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Abstract Background Glioma is considered the most common primary malignant tumor of the central nervous system. Although traditional treatments have not achieved satisfactory outcomes, recently, targeted therapies for glioma have shown promising efficacy. However, due to the single-target nature of targeted therapy, traditional targeted therapies are ineffective; thus, novel therapeutic targets are urgently needed. Methods The gene expression data for glioma patients were derived from the GEO (GSE4290, GSE50161), TCGA and CGGA databases. Next, the upregulated genes obtained from the above databases were cross-analyzed, finally, 10 overlapping genes (BIRC5, FOXM1, EZH2, CDK1, KIF11, KIF4A, NDC80, PBK, RRM2, and TOP2A) were ultimately screened and only KIF4A expression has the strongest correlation with clinical characteristics in glioma patients. Futher, the TCGA and CGGA database were utilized to explore the correlation of KIF4A expression with glioma prognosis. Then, qRT-PCR and Western blot was used to detect the KIF4A mRNA and protein expression level in glioma cells, respectively. And WZ-3146, the small molecule inhibitor targeting KIF4A, were screened by Cmap analysis. Subsequently, the effect of KIF4A knockdown or WZ-3146 treatment on glioma was measured by the MTT, EdU, Colony formation assay and Transwell assay. Ultimately, GSEA enrichment analysis was performed to find that the apoptotic pathway could be regulated by KIF4A in glioma, in addition, the effect of WZ-3146 on glioma apoptosis was detected by flow cytometry and Western blot. Results In the present study, we confirmed that KIF4A is abnormally overexpressed in glioma. In addition, KIF4A overexpression is a key indicator of glioma prognosis; moreover, suppressing KIF4A expression can inhibit glioma progression. We also discovered that WZ-3146, a small molecule inhibitor of KIF4A, can induce apoptosis in glioma cells and exhibit antiglioma effects. Conclusion In conclusion, these observations demonstrated that targeting KIF4A can inhibit glioma progression. With further research, WZ-3146, a small molecule inhibitor of KIF4A, could be combined with other molecular targeted drugs to cooperatively inhibit glioma progression.

Background: Glioma is considered the most common primary malignant tumor of the central nervous system. Although traditional treatments have not achieved satisfactory outcomes, recently, targeted therapies for glioma have shown promising efficacy. However, due to the single-target nature of targeted therapy, traditional targeted therapies are ineffective; thus, novel therapeutic targets are urgently needed. Methods: The gene expression data for glioma patients were derived from the GEO (GSE4290, GSE50161), TCGA and CGGA databases. Next, the upregulated genes obtained from the above databases were cross-analyzed, finally, 10 overlapping genes (BIRC5, FOXM1, EZH2, CDK1, KIF11, KIF4A, NDC80, PBK, RRM2, and TOP2A) were ultimately screened and only KIF4A expression has the strongest correlation with clinical characteristics in glioma patients. Futher, the TCGA and CGGA database were utilized to explore the correlation of KIF4A expression with glioma prognosis. Then, qRT-PCR and Western blot was used to detect the KIF4A mRNA and protein expression level in glioma cells, respectively. And WZ-3146, the small molecule inhibitor targeting KIF4A, were screened by Cmap analysis. Subsequently, the effect of KIF4A knockdown or WZ-3146 treatment on glioma was measured by the MTT, EdU, Colony formation assay and Transwell assay. Ultimately, GSEA enrichment analysis was performed to find that the apoptotic pathway could be regulated by KIF4A in glioma, in addition, the effect of WZ-3146 on glioma apoptosis was detected by flow cytometry and Western blot. Results: In the present study, we confirmed that KIF4A is abnormally overexpressed in glioma. In addition, KIF4A overexpression is a key indicator of glioma prognosis; moreover, suppressing KIF4A expression can inhibit glioma progression. We also discovered that WZ-3146, a small molecule inhibitor of KIF4A, can induce apoptosis in glioma cells and exhibit antiglioma effects. Conclusion: In conclusion, these observations demonstrated that targeting KIF4A can inhibit glioma progression. With further research, WZ-3146, a small molecule inhibitor of KIF4A, could be combined with other molecular targeted drugs to cooperatively inhibit glioma progression. [ABSTRACT FROM AUTHOR]

Abstract Background Breast cancer (BC) is the leading cause of morbidity and the second leading cause of death among female malignant tumors. Although available drugs have been approved for the corresponding breast cancer subtypes (ER-positive, HER2+) currently, there are still no effective targeted drugs or treatment strategies for metastatic breast cancer or triple-negative breast cancer that lack targets. Therefore, it is urgent to discover new potential targets. ERCC6L is an essential protein involved in chromosome separation during cell mitosis. However, the effect of ERCC6L on the tumorigenesis and progression of breast cancer is unclear. Methods and results Here, we found that ERCC6L was highly expressed in breast cancer, especially in TNBC, which was closely related to poor outcomes of patients. An ERCC6L conditional knockout mouse model was first established in this study, and the results confirmed that ERCC6L was required for the development of the mammary gland and the tumorigenesis and progression of mammary gland cancers. In in vitro cell culture, ERCC6L acted as a tumor promoter in the malignant progression of breast cancer cells. Overexpression of ERCC6L promoted cell proliferation, migration and invasion, while knockdown of ERCC6L caused the opposite results. Mechanistically, ERCC6L accelerated the cell cycle by regulating the G2/M checkpoint signalling pathway. Additionally, we demonstrated that there is an interaction between ERCC6L and KIF4A, both of which are closely related factors in mitosis and are involved in the malignant progression of breast cancer. Conclusions We first demonstrated that ERCC6L deficiency can significantly inhibit the occurrence and development of mammary gland tumors. ERCC6L was found to accelerate the cell cycle by regulating the p53/p21/CDK1/Cyclin B and PLK/CDC25C/CDK1/Cyclin B signalling pathways, thereby promoting the malignant progression of breast cancer cell lines. There was a direct interaction between KIF4A and ERCC6L, and both are closely associated with mitosis and contribute to growth and metastasis of breast tumor. To sum up, our results suggest that ERCC6L may be used as a promising target for the treatment of BC.

Background: Breast cancer (BC) is the leading cause of morbidity and the second leading cause of death among female malignant tumors. Although available drugs have been approved for the corresponding breast cancer subtypes (ER-positive, HER2+) currently, there are still no effective targeted drugs or treatment strategies for metastatic breast cancer or triple-negative breast cancer that lack targets. Therefore, it is urgent to discover new potential targets. ERCC6L is an essential protein involved in chromosome separation during cell mitosis. However, the effect of ERCC6L on the tumorigenesis and progression of breast cancer is unclear. Methods and results: Here, we found that ERCC6L was highly expressed in breast cancer, especially in TNBC, which was closely related to poor outcomes of patients. An ERCC6L conditional knockout mouse model was first established in this study, and the results confirmed that ERCC6L was required for the development of the mammary gland and the tumorigenesis and progression of mammary gland cancers. In in vitro cell culture, ERCC6L acted as a tumor promoter in the malignant progression of breast cancer cells. Overexpression of ERCC6L promoted cell proliferation, migration and invasion, while knockdown of ERCC6L caused the opposite results. Mechanistically, ERCC6L accelerated the cell cycle by regulating the G2/M checkpoint signalling pathway. Additionally, we demonstrated that there is an interaction between ERCC6L and KIF4A, both of which are closely related factors in mitosis and are involved in the malignant progression of breast cancer. Conclusions: We first demonstrated that ERCC6L deficiency can significantly inhibit the occurrence and development of mammary gland tumors. ERCC6L was found to accelerate the cell cycle by regulating the p53/p21/CDK1/Cyclin B and PLK/CDC25C/CDK1/Cyclin B signalling pathways, thereby promoting the malignant progression of breast cancer cell lines. There was a direct interaction between KIF4A and ERCC6L, and both are closely associated with mitosis and contribute to growth and metastasis of breast tumor. To sum up, our results suggest that ERCC6L may be used as a promising target for the treatment of BC. [ABSTRACT FROM AUTHOR]

Abstract The treatment of osteosarcoma (OS) is still mainly surgery combined with systematic chemotherapy, and gene therapy is expected to improve the survival rate of patients. This study aimed to explore the effect of DEP domain 1 protein (DEPDC1) and kinesin super-family protein 4A (KIF4A) in OS and understand its mechanism. Th expression of DEPDC1 and KIF4A in OS cells was detected by RT-PCR and western blot. The viability, proliferation, invasion and migration of OS cells and tube formation of human umbilical vein endothelial cells (HUVECs) after indicated treatment were in turn detected by CCK-8 assay, EdU staining, wound healing assay, transwell assay and tube formation assay. The interaction between DEPDC1 and KIF4A was predicted by STRING and confirmed by co-immunoprecipitation. The expression of epithelial-mesenchymal transition (EMT)-related proteins, tube formation-related proteins and Hippo signaling pathway proteins was detected by western blot. As a result, the expression of DEPDC1 and KIF4A was all increased in U2OS cells. Down-regulation of DEPDC1 suppressed the viability, proliferation, invasion and migration of U2OS cells and tube formation of HUVECs, accompanied by the increased expression of E-cadherin and decreased expression of N-cadherin, Vimentin and VEGF. DEPDC1 was confirmed to be interacted with KIF4A. Upregulation of KIF4A partially reversed the effect of DEPDC1 interference on the above biological behaviors of U2OS cells. Down-regulation of DEPDC1 promoted the expression of p-LATS1 and p-YAP in Hippo signaling pathway, which was reversed by upregulation of KIF4A. In conclusion, down-regulation of DEPDC1 inhibited the malignant biological behavior of OS cells through the activation of Hippo signaling pathway, which could be reversed by upregulation of KIF4A.

Abstract Background Many studies have shown that microRNAs (miRNAs) play an essential role in gene regulation and tumor development. This study aimed to explore the expression of miR‐379‐5p and its mechanisms of affecting proliferation, migration, and invasion in breast cancer (BC). Methods MiRNAs and mRNAs expression data of BC and normal breast tissue samples were downloaded from the TCGA and GEO databases. qRT‐PCR was used to detect the expression of miR‐379‐5p in human normal breast epithelial cell lines and human BC cell lines. The proliferation ability of transfected cells was detected by colony formation and EdU assays. The mobility and invasion ability of transfected cells was measured by wound healing and transwell assays. The relative protein expression of transfected cells was detected by western blot. Dual luciferase reporter assay was performed to identify the targeted binding of miR‐379‐5p and KIF4A. Results MiR‐379‐5p was lowly expressed in BC tissue samples and BC cell lines. The target genes of miR‐379‐5p were involved in many cancer‐related signaling pathways. PPI analysis and the cytoHubba algorithm of Cytoscape identified 10 genes as the hub genes. Survival analysis showed that only KIF4A expression in 10 hub genes was significantly associated with the prognosis of BC patients and was significantly upregulated in BC. Overexpression of miR‐379‐5p inhibited proliferation, migration, and invasion in the BC cell line MDA‐MB‐231, which could be reversed by KIF4A. Conclusions MiR‐379‐5p inhibits proliferation, migration, and invasion of BC by targeting KIF4A.

More and more patients with advanced colorectal cancer (CRC) have benefited from surgical resection or ablation following neoadjuvant chemoradiotherapy (nCRT), but nCRT may be ineffective and have potential risks to some patients. Therefore, it is necessary to discover effective biomarkers for predicting the nCRT efficacy in CRC patients. Chromokinesin Kif4A plays a critical role in mitosis, DNA damage repair and tumorigenesis, but its relationship with nCRT efficacy in advanced CRC remains unclear. Here, we find that Kif4A expression in pretreated tumor tissue is positively correlated with poorer tumor regression after receiving nCRT ( P=0.005). Knockdown of endogenous Kif4A causes an increased sensitivity of CRC cells to chemotherapeutic drugs 5-fluorouracil (5-FU) and Cisplatin (DDP), while overexpression of Kif4A enhances resistance of CRC cells to the chemotherapeutic drugs. Furthermore, depending on its motor domain and tail domain, Kif4A regulates DNA damage response (DDR) induced by 5-FU or DDP treatment in CRC cells. In conclusion, we demonstrate that Kif4A may be a potential independent biomarker for predicting the nCRT efficacy in advanced CRC patients, and Kif4A regulates chemosensitivity of CRC cells through controlling DDR.

Background: Many studies have shown that microRNAs (miRNAs) play an essential role in gene regulation and tumor development. This study aimed to explore the expression of miR‐379‐5p and its mechanisms of affecting proliferation, migration, and invasion in breast cancer (BC). Methods: MiRNAs and mRNAs expression data of BC and normal breast tissue samples were downloaded from the TCGA and GEO databases. qRT‐PCR was used to detect the expression of miR‐379‐5p in human normal breast epithelial cell lines and human BC cell lines. The proliferation ability of transfected cells was detected by colony formation and EdU assays. The mobility and invasion ability of transfected cells was measured by wound healing and transwell assays. The relative protein expression of transfected cells was detected by western blot. Dual luciferase reporter assay was performed to identify the targeted binding of miR‐379‐5p and KIF4A. Results: MiR‐379‐5p was lowly expressed in BC tissue samples and BC cell lines. The target genes of miR‐379‐5p were involved in many cancer‐related signaling pathways. PPI analysis and the cytoHubba algorithm of Cytoscape identified 10 genes as the hub genes. Survival analysis showed that only KIF4A expression in 10 hub genes was significantly associated with the prognosis of BC patients and was significantly upregulated in BC. Overexpression of miR‐379‐5p inhibited proliferation, migration, and invasion in the BC cell line MDA‐MB‐231, which could be reversed by KIF4A. Conclusions: MiR‐379‐5p inhibits proliferation, migration, and invasion of BC by targeting KIF4A. [ABSTRACT FROM AUTHOR]

Abstract Background Karyopherin α-2 (KPNA2) is a member of karyopherin family, which is proved to be responsible for the import or export of cargo proteins. Studies have determined that KPNA2 is associated with the development and prognosis of various cancers, yet the role of KPNA2 in ovarian carcinoma and its potential molecular mechanisms remains unclear. Materials and methods The expression and prognosis of KPNA2 in ovarian cancer was investigated using GEPIA and Oncomine analyses. Mutations of KPNA2 in ovarian cancer were analyzed by cBioPortal database. The prognostic value of KPNA2 expression was evaluated by our own ovarian carcinoma samples using RT-qPCR. Subsequently, the cell growth, migration and invasion of ovarian cancer cells were investigated by CCK-8 and transwell assay, respectively. The protein levels of KPNA2 and KIF4A were determined by western blot. Results We obtained the following important results. (1) KPNA2 and KIF4A wereoverexpressed in ovairan cancer tissues and cells. (2) Among patients with ovarian cancer, overexpressed KPNA2 was associated with lower survival rate. (3) Mutations (R197* and S140F) in KPNA2 will have some influences on protein structure, and then may cause protein function abnormal. (4) KPNA2 konckdown inhibited proliferation, migration, invasion, as well as the expression of KIF4A. Conclusion KPNA2, as a tumorigenic gene in ovarian cancer, accelerated tumor progression by up-regulating KIF4A, suggesting that KPNA2 might be a hopeful indicator of treatment and poor prognosis.

Breast cancer (BC) is the most frequent cancer in women and the main cause of cancer-related deaths in the globe, according to the World Health Organization. The need for biomarkers that can help predict survival or guide treatment decisions in BC patients is critical in order to provide each patient with an individualized treatment plan due to the wide range of prognoses and therapeutic responses. A reliable prognostic model is essential for determining the best course of treatment for patients. Patients' clinical and pathological data, as well as their mRNA expression levels at level 3, were gleaned from the TCGA databases. Differentially expressed genes (DEGs) between BC and non-tumor specimens were identified. Tumor immunity analyses have been utilized in order to decipher molecular pathways and their relationship to the immune system. The expressions of KIF4A in BC cells were determined by RT-PCR. To evaluate the involvement of KIF4A in BC cell proliferation, CCK-8 tests were used. In this study, utilizing FC > 4 and p < 0.05, we identified 140 upregulated genes and 513 down-regulated genes. A five-gene signature comprising SFRP1, SAA1, RBP4, KIF4A and COL11A1 was developed for the prediction of overall survivals of BC. Overall survival was distinctly worse for patients in the high-risk group than those in the low-risk group. Cancerous and aggressiveness-related pathways and decreased B cell, T cell CD4+, T cell CD8+, Neutrophil and Myeloid dendritic cells levels were seen in the high-risk group. In addition, we found that KIF4A was highly expressed in BC and its silence resulted in the suppression of the proliferation of BC cells. Taken together, as a possible prognostic factor for BC, the five-gene profile created and verified in this investigation could guide the immunotherapy selection. [ABSTRACT FROM AUTHOR]

Background In this study, we aimed to explore and clarify the function of KIF4A in esophageal squamous cell carcinoma (ESCC). Methods The microarray data were extracted from the Gene Expression Omnibus (GEO) database. We then used the database for Annotation, Visualization, and Integrated Discovery (DAVID) to perform the gene ontology function (GO) and KEGG Orthology‐Based Annotation System (KOBAS) to perform Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differentially expressed genes (DEGs). The six core candidate genes were identified using protein–protein interaction (PPI) network analysis and Cytoscape software. Among them, the expression of KIF4A were validated by UALCAN database from the Cancer Genome Atlas (TCGA) (P

Abstract Background Increasing evidence suggested that microRNA and kinesin superfamily proteins play an essential role in ovarian cancer. The association between KIF4A and ovarian cancer (OC) was investigated in this study. Methods We performed bioinformatics analysis in the GEO database to screen out the differentially expressed miRNAs (DEmiRNAs) associated with ovarian cancer prognosis. Upstream targeting prediction for KIF4A was acquired by using the mirDIP database. The potential regulatory factor miR-29c-3p for KIF4A was obtained from the intersection of the above all miRNAs. The prognosis of KIF4A and target-miRNA in OC was obtained in the subsequent analysis. qRT-PCR and Western blot detected KIF4A expression level in IOSE80 (human normal ovarian epithelial cell line). In the meantime, the gene expression level was detected in A2780, HO-8910PM, COC1, and SKOV3 cell lines (human ovarian carcinoma cell line). MTT and colony formation assays were used to detect cell proliferation of SKOV3 cell line. The following assays detected cell migration through the use of transwell and wound heal assays. Targeted binding relationship between KIF4A and miRNA was detected by using the dual-luciferase reporter assay. Results Both high expression of KIF4A and lower expression of miR-29c-3p could be used as biomarkers indicating poor prognosis in OC patients. Cellular function tests confirmed that when KIF4A was silenced, it inhibited the proliferation and migration of OC cells. In addition, 3′-UTR of KIF4A had a direct binding site with miR-29c-3p, which indicated that the expression of KIF4A could be regulated by miR-29c-3p. In subsequent assays, the proliferation and migration of OC cells were inhibited by the overexpression of miR-29c-3p. At the same time, rescue experiments also confirmed that the promotion of KIF4A could be reversed by miR-29c-3p. Conclusion In a word, our data revealed a new mechanism for the role of KIF4A in the occurrence and development of OC.

Breast cancer (BC) is the most frequent cancer in women and the main cause of cancer-related deaths in the globe, according to the World Health Organization. The need for biomarkers that can help predict survival or guide treatment decisions in BC patients is critical in order to provide each patient with an individualized treatment plan due to the wide range of prognoses and therapeutic responses. A reliable prognostic model is essential for determining the best course of treatment for patients. Patients’ clinical and pathological data, as well as their mRNA expression levels at level 3, were gleaned from the TCGA databases. Differentially expressed genes (DEGs) between BC and non-tumor specimens were identified. Tumor immunity analyses have been utilized in order to decipher molecular pathways and their relationship to the immune system. The expressions of KIF4A in BC cells were determined by RT-PCR. To evaluate the involvement of KIF4A in BC cell proliferation, CCK-8 tests were used. In this study, utilizing FC > 4 and p < 0.05, we identified 140 upregulated genes and 513 down-regulated genes. A five-gene signature comprising SFRP1, SAA1, RBP4, KIF4A and COL11A1 was developed for the prediction of overall survivals of BC. Overall survival was distinctly worse for patients in the high-risk group than those in the low-risk group. Cancerous and aggressiveness-related pathways and decreased B cell, T cell CD4+, T cell CD8+, Neutrophil and Myeloid dendritic cells levels were seen in the high-risk group. In addition, we found that KIF4A was highly expressed in BC and its silence resulted in the suppression of the proliferation of BC cells. Taken together, as a possible prognostic factor for BC, the five-gene profile created and verified in this investigation could guide the immunotherapy selection.

Background: Osteosarcoma (OS) is a primary malignant tumor of the bone that occurs in adolescents and is characterized by a young age at onset, high malignancy, high rate of metastasis, and poor prognosis. However, the factors influencing disease progression and prognosis remain unclear. Methods: In this study, we aimed to investigate the role of chondrocyte-derived exosomal miR-195 in OS. We used normal human chondrocytes to form miR-195-carrying exosomes to deliver miR-195 into OS cells. Xenograft tumor experiments were performed in mice intratumorally injected with exosomal miR-195. We found that kinesin superfamily protein 4A (KIF4A) promoted OS tumor progression and anti-apoptotic. Resules: We demonstrated that miR-195 inhibited the expression of KIF4A by directly targeting its 3’-untranslated region. Moreover, we observed that exosomal miR-195 successfully inhibited OS cell tumor growth and antiapoptotic in vitro and suppressed tumor growth in vivo. Conclusion: Collectively, these results demonstrate that normal human chondrocyte-derived exosomal miR-195 can be internalized by OS cells and inhibit tumor growth and antiapoptotic by targeting KIF4A, providing a new direction for clarifying the molecular mechanism underlying OS development.

Abstract 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.

Abstract Background Increasing studies has found that circular RNAs (circRNAs) play vital roles in cancer progression. But the expression profile and function of circRNAs in triple-negative breast cancer (TNBC) are unclear. Methods We used a circRNA microarray to explore the circRNA expression profile of TNBC. The expression of the top upregulated circRNA, circKIF4A, was confirmed by qRT-PCR in breast cancer cell lines and tissues. Kaplan-Meier survival analysis was conducted to analyze the clinical impact of circKIF4A on TNBC. A series of experiments was performed to explore the functions of circKIF4A in TNBC progression, such as cell proliferation and migration. We investigated the regulatory effect of circKIF4A on miRNA and its target genes to explore the potential regulatory mechanisms of circKIF4A in TNBC. Results qRT-PCR analyses verified that circKIF4A was significantly upregulated and positively associated with poorer survival of TNBC. The inhibition of circKIF4A suppressed cell proliferation and migration in TNBC. Luciferase reporter assay and RNA immunoprecipitation assay revealed that circKIF4A and KIF4A could bind to miR-375 and that circKIF4A regulated the expression of KIF4A via sponging miR-375. Conclusions The circKIF4A-miR-375-KIF4A axis regulates TNBC progression via the competitive endogenous RNA (ceRNA) mechanism. circKIF4A may therefore serve as a prognostic biomarker and therapeutic target for TNBC.

Background Cancer is a disease of abnormal cell proliferation caused by abnormal expression of cancer-related genes. However, it is still difficult to distinguish benign and malignant lesions in many cases. KIF4A has been reported to be associated with a variety of cancer lesions. We aimed to explore whether KIF4A could be used as a biomarker of pan-cancer diagnostic. Methods We identified twenty-eight cell cycle-related genes that were overexpressed in no less than ten types of cancer. We determined KIF4A mRNA and protein expression in osteosarcoma (OS) cells. Furthermore, to determine the effect of KIF4A in OS, we silenced KIF4A in OS cells and detected cell viability, colony formation, invasion, migration, apoptosis and cell cycle parameters. Results KIF4A exhibited upregulated expression in eleven types of cancer. Cell cycle-related genes are extensively overexpressed in various types of cancers. KIF4A overexpression can serve as a diagnostic and prognostic marker in various cancers. Silencing KIF4A inhibited the viability, colony formation, invasion and migration and induced apoptosis and cell cycle arrest of OS cells. Our findings revealed that high expression of KIF4A could serve as a diagnostic and prognostic marker in OS cancers. Conclusion KIF4A could serve as a pan-cancer diagnostic and prognostic marker. KIF4A could be used as a novel therapeutic target for OS.

Background: Karyopherin α-2 (KPNA2) is a member of karyopherin family, which is proved to be responsible for the import or export of cargo proteins. Studies have determined that KPNA2 is associated with the development and prognosis of various cancers, yet the role of KPNA2 in ovarian carcinoma and its potential molecular mechanisms remains unclear. Materials and methods: The expression and prognosis of KPNA2 in ovarian cancer was investigated using GEPIA and Oncomine analyses. Mutations of KPNA2 in ovarian cancer were analyzed by cBioPortal database. The prognostic value of KPNA2 expression was evaluated by our own ovarian carcinoma samples using RT-qPCR. Subsequently, the cell growth, migration and invasion of ovarian cancer cells were investigated by CCK-8 and transwell assay, respectively. The protein levels of KPNA2 and KIF4A were determined by western blot. Results: We obtained the following important results. (1) KPNA2 and KIF4A wereoverexpressed in ovairan cancer tissues and cells. (2) Among patients with ovarian cancer, overexpressed KPNA2 was associated with lower survival rate. (3) Mutations (R197* and S140F) in KPNA2 will have some influences on protein structure, and then may cause protein function abnormal. (4) KPNA2 konckdown inhibited proliferation, migration, invasion, as well as the expression of KIF4A. Conclusion: KPNA2, as a tumorigenic gene in ovarian cancer, accelerated tumor progression by up-regulating KIF4A, suggesting that KPNA2 might be a hopeful indicator of treatment and poor prognosis. [ABSTRACT FROM AUTHOR]

Protein regulator of cytokinesis 1 (PRC1) is a microtubule bundling protein that is involved in the regulation of the central spindle bundle and spindle orientation during mitosis. However, the functions of PRC1 during meiosis have rarely been studied. In this study, we explored the roles of PRC1 during meiosis using an oocyte model. Our results found that PRC1 was expressed at all stages of mouse oocyte meiosis, and PRC1 accumulated in the midzone/midbody during anaphase/telophase I. Moreover, depleting PRC1 caused defects in polar body extrusion during mouse oocyte maturation. Further analysis found that PRC1 knockdown did not affect meiotic spindle formation or chromosome segregation; however, deleting PRC1 prevented formation of the midzone and midbody at the anaphase/telophase stage of meiosis I, which caused cytokinesis defects and further induced the formation of two spindles in the oocytes. PRC1 knockdown increased the level of tubulin acetylation, indicating that microtubule stability was affected. Furthermore, KIF4A and PRC1 showed similar localization in the midzone/midbody of oocytes at anaphase/telophase I, while the depletion of KIF4A affected the expression and localization of PRC1. The PRC1 mRNA injection rescued the defects caused by PRC1 knockdown in oocytes. In summary, our results suggest that PRC1 is critical for midzone/midbody formation and cytokinesis under regulation of KIF4A in mouse oocytes. [ABSTRACT FROM AUTHOR]

Background: In this study, we aimed to explore and clarify the function of KIF4A in esophageal squamous cell carcinoma (ESCC). Methods: The microarray data were extracted from the Gene Expression Omnibus (GEO) database. We then used the database for Annotation, Visualization, and Integrated Discovery (DAVID) to perform the gene ontology function (GO) and KEGG Orthology‐Based Annotation System (KOBAS) to perform Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differentially expressed genes (DEGs). The six core candidate genes were identified using protein–protein interaction (PPI) network analysis and Cytoscape software. Among them, the expression of KIF4A were validated by UALCAN database from the Cancer Genome Atlas (TCGA) (P < 0.05). Western blotting, qRT‐PCR and IHC were used to detect the expression of KIF4A in tissues. Cell experiments (transwell migration assays, wound healing assay, CCK8 assay, and clone formation experiment) were utilized to verify the roles of KIF4A on the ESCC cells. Western blotting was used to explore the mechanism of KIF4A in ESCC. Results: The expression level of KIF4A was upregulated in ESCC samples compared to those in paracancerous tissues. Transwell migration and wound healing assay showed overexpression of KIF4A significantly promoted the migration of ESCC cells. CCK8 assay and clone formation experiment analysis showed that overexpression of KIF4A promoted proliferation of ESCC cells. Western blot detection found that KIF4A could affect the phosphorylation level of Hippo signaling pathway related proteins. Conclusions: In summary, KIF4A promotes ESCC cell proliferation and migration by regulating the biological function of ESCC cells through the Hippo signaling pathway. Key points: Significant findings of the study: We found that high KIF4A expression was associated with poor overall survival in esophageal squamous cell carcinoma. KIF4A expression also promoted the proliferation and migration of ESCC cells in vitro. What this study adds: Our experimental results explain the role of KIF4A in ESCC, and provide a new biomolecular target for the treatment of ESCC. [ABSTRACT FROM AUTHOR]

The recruitment of substrates by the ser/thr protein phosphatase 2A (PP2A) is poorly understood, limiting our understanding of PP2A-regulated signaling. Recently, the first PP2A:B56 consensus binding motif, LxxIxE, was identified. However, most validated LxxIxE motifs bind PP2A:B56 with micromolar affinities, suggesting that additional motifs exist to enhance PP2A:B56 binding. Here, we report the requirement of a positively charged motif in a subset of PP2A:B56 interactors, including KIF4A, to facilitate B56 binding via dynamic, electrostatic interactions. Using molecular and cellular experiments, we show that a conserved, negatively charged groove on B56 mediates dynamic binding. We also discovered that this positively charged motif, in addition to facilitating KIF4A dephosphorylation, is essential for condensin I binding, a function distinct and exclusive from PP2A-B56 binding. Together, these results reveal how dynamic, charge-charge interactions fine-tune the interactions mediated by specific motifs, providing a new framework for understanding how PP2A regulation drives cellular signaling.

Cell division ends when two daughter cells physically separate via abscission, the cleavage of the intercellular bridge. It is not clear how the anti-parallel microtubule bundles bridging daughter cells are severed. Here, we present a novel abscission mechanism. We identified chromokinesin KIF4A, which is adjacent to the midbody during cytokinesis, as being required for efficient abscission. KIF4A is regulated by post-translational modifications. We evaluated modification of KIF4A by the ubiquitin-like protein SUMO. We mapped lysine 460 in KIF4A as the SUMO acceptor site and employed CRISPR-Cas9-mediated genome editing to block SUMO conjugation of endogenous KIF4A. Failure to SUMOylate this site in KIF4A delayed cytokinesis. SUMOylation of KIF4A enhanced the affinity for the microtubule destabilizer stathmin 1 (STMN1). We here present a new level of abscission regulation through the dynamic interactions between KIF4A and STMN1 as controlled by SUMO modification of KIF4A. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) have been proposed as suppressors or promoters in many tumor processes. LncRNA LINC01123 (LINC01123) was a newly identified lncRNA which was firstly functionally analyzed in lung cancer. However, its expression and function in other tumor types were rarely reported. In this study, we firstly confirmed that LINC01123 was highly expressed in both endometrial cancer (EC) tissues and cell lines using bioinformatics analysis and RT-CPR. Then, we preliminarily analyzed the mechanisms involved in overexpression of LINC01123 in EC, finding that STAT1 could bind directly to the LINC01123 promoter region and activate its transcription. Clinical research with 106 patients indicated that high expression of LINC01123 was associated with advanced clinical progression and poor clinical outcome of EC patients. Functionally, knockdown of LINC01123 suppressed the proliferation, migration and invasion of EC cells, and promoted apoptosis. Mechanistically, we observed that LINC01123 may act as an endogenous sponge by competing for miR-516b, thereby regulating KIF4A. Overall, our study revealed a novel LINC01123/miR-516b/KIF4A pathway regulatory axis in EC pathogenesis. LINC01123 may be a novel prognostic biomarker and therapeutic target in EC.Abbreviations: EC: Endometrial cancer; LncRNA: Long non-coding RNA; EMT: epithelial–mesenchymal transition; miRNA: microRNA; qRT-PCR: Quantitative real-time polymerase chain reaction; SPSS: Statistical Package for Social Sciences; Chip: chromatin-immunoprecipitation, TCGA: The Cancer Genome Atlas; CCK-8: Cell Counting Kit-8; KIF4A: Chromosome-associated kinesin KIF4A. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the expression in human clear cell renal cell carcinoma (ccRCC) tissues and explore the effects of kinesin family member 4A (KIF4A) on ccRCC progression. Methods: GEPIA was used to evaluate the mRNA levels of KIF4A in human ccRCC tissues from TCGA database, and Immunohistochemistry (IHC) assays were performed to assess its expression in human ccRCC tissues collected in our hospital. The clinical-pathological analysis was performed to explore the correlation with KIF4A expression. The effects of KIF4A on ccRCC cell proliferation were detected through colony formation and MTT assays. Finally, the effects of KIF4A on tumor growth were measured using a mice model. Results: Bioinformation results showed the expression of KIF4A mRNA was upregulated in ccRCC tissues and high expression of KIF4A was related with poor prognosis in ccRCC patients. We also found a high expression of KIF4A in human ccRCC tissues collected in our hospital. We also found its expression level was correlated with clinical characteristics, including T stage (P=0.035*) and lymphatic metastasis (P=0.028*). We further confirmed that knockdown of KIF4A suppressed cell proliferation in HTB-47 and CRL-1932 cells. Furthermore, KIF4A contributes to tumor growth of ccRCC cells in mice. Conclusion: We found the abnormal high expression of KIF4A in human ccRCC tissues and demonstrated that KIF4A could serve as a tumor induction gene. [ABSTRACT FROM AUTHOR]

Kif4a, a member of the kinesin superfamily, has been reported to participate in a series of cellular processes such as chromosome condensation and cytokinesis during mitosis. However, the roles of KIF4a in meiosis are still unknown. In present study we found that the Kif4a protein expression decreased in maternal aged mouse oocytes. We then explored the roles of Kif4a in mouse oocyte meiosis by knockdown analysis. Kif4a was enriched at the spindle during mouse oocyte maturation. By specific knock down of the Kif4a using morpholino microinjection, we found that the disruption of Kif4a caused the failure of polar body extrusion. Further analysis indicated that Kif4a might affect the spindle morphology and chromosome alignment in the mouse oocytes, and this might be due to the regulation of tubulin acetylation. Moreover, our results showed that an increased proportion of aneuploidy in the Kif4a knock down oocytes, and this might be due to the loss of kinetochore-microtubule attachment. Taken together, these results suggested that Kif4a possibly regulated mouse oocyte meiosis through its effects on the spindle organization and accurate chromosome segregation, and the loss of Kif4a might be related with aneuploidy of aging oocytes. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the diagnostic and prognostic value of human kinesin family member 4A (KIF4A) as an effective biomarker for breast cancer.Materials and methods: Cancer Genome Atlas data and 12 independent public breast cancer microarray data sets were downloaded and analyzed using individual and pooled approaches.Results: The results of our study revealed a strong and positive correlation between KIF4A expression and malignant features of breast cancer. KIF4A had a strong prognostic value in both ER-positive and ER-negative breast cancers comparable to or even better than tumor size, lymph node invasion, and Elston grade. We also found that KIF4A might be the target gene of microRNA-335, which can suppress KIF4A expression by targeting the 3′-untranslated region of its mRNA.Conclusion: KIF4A might serve as a robust prognostic predictor for breast cancer. Targeting KIF4A activity could be a promising therapeutic option in breast cancer treatment. [ABSTRACT FROM AUTHOR]

The chromokinesin Kif4A controls proper chromosome condensation, congression/alignment, and cytokinesis to ensure faithful genetic inheritance. Here, we report that Cdk phosphorylation of human Kif4A at T1161 licenses Kif4A chromosomal localization, which, in turn, controls Kif4A early mitotic function. Phosphorylated Kif4A (Kif4AWT) or Cdk phospho-mimetic Kif4A mutant (Kif4ATE) associated with chromosomes and condensin I (non-SMC subunit CAP-G and core subunit SMC2) to regulate chromosome condensation, spindle morphology, and chromosome congression/alignment in early mitosis. In contrast, Cdk non-phosphorylatable Kif4A mutant (Kif4ATA) could neither localize on chromosomes nor associate with CAP-G and SMC2. Furthermore, Kif4ATA could not rescue defective chromosome condensation, spindle morphology, or chromosome congression/alignment in cells depleted of endogenous Kif4A, which activated a mitotic checkpoint and delayed early mitotic progression. However, targeting Kif4ATA to chromosomes by fusion of Kif4ATA with Histone H1 resulted in restoration of chromosome and spindle functions of Kif4A, similar to Kif4AWT and Kif4ATE, in cells depleted of endogenous Kif4A. Thus, our results demonstrate that Cdk phosphorylation-licensed chromosomal localization of Kif4A plays a critical role in regulating early mitotic functions of Kif4A that are important for early mitotic progression. [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (AMPK) is an energy sensor that couples the cellular energy state with basic biological processes. AMPK is thought to be linked with cell division although the underlying mechanisms remain largely unknown. Here, we show that AMPK functionally participates throughout cell division and that AMPK catalytic subunits, especially α2, are sequentially associated with separate mitotic apparatus. Using quantitative phosphoproteomics analysis, we found that the strong direct substrate KIF4A is phosphorylated by AMPK at Ser801. Further analysis revealed that AMPK and Aurora B competitively phosphoregulates KIF4A during mitotic phase due to overlapping recognition motifs, resulting in the elaborate phosphoregulation for KIF4A-dependent central spindle length control. Given the intrinsic energy-sensing function of AMPK, our study links the KIF4Adependent control of central spindle length with cellular glucose stress. [ABSTRACT FROM AUTHOR]

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