunction by activating Kif15-TGF-ß1 under aggravated afterload.

Pathological cardiac hypertrophy exhibits complex and abnormal gene expression patterns and progresses to heart failure. Forkhead box protein O6 (FoxO6) is a key transcription factor involved in many biological processes. This study aimed to explore the role of FoxO6 in cardiac hypertrophy. Three groups of mice were established: wild-type, FoxO6 knockout, and FoxO6-overexpressing. The mice received daily administration of angiotensin-II (Ang-II) or saline for 4 weeks, after which they were examined for cardiac hypertrophy, fibrosis, and function. Elevated cardiac expression of FoxO6 was observed in Ang-II-treated mice. FoxO6 deficiency attenuated contractile dysfunction and cardiac remodeling, including cardiomyocyte hypertrophy and fibroblast proliferation and differentiation. Conversely, FoxO6 overexpression aggravated the cardiomyopathy and heart dysfunction. Further studies identified kinesin family member 15 (Kif15) as downstream molecule of FoxO6. Kif15 inhibition attenuated the aggravating effect of FoxO6 overexpression. In vitro, FoxO6 overexpression increased Kif15 expression in cardiomyocytes and elevated the concentration of transforming growth factor-ß1 (TGF-ß1) in the medium where fibroblasts were grown, exhibiting increased proliferation and differentiation, while FoxO6 knockdown attenuated this effect. Cardiac-derived FoxO6 promoted pathological cardiac remodeling induced by aggravated afterload largely by activating the Kif15/TGF-ß1 axis. This result further complements the mechanisms of communication among different cells in the heart, providing novel therapeutic targets for heart failure.

VIRMA Facilitates Triple-Negative Breast Cancer Progression via Increasing m6A-Dependent KIF15 Expression.

BACKGROUND: Vir like N6-methyladenosine (m6A) methyltransferase associated protein (VIRMA) is associated with various tumors, but the specific role of VIRMA in triple-negative breast cancer (TNBC) and the mechanisms are still unclear. Thus, in this study, in addition to the effect of VIRMA on TNBC, the underlying mechanisms were also explored. METHODS: In vitro, VIRMA expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot; VIRMA lentiviral overexpression vector (LV-VIRMA) and lentiviral vector connected with the shRNA targeting VIRMA (LV-shVIRMA) were constructed to explore the functional role of VIRMA; RNA immunoprecipitation and qRT-PCR were performed to assess the relationship between VIRMA and kinesin family 15 (KIF15). In vivo, female Balb/C mice (n = 6) were subcutaneously injected with TNBC cells transfected with LV-shRNA + LV-NC (negative control), LV-shVIRMA + LV-NC, and LV-shVIRMA + LV-KIF15, tumor volume, weight and immunohistochemistry staining of Ki-67 were employed to assess breast tumor growth; immunohistochemistry of VIRMA and KIF15 were performed to examine VIRMA and KIF15 expression in breast tumor tissues. RESULTS: Compared to normal breast epithelial cells, VIRMA was increased in TNBC cells (p < 0.01 and p < 0.001). LV-VIRMA elevated proliferation, metastasis and invasion of TNBC cells in comparison with LV-NC (p < 0.001), while VIRMA knockdown resulted in the opposite effects in comparison with LV-shRNA NC (p < 0.01 and p < 0.001). Also, compared to LV-shRNA NC, LV-shVIRMA downregulated KIF15 expression by reducing KIF15 mRNA stability (p < 0.05 and p < 0.001), which was dependent on m6A. Furthermore, compared to LV-shVIRMA + LV-NC, LV-shVIRMA + LV-KIF15 not only reversed the reduced proliferation, metastasis and invasion of TNBC cells (p < 0.05, p < 0.01, and p < 0.001), but also reversed the decreased tumor weight and volume (p < 0.05, p < 0.01, and p < 0.001). CONCLUSIONS: The above results indicated that VIRMA promoted TNBC progression by upregulating m6A-dependent KIF15 expression, providing a better understanding of the pathogenesis of TNBC.

KIF15 missense variant is associated with the early onset of idiopathic pulmonary fibrosis.

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.

Kif15 deficiency contributes to depression-like behavior in mice.

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-1ß 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.

KIF15 knockdown inhibits the development of endometrial cancer by suppressing epithelial-mesenchymal transition and stemness through Wnt/ß-catenin signaling.

Endometrial cancer (EC) is one of the most common cancers among women, while the incidence of EC is rising. Many studies have found that Kinesin family member 15 (KIF15) is highly expressed in a series of cancers, but the role of KIF15 in EC is unclear. We detected the expression level of KIF15 in a microarray of EC tissues by immunohistochemical staining (IHC), and analyzed the correlation between the expression level of KIF15 and the pathological characteristics of patients. After inhibit the expression of KIF15 in EC cells with lentivirus, cell proliferation and apoptosis were detected respectively by CCK8 assay, flow cytometry and tunnel assay. Transwell assay and wound healing assay were used to examine the migration ability and invasion ability of EC cells. Spheroid formation assay was used to evaluate cell self-renewal ability. In vivo tumor xenograft model was used for validation. The expressions of epithelial-mesenchymal transition, cancer stem cells, and Wnt/ß-catenin signaling molecules were detected by Western blotting. The results showed that the expression of KIF15 in EC tissues was higher than that in normal endometrial tissues, while the expression level of KIF15 in EC was positively correlated with the pathological grade of the tumor. The down-regulation of KIF15 reduced the proliferation, colony formation, invasion, migration and self-renewal ability of EC cells, while promoted cell apoptosis. Knockdown of KIF15 inactivates the Wnt/ß-catenin signaling of EC cells, inhibitors of Wnt signaling can counteract the enhanced self-renewal ability caused by KIF15 overexpression. Therefore, KIF15 may be a new potential target for diagnosis and treatment of EC.

Anti-aging Effects of Alu Antisense RNA on Human Fibroblast Senescence Through the MEK-ERK Pathway Mediated by KIF15.

OBJECTIVE: To investigate whether human short interspersed nuclear element antisense RNA (Alu antisense RNA; Alu asRNA) could delay human fibroblast senescence and explore the underlying mechanisms. METHODS: We transfected Alu asRNA into senescent human fibroblasts and used cell counting kit-8 (CCK-8), reactive oxygen species (ROS), and senescence-associated beta-galactosidase (SA-ß-gal) staining methods to analyze the anti-aging effects of Alu asRNA on the fibroblasts. We also used an RNA-sequencing (RNA-seq) method to investigate the Alu asRNA-specific mechanisms of anti-aging. We examined the effects of KIF15 on the anti-aging role induced by Alu asRNA. We also investigated the mechanisms underlying a KIF15-induced proliferation of senescent human fibroblasts. RESULTS: The CCK-8, ROS and SA-ß-gal results showed that Alu asRNA could delay fibroblast aging. RNA-seq showed 183 differentially expressed genes (DEGs) in Alu asRNA transfected fibroblasts compared with fibroblasts transfected with the calcium phosphate transfection (CPT) reagent. The KEGG analysis showed that the cell cycle pathway was significantly enriched in the DEGs in fibroblasts transfected with Alu asRNA compared with fibroblasts transfected with the CPT reagent. Notably, Alu asRNA promoted the KIF15 expression and activated the MEK-ERK signaling pathway. CONCLUSION: Our results suggest that Alu asRNA could promote senescent fibroblast proliferation via activation of the KIF15-mediated MEK-ERK signaling pathway.

Combined Inhibition of KIF11 and KIF15 as an Effective Therapeutic Strategy for Gastric Cancer.

BACKGROUND: Novel therapeutic strategies are urgently required to improve clinical outcomes of gastric cancer (GC). KIF15 cooperates with KIF11 to promote bipolar spindle assembly and formation, which is essential for proper sister chromatid segregation. Therefore, we speculated that the combined inhibition of KIF11 and KIF15 might be an effective strategy for GC treatment. Hence, to test this hypothesis, we aimed to evaluate the combined therapeutic effect of KIF15 inhibitor KIF15- IN-1 and KIF11 inhibitor ispinesib in GC. METHODS: We validated the expression of KIF11 and KIF15 in GC tissues using immunohistochemistry and immunoblotting. Next, we determined the effects of KIF11 or KIF15 knockout on the proliferation of GC cell lines. Finally, we investigated the combined effects of the KIF11 and KIF15 inhibitors both in vitro and in vivo. RESULTS: KIF11 and KIF15 were overexpressed in GC tissues than in the adjacent normal tissues. Knockout of either KIF11 or KIF15 inhibited the proliferative and clonogenic abilities of GC cells. We found that the KIF15 knockout significantly increased ispinesib sensitivity in GC cells, while its overexpression showed the opposite effect. Further, using KIF15-IN-1 and ispinesib together had a synergistic effect on the antitumor proliferation of GC both in vitro and in vivo. CONCLUSION: This study shows that the combination therapy of inhibiting KIF11 and KIF15 might be an effective therapeutic strategy against gastric cancer.

PSMD12 promotes the activation of the MEK-ERK pathway by upregulating KIF15 to promote the malignant progression of liver cancer.

The tumor recurrence and drug resistance of hepatocellular carcinoma (HCC) threatened patients a lot. The mechanism should be further explored. The information of expression status and survival were available in public databases. The Western blot and immunohistochemistry staining displayed the level of related proteins. CCK-8, colony-formation assays, transwell assay and wound healing assay were performed to illustrate the ability of tumor growth, invasion and migration. In vivo model was established to verify our cell experiments. In our study, we revealed that proteasome 26S subunit, non-ATPase 12 (PSMD12) was high expressed in HCC tissues and positive related to the survival. In vitro experiments suggested that PSMD12 knockdown attenuated tumor cell growth, invasion and migration. Moreover, PSMD12 interference blocked the activation of MEK-ERK pathway. The ERK inhibitor could alleviate the tumor-promoting effect in PSMD12-overexpression cells. In addition, kinesin family member 15 (KIF15) was also observed to be highly expressed in HCC and be harmful to the survival. The public database, the images of immunohistochemistry and the western blot illustrated that PSMD12 and KIF15 was positive correlated. KIF15 knockdown impaired tumor progression and tumor-promoting effect of PSMD12. The xenograft models supported the results of cell experiments. In conclusion, PSMD12 could activated MEK-ERK pathway via KIF15 upregulation, thereby promoting tumor progression.

Kinesin family member 15 can promote the proliferation of glioblastoma.

Glioblastoma is one of the most dangerous tumors for patients in clinical practice at present, and since glioblastoma originates from the brain, it will have a serious impact on patients. Therefore, more effective clinical therapeutic targets are still needed at this stage. Kinesin family member 15 (KIF15) promotes proliferation in several cancers, but its effect on glioblastoma is unclear. In this study, differentially expressed gene analysis and network analysis were performed to identify critical genes affecting glioma progression. The samples were divided into a KIF15 high-expression group and KIF15 low-expression group, and the association between FIK15 expression level and clinical characteristics was summarized and analyzed by performing medical data analysis; the effect of KIF15 on glioblastoma cell proliferation was detected by employing colony formation and MTT assays. The effect of KIF15 on tumor growth in mice was determined. It was found that KIF15 was a potential gene affecting the progression of glioblastoma. In addition, KIF15 was highly expressed in glioblastoma tumor tissues, and KIF15 was correlated with tumor size, clinical stage and other clinical characteristics. After the KIF15 gene was knocked out, the proliferation ability of glioblastoma was significantly inhibited. KIF15 also contributed to the growth of glioblastoma tumors in mice. Therefore, we found KIF15 to be a promising clinical therapeutic target.

Kif15 Is Required in the Development of Auditory System Using Zebrafish as a Model.

Kif15, a kinesin family member, is powerful in the formation of bipolar spindles. There is emerging evidence indicating that Kif15 plays vital roles in influencing the growth of axons and interference with the progression of the tumor. However, the function of Kif15 in the auditory organs remains unknown. The Western blotting test was used to examine the effect of Kif15 downregulation by specific morpholino targeting Kif15 (Kif15-MO). The development of the inner ear and posterior lateral line (PLL) system in zebrafish was under continuous observation from spawns to 96 h postfertilization (hpf) to investigate the potential role of Kif15 in the auditory and vestibular system. We uncovered that Kif15 inhibition induced otic organ deformities in zebrafish, including malformed semicircular canals, abnormal number and location of otoliths, and reduced number of hair cells (HCs) both in utricle and saccule. Furthermore, a remarkable reduction in the number of PLL neuromasts was also explored in Kif15-MO morphants compared to the normal larvae. We also detected notably reduced activity in locomotion after Kif15 was knocked down. Additionally, we performed rescue experiments with co-injection of Kif15 mRNA and found that the Kif15 splicing MO-induced deformities in otic vesicle and PLL of zebrafish were successfully rescued, and the severely reduced locomotor activity caused by Kif15-MO was partially rescued compared to the control-MO (Con-MO) embryos. Our findings uncover that Kif15 is essential in the early development of auditory and vestibular organs using zebrafish as models.

Integrative Pan-Cancer Analysis of KIF15 Reveals Its Diagnosis and Prognosis Value in Nasopharyngeal Carcinoma.

Background: KIF15 plays a vital role in many biological processes and has been reported to influence the occurrence and development of certain human cancers. However, there are few systematic evaluations on the role of KIF15 in human cancers, and the role of KIF15 in the diagnosis and prognosis of nasopharyngeal carcinoma (NPC) also remains unexplored. Therefore, this study aimed to conduct a pan-cancer analysis of KIF15 and evaluate its diagnostic and prognostic potential in NPC. Methods: The expression pattern, prognostic value, molecular function, tumor mutation burden, microsatellite instability, and immune cell infiltration of KIF15 were examined based on public databases. Next, the diagnostic value of KIF15 in NPC was analyzed using the Gene Expression Omnibus (GEO) database and immunohistochemistry (IHC). Kaplan-Meier curves, Cox regression analyses, and nomograms were used to evaluate the effects of KIF15 expression on NPC prognosis. Finally, the effect of KIF15 on NPC was explored by in vitro experiments. Results: The expression of KIF15 was significantly upregulated in 20 out of 33 cancer types compared to adjacent normal tissue. Kyoto Encyclopedia of Genes and Genomes enrichment (KEGG) analysis showed that KIF15 could participate in several cancer-related pathways. The increased expression level of KIF15 was correlated with worse clinical outcomes in many types of human cancers. Additionally, KIF15 expression was related to cancer infiltration of immune cells, tumor mutation burden, and microsatellite instability. In the analysis of NPC, KIF15 was significantly upregulated based on the GEO database and immunohistochemistry. A high expression of KIF15 was negatively associated with the prognosis of patients with NPC. A nomogram model integrating clinical characteristics and KIF15 expression was established, and it showed good predictive ability with an area under the curve value of 0.73. KIF15 knockdown significantly inhibited NPC cell proliferation and migration. Conclusions: Our findings revealed the important and functional role of KIF15 as an oncogene in pan-cancer. Moreover, high expression of KIF15 was found in NPC tissues, and was correlated with poor prognosis in NPC. KIF15 may serve as a potential therapeutic target in NPC treatment.

Rare and Common Variants in KIF15 Contribute to Genetic Risk of Idiopathic Pulmonary Fibrosis.

Rationale: Genetic studies of idiopathic pulmonary fibrosis (IPF) have improved our understanding of this disease, but not all causal loci have been identified. Objectives: To identify genes enriched with rare deleterious variants in IPF and familial pulmonary fibrosis. Methods: We performed gene burden analysis of whole-exome data, tested single variants for disease association, conducted KIF15 (kinesin family member 15) functional studies, and examined human lung single-cell RNA sequencing data. Measurements and Main Results: Gene burden analysis of 1,725 cases and 23,509 control subjects identified heterozygous rare deleterious variants in KIF15, a kinesin involved in spindle separation during mitosis, and three telomere-related genes (TERT [telomerase reverse transcriptase], RTEL1 [regulator of telomere elongation helicase 1], and PARN [poly(A)-specific ribonuclease]). KIF15 was implicated in autosomal-dominant models of rare deleterious variants (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.7-8.8; P = 2.55 × 10-7) and rare protein-truncating variants (OR, 7.6; 95% CI, 3.3-17.1; P = 8.12 × 10-7). Meta-analyses of the discovery and replication cohorts, including 2,966 cases and 29,817 control subjects, confirm the involvement of KIF15 plus the three telomere-related genes. A common variant within a KIF15 intron (rs74341405; OR, 1.6; 95% CI, 1.4-1.9; P = 5.63 × 10-10) is associated with IPF risk, confirming a prior report. Lymphoblastoid cells from individuals heterozygous for the common variant have decreased KIF15 and reduced rates of cell growth. Cell proliferation is dependent on KIF15 in the presence of an inhibitor of Eg5/KIF11, which has partially redundant function. KIF15 is expressed specifically in replicating human lung cells and shows diminished expression in replicating epithelial cells of patients with IPF. Conclusions: Both rare deleterious variants and common variants in KIF15 link a nontelomerase pathway of cell proliferation with IPF susceptibility.

Chemical Biology of Mitotic Spindle Assembly Motors.

Mitotic kinesins play essential roles during mitotic spindle assembly and in ensuring proper chromosome segregation. Chemical inhibitors of mitotic kinesins are therefore valuable tools to study kinesin function in vitro and in cells. Because cancer is a disease of unregulated cell division, inhibitors also represent potential chemotherapeutic agents. Here, we present assays that can be used to evaluate the potency and specificity of mitotic kinesin inhibitors identified from high-throughput screening. By evaluating their effects in a variety of in vitro, fixed-cell, and live cell assays, screening hits can be prioritized and optimized to produce effective, on-target inhibitors.

KIF15 knockdown suppresses gallbladder cancer development.

Gallbladder cancer (GBC) is commonly regarded as one of the most lethal malignant tumor types with poor prognosis. Kinesin family member 15 (KIF15) is reported to be tightly related with progression of multiple cancer types which, however, has not been clarified in GBC so far. KIF15 was significantly up-regulated in clinical GBC tissues compared with that in para-carcinoma tissues and the expression level was also correlated with tumor malignancies. In addition to tissues, GBC cells also exhibited a high expression abundance of KIF15. After down-regulating KIF15 via lentiviral transfection, GBC cell proliferation and migration were both inhibited, while cell apoptosis was promoted markedly. Likewise, silencing KIF15 significantly interfered the growth of nude mouse xenografts. Our experiments in GBC cell lines also demonstrated that KIF15 overexpression accelerated cell proliferation but lessened cell apoptosis in both GBC-SD and SGC-996 cells. Further investigation of the mechanism occurring in GBC inhibition mediated by KIF15 knockdown revealed that KIF15 deficiency led to decreased activity of several signaling pathways (TNF, PI3K/AKT and MAPK), a reduction of CDK6 expression regulated by enhanced p21, and HSP60 absence. Following the treatment of shCtrl- and shKIF15-transfected cells with AKT activator, we found that anti-tumor effects resulting from KIF15 deficiency could be relieved by AKT activator in both experimental cells. Overall, for the first time, we demonstrated that KIF15 was overexpressed in GBC and displayed a close relationship between KIF15 levels and GBC clinical stages. Furthermore, low expression of KIF15 resulted in obvious anti-tumor effects.

KIF15 Promotes Progression of Castration Resistant Prostate Cancer by Activating EGFR Signaling Pathway.

Castration-resistant prostate cancer (CRPC) continues to be a major clinical problem and its underlying mechanisms are still not fully understood. The epidermal growth factor receptor (EGFR) activation is an important event that regulates mitogenic signaling. EGFR signaling plays an important role in the transition from androgen dependence to castration-resistant state in prostate cancer (PCa). Kinesin family member 15 (KIF15) has been suggested to be overexpressed in multiple malignancies. Here, we demonstrate that KIF15 expression is elevated in CRPC. We show that KIF15 contributes to CRPC progression by enhancing the EGFR signaling pathway, which includes complex network intermediates such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. In CRPC tumors, increased expression of KIF15 is positively correlated with EGFR protein level. KIF15 binds to EGFR, and prevents EGFR proteins from degradation in a Cdc42-dependent manner. These findings highlight the key role of KIF15 in the development of CRPC and rationalize KIF15 as a potential therapeutic target.

Kinesin 12 (KIF15) contributes to the development and tumorigenicity of prostate cancer.

In Asia, prostate cancer is becoming a growing concern, impacting both socially and economically, compared with what is seen in western countries. Hence, it is essential to know the mechanisms associated with the development and tumorigenesis of PCa for primary diagnosis, risk management, and development of therapy strategies against PCa. Kinesin family member 15 (KIF15), a kinesin family member, is a plus-end-directed kinesin that functions to form bipolar spindles. There is emerging evidence indicating that KIF15 plays a significant role in several malignancies, such as pancreatic cancer, hepatocellular carcinoma, lung adenocarcinoma, and breast cancer. Still, the function of KIF15 remains unclear in prostate cancer. Here, we study the functional importance of KIF15 in the tumorigenesis of PCa. The bioinformatic analysis from PCa patients revealed high KIF15 expression compared to normal prostate tissues. High expression hinting at a possible functional role of KIF15 in regulating cell proliferation of PCa, which was demonstrated by both in vitro and in vivo assays. Downregulation of KIF15 silenced the expression of CDK2, p-RB, and Cyclin D1 and likewise blocked the cells at the G1 stage of the cell cycle. In addition, KIF15 downregulation inhibited MEK-ERK signaling by significantly silencing p-ERK and p-MEK levels. In conclusion, this study confirmed the functional significance of KIF15 in the growth and development of prostate cancer and could be a novel therapeutic target for the treatment of PCa.