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Antosik P, Durślewicz J, Smolińska-Świtała M, Podemski J, Podemska E, Neska-Długosz I, Jóźwicki J, Grzanka D. KIF11 and KIF14 Are a Novel Potential Prognostic Biomarker in Patients with Endometrioid Carcinoma. Cancers (Basel) 2025; 17:804. [PMID: 40075652 PMCID: PMC11898751 DOI: 10.3390/cancers17050804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 02/10/2025] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
Background The current study aimed to evaluate the function of KIF11 and KIF14 in endometroid cancer and assess their role as a prognostic biomarker and therapeutic target for treating endometroid cancer. Methods Therefore, we immunohistochemically tested KIF11 and KIF14 proteins in tumoral and non-tumoral tissue sections from n = 92 endometroid cancer patients with respect to major prognostic and predictive characteristics, as well as treatment outcome. Results We found that KIF11 protein levels were higher in tumor tissues as compared to normal tissues, whereas KIF14 protein levels were lower in cancer tissue. High KIF11 protein levels and low KIF14 protein levels were independent prognostic factors for poor OS. Furthermore, the expression profile of KIF11highKIF14low was associated with the worst OS, and it was superior to each single protein alone in predicting patient prognosis. Conclusions In summary, individual and combined expression of KIF11 and KIF14 proteins may serve as potential prognostic biomarkers for endometroid cancer.
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Affiliation(s)
- Paulina Antosik
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland; (J.D.); (M.S.-Ś.); (J.P.); (E.P.); (J.J.); (D.G.)
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Lu X, Luo Y, Huang Y, Zhu Z, Yin H, Xu S. Cellular Senescence in Hepatocellular Carcinoma: Immune Microenvironment Insights via Machine Learning and In Vitro Experiments. Int J Mol Sci 2025; 26:773. [PMID: 39859485 PMCID: PMC11765518 DOI: 10.3390/ijms26020773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 01/14/2025] [Accepted: 01/14/2025] [Indexed: 01/27/2025] Open
Abstract
Hepatocellular carcinoma (HCC), a leading liver tumor globally, is influenced by diverse risk factors. Cellular senescence, marked by permanent cell cycle arrest, plays a crucial role in cancer biology, but its markers and roles in the HCC immune microenvironment remain unclear. Three machine learning methods, namely k nearest neighbor (KNN), support vector machine (SVM), and random forest (RF), are utilized to identify eight key HCC cell senescence markers (HCC-CSMs). Consensus clustering revealed molecular subtypes. The single-cell analysis explored the tumor microenvironment, immune checkpoints, and immunotherapy responses. In vitro, RNA interference mediated BIRC5 knockdown, and co-culture experiments assessed its impact. Cellular senescence-related genes predicted HCC survival information better than differential expression genes (DEGs). Eight key HCC-CSMs were identified, which revealed two distinct clusters with different clinical characteristics and mutation patterns. By single-cell RNA-seq data, we investigated the immunological microenvironment and observed that increasing immune cells allow hepatocytes to regain population dominance. This phenomenon may be associated with the HCC-CSMs identified in our study. By combining bulk RNA sequencing and single-cell RNA sequencing data, we identified the key gene BIRC5 and the natural killer (NK) cells that express BIRC5 at the highest levels. BIRC5 knockdown increased NK cell proliferation but reduced function, potentially aiding tumor survival. These findings provide insights into senescence-driven HCC progression and potential therapeutic targets.
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Affiliation(s)
- Xinhe Lu
- School of Life and Health Sciences, Hainan University, Haikou 570228, China
| | - Yuhang Luo
- School of Life and Health Sciences, Hainan University, Haikou 570228, China
| | - Yun Huang
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zhiqiang Zhu
- School of Environmental Science and Engineering, Hainan University, Haikou 570228, China
| | - Hongyan Yin
- School of Tropical Agriculture and Forestry, Hainan University, Haikou 570228, China
| | - Shunqing Xu
- School of Environmental Science and Engineering, Hainan University, Haikou 570228, China
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Peng P, Zheng J, He K, Wang K, Wang L, Zheng X, Wu H, Yang Z, Zhang S, Zhao L. CENPE is a diagnostic and prognostic biomarker for cervical cancer. Heliyon 2024; 10:e40860. [PMID: 39759304 PMCID: PMC11698922 DOI: 10.1016/j.heliyon.2024.e40860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 11/26/2024] [Accepted: 11/30/2024] [Indexed: 01/07/2025] Open
Abstract
Cervical squamous cell carcinoma (CESC) is a common cancer in women. Despite advancements in early diagnosis through high-risk human papillomavirus (HPV) screening, challenges remain in predicting and treating the disease. Hence, the identification of novel biomarkers for prognosis and therapeutic targets is crucial. CENPE, a microtubule-end directed motor protein that accumulates during the G2 phase, is recognized for its involvement in promoting cancer growth and progression. However, its specific role in CESC remains unclear. This research investigated the expression of CENPE in CESC utilizing data from The Cancer Genome Atlas (TCGA), which was further validated through gene expression profiles, the Human Protein Atlas (HPA), and clinical data. The study utilized Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and immune infiltration analysis to elucidate the role of CENPE in CESC. Additionally, Protein-protein interaction (PPI) networks and competing endogenous RNA (CeRNA) networks involving CENPE and its differentially expressed genes were established. Furthermore, Kaplan-Meier survival analysis was conducted to evaluate the impact of CENPE on patient prognosis. Our study revealed an upregulation of CENPE expression in cervical cancer tissues, which promotes the progression of CESC through IL-6-mediated PI3K-Akt and MAPK signaling pathways. The significant associations with ACNG3, LY6H, and SLC6A7 suggest that CENPE may play a role in tumor growth and metastasis, potentially involving the nervous system. Moreover, the correlations with ARIH1, KDM1A, KDM5B, and NSD3 indicate that CENPE could be a promising target for drug development. Our analysis of the ROC curve demonstrated a high diagnostic accuracy of CENPE in CESC (AUC: 0.997, CI: 0.990-1.000). Subgroup analysis highlighted substantial effects in patients under 50 years old, those with a height under 160 cm, individuals in peri- and post-menopausal stages, and patients in clinical stages 1 and 4. Additionally, COX regression analysis indicated that older age, lower BMI, and higher CENPE expression are associated with decreased 1-year, 3-year, and 5-year survival rates. In conclusion, CENPE emerges as a crucial factor in the initiation and advancement of cervical cancer, showing potential as a novel target for therapeutic interventions.
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Affiliation(s)
- Peiqiang Peng
- Department of Medical Rehabilitation, School of Nursing, Jilin University, 965 Xinjiang Street, Chaoyang District, Changchun, 130021, China
| | - Jingying Zheng
- Department of Gynecology and Obstetrics, The Second Hospital of Jilin University, No.4026, Yatai Street, Changchun City, 130000, Jilin Province, China
| | - Kang He
- Department of Medical Rehabilitation, School of Nursing, Jilin University, 965 Xinjiang Street, Chaoyang District, Changchun, 130021, China
| | - Kai Wang
- Department of Medical Rehabilitation, School of Nursing, Jilin University, 965 Xinjiang Street, Chaoyang District, Changchun, 130021, China
| | - Longyun Wang
- Department of Medical Rehabilitation, School of Nursing, Jilin University, 965 Xinjiang Street, Chaoyang District, Changchun, 130021, China
| | - Xufei Zheng
- Department of Medical Rehabilitation, School of Nursing, Jilin University, 965 Xinjiang Street, Chaoyang District, Changchun, 130021, China
| | - Hao Wu
- Department of Medical Rehabilitation, School of Nursing, Jilin University, 965 Xinjiang Street, Chaoyang District, Changchun, 130021, China
| | - Zhenning Yang
- Department of Medical Rehabilitation, School of Nursing, Jilin University, 965 Xinjiang Street, Chaoyang District, Changchun, 130021, China
| | - Shuang Zhang
- Department of Medical Rehabilitation, School of Nursing, Jilin University, 965 Xinjiang Street, Chaoyang District, Changchun, 130021, China
| | - Lijing Zhao
- Department of Medical Rehabilitation, School of Nursing, Jilin University, 965 Xinjiang Street, Chaoyang District, Changchun, 130021, China
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Jazayeri SM, Aarrouf J, Urban L, Lopez-Lauri F. Comparison of the Effects of UV-C Light in the Form of Flash or Continuous Exposure: A Transcriptomic Analysis on Arabidopsis thaliana L. Int J Mol Sci 2024; 25:13718. [PMID: 39769480 PMCID: PMC11676349 DOI: 10.3390/ijms252413718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 12/17/2024] [Accepted: 12/20/2024] [Indexed: 01/11/2025] Open
Abstract
Ultraviolet C (UV-C) flash treatment represents a promising method for priming plants. This study compared the effects of 1 s (flash) and 60 s (60 s) UV-C exposures on the transcriptome of Arabidopsis thaliana L. plants. A dose of 200 J m-2 delivered in one second was observed to effectively stimulate plant defenses without causing any adverse effects on plant health. A total of 3054 and 1865 differentially expressed genes (DEGs) were identified in the flash and 60 s treatments, respectively, in comparison to the control plants. Of these, 1131 were common to both treatments. The flash treatment affected a greater number of transcription factors (415 genes) than the 60 s treatment (254 genes), indicating more pronounced alterations in gene expression. The flash treatment resulted in a significant overexpression of heat shock proteins (HSPs), heat shock factors (HSFs), and their associated genes, which impacted oxidative stress, proteostasis, genome stability, cell survival, and thermotolerance. The majority of mitochondrial genes were found to be upregulated, while photosynthetic genes exhibited a downregulation. These expression patterns coordinate electron transport and crosstalk between the nucleus, chloroplasts, and mitochondria, eliciting an adaptive protective response to UV-C flash. Additionally, the flash treatment resulted in alterations to several genes involved in cell cycle regulation, division, and DNA replication. These included ATP BMMs, BRCA2 s, IQDs, kinesin complex, MCM complex, CYCs, and CDKs, which ultimately led to cell cycle arrest as a temporary preparation for subsequent conditions. The present study demonstrates that a 1 s exposure to UV-C induces distinctive plant responses through coordinated gene expression. The findings suggest that the flash treatment is an innovative method that triggers a unique cellular response, prioritizing repair mechanisms and potentially enhancing plant immunity, resilience, and priming. It can be used as a plant resistance inducer and stimulator.
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Affiliation(s)
- Seyed Mehdi Jazayeri
- Unité Propre de Recherche Innovante, ERIT Plant Science, Interactions and Innovation, Avignon Université, 301 Rue Baruch de Spinoza, 84140 Avignon, France; (J.A.); (L.U.); (F.L.-L.)
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Li H, Chen J, Liu Z, Pan L, Lan X, Jiang L, Huang F. Construction of a novel copper-induced-cell-death-related gene signature for prognosis in colon cancer, with focus on KIF7. BMC Cancer 2024; 24:1532. [PMID: 39695482 DOI: 10.1186/s12885-024-13315-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 12/09/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Colon cancer (CC) is a leading cause of cancer-related mortality worldwide. Accurate prognostic markers are essential for patient risk stratification and personalized treatment. Copper-induced cell-death-related genes (CRG) have emerged as potential players in cancer prognosis, yet their role in CC remains unclear. METHODS This study aimed to comprehensively evaluate the expression of CRG and their roles in CC using gene expression and clinical data from TCGA and GEO databases. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analyses identified prognostic genes, leading to the construction of a CRG prognostic signature. The signature's predictive accuracy was validated using Kaplan-Meier survival curves, Receiver Operating Characteristic (ROC) curves, and a nomogram model. Additionally, we conducted experiments including immunofluorescence staining and cellular assays to validate the key genes' biological functions. RESULTS A 12-gene CRG signature was significantly associated with overall survival in CC patients. The high-risk group, as classified by median risk score, exhibited significantly shorter survival times compared to the low-risk group. The signature's predictive accuracy was further confirmed with Area Under the Curve (AUC) scores exceeding 0.75 in TCGA and GSE17536 cohorts. Notably, the risk score was significantly correlated with immune checkpoints, chemotherapy sensitivity, and tumor microenvironment. Furthermore, the risk score showed a strong association with immunotherapy response in patients from GSE78220 and GSE39688 cohorts. Bioinformatics analysis of KIF7, a key gene within the signature, revealed its upregulation in CC and significant associations with tumor mutation burden, microsatellite instability, and immune cell infiltration across various cancers. Experiments confirmed that KIF7 was upregulated in CC and its knockdown reduced cell proliferation, migration, and invasion. CONCLUSION The CRG prognostic signature can effectively predict overall survival, immune microenvironment and chemotherapy response in CC. KIF7, as a potential prognostic marker, has significant potential for the prediction and treatment of CC.
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Affiliation(s)
- Hua Li
- Department of General Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, No. 18 Zhongshan 2nd Road, Baise, Guangxi, 533000, China
- Key Laboratory of Tumor Molecular Pathology of Baise, Baise, Guangxi, China
| | - Jingying Chen
- Department of General Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, No. 18 Zhongshan 2nd Road, Baise, Guangxi, 533000, China
- Graduate School, Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Zhengxian Liu
- Department of General Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, No. 18 Zhongshan 2nd Road, Baise, Guangxi, 533000, China
- Graduate School, Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Lujuan Pan
- Department of Gastroenterology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Xiaoling Lan
- Key Laboratory of Tumor Molecular Pathology of Baise, Baise, Guangxi, China
| | - Lihe Jiang
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, No. 98 Chengxiang Road, Baise, Guangxi, 533000, China.
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, Fuzhou, Fujian, China.
| | - Fuda Huang
- Department of General Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, No. 18 Zhongshan 2nd Road, Baise, Guangxi, 533000, China.
- Key Laboratory of Tumor Molecular Pathology of Baise, Baise, Guangxi, China.
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Piredda R, Martínez LGR, Stamatakis K, Martinez-Ortega J, Ferráz AL, Almendral JM, Revilla Y. Assessment of molecular modulation by multifrequency electromagnetic pulses to preferably eradicate tumorigenic cells. Sci Rep 2024; 14:30150. [PMID: 39627265 PMCID: PMC11615363 DOI: 10.1038/s41598-024-81171-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 11/25/2024] [Indexed: 12/06/2024] Open
Abstract
Physics methods of cancer therapy are extensively used in clinical practice, but they are invasive and often confront undesired side effects. A fully new equipment that allows sustained emission of intense and time-controlled non-ionizing multifrequency electromagnetic pulse (MEMP), has been applied to eukaryotic cells in culture. The equipment discriminates the overall electronegative charge of the cell cultures, and its subsequent proportional emission may thereby become higher and lethal to cancer cells of generally high metabolic activity. In contrast, low tumorigenic cells would be much less affected. We tested the specificity and efficacy of the equipment against a collection of (i) highly tumorigenic cells of human (glioblastoma, cervical carcinoma, and skin) and mouse (colon adenocarcinoma) origin; (ii) cell lines of much lower tumorigenicity (non-human primate kidney and mouse fibroblasts), and (iii) primary porcine macrophages lacking tumorigenicity. Time and intensity control of the MEMP allowed progressive decay of viability fairly correlating to cell tumorigenicity, which was provoked by a proportional alteration of the cytoplasmic membrane permeability, cell cycle arrest at G2, and general collapse of the actin cytoskeleton to the perinuclear region. Correspondingly, these effects drastically inhibited the proliferative capacity of the most tumorigenic cells in clonogenic assays. Moreover, MEMP suppressed in a dose-dependent manner the tumorigenicity of retrovirally transduced luciferase expressing colon adenocarcinoma cells in xenografted immune-competent mice, as determined by tumor growth in a bioluminescence imaging system. Our results support MEMP as an anti-cancer non-invasive physical treatment of substantial specificity for tumorigenic cells with promising therapeutic potential in oncology.
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Affiliation(s)
- Roberta Piredda
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Cantoblanco, Madrid, 28049, Spain
| | | | - Konstantinos Stamatakis
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Cantoblanco, Madrid, 28049, Spain
- IRYCIS, Madrid, Spain
| | - Jorge Martinez-Ortega
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Cantoblanco, Madrid, 28049, Spain
| | | | - José M Almendral
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Cantoblanco, Madrid, 28049, Spain.
| | - Yolanda Revilla
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Cantoblanco, Madrid, 28049, Spain.
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Mohd Amin AS, Eastwood S, Pilcher C, Truong JQ, Foitzik R, Boag J, Gorringe KL, Holien JK. KIF18A inhibition: the next big player in the search for cancer therapeutics. Cancer Metastasis Rev 2024; 44:3. [PMID: 39580563 DOI: 10.1007/s10555-024-10225-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 10/17/2024] [Indexed: 11/25/2024]
Abstract
Kinesin-like protein 18A (KIF18A) is a member of the kinesin family of molecular motor proteins, which utilise energy from the hydrolysis of adenosine triphosphate (ATP) to regulate critical cellular processes such as chromosome movement and microtubule dynamics. KIF18A plays a vital role in controlling microtubule length, which is crucial for maintaining proper cell function and division. Notably, increased expression levels of KIF18A have been observed in various types of cancer, indicating its potential involvement in tumour progression. Although preclinical studies have demonstrated that KIF18A is not essential for normal somatic cell division, it appears to be crucial for the survival and division of cancer cells, particularly those exhibiting chromosomal instability. This dependency makes KIF18A a promising target for developing new therapeutic strategies aimed at treating chromosomally unstable cancers. This review delves into the structural and functional aspects of KIF18A, and its role in cancer development, and evaluates current and emerging approaches to targeting KIF18A with innovative cancer treatments.
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Affiliation(s)
| | - Sarah Eastwood
- STEM College, RMIT University, 225-245 Plenty Rd, Bundoora, VIC, 3083, Australia
| | - Courtney Pilcher
- STEM College, RMIT University, 225-245 Plenty Rd, Bundoora, VIC, 3083, Australia
| | - Jia Q Truong
- STEM College, RMIT University, 225-245 Plenty Rd, Bundoora, VIC, 3083, Australia
| | - Richard Foitzik
- Oncology One Pty Ltd, 305 Grattan St, Melbourne, VIC, 3000, Australia
- Inosi Therapeutics Pty Ltd, 655 Elizabeth St, Melbourne, VIC, 3000, Australia
| | - Joanne Boag
- Oncology One Pty Ltd, 305 Grattan St, Melbourne, VIC, 3000, Australia
- The Walter and Eliza Hall Institute of Medical Research, 4 Research Avenue, Bundoora, VIC, 3083, Australia
- Ternarx Pty Ltd, 4 Research Avenue, Bundoora, VIC, 3083, Australia
| | - Kylie L Gorringe
- Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC, 3000, Australia
- Department of Oncology, Sir Peter MacCallum, The University of Melbourne, Grattan St, Parkville, VIC, 3010, Australia
| | - Jessica K Holien
- STEM College, RMIT University, 225-245 Plenty Rd, Bundoora, VIC, 3083, Australia.
- The Faculty of Medicine, Dentistry and Health Science, The University of Melbourne, Grattan St, Parkville, VIC, 3010, Australia.
- St Vincent's Institute of Medical Research, 9 Princes St, Fitzroy, VIC, 3052, Australia.
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Li X, Qian B, Chen X, Shen M, Zhao S, Zhang X, He J. The role of miR-152 in urological tumors: potential biomarkers and therapeutic targets. Front Immunol 2024; 15:1464327. [PMID: 39606232 PMCID: PMC11599204 DOI: 10.3389/fimmu.2024.1464327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 10/28/2024] [Indexed: 11/29/2024] Open
Abstract
Urological malignant tumors pose a significant threat to human health, with a high incidence rate each year. Prostate cancer, bladder cancer, and renal cell carcinoma are among the most prevalent and extensively researched urological malignancies. Despite advancements in research, the prognosis for these tumors remains unfavorable due to late detection, postoperative recurrence, and treatment resistance. A thorough investigation into their pathogenesis is crucial for early diagnosis and treatment. Recent studies have highlighted the close association between microRNAs (miRNAs) and cancer progression. miRNAs are small non-coding RNAs composed of 19-23 nucleotides that regulate gene expression by binding to the 3' untranslated region (3'UTR) of target mRNAs, impacting key cellular processes such as proliferation, differentiation, apoptosis, and migration. Dysregulation of miRNAs can disrupt the expression of oncogenes and tumor suppressor genes, contributing to cancer development. Among the various miRNAs studied, miR-152 has garnered attention for its role in urological malignancies. Several studies have indicated that dysregulation of miR-152 expression is significant in these cancers, warranting a comprehensive review of the evidence. This review focuses on the expression and function of miR-152 in prostate cancer, bladder cancer, and renal cell carcinoma, elucidating its mechanisms in cancer progression and exploring its potential as a therapeutic target and biomarker in urological malignancies.
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Affiliation(s)
- Xin Li
- Department of Urology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Biao Qian
- Department of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xu Chen
- Department of Pathology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Maolei Shen
- Department of Urology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Shankun Zhao
- Department of Urology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Xinsheng Zhang
- Department of Urology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Jian He
- Department of Urology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
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Su Z, Zhong Y, He Y, You L, Xin F, Wang L, Liu Z. Bulk- and single cell-RNA sequencing reveal KIF20A as a key driver of hepatocellular carcinoma progression and immune evasion. Front Immunol 2024; 15:1469827. [PMID: 39555078 PMCID: PMC11563802 DOI: 10.3389/fimmu.2024.1469827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/14/2024] [Indexed: 11/19/2024] Open
Abstract
Introduction Kinesin family member 20A (KIF20A) is essential for cell proliferation and is implicated in promoting tumor progression, but its role in hepatocellular carcinoma (HCC) remains poorly studied. Methods Through the analysis of bulk RNA-sequencing (bulk RNA-seq) and single-cell RNA sequencing (scRNA-seq) data, the expression of KIF20A and its relationship with diagnosis, prognosis, and the immune microenvironment were examined. The association between KIF20A and the malignant progression and metastasis of HCC was confirmed through in vitro and in vivo experiments. Furthermore, patient re-staging was performed using Recursive Partitioning Analysis (RPA) to enhance clinical benefit. Results In this study, we firstly found KIF20A was overexprerssed in HCC both by bulk RNA-seq and scRNA-seq, and then the overexpression of KIF20A significantly promoted the proliferation, invasion, and metastasis in vitro. In vivo, the overexpression of KIF20A promoted the growth and lung metastasis of HCC. Furthermore, gene set variation analysis of bulk RNA-seq and scRNA-seq revealed that KIF20A might be associated with cell cycle related signaling pathways of E2F and G2M, and overexpression of KIF20A inhibited the activity of p21 and bax, as well as shortened G2 phase. Importantly, we found that KIF20A could induce T cell exhaustion via the SPP1-CD44 axe using scRNA-seq. Additionally, KIF20A was also correlated with the expression of immune checkpoint inhibitors (ICIs), and KIF20Ahigh subgroup might be benefited from the ICIs therapy. Conclusion KIF20A emerges as a pivotal driver of HCC progression, intricately regulating cell cycle pathways and modulating immune responses, which position KIF20A as a promising target for HCC management.
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Affiliation(s)
- Zhixiong Su
- Department of Radiation Oncology, Jiangxi Clinical Research Center for Cancer, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China
- Department of Oncology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Yaqi Zhong
- Department of Hepatopancreatobiliary Surgery, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Yufang He
- Department of Oncology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Lijie You
- Department of Oncology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Fuli Xin
- Department of Hepatopancreatobiliary Surgery, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, Fujian, China
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Lei Wang
- Department of Radiation Oncology, Jiangxi Clinical Research Center for Cancer, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China
| | - Zhihua Liu
- Department of Radiation Oncology, Jiangxi Clinical Research Center for Cancer, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China
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Mu Y, Liu H, Luo A, Zhang Q. KIFC3 promotes the progression of non-small cell lung cancer cells through the PI3K/Akt pathway. Thorac Cancer 2024; 15:2356-2364. [PMID: 39390964 PMCID: PMC11586134 DOI: 10.1111/1759-7714.15465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 09/19/2024] [Accepted: 09/24/2024] [Indexed: 10/12/2024] Open
Abstract
BACKGROUND Kinesin family member C3 (KIFC3), as reported, plays important roles in several tumor types. Nevertheless, it is unknown whether KIFC3 has effects on non-small cell lung cancer (NSCLC) development. MATERIALS AND METHODS KIFC3 expression was detected by RT-PCR, and its correlation with prognosis was analyzed by GEPIA website. Small interfering RNA against KIFC3 were adopted for modulating KIFC3 expression in NSCLC cells. KIFC3 effects on NSCLC cell proliferation were determined using the MTT and clone formation assay. Matrigel invasion and wound healing assays were adopted for measuring the invasion and migration capability of NSCLC cells. Western blot was applied for measuring the levels of proteins associated with the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) pathway in NSCLC cells. RESULTS KIFC3 was markedly increased in NSCLC samples and cells. KIFC3 knockdown suppressed the proliferation, invasion, and migration in NSCLC. Mechanically, KIFC3 silencing suppressed NSCLC progression through inhibiting the PI3K/Akt pathway. CONCLUSIONS KIFC3 lack suppressed the proliferation, invasion, and migration which works, at least partially, by the PI3K/Akt pathway. These findings suggest that targeting KIFC3 via the PI3K/Akt pathway may offer a novel therapeutic strategy for NSCLC.
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Affiliation(s)
- Yu Mu
- School of Traditional Chinese MedicineShandong University of Traditional Chinese MedicineJinanChina
| | - Haoxiang Liu
- School of Traditional Chinese MedicineShandong University of Traditional Chinese MedicineJinanChina
| | - Anni Luo
- School of Traditional Chinese MedicineTexas Health and Science UniversityAustinTexasUSA
| | - Qingxiang Zhang
- School of Traditional Chinese MedicineShandong University of Traditional Chinese MedicineJinanChina
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11
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Chen Q, Le X, Li Q, Liu S, Chen Z. Exploration of inhibitors targeting KIF18A with ploidy-specific lethality. Drug Discov Today 2024; 29:104142. [PMID: 39168405 DOI: 10.1016/j.drudis.2024.104142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 08/06/2024] [Accepted: 08/14/2024] [Indexed: 08/23/2024]
Abstract
Currently, various antimitotic inhibitors applied in tumor therapy. However, these inhibitors exhibit targeted toxicity to some extent. As a motor protein, kinesin family member 18A (KIF18A) is crucial to spindle formation and is associated with tumors exhibiting ploidy-specific characteristics such as chromosomal aneuploidy, whole-genome doubling (WGD), and chromosomal instability (CIN). Differing from traditional antimitotic targets, KIF18A exhibits tumor-specific selectivity. The functional loss or attenuation of KIF18A results in vulnerability of tumor cells with ploidy-specific characteristics, with lesser effects on diploid cells. Research on inhibitors targeting KIF18A with ploidy-specific lethality holds significant importance. This review provides a brief overview of the regulatory mechanisms of the ploidy-specific lethality target KIF18A and the research advancements in its inhibitors, aiming to facilitate the development of KIF18A inhibitors.
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Affiliation(s)
- Qingsong Chen
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, China; Hunan Key Laboratory of Small Molecules for Diagnosis and Treatment of Chronic Disease, Changsha 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha 410013, Hunan, China
| | - Xiangyang Le
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, China; Hunan Key Laboratory of Small Molecules for Diagnosis and Treatment of Chronic Disease, Changsha 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha 410013, Hunan, China
| | - Qianbin Li
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, China; Hunan Key Laboratory of Small Molecules for Diagnosis and Treatment of Chronic Disease, Changsha 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha 410013, Hunan, China
| | - Suyou Liu
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, China; Hunan Key Laboratory of Small Molecules for Diagnosis and Treatment of Chronic Disease, Changsha 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha 410013, Hunan, China
| | - Zhuo Chen
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, China; Hunan Key Laboratory of Small Molecules for Diagnosis and Treatment of Chronic Disease, Changsha 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha 410013, Hunan, China.
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12
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Chen S, Yu B, DU GT, Huang TY, Zhang N, Fu N. KIF18B: an important role in signaling pathways and a potential resistant target in tumor development. Discov Oncol 2024; 15:430. [PMID: 39259333 PMCID: PMC11390998 DOI: 10.1007/s12672-024-01330-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 09/09/2024] [Indexed: 09/13/2024] Open
Abstract
KIF18B is a key member of the kinesin-8 family, involved in regulating various physiological processes such as microtubule length, spindle assembly, and chromosome alignment. This article briefly introduces the structure and physiological functions of KIF18B, examines its role in malignant tumors, and the associated carcinogenic signaling pathways such as PI3K/AKT, Wnt/β-catenin, and mTOR pathways. Research indicates that the upregulation of KIF18B enhances tumor malignancy and resistance to radiotherapy and chemotherapy. KIF18B could become a new target for anticancer drugs, offering significant potential for the treatment of malignant tumors and reducing chemotherapy resistance.
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Affiliation(s)
- Shicheng Chen
- Department of Urology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, P. R. China
| | - Bo Yu
- Department of Urology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, P. R. China
| | - Guo Tu DU
- Department of Urology, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, P. R. China
| | - Tian Yu Huang
- Department of Urology, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, P. R. China
| | - Neng Zhang
- Department of Urology, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, P. R. China.
| | - Ni Fu
- Department of Urology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, P. R. China.
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13
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Kreis NN, Moon HH, Wordeman L, Louwen F, Solbach C, Yuan J, Ritter A. KIF2C/MCAK a prognostic biomarker and its oncogenic potential in malignant progression, and prognosis of cancer patients: a systematic review and meta-analysis as biomarker. Crit Rev Clin Lab Sci 2024; 61:404-434. [PMID: 38344808 PMCID: PMC11815995 DOI: 10.1080/10408363.2024.2309933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/05/2023] [Accepted: 01/22/2024] [Indexed: 03/24/2024]
Abstract
KIF2C/MCAK (KIF2C) is the most well-characterized member of the kinesin-13 family, which is critical in the regulation of microtubule (MT) dynamics during mitosis, as well as interphase. This systematic review briefly describes the important structural elements of KIF2C, its regulation by multiple molecular mechanisms, and its broad cellular functions. Furthermore, it systematically summarizes its oncogenic potential in malignant progression and performs a meta-analysis of its prognostic value in cancer patients. KIF2C was shown to be involved in multiple crucial cellular processes including cell migration and invasion, DNA repair, senescence induction and immune modulation, which are all known to be critical during the development of malignant tumors. Indeed, an increasing number of publications indicate that KIF2C is aberrantly expressed in multiple cancer entities. Consequently, we have highlighted its involvement in at least five hallmarks of cancer, namely: genome instability, resisting cell death, activating invasion and metastasis, avoiding immune destruction and cellular senescence. This was followed by a systematic search of KIF2C/MCAK's expression in various malignant tumor entities and its correlation with clinicopathologic features. Available data were pooled into multiple weighted meta-analyses for the correlation between KIF2Chigh protein or gene expression and the overall survival in breast cancer, non-small cell lung cancer and hepatocellular carcinoma patients. Furthermore, high expression of KIF2C was correlated to disease-free survival of hepatocellular carcinoma. All meta-analyses showed poor prognosis for cancer patients with KIF2Chigh expression, associated with a decreased overall survival and reduced disease-free survival, indicating KIF2C's oncogenic potential in malignant progression and as a prognostic marker. This work delineated the promising research perspective of KIF2C with modern in vivo and in vitro technologies to further decipher the function of KIF2C in malignant tumor development and progression. This might help to establish KIF2C as a biomarker for the diagnosis or evaluation of at least three cancer entities.
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Affiliation(s)
- Nina-Naomi Kreis
- Obstetrics and Prenatal Medicine, Gynaecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University, Frankfurt, Germany
| | - Ha Hyung Moon
- Obstetrics and Prenatal Medicine, Gynaecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University, Frankfurt, Germany
| | - Linda Wordeman
- Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA, USA
| | - Frank Louwen
- Obstetrics and Prenatal Medicine, Gynaecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University, Frankfurt, Germany
| | - Christine Solbach
- Obstetrics and Prenatal Medicine, Gynaecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University, Frankfurt, Germany
| | - Juping Yuan
- Obstetrics and Prenatal Medicine, Gynaecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University, Frankfurt, Germany
| | - Andreas Ritter
- Obstetrics and Prenatal Medicine, Gynaecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University, Frankfurt, Germany
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14
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Balasundaram A, Mitra TS, Tayubi IA, Zayed H, Doss GPC. Deciphering the miRNA-mRNA Interaction Landscape between Breast Cancer and Triple-Negative Breast Cancer: An Integrated Bioinformatics Approach. ACS OMEGA 2024; 9:24379-24395. [PMID: 38882157 PMCID: PMC11170726 DOI: 10.1021/acsomega.4c00011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 04/13/2024] [Accepted: 04/19/2024] [Indexed: 06/18/2024]
Abstract
Breast cancer (BC) is globally recognized as the second most prevalent form of cancer. It predominantly affects women and can be categorized into distinct types based on the overexpression of specific cancer receptors.The key receptors implicated in this context are the human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER), and progesterone receptor (PR), alongside a particularly intricate subclass known as triple-negative breast cancer (TNBC). This subclassification is critical for the stratification of breast cancer and informs therapeutic decision-making processes. Due to a lack of therapeutic targets, such as growth factor receptors, TNBC is the most aggressive type. Hence, identifying targetable regulators such as miRNAs could pave the way for potential therapeutic interventions. To identify common differentially expressed mRNAs (DE-mRNAs) in BC, including TNBC, we leveraged two data sets from the GEO collection and The Cancer Genome Atlas (TCGA). Significant DE-mRNAs were identified through PPI, MCODE, CytoNCA, and CytoHubba analyses. Following this, miRNAs were predicted using mirDIP. We utilized GSE42568, GSE185645, and TCGA and identified 159 common DE-mRNAs. Using Cytoscape plug-ins, we identified the 10 most significant DE-mRNAs in BC. Using mirDIP, target miRNAs for 10 DE-mRNAs were identified. We conducted an advanced analysis on the TNBC GEO data set (GSE45498) to corroborate the significance of shared DE-mRNAs and DE-miRNAs in TNBC. We identified four downregulated DE-miRNAs, including hsa-miR-802, hsa-miR-1258, hsa-miR-548a-3p, and hsa-miR-2053, significantly associated with TNBC. Our study revealed significant miRNA-mRNA interactions, specifically hsa-miR-802/MELK, hsa-miR-1258/NCAPG, miR-548a-3p/CCNA2, and hsa-miR-2053/NUSAP1, in both BC and TNBC. The observed downregulation of hsa-miR-548a-3p is associated with diminished survival rates in BC patients, emphasizing their potential utility as prognostic indicators. Furthermore, the differential expression of mRNAs, including CCNB2, UBE2C, MELK, and KIF2C, correlates with reduced survival outcomes, signifying their critical role as potential targets for therapeutic intervention in both BC and TNBC. These findings highlight specific regulatory mechanisms that are potentially crucial for understanding and treating these cancer types.
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Affiliation(s)
- Ambritha Balasundaram
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of BioSciences and Technology, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India
| | - Tanisha Saurav Mitra
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of BioSciences and Technology, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India
| | - Iftikhar Aslam Tayubi
- Department of Computer Science, Faculty of Computing and Information Technology, Rabigh (FCITR), King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Hatem Zayed
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha 2713, Qatar
| | - George Priya C Doss
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of BioSciences and Technology, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India
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15
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Huang LM, Zhang MJ. Kinesin 26B modulates M2 polarization of macrophage by activating cancer-associated fibroblasts to aggravate gastric cancer occurrence and metastasis. World J Gastroenterol 2024; 30:2689-2708. [PMID: 38855156 PMCID: PMC11154681 DOI: 10.3748/wjg.v30.i20.2689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 02/28/2024] [Accepted: 04/19/2024] [Indexed: 05/27/2024] Open
Abstract
BACKGROUND The regulatory effects of KIF26B on gastric cancer (GC) have been confirmed, but the specific mechanism still needs further exploration. Pan-cancer analysis shows that the KIF26B expression is highly related to immune infiltration of cancer-associated fibroblasts (CAFs), and CAFs promote macrophage M2 polarization and affect cancers' progression. AIM To investigate the regulatory functions of KIF26B on immune and metastasis of GC. METHODS We analyzed genes' mRNA levels by quantitative real-time polymerase chain reaction. Expression levels of target proteins were detected by immunohistochemistry, ELISA, and Western blotting. We injected AGS cells into nude mice for the establishment of a xenograft tumor model and observed the occurrence and metastasis of GC. The degree of inflammatory infiltration in pulmonary nodes was observed through hematoxylin-eosin staining. Transwell and wound healing assays were performed for the evaluation of cell invasion and migration ability. Tube formation assay was used for detecting angiogenesis. M2-polarized macrophages were estimated by immunofluorescence and flow cytometry. RESULTS KIF26B was significantly overexpressed in cells and tissues of GC, and the higher expression of KIF26B was related to GC metastasis and prognosis. According to in vivo experiments, KIF26B promoted tumor formation and metastasis of GC. KIF26B expression was positively associated with CAFs' degree of infiltration. Moreover, CAFs could regulate M2-type polarization of macrophages, affecting GC cells' migration, angiogenesis, invasion, and epithelial-mesenchymal transition process. CONCLUSION KIF26B regulated M2 polarization of macrophage through activating CAFs, regulating the occurrence and metastasis of GC.
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Affiliation(s)
- Lian-Meng Huang
- Department of General Surgery, The 901st Hospital of PLA, Hefei 230031, Anhui Province, China
| | - Ming-Jin Zhang
- Department of General Surgery, The 901st Hospital of PLA, Hefei 230031, Anhui Province, China
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16
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Zhai M, Miao J, Zhang R, Liu R, Li F, Shen Y, Wang T, Xu X, Gao G, Hu J, He A, Bai J. KIF22 promotes multiple myeloma progression by regulating the CDC25C/CDK1/cyclinB1 pathway. J Cancer Res Clin Oncol 2024; 150:239. [PMID: 38713252 PMCID: PMC11076398 DOI: 10.1007/s00432-024-05747-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 04/08/2024] [Indexed: 05/08/2024]
Abstract
PURPOSE Multiple myeloma (MM) is an incurable hematological malignancy characterized by clonal proliferation of malignant plasma B cells in bone marrow, and its pathogenesis remains unknown. The aim of this study was to determine the role of kinesin family member 22 (KIF22) in MM and elucidate its molecular mechanism. METHODS The expression of KIF22 was detected in MM patients based upon the public datasets and clinical samples. Then, in vitro assays were performed to investigate the biological function of KIF22 in MM cell lines, and subcutaneous xenograft models in nude mice were conducted in vivo. Chromatin immunoprecipitation (ChIP) and luciferase reporter assay were used to determine the mechanism of KIF22-mediated regulation. RESULTS The results demonstrated that the expression of KIF22 in MM patients was associated with several clinical features, including gender (P = 0.016), LDH (P < 0.001), β2-MG (P = 0.003), percentage of tumor cells (BM) (P = 0.002) and poor prognosis (P < 0.0001). Furthermore, changing the expression of KIF22 mainly influenced the cell proliferation in vitro and tumor growth in vivo, and caused G2/M phase cell cycle dysfunction. Mechanically, KIF22 directly transcriptionally regulated cell division cycle 25C (CDC25C) by binding its promoter and indirectly influenced CDC25C expression by regulating the ERK pathway. KIF22 also regulated CDC25C/CDK1/cyclinB1 pathway. CONCLUSION KIF22 could promote cell proliferation and cell cycle progression by transcriptionally regulating CDC25C and its downstream CDC25C/CDK1/cyclinB1 pathway to facilitate MM progression, which might be a potential therapeutic target in MM.
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Affiliation(s)
- Meng Zhai
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Xi'an Key Laboratory of Hematological Diseases, Xi'an, China
| | - Jiyu Miao
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Xi'an Key Laboratory of Hematological Diseases, Xi'an, China
| | - Ru Zhang
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Xi'an Key Laboratory of Hematological Diseases, Xi'an, China
| | - Rui Liu
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Xi'an Key Laboratory of Hematological Diseases, Xi'an, China
| | - Fangmei Li
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Xi'an Key Laboratory of Hematological Diseases, Xi'an, China
| | - Ying Shen
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Xi'an Key Laboratory of Hematological Diseases, Xi'an, China
- National Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ting Wang
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Xi'an Key Laboratory of Hematological Diseases, Xi'an, China
| | - Xuezhu Xu
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Xi'an Key Laboratory of Hematological Diseases, Xi'an, China
| | - Gongzhizi Gao
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Xi'an Key Laboratory of Hematological Diseases, Xi'an, China
| | - Jinsong Hu
- Department of Cell Biology and Genetics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'anShaanxi, 710061, China
| | - Aili He
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Xi'an Key Laboratory of Hematological Diseases, Xi'an, China.
- National Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Department of Tumor and Immunology in Precision Medical Institute, Xi'an Jiaotong University, Xi'an, China.
| | - Ju Bai
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Xi'an Key Laboratory of Hematological Diseases, Xi'an, China.
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Huang L, Zhang J, Songyang Z, Xiong Y. Identification and Validation of eRNA as a Prognostic Indicator for Cervical Cancer. BIOLOGY 2024; 13:227. [PMID: 38666838 PMCID: PMC11048606 DOI: 10.3390/biology13040227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 04/28/2024]
Abstract
The survival of CESC patients is closely related to the expression of enhancer RNA (eRNA). In this work, we downloaded eRNA expression, clinical, and gene expression data from the TCeA and TCGA portals. A total of 7936 differentially expressed eRNAs were discovered by limma analysis, and the relationship between these eRNAs and survival was analyzed by univariate Cox hazard analysis, LASSO regression, and multivariate Cox hazard analysis to obtain an 8-eRNA model. Risk score heat maps, KM curves, ROC analysis, robustness analysis, and nomograms further indicate that this 8-eRNA model is a novel indicator with high prognostic performance independent of clinicopathological classification. The model divided patients into high-risk and low-risk groups, compared pathway diversity between the two groups through GSEA analysis, and provided potential therapeutic agents for high-risk patients.
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Affiliation(s)
- Lijing Huang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China; (L.H.); (J.Z.)
| | - Jingkai Zhang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China; (L.H.); (J.Z.)
| | - Zhou Songyang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China; (L.H.); (J.Z.)
- Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Yuanyan Xiong
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China; (L.H.); (J.Z.)
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Di Palma S, Koliou P, Simonovic A, Costa D, Faulkes C, Kobutungi B, Paterson F, Horsnell JD, Pakzad F, Irvine T, Partlett P, Clayton E, Collins N. Breast Cancer Molecular Subtyping in Practice: A Real-World Study of the APIS Breast Cancer Subtyping Assay in a Consecutive Series of Breast Core Biopsies. Int J Mol Sci 2024; 25:2616. [PMID: 38473863 DOI: 10.3390/ijms25052616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 01/25/2024] [Accepted: 01/26/2024] [Indexed: 03/14/2024] Open
Abstract
The APIS Breast Cancer Subtyping Kit is an mRNA-based assessment of the seven parameters including three biomarkers routinely assessed in all the newly diagnosed breast cancers (BC), oestrogen receptor (ER), progesterone receptor (PR) and HER-2 and an additional four genes that create a novel proliferation signature, MKI67, PCNA, CCNA2 and KIF23. Taken together, the data are used to produce a molecular subtype for every sample. The kit was evaluated against the current standard protocol of immunohistochemistry (IHC) and/or in situ hybridisation (ISH) in breast cancer patients. The data were presented at the weekly breast multidisciplinary team (MDT) meeting. A total of 98 consecutive cases of pre-operative breast cancer core biopsies and two core biopsies of nodal metastases yielding 100 cases were assessed. IHC and APIS results were available for 100 and 99 cases. ER was concordant in 97% cases, PR was concordant in 89% and HER-2 results were concordant with IHC/ISH in 100% of the cases. Ki-67 IHC was discordant in 3% of cases when compared with MK167 alone but discordant in 24% when compared with the four-gene proliferation signature. In conclusion, our study indicates that the APIS Breast Cancer Subtyping Kit is highly concordant when compared to the results produced for ER/PR/HER-2 by IHC and/or ISH. The assay could play a role in the routine assessment of newly diagnosed breast cancer (BC) specimens.
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Affiliation(s)
- Silvana Di Palma
- Department of Cellular Pathology, Berkshire & Surrey Pathology Services, The Royal Surrey Hospital NHS Foundation Trust, University of Surrey, Egerton Road, Guildford GU2 7XX, UK
| | - Panagiotis Koliou
- Department of Oncology, The Royal Surrey Hospital NHS Foundation Trust, Egerton Road, Guildford GU2 7XX, UK
| | - Alex Simonovic
- Department of Cellular Pathology, Berkshire & Surrey Pathology Services, The Royal Surrey Hospital NHS Foundation Trust, University of Surrey, Egerton Road, Guildford GU2 7XX, UK
| | - Daniela Costa
- Molecular Diagnostics, Berkshire & Surrey Pathology Services, The Royal Surrey Hospital NHS Foundation Trust, Egerton Road, Guildford GU2 7XX, UK
| | - Catherine Faulkes
- Molecular Diagnostics, Berkshire & Surrey Pathology Services, The Royal Surrey Hospital NHS Foundation Trust, Egerton Road, Guildford GU2 7XX, UK
| | - Brenda Kobutungi
- Molecular Diagnostics, Berkshire & Surrey Pathology Services, The Royal Surrey Hospital NHS Foundation Trust, Egerton Road, Guildford GU2 7XX, UK
| | - Felicity Paterson
- Department of Oncology, The Royal Surrey Hospital NHS Foundation Trust, Egerton Road, Guildford GU2 7XX, UK
| | - Jonathan David Horsnell
- Breast Unit, The Royal Surrey Hospital NHS Foundation Trust, Egerton Road, Guildford GU2 7XX, UK
| | - Farrokh Pakzad
- Breast Unit, The Royal Surrey Hospital NHS Foundation Trust, Egerton Road, Guildford GU2 7XX, UK
| | - Tracey Irvine
- Breast Unit, The Royal Surrey Hospital NHS Foundation Trust, Egerton Road, Guildford GU2 7XX, UK
| | - Polly Partlett
- Breast Unit, The Royal Surrey Hospital NHS Foundation Trust, Egerton Road, Guildford GU2 7XX, UK
| | - Elizabeth Clayton
- Breast Unit, The Royal Surrey Hospital NHS Foundation Trust, Egerton Road, Guildford GU2 7XX, UK
| | - Nadine Collins
- Molecular Diagnostics, Berkshire & Surrey Pathology Services, The Royal Surrey Hospital NHS Foundation Trust, Egerton Road, Guildford GU2 7XX, UK
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19
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Wegscheider AS, Gorniak J, Rollinson S, Gough L, Dhaliwal N, Guardiola A, Gasior A, Helmer D, Pounce Z, Niendorf A. Comprehensive and Accurate Molecular Profiling of Breast Cancer through mRNA Expression of ESR1, PGR, ERBB2, MKI67, and a Novel Proliferation Signature. Diagnostics (Basel) 2024; 14:241. [PMID: 38337757 PMCID: PMC10855423 DOI: 10.3390/diagnostics14030241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 01/13/2024] [Accepted: 01/19/2024] [Indexed: 02/12/2024] Open
Abstract
BACKGROUND An accurate status determination of breast cancer biomarkers (ER, PR, HER2, Ki67) is crucial for guiding patient management. The "gold standard" for assessing these biomarkers in FFPE tissue is IHC, which faces challenges in standardization and exhibits substantial variability. In this study, we compare the concordance of a new commercial RT-qPCR kit with IHC in determining BC biomarker status. METHODS The performance was evaluated using 634 FFPE specimens, which underwent histological analysis in accordance with standard of care methods. HER2 2+ tumors were referred to ISH testing. An immunoreactive score of ≥2/12 was considered positive for ER/PR and 20% staining was used as a cut-off for Ki67 high/low score. RT-qPCR and results calling were performed according to the manufacturer's instructions. RESULTS High concordance with IHC was seen for all markers (93.2% for ER, 87.1% for PR, 93.9% for HER2, 77.9% for Ki67 and 80.1% for proliferative signature (assessed against Ki67 IHC)). CONCLUSIONS By assessing the concordance with the results obtained through IHC, we sought to demonstrate the reliability and utility of the kit for precise BC subtyping. Our findings suggest that the kit provides a highly precise and accurate quantitative assessment of BC biomarkers.
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Affiliation(s)
- Anne-Sophie Wegscheider
- MVZ Prof. Dr. Med. A. Niendorf Pathologie Hamburg-West GmbH, Institute for Histology, Cytology and Molecular Diagnostics, Lornsenstr. 4, 22767 Hamburg, Germany (D.H.)
| | - Joanna Gorniak
- APIS Assay Technologies Ltd., Second Floor, Citylabs 1.0, Nelson Street, Manchester M13 9NQ, UK
| | - Sara Rollinson
- APIS Assay Technologies Ltd., Second Floor, Citylabs 1.0, Nelson Street, Manchester M13 9NQ, UK
| | - Leanne Gough
- APIS Assay Technologies Ltd., Second Floor, Citylabs 1.0, Nelson Street, Manchester M13 9NQ, UK
| | - Navdeep Dhaliwal
- APIS Assay Technologies Ltd., Second Floor, Citylabs 1.0, Nelson Street, Manchester M13 9NQ, UK
| | - Agustin Guardiola
- APIS Assay Technologies Ltd., Second Floor, Citylabs 1.0, Nelson Street, Manchester M13 9NQ, UK
| | - Anna Gasior
- APIS Assay Technologies Ltd., Second Floor, Citylabs 1.0, Nelson Street, Manchester M13 9NQ, UK
| | - Denise Helmer
- MVZ Prof. Dr. Med. A. Niendorf Pathologie Hamburg-West GmbH, Institute for Histology, Cytology and Molecular Diagnostics, Lornsenstr. 4, 22767 Hamburg, Germany (D.H.)
| | - Zoe Pounce
- APIS Assay Technologies Ltd., Second Floor, Citylabs 1.0, Nelson Street, Manchester M13 9NQ, UK
| | - Axel Niendorf
- MVZ Prof. Dr. Med. A. Niendorf Pathologie Hamburg-West GmbH, Institute for Histology, Cytology and Molecular Diagnostics, Lornsenstr. 4, 22767 Hamburg, Germany (D.H.)
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20
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Meng F, Zhang Z. MicroRNA-152 specifically targets kinesin family member 14 to suppress the advancement of bladder cancer cells via PI3K/AKT pathway. Biochem Biophys Res Commun 2024; 692:149337. [PMID: 38070277 DOI: 10.1016/j.bbrc.2023.149337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 11/16/2023] [Accepted: 11/23/2023] [Indexed: 01/06/2024]
Abstract
BACKGROUND Kinesin family member 14 (KIF14) overexpression has been linked to tumor progression and metastasis in different malignancies, but its precise molecular mechanism in bladder cancer (BLCA) remains unclear. METHODS The expression of KIF14 in BLCA and its relationship with clinical outcomes were assessed. Functional investigations on KIF14 were conducted using CCK-8, Transwell experiment, colony formation, scratch motility assays, and flow cytometry. We examined the downstream route of KIF14 and identified its upstream regulatory factor through luciferase reporter experiments and bioinformatics tools. RESULTS Our findings demonstrated that increased KIF14 expression was associated with poor survival prognosis in BLCA patients. Deletion of KIF14 affected cell cycle progression, induced apoptosis, and inhibited cell growth, migration, and invasion. GSEA analysis revealed a strong association between KIF14 expression and the PI3K/AKT signaling pathway. Further research showed that KIF14 deletion decreased the levels of p-PI3K, p-AKT, FOXM1, and CCNB1. We also found that has-miR-152-3p (miR-152) suppressed BLCA cell growth by post-transcriptionally regulating KIF14 expression. CONCLUSIONS Our findings suggest that targeting KIF14 could alter the PI3K/AKT and FOXM1-CCNB1 axis, leading to growth inhibition, cell cycle arrest, and induction of apoptosis in BLCA cells. Additionally, miR-152 directly regulates KIF14 expression at the post-transcriptional level. Overall, KIF14 represents a promising therapeutic target for BLCA clinical therapy.
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Affiliation(s)
- Fang Meng
- Department of Urology, Changhai Hospital, Naval Military Medical University, Shanghai, China.
| | - Zhensheng Zhang
- Department of Urology, Changhai Hospital, Naval Military Medical University, Shanghai, China.
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21
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Wu M, Wu X, Han J. KIF20A Promotes CRC Progression and the Warburg Effect through the C-Myc/HIF-1α Axis. Protein Pept Lett 2024; 31:107-115. [PMID: 38037834 DOI: 10.2174/0109298665256238231120093150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 09/01/2023] [Accepted: 10/24/2023] [Indexed: 12/02/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is a prevalent form of cancer globally, characterized by a high mortality rate. Therefore, discovering effective therapeutic approaches for CRC treatment is critical. METHODS The levels of KIF20A in CRC clinical samples were determined using Western Blot and immunofluorescence assay. SW480 cells were transfected with siRNA targeting KIF20A, while HT-29 cells were transfected with a KIF20A overexpression vector. Cell viability and apoptosis of CRC cells were assessed using CCK-8 and TUNEL analysis. Migration ability was investigated using Transwell. The levels of pyruvate, lactate and ATP were determined through corresponding assay kits. Western Blot was applied to confirm the level of proteins associated with glycolysis, c- Myc, HIF-1α, PKM2 and LDHA. Subsequently, functional rescue experiments were conducted to investigate further the regulatory relationship between KIF20A, c-Myc, and HIF-1α in colorectal cancer (CRC), employing the c-Myc inhibitor 10058-F4 and c-Myc overexpression plasmids. RESULTS KIF20A was up-regulated in vivo and in vitro in CRC. KIF20A knockdown inhibited cell viability and migration while promoting cell apoptosis in SW480 cells. Conversely, overexpression of KIF20A yielded contrasting effects in HT-29 cells. Moreover, inhibition of KIF20A restrained the pyruvate, lactate production and ATP level, whereas overexpression of KIF20A enhanced the Warburg effect. Western Blot indicated that knockdown KIF20A attenuated the levels of c-Myc, HIF-1α, PKM2 and LDHA. In addition, rescue experiments further verified that KIF20A enhanced the Warburg effect by the KIF20A/c-Myc/HIF-1α axis in CRC. CONCLUSION KIF20A, being a crucial regulator in the progression of CRC, has the potential to be a promising therapeutic target for the treatment of CRC.
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Affiliation(s)
- Min Wu
- Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Gaotanyan Zhengjie No. 30, Shapingba District, ChongQing, 400038, China
| | - Xianqiang Wu
- Haisco Pharmaceutical Group Company Ltd., 136 Baili Road, Wenjiang District, Chengdu, 611130, China
| | - Jie Han
- Department of General Surgery, The Third Affiliated Hospital of Chongqing Medical University, Shuanghu Branch Road No. 1, Yubei District, Chongqing, 401120, China
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22
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Zheng C, Li Z, Zhao C, Yin X, Feng L, Wang Z, Liu C, Li B. YY1 modulates the radiosensitivity of esophageal squamous cell carcinoma through KIF3B-mediated Hippo signaling pathway. Cell Death Dis 2023; 14:806. [PMID: 38065955 PMCID: PMC10709558 DOI: 10.1038/s41419-023-06321-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 11/16/2023] [Accepted: 11/21/2023] [Indexed: 12/18/2023]
Abstract
Radiotherapy is an important strategy in the comprehensive treatment of esophageal squamous cell carcinoma (ESCC). However, effectiveness of radiotherapy is still restricted by radioresistance. Herein, we aimed to understand the mechanisms underlying ESCC radioresistance, for which we looked into the potential role of YY1. YY1 was upregulated in radioresistant tissues and correlated with poor prognosis of patients with ESCC. YY1 depletion enhanced the radiosensitivity of ESCC in vitro and in vivo. Multi-group sequencing showed that downregulation of YY1 inhibited the transcriptional activity of Kinesin Family Member 3B (KIF3B), which further activated the Hippo signaling pathway by interacting with Integrin-beta1 (ITGB1). Once the Hippo pathway was activated, its main effector, Yes-associated protein 1 (YAP1), was phosphorylated in the cytoplasm and its expression reduced in the nucleus, thus enhancing the radiosensitivity by regulating its targeted genes. Our study provides new insights into the mechanisms underlying ESCC radioresistance and highlights the potential role of YY1 as a therapeutic target for ESCC.
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Affiliation(s)
- Chunyan Zheng
- Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- National Key Laboratory of Advanced Drug Delivery and Release Systems, Jinan, China
| | - Zhe Li
- Department of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chuanxi Zhao
- Department of Clinical Laboratory, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Xiaoyang Yin
- Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lei Feng
- Department of Radiation Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zhongtang Wang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Chengxin Liu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Baosheng Li
- Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
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23
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Dou R, Kang S, Yang H, Zhang W, Zhang Y, Liu Y, Ping Y, Pang B. Identifying the driver miRNAs with somatic copy number alterations driving dysregulated ceRNA networks in cancers. Biol Direct 2023; 18:79. [PMID: 37993951 PMCID: PMC10666415 DOI: 10.1186/s13062-023-00438-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 11/15/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) play critical roles in cancer initiation and progression, which were critical components to maintain the dynamic balance of competing endogenous RNA (ceRNA) networks. Somatic copy number alterations (SCNAs) in the cancer genome could disturb the transcriptome level of miRNA to deregulate this balance. However, the driving effects of SCNAs of miRNAs were insufficiently understood. METHODS In this study, we proposed a method to dissect the functional roles of miRNAs under different copy number states and identify driver miRNAs by integrating miRNA SCNAs profile, miRNA-target relationships and expression profiles of miRNA, mRNA and lncRNA. RESULTS Applying our method to 813 TCGA breast cancer (BRCA) samples, we identified 29 driver miRNAs whose SCNAs significantly and concordantly regulated their own expression levels and further inversely dysregulated expression levels of their targets or disturbed the miRNA-target networks they directly involved. Based on miRNA-target networks, we further constructed dynamic ceRNA networks driven by driver SCNAs of miRNAs and identified three different patterns of SCNA interference in the miRNA-mediated dynamic ceRNA networks. Survival analysis of driver miRNAs showed that high-level amplifications of four driver miRNAs (including has-miR-30d-3p, has-mir-30b-5p, has-miR-30d-5p and has-miR-151a-3p) in 8q24 characterized a new BRCA subtype with poor prognosis and contributed to the dysfunction of cancer-associated hallmarks in a complementary way. The SCNAs of driver miRNAs across different cancer types contributed to the cancer development by dysregulating different components of the same cancer hallmarks, suggesting the cancer specificity of driver miRNA. CONCLUSIONS These results demonstrate the efficacy of our method in identifying driver miRNAs and elucidating their functional roles driven by endogenous SCNAs, which is useful for interpreting cancer genomes and pathogenic mechanisms.
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Affiliation(s)
- Renjie Dou
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Shaobo Kang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Huan Yang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Wanmei Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Yijing Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Yuanyuan Liu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Yanyan Ping
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, Heilongjiang, China.
| | - Bo Pang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, Heilongjiang, China.
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24
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Jinna N, Yuan YC, Rida P. Kinesin Family Member C1 (KIFC1/HSET) Underlies Aggressive Disease in Androgen Receptor-Low and Basal-Like Triple-Negative Breast Cancers. Int J Mol Sci 2023; 24:16072. [PMID: 38003261 PMCID: PMC10671256 DOI: 10.3390/ijms242216072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/30/2023] [Accepted: 10/31/2023] [Indexed: 11/26/2023] Open
Abstract
Quadruple-negative breast cancer (QNBC) lacks traditional actionable targets, including androgen receptor (AR). QNBC disproportionately afflicts and impacts patients of African genetic ancestry. Kinesin family member C1 (KIFC1/HSET), a centrosome clustering protein that prevents cancer cells from undergoing centrosome-amplification-induced apoptosis, has been reported to be upregulated in TNBCs and African-American (AA) TNBCs. Herein, we analyzed KIFC1 RNA levels and their associations with clinical features and outcomes among AR-low and AR-high TNBC tumors in three distinct publicly available gene expression datasets and in the breast cancer gene expression database (bc-GenExMiner). KIFC1 levels were significantly higher in AR-low and basal-like TNBCs than in AR-high and non-basal-like TNBCs, irrespective of the stage, grade, tumor size, and lymph node status. KIFC1 levels were also upregulated in AR-low tumors relative to AR-high tumors among Black and premenopausal women with TNBC. High KIFC1 levels conferred significantly shorter overall survival, disease-free survival, and distant metastasis-free survival among AR-low and basal-like TNBC patients in Kaplan-Meier analyses. In conclusion, KIFC1 levels may be upregulated in AR-low tumors and, specifically, in those of African descent, wherein it may promote poor outcomes. KIFC1 may be an actionable cancer-cell-specific target for the AR-low TNBC subpopulation and could aid in alleviating racial disparities in TNBC outcomes.
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Affiliation(s)
- Nikita Jinna
- Department of Population Science, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Yate-Ching Yuan
- Department of Integrative Genomics and Bioinformatics, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
| | - Padmashree Rida
- Department of Science, Rowland Hall, Salt Lake City, UT 84102, USA;
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25
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Wu HF, Liu H, Zhang ZW, Chen JM. CENPE and LDHA were potential prognostic biomarkers of chromophobe renal cell carcinoma. Eur J Med Res 2023; 28:481. [PMID: 37925501 PMCID: PMC10625266 DOI: 10.1186/s40001-023-01449-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 10/15/2023] [Indexed: 11/06/2023] Open
Abstract
BACKGROUND Most sarcomatoid differentiated renal cell carcinoma was differentiated from Chromophobe renal cell carcinoma (KICH) and related to a bad prognosis. Thus, finding biomarkers is important for the therapy of KICH. METHODS The UCSC was used for determining the expression of mRNA and miRNA and clinical data in KICH and normal samples. KEGG and GO were used for predicting potential function of differently expressed genes (DEGs). Optimal prognostic markers were determined by Lasso regression. Kaplan-Meier survival, ROC, and cox regression were used for assessing prognosis value. GSEA was used for predicting potential function of markers. The relations between markers and immune cell infiltration were determined by Pearson method. The upstream miRNA of markers was predicted in TargetScan and DIANA. RESULTS The 6162 upregulated and 13,903 downregulated DEGs were identified in KICH. Further CENPE and LDHA were screened out as optimal prognostic risk signatures. CENPE was highly expressed while LDHA was lowly expressed in KICH samples, and the high expressions of 2 genes contributed to bad prognosis. The functions of CENPE and LDHA were mainly enriched in proliferation related pathways such as cell cycle and DNA replication. In addition, the correlation of 2 genes with immune infiltrates in KICH was also observed. Finally, we found that has-miR-577 was the common upstream of 2 genes and the binding sites can be predicted. CONCLUSION CENPE and LDHA were identified as the important prognostic biomarkers in KICH, and they might be involved in the proliferation of cancer cell.
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Affiliation(s)
- Hui-Feng Wu
- Department of Urology, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, Zhejiang, China
| | - Hao Liu
- Department of Urology, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, Zhejiang, China.
| | - Zhe-Wei Zhang
- Department of Urology, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, Zhejiang, China
| | - Ji-Min Chen
- Department of Urology, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, Zhejiang, China
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26
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Rodrigues-Ferreira S, Morin M, Guichaoua G, Moindjie H, Haykal MM, Collier O, Stoven V, Nahmias C. A Network of 17 Microtubule-Related Genes Highlights Functional Deregulations in Breast Cancer. Cancers (Basel) 2023; 15:4870. [PMID: 37835564 PMCID: PMC10571893 DOI: 10.3390/cancers15194870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/29/2023] [Accepted: 10/04/2023] [Indexed: 10/15/2023] Open
Abstract
A wide panel of microtubule-associated proteins and kinases is involved in coordinated regulation of the microtubule cytoskeleton and may thus represent valuable molecular markers contributing to major cellular pathways deregulated in cancer. We previously identified a panel of 17 microtubule-related (MT-Rel) genes that are differentially expressed in breast tumors showing resistance to taxane-based chemotherapy. In the present study, we evaluated the expression, prognostic value and functional impact of these genes in breast cancer. We show that 14 MT-Rel genes (KIF4A, ASPM, KIF20A, KIF14, TPX2, KIF18B, KIFC1, AURKB, KIF2C, GTSE1, KIF15, KIF11, RACGAP1, STMN1) are up-regulated in breast tumors compared with adjacent normal tissue. Six of them (KIF4A, ASPM, KIF20A, KIF14, TPX2, KIF18B) are overexpressed by more than 10-fold in tumor samples and four of them (KIF11, AURKB, TPX2 and KIFC1) are essential for cell survival. Overexpression of all 14 genes, and underexpression of 3 other MT-Rel genes (MAST4, MAPT and MTUS1) are associated with poor breast cancer patient survival. A Systems Biology approach highlighted three major functional networks connecting the 17 MT-Rel genes and their partners, which are centered on spindle assembly, chromosome segregation and cytokinesis. Our studies identified mitotic Aurora kinases and their substrates as major targets for therapeutic approaches against breast cancer.
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Affiliation(s)
- Sylvie Rodrigues-Ferreira
- Gustave Roussy Cancer Center, F-94800 Villejuif, France; (S.R.-F.); (M.M.); (H.M.); (M.M.H.)
- INSERM U981, Université Paris-Saclay, F-94800 Villejuif, France
- Inovarion, F-75005 Paris, France
| | - Morgane Morin
- Gustave Roussy Cancer Center, F-94800 Villejuif, France; (S.R.-F.); (M.M.); (H.M.); (M.M.H.)
- INSERM U981, Université Paris-Saclay, F-94800 Villejuif, France
| | - Gwenn Guichaoua
- CBIO (Centre de Bioinformatique), Mines Paris-PSL, PSL Research University, F-75005 Paris, France;
- INSERM U900, Institut Curie, F-75005 Paris, France
| | - Hadia Moindjie
- Gustave Roussy Cancer Center, F-94800 Villejuif, France; (S.R.-F.); (M.M.); (H.M.); (M.M.H.)
- INSERM U981, Université Paris-Saclay, F-94800 Villejuif, France
| | - Maria M. Haykal
- Gustave Roussy Cancer Center, F-94800 Villejuif, France; (S.R.-F.); (M.M.); (H.M.); (M.M.H.)
- INSERM U981, Université Paris-Saclay, F-94800 Villejuif, France
| | - Olivier Collier
- MODAL’X, UPL, Université Paris Nanterre, CNRS, F-92000 Nanterre, France;
| | - Véronique Stoven
- CBIO (Centre de Bioinformatique), Mines Paris-PSL, PSL Research University, F-75005 Paris, France;
- INSERM U900, Institut Curie, F-75005 Paris, France
| | - Clara Nahmias
- Gustave Roussy Cancer Center, F-94800 Villejuif, France; (S.R.-F.); (M.M.); (H.M.); (M.M.H.)
- INSERM U981, Université Paris-Saclay, F-94800 Villejuif, France
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27
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He Y, He P, Lu S, Dong W. KIFC3 Regulates the progression and metastasis of gastric cancer via Notch1 pathway. Dig Liver Dis 2023; 55:1270-1279. [PMID: 36890049 DOI: 10.1016/j.dld.2023.02.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 01/19/2023] [Accepted: 02/14/2023] [Indexed: 03/10/2023]
Abstract
INTRODUCTION KIFC3 is a member of the kinesin family which has shown great promise in cancer therapy recently. In this study, we sought to elucidate the role of KIFC3 in the development of GC and its possible mechanisms. METHODS Two databases and a tissue microarray were used to explore the expression of KIFC3 and its correlation with patients' clinicopathological characteristics. Cell proliferation was examined by cell counting kit-8 assay and colony formation assay. Wound healing assay and transwell assay were performed to examine cell metastasis ability. EMT and Notch signaling related proteins were detected by western blot. Additionally, a xenograft tumor model was established to investigate the function of KIFC3 in vivo. RESULTS The expression of KIFC3 was upregulated in GC, and was associated with higher T stage and poor prognosis in GC patients. The proliferation and metastasis ability of GC cells were promoted by KIFC3 overexpression while inhibited by KIFC3 knockdown in vitro and in vivo. Furthermore, KIFC3 might activate the Notch1 pathway to facilitate the progression of GC, and DAPT, an inhibitor of Notch signaling, could reverse this effect. CONCLUSION Together, our data revealed that KIFC3 could enhance the progression and metastasis of GC by activating the Notch1 pathway.
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Affiliation(s)
- Yang He
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China; Central Laboratory of Renmin Hospital, Wuhan, Hubei Province, China
| | - Pengzhan He
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China; Central Laboratory of Renmin Hospital, Wuhan, Hubei Province, China
| | - Shimin Lu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China; Central Laboratory of Renmin Hospital, Wuhan, Hubei Province, China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China; Central Laboratory of Renmin Hospital, Wuhan, Hubei Province, China.
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28
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Timofeeva AV, Fedorov IS, Asaturova AV, Sannikova MV, Tregubova AV, Mayboroda OA, Khabas GN, Frankevich VE, Sukhikh GT. Blood Plasma Small Non-Coding RNAs as Diagnostic Molecules for the Progesterone-Receptor-Negative Phenotype of Serous Ovarian Tumors. Int J Mol Sci 2023; 24:12214. [PMID: 37569592 PMCID: PMC10419267 DOI: 10.3390/ijms241512214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 07/28/2023] [Accepted: 07/28/2023] [Indexed: 08/13/2023] Open
Abstract
The expression level of the progesterone receptor (PGR) plays a crucial role in determining the biological characteristics of serous ovarian carcinoma. Low PGR expression is associated with chemoresistance and a poorer outcome. In this study, our objective was to explore the relationship between tumor progesterone receptor levels and RNA profiles (miRNAs, piwiRNAs, and mRNAs) to understand their biological characteristics and behavior. To achieve this, we employed next-generation sequencing of small non-coding RNAs, quantitative RT-PCR, and immunohistochemistry to analyze both FFPE and frozen tumor samples, as well as blood plasma from patients with benign cystadenoma (BSC), serous borderline tumor (SBT), low-grade serous ovarian carcinoma (LGSOC), and high-grade serous ovarian carcinoma (HGSOC). Our findings revealed significant upregulation of MMP7 and MUC16, along with downregulation of PGR, in LGSOC and HGSOC compared to BSC. We observed significant correlations of PGR expression levels in tumor tissue with the contents of miR-199a-5p, miR-214-3p, miR-424-3p, miR-424-5p, and miR-125b-5p, which potentially target MUC16, MMP7, and MMP9, as well as with the tissue content of miR-16-5p, miR-17-5p, miR-20a-5p, and miR-93-5p, which are associated with the epithelial-mesenchymal transition (EMT) of cells. The levels of EMT-associated miRNAs were significantly correlated with the content of hsa_piR_022437, hsa_piR_009295, hsa_piR_020813, hsa_piR_004307, and hsa_piR_019914 in tumor tissues. We developed two optimal logistic regression models using the quantitation of hsa_piR_020813, miR-16-5p, and hsa_piR_022437 or hsa_piR_004307, hsa_piR_019914, and miR-93-5p in the tumor tissue, which exhibited a significant ability to diagnose the PGR-negative tumor phenotype with 93% sensitivity. Of particular interest, the blood plasma levels of miR-16-5p and hsa_piR_022437 could be used to diagnose the PGR-negative tumor phenotype with 86% sensitivity even before surgery and chemotherapy. This knowledge can help in choosing the most effective treatment strategy for this aggressive type of ovarian cancer, such as neoadjuvant chemotherapy followed by cytoreduction in combination with hyperthermic intraperitoneal chemotherapy and targeted therapy, thus enhancing the treatment's effectiveness and the patient's longevity.
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Affiliation(s)
- Angelika V. Timofeeva
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of the Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia; (I.S.F.); (A.V.A.); (M.V.S.); (A.V.T.); (G.N.K.); (V.E.F.); (G.T.S.)
| | - Ivan S. Fedorov
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of the Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia; (I.S.F.); (A.V.A.); (M.V.S.); (A.V.T.); (G.N.K.); (V.E.F.); (G.T.S.)
| | - Aleksandra V. Asaturova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of the Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia; (I.S.F.); (A.V.A.); (M.V.S.); (A.V.T.); (G.N.K.); (V.E.F.); (G.T.S.)
| | - Maya V. Sannikova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of the Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia; (I.S.F.); (A.V.A.); (M.V.S.); (A.V.T.); (G.N.K.); (V.E.F.); (G.T.S.)
| | - Anna V. Tregubova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of the Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia; (I.S.F.); (A.V.A.); (M.V.S.); (A.V.T.); (G.N.K.); (V.E.F.); (G.T.S.)
| | - Oleg A. Mayboroda
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands;
| | - Grigory N. Khabas
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of the Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia; (I.S.F.); (A.V.A.); (M.V.S.); (A.V.T.); (G.N.K.); (V.E.F.); (G.T.S.)
| | - Vladimir E. Frankevich
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of the Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia; (I.S.F.); (A.V.A.); (M.V.S.); (A.V.T.); (G.N.K.); (V.E.F.); (G.T.S.)
- Laboratory of Translational Medicine, Siberian State Medical University, 634050 Tomsk, Russia
| | - Gennady T. Sukhikh
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of the Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia; (I.S.F.); (A.V.A.); (M.V.S.); (A.V.T.); (G.N.K.); (V.E.F.); (G.T.S.)
- Department of Obstetrics, Gynecology, Perinatology and Reproductology, First Moscow State Medical University Named after I.M. Sechenov, 119991 Moscow, Russia
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Huang P, Hu YD, Liu YJ, Li JP, Zhang YH. An Analysis Regarding the Association Between the Nuclear Pore Complex (NPC) and Hepatocellular Carcinoma (HCC). J Hepatocell Carcinoma 2023; 10:959-978. [PMID: 37377841 PMCID: PMC10292625 DOI: 10.2147/jhc.s417501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
Background The nuclear pore complex (NPC) is the main mediator of nuclear and cytoplasmic communication, and delaying or blocking nuclear RNA export and protein shuttling can inhibit cell proliferation and induce apoptosis. Although NPC is a research hotspot in structural biology, relevant studies in hepatocellular carcinoma are scarce, especially in terms of translation into clinical practice. Methods This study used a bioinformatics approach combining validation experiments to investigate the biological mechanisms that may be related with NPC. A series of experiments performed to explore the function of the Targeting protein for Xenopus kinesin-like protein 2 (TPX2) in HCC. Results Patients with HCC can be divided into two NPC clusters. Patients with high NPC levels (C1) had a shorter survival time than those with low NPC levels (C2) and are characterised by high levels of proliferative signals. We demonstrated that TPX2 regulates HCC growth and inhibits apoptosis in an NPC-dependent manner and contributes to the maintenance of HCC stemness. We developed the NPCScore to predict the prognosis and degree of differentiation in HCC patients. Conclusion NPC plays an important role in the malignant proliferation of HCC. Assessing NPC expression patterns could help enhance our understanding of tumor cell proliferation and could guide more effective chemotherapeutic strategies.
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Affiliation(s)
- Pan Huang
- Department of Oncology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, 215600, People’s Republic of China
| | - Yi-dou Hu
- Department of Oncology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, 215600, People’s Republic of China
| | - Yuan-jie Liu
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
| | - Jie-pin Li
- Department of Oncology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, 215600, People’s Republic of China
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China
- Key Laboratory of Tumor System Biology of Traditional Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
| | - Yong-hua Zhang
- Department of Oncology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, 215600, People’s Republic of China
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Liu S, Ye Z, Xue VW, Sun Q, Li H, Lu D. KIF2C is a prognostic biomarker associated with immune cell infiltration in breast cancer. BMC Cancer 2023; 23:307. [PMID: 37016301 PMCID: PMC10071625 DOI: 10.1186/s12885-023-10788-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 03/29/2023] [Indexed: 04/06/2023] Open
Abstract
BACKGROUND The kinesin-13 family member 2C (KIF2C) is a versatile protein participating in many biological processes. KIF2C is frequently up-regulated in multiple types of cancer and is associated with cancer development. However, the role of KIF2C in immune cell infiltration of tumor microenvironment and immunotherapy in breast cancer remains unclear. METHODS The expression of KIF2C was analyzed using Tumor Immune Estimation Resource (TIMER) database and further verified by immunohistochemical staining in human breast cancer tissues. The correlation between KIF2C expression and clinical parameters, the impact of KIF2C on clinical prognosis and independent prognostic factors were analyzed by using TCGA database, the Kaplan-Meier plotter, and Univariate and multivariate Cox analyses, respectively. The nomograms were constructed according to independent prognostic factors and validated with C-index, calibration curves, ROC curves, and decision curve analysis. A gene set enrichment analysis (GSEA) was performed to explore the underlying molecular mechanisms of KIF2C. The degree of immune infiltration was assessed by the Estimation of Stromal and Immune cells in Malignant Tumor tissues using the Expression (ESTIMATE) algorithm and the single sample GSEA (ssGSEA). The Tumor mutational burden and Tumor Immune Dysfunction and Rejection (TIDE) were used to analyze immunotherapeutic efficiency. Finally, the KIF2C-related competing endogenous RNA (ceRNA) network was constructed to predict the putative regulatory mechanisms of KIF2C. RESULTS KIF2C was remarkably up-regulated in 18 different types of cancers, including breast cancer. Kaplan-Meier survival analysis showed that high KIF2C expression was associated with poor overall survival (OS). KIF2C expression was associated with clinical parameters such as age, TMN stage, T status, and molecular subtypes. We identified age, stage, estrogen receptor (ER) and KIF2C expression as OS-related independent prognosis factors for breast cancer. An OS-related nomogram was developed based on these independent prognosis factors and displayed good predicting ability for OS of breast cancer patients. Finally, our results revealed that KIF2C was significantly related to immune cell infiltration, tumor mutational burden, and immunotherapy in patients with breast cancer. CONCLUSION KIF2C was overexpressed in breast cancer and was positively correlated with immune cell infiltration and immunotherapy response. Therefore, KIF2C can serve as a potential biomarker for prognosis and immunotherapy in breast cancer.
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Affiliation(s)
- Shanshan Liu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology, Carson International Cancer Center, Shenzhen University Medical School, Shenzhen, Guangdong, 518055, China
| | - Ziwei Ye
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology, Carson International Cancer Center, Shenzhen University Medical School, Shenzhen, Guangdong, 518055, China
| | - Vivian Weiwen Xue
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology, Carson International Cancer Center, Shenzhen University Medical School, Shenzhen, Guangdong, 518055, China
| | - Qi Sun
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology, Carson International Cancer Center, Shenzhen University Medical School, Shenzhen, Guangdong, 518055, China
| | - Huan Li
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology, Carson International Cancer Center, Shenzhen University Medical School, Shenzhen, Guangdong, 518055, China
| | - Desheng Lu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology, Carson International Cancer Center, Shenzhen University Medical School, Shenzhen, Guangdong, 518055, China.
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Lu S, Liu Y, Tian S, He Y, Dong W. KIFC3 regulates progression of hepatocellular carcinoma via EMT and the AKT/mTOR pathway. Exp Cell Res 2023; 426:113564. [PMID: 36948354 DOI: 10.1016/j.yexcr.2023.113564] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 03/17/2023] [Accepted: 03/18/2023] [Indexed: 03/24/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. Despite an overall downward trend in cancer mortality, HCC-related mortality continues to increase. KIFC3 is involved in cell division and cancers. However, the role of KIFC3 in HCC has yet to be elucidated. METHODS A total of 36 cases of HCC tissues, 4 HCC cell lines, and TCGA databases were searched to explore the expression of KIFC3 in HCC. Subsequently, Western blot analysis, immunofluorescence, bioinformatic analysis, molecular docking, and Co-IP were performed to investigate the molecular mechanisms of KIFC3 in HCC. RESULT We found that the expression of KIFC3 was upregulated in HCC, and high KIFC3 expression was related to poor overall survival. In addition, the knockdown of KIFC3 inhibited the proliferation, migration, and invasion of HCC cells in vitro, and impeded the growth of HCC in vivo, while overexpression of KIFC3 in HCC cells revealed the opposite effect. Mechanistically, KIFC3 promotes the progression of HCC through the PI3K/AKT/mTOR signalling. And KIFC3 had slight effect on the protein expression of p-PI3K, p-AKT and p-mTOR in TRIP13-ablated or LY294002-treated HCC cells. The KIFC3 knockdown could further enhance the inhibitory effect of LY294002. CONCLUSION Our data revealed that KIFC3 is upregulated in HCC and may serve as a novel biomarker for predicting survival in HCC patients. Targeting KIFC3 may serve as a novel therapeutic strategy for HCC patients.
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Affiliation(s)
- Shimin Lu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China; Central Laboratory of Renmin Hospital, Wuhan 430060, Hubei Province, China
| | - Yinghui Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China; Central Laboratory of Renmin Hospital, Wuhan 430060, Hubei Province, China
| | - Shan Tian
- Department of Infectious Disease, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang He
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China; Central Laboratory of Renmin Hospital, Wuhan 430060, Hubei Province, China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China; Central Laboratory of Renmin Hospital, Wuhan 430060, Hubei Province, China.
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Ji J, Fu J. MiR-17-3p Facilitates Aggressive Cell Phenotypes in Colon Cancer by Targeting PLCD1 Through Affecting KIF14. Appl Biochem Biotechnol 2023; 195:1723-1735. [PMID: 36367621 DOI: 10.1007/s12010-022-04218-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/21/2022] [Indexed: 11/13/2022]
Abstract
Colon cancer (CC) is a common and lethal cancer to be further elucidated. Accumulating studies elaborated the crucial role of miRNAs differentially expressed in cancer cell growth. In the present study, differentially expressed miRNAs related to CC were screened by the bioinformatics methods on the strength of TCGA database. Highly expressed miR-17-3p was proved to notably influence CC cell proliferative, migratory, invasion, and apoptotic levels. By using TargetScan and miRTarBase databases, phospholipase C delta 1 (PLCD1) was predicted as a target downstream of miR-17-3p, and their binding site was predicted. Through TCGA database, low expression of PLCD1 and its significant negative correlation with miR-17-3p were identified in CC. Dual-luciferase reporter gene analysis ascertained the targeting relationship between miR-17-3p and PLCD1. Cell Counting Kit-8, colony formation, and transwell assays were introduced to detect CC cell malignant progression. Flow cytometry was applied to detect CC cell apoptosis. As result revealed, miR-17-3p was markedly highly expressed, and PLCD1, the target of miR-17-3p, was remarkably lowly expressed in CC cells. Forced expression of miR-17-3p facilitated CC cell proliferation, migration, invasion, and suppressed apoptosis. Biological roles of upregulating miR-17-3p in the colon cancer cells were markedly weakened by over-expressing PLCD1 simultaneously. MiR-17-3p regulated CC cell malignant progression, as well as apoptosis by targeting PLCD1. Moreover, KIF14 was extensively considered as an involved tumor-promoting gene that could be affected by miR-17-3p/PLCD1 axis based on BioGRID analysis and CO-IP assay. Concludingly, this study exhibited that miR-17-3p facilitated CC progression by PLCD1 downregulation.
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Affiliation(s)
- Jinxing Ji
- Department of Oncology, The First Clinical Medical College of China Three Gorges University, Yichang Central People's Hospital, Yichang, 443000, Hubei, China
| | - Jun Fu
- Department of Gastrointestinal and Anal Surgery, The First Affiliated Hospital of Guangxi University of Chinese Medicine, No. 89-9 Dongge Road, Nanning, 530000, Guangxi, China.
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KIF2C Facilitates Tumor Growth and Metastasis in Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2023; 15:cancers15051502. [PMID: 36900292 PMCID: PMC10000478 DOI: 10.3390/cancers15051502] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 02/16/2023] [Accepted: 02/19/2023] [Indexed: 03/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with a poor prognosis. For PDAC, an increase in the survival time of patients and a reduction mortality have not yet successfully been achieved. In many research works, Kinesin family member 2C (KIF2C) is highly expressed in several tumors. Nevertheless, the role of KIF2C in pancreatic cancer is unknown. In this study, we found that KIF2C expression is significantly upregulated in human PDAC tissues and cell lines such as ASPC-1 and MIA-PaCa2. Moreover, KIF2C upregulation is associated with a poor prognosis when combining the expression of KIF2C with clinical information. Through cell functional assays and the construction of animal models, we showed that KIF2C promotes PDAC cell proliferation, migration, invasion, and metastasis, both in vitro and in vivo. Finally, the results of sequencing showed that the overexpression of KIF2C causes a decrease in some proinflammatory factors and chemokines. The cell cycle detection indicated that the pancreatic cancer cells in the overexpressed group had abnormal proliferation in the G2 and S phases. These results revealed the potential of KIF2C as a therapeutic target for the treatment of PDAC.
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Bernal L, Pinzi L, Rastelli G. Identification of Promising Drug Candidates against Prostate Cancer through Computationally-Driven Drug Repurposing. Int J Mol Sci 2023; 24:ijms24043135. [PMID: 36834548 PMCID: PMC9964599 DOI: 10.3390/ijms24043135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/02/2023] [Accepted: 02/03/2023] [Indexed: 02/08/2023] Open
Abstract
Prostate cancer (PC) is one of the most common types of cancer in males. Although early stages of PC are generally associated with favorable outcomes, advanced phases of the disease present a significantly poorer prognosis. Moreover, currently available therapeutic options for the treatment of PC are still limited, being mainly focused on androgen deprivation therapies and being characterized by low efficacy in patients. As a consequence, there is a pressing need to identify alternative and more effective therapeutics. In this study, we performed large-scale 2D and 3D similarity analyses between compounds reported in the DrugBank database and ChEMBL molecules with reported anti-proliferative activity on various PC cell lines. The analyses included also the identification of biological targets of ligands with potent activity on PC cells, as well as investigations on the activity annotations and clinical data associated with the more relevant compounds emerging from the ligand-based similarity results. The results led to the prioritization of a set of drugs and/or clinically tested candidates potentially useful in drug repurposing against PC.
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Affiliation(s)
- Leonardo Bernal
- Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 103, 41125 Modena, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Luca Pinzi
- Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 103, 41125 Modena, Italy
| | - Giulio Rastelli
- Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 103, 41125 Modena, Italy
- Correspondence: ; Tel.: +39-059-2058564
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Furth PA, Wang W, Kang K, Rooney BL, Keegan G, Muralidaran V, Wong J, Shearer C, Zou X, Flaws JA. Overexpression of Estrogen Receptor α in Mammary Glands of Aging Mice Is Associated with a Proliferative Risk Signature and Generation of Estrogen Receptor α-Positive Mammary Adenocarcinomas. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:103-120. [PMID: 36464513 PMCID: PMC9768686 DOI: 10.1016/j.ajpath.2022.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/29/2022] [Accepted: 09/28/2022] [Indexed: 12/03/2022]
Abstract
Age is a risk factor for human estrogen receptor-positive breast cancer, with highest prevalence following menopause. While transcriptome risk profiling is available for human breast cancers, it is not yet developed for prognostication for primary or secondary breast cancer development utilizing at-risk breast tissue. Both estrogen receptor α (ER) and aromatase overexpression have been linked to human breast cancer. Herein, conditional genetically engineered mouse models of estrogen receptor 1 (Esr1) and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) were used to show that induction of Esr1 overexpression just before or with reproductive senescence and maintained through age 30 months resulted in significantly higher prevalence of estrogen receptor-positive adenocarcinomas than CYP19A1 overexpression. All adenocarcinomas tested showed high percentages of ER+ cells. Mammary cancer development was preceded by a persistent proliferative transcriptome risk signature initiated within 1 week of transgene induction that showed parallels to the Prosigna/Prediction Analysis of Microarray 50 human prognostic signature for early-stage human ER+ breast cancer. CYP19A1 mice also developed ER+ mammary cancers, but histology was more divided between adenocarcinoma and adenosquamous, with one ER- adenocarcinoma. Results demonstrate that, like humans, generation of ER+ adenocarcinoma in mice was facilitated by aging mice past the age of reproductive senescence. Esr1 overexpression was associated with a proliferative estrogen pathway-linked signature that preceded appearance of ER+ mammary adenocarcinomas.
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Affiliation(s)
- Priscilla A Furth
- Department of Oncology, Georgetown University, Washington, District of Columbia; Department of Medicine, Georgetown University, Washington, District of Columbia.
| | - Weisheng Wang
- Department of Oncology, Georgetown University, Washington, District of Columbia
| | - Keunsoo Kang
- Department of Microbiology, College of Science and Technology, Dankook University, Cheonan, Republic of Korea
| | - Brendan L Rooney
- Department of Oncology, Georgetown University, Washington, District of Columbia
| | - Grace Keegan
- Department of Oncology, Georgetown University, Washington, District of Columbia
| | - Vinona Muralidaran
- Department of Oncology, Georgetown University, Washington, District of Columbia
| | - Justin Wong
- Department of Oncology, Georgetown University, Washington, District of Columbia
| | - Charles Shearer
- Department of Oncology, Georgetown University, Washington, District of Columbia
| | - Xiaojun Zou
- Department of Oncology, Georgetown University, Washington, District of Columbia
| | - Jodi A Flaws
- Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, Illinois
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Guo X, Zhou L, Wu Y, Li J. KIF11 As a Potential Pan-Cancer Immunological Biomarker Encompassing the Disease Staging, Prognoses, Tumor Microenvironment, and Therapeutic Responses. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2764940. [PMID: 36742345 PMCID: PMC9893523 DOI: 10.1155/2022/2764940] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 11/13/2022] [Accepted: 11/14/2022] [Indexed: 12/23/2022]
Abstract
KIF11 is one of the 45 family members of kinesin superfamily proteins that functions as a motor protein in mitosis. Emerging evidence revealed that KIF11 plays pivotal roles in cancer initiation, development, and progression. However, the prognostic, oncological, and immunological values of KIF11 have not been comprehensively explored in pan-cancer. In present study, we comprehensively interrogated the role of KIF11 in tumor progression, tumor stemness, genomic heterogeneity, tumor immune infiltration, immune evasion, therapy response, and prognosis of cohorts from various cancer types. In general, KIF11 was significantly upregulated in tumors compared with paired normal tissues. KIF11 showed strong relationships with pathological stage, prognosis, tumor stemness, genomic heterogeneity, neoantigens, ESTIMATE, immune checkpoint, and drug sensitivity. The methylation level of KIF11 decreased in most cancers and was correlated with the survival probability in different human cancers. The expression of KIF11 was diverse in different molecular and immune subtypes and remarkably correlated with immune cell infiltration in the tumor microenvironment. Comparative study revealed that KIF11 was a powerful biomarker and associated with immune, targeted, and chemotherapeutic outcomes in various cancers. In addition, KIF11 interaction and coexpression networks mainly participated in the regulation of cell cycle, cell division, p53 signaling pathway, DNA repair and recombination, chromatin organization, antigen processing and presentation, and drug resistance. Our pan-cancer analysis provides a comprehensive understanding of the functions of KIF11 in oncogenesis, progression, and therapy in different cancers. KIF11 may serve as a potential prognostic and immunological pan-cancer biomarker. Moreover, KIF11 could be a novel target for tumor immunotherapy.
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Affiliation(s)
- Xiuhong Guo
- Luzhou Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou 646000, China
| | - Li Zhou
- State Key Laboratory of Biotherapy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Yuening Wu
- Luzhou Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou 646000, China
| | - Jingxiang Li
- Luzhou Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou 646000, China
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Singharajkomron N, Yodsurang V, Seephan S, Kungsukool S, Petchjorm S, Maneeganjanasing N, Promboon W, Dangwilailuck W, Pongrakhananon V. Evaluating the Expression and Prognostic Value of Genes Encoding Microtubule-Associated Proteins in Lung Cancer. Int J Mol Sci 2022; 23:ijms232314724. [PMID: 36499051 PMCID: PMC9738182 DOI: 10.3390/ijms232314724] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/19/2022] [Accepted: 11/23/2022] [Indexed: 11/27/2022] Open
Abstract
Microtubule-associated proteins (MAPs) play essential roles in cancer development. This study aimed to identify transcriptomic biomarkers among MAP genes for the diagnosis and prognosis of lung cancer by analyzing differential gene expressions and correlations with tumor progression. Gene expression data of patients with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) from the Cancer Genome Atlas (TCGA) database were used to identify differentially expressed MAP genes (DEMGs). Their prognostic value was evaluated by Kaplan-Meier and Cox regression analysis. Moreover, the relationships between alterations in lung cancer hallmark genes and the expression levels of DEMGs were investigated. The candidate biomarker genes were validated using three independent datasets from the Gene Expression Omnibus (GEO) database and by quantitative reverse transcription polymerase chain reaction (qRT-PCR) on clinical samples. A total of 88 DEMGs were identified from TCGA data. The 20 that showed the highest differential expression were subjected to association analysis with hallmark genes. Genetic alterations in TP53, EGFR, PTEN, NTRK1, and PIK3CA correlated with the expression of most of these DEMGs. Of these, six candidates-NUF2, KIF4A, KIF18B, DLGAP5, NEK2, and LRRK2-were significantly differentially expressed and correlated with the overall survival (OS) of the patients. The mRNA expression profiles of these candidates were consistently verified using three GEO datasets and qRT-PCR on patient lung tissues. The expression levels of NUF2, KIF4A, KIF18B, DLGAP5, NEK2, and LRRK2 can serve as diagnostic biomarkers for LUAD and LUSC. Moreover, the first five can serve as prognostic biomarkers for LUAD, while LRRK2 can be a prognostic biomarker for LUSC. Our research describes the novel role and potential application of MAP-encoding genes in clinical practice.
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Affiliation(s)
- Natsaranyatron Singharajkomron
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Varalee Yodsurang
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
- Preclinical Toxicity and Efficacy, Assessment of Medicines and Chemicals Research Unit, Chulalongkorn University, Bangkok 10330, Thailand
| | - Suthasinee Seephan
- Pharmaceutical Sciences and Technology Graduate Program, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Sakkarin Kungsukool
- Respiratory Medicine Department, Central Chest Institute of Thailand, Muang District, Nonthaburi 11000, Thailand
| | - Supinda Petchjorm
- Division of Anatomical Pathology, Central Chest Institute of Thailand, Muang District, Nonthaburi 11000, Thailand
| | - Nara Maneeganjanasing
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Warunyu Promboon
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Wadsana Dangwilailuck
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Varisa Pongrakhananon
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
- Preclinical Toxicity and Efficacy, Assessment of Medicines and Chemicals Research Unit, Chulalongkorn University, Bangkok 10330, Thailand
- Correspondence: ; Tel.: +662-218-8325; Fax: +662-218-8340
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Liu JY, Liu LP, Li Z, Luo YW, Liang F. The role of cuproptosis-related gene in the classification and prognosis of melanoma. Front Immunol 2022; 13:986214. [PMID: 36341437 PMCID: PMC9632664 DOI: 10.3389/fimmu.2022.986214] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 09/28/2022] [Indexed: 11/29/2022] Open
Abstract
Background Melanoma, as one of the most aggressive and malignant cancers, ranks first in the lethality rate of skin cancers. Cuproptosis has been shown to paly a role in tumorigenesis, However, the role of cuproptosis in melanoma metastasis are not clear. Studying the correlation beteen the molecular subtypes of cuproptosis-related genes (CRGs) and metastasis of melanoma may provide some guidance for the prognosis of melanoma. Methods We collected 1085 melanoma samples in The Cancer Genome Atlas(TCGA) and Gene Expression Omnibus(GEO) databases, constructed CRGs molecular subtypes and gene subtypes according to clinical characteristics, and investigated the role of CRGs in melanoma metastasis. We randomly divide the samples into train set and validation set according to the ratio of 1:1. A prognostic model was constructed using data from the train set and then validated on the validation set. We performed tumor microenvironment analysis and drug sensitivity analyses for high and low risk groups based on the outcome of the prognostic model risk score. Finally, we established a metastatic model of melanoma. Results According to the expression levels of 12 cuproptosis-related genes, we obtained three subtypes of A1, B1, and C1. Among them, C1 subtype had the best survival outcome. Based on the differentially expressed genes shared by A1, B1, and C1 genotypes, we obtained the results of three gene subtypes of A2, B2, and C2. Among them, the B2 group had the best survival outcome. Then, we constructed a prognostic model consisting of 6 key variable genes, which could more accurately predict the 1-, 3-, and 5-year overall survival rates of melanoma patients. Besides, 98 drugs were screened out. Finally, we explored the role of cuproptosis-related genes in melanoma metastasis and established a metastasis model using seven key genes. Conclusions In conclusion, CRGs play a role in the metastasis and prognosis of melanoma, and also provide new insights into the underlying pathogenesis of melanoma.
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Affiliation(s)
- Jin-Ya Liu
- Department of Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Le-Ping Liu
- Department of Blood Transfusion, The Third Xiangya Hospital of Central South University, Changsha, China,Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Ze Li
- Department of Hematology and Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yan-Wei Luo
- Department of Blood Transfusion, The Third Xiangya Hospital of Central South University, Changsha, China,*Correspondence: Fang Liang, ; Yan-Wei Luo,
| | - Fang Liang
- Department of Hematology and Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Fang Liang, ; Yan-Wei Luo,
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KIF17 maintains the epithelial phenotype of breast cancer cells and curbs tumour metastasis. Cancer Lett 2022; 548:215904. [PMID: 36089118 DOI: 10.1016/j.canlet.2022.215904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 08/31/2022] [Accepted: 09/03/2022] [Indexed: 11/24/2022]
Abstract
Kinesin superfamily motor protein 17 (KIF17) was previously identified downregulated in breast cancer and correlated with patient prognosis. However, its pathophysiological role in tumours remains unknown. Here, we confirmed that KIF17 was significantly under-expressed in breast cancer tissues and low KIF17 expression correlated with poor outcomes in patients with breast cancer. In vitro and in vivo experiments demonstrated that KIF17 overexpression in breast cancer cell lines significantly inhibited breast cancer invasion and metastasis. By establishing the lung metastatic MDA-MB-231 cell lines, we found a transient silence of KIF17 during the initiation of breast cancer metastasis. Further experiments revealed that KIF17 might suppress metastasis by regulating the level of acetylated tubulin to maintain cytoskeleton stability. Eventually, we found that the low expression of KIF17 in breast cancer is regulated by DNMT1-mediated 5-mC DNA methylation and epigenetic silencing. Decitabine can effectively improve the expression level of KIF17 in breast cancer cells. Our study demonstrates that KIF17 mediates microtubule acetylation to maintain the stability of microtubules, thereby inhibiting tumour invasion and metastasis.
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Wang H, Li S, Liu B, Wei S, Wang T, Li T, Lin J, Ni X. KIF11: A potential prognostic biomarker for predicting bone metastasis‑free survival of prostate cancer. Oncol Lett 2022; 24:312. [PMID: 35949593 PMCID: PMC9353809 DOI: 10.3892/ol.2022.13432] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 06/20/2022] [Indexed: 11/17/2022] Open
Abstract
Most prostate cancer (PCa) cases remain indolent with a relatively good prognosis. However, bone metastasis of PCa can quickly worsen prognoses and lead to mortality. Metastasis-free survival (MFS), a strong surrogate for overall survival, is widely used in PCa prognosis research. The present study identified molecules that affect bone MFS in PCa, with clinical validation. Three datasets (GSE32269, GSE74367 and GSE77930) were downloaded from the Gene Expression Omnibus database. Hub genes most relevant to clinical traits (bone metastasis-associated morbidity) were identified by weighted gene co-expression network analysis (WGCNA) and subjected to logistic regression analysis. Patient samples were obtained between January 2014 and December 2016, with a clinically annotated follow-up in December 2021. Clinical data and follow-up information for 60 patients with PCa were used in MFS analysis. Tumor samples were retrieved, and immunohistochemistry was performed to detect vascular endothelial growth factor (VEGF). The prognostic potential of the two molecules was assessed using Cox proportional hazards regression analysis. A total of 16 gene modules were obtained via WGCNA, and the tan module, containing 147 genes, was most closely linked to bone metastasis. In total, 877 differentially expressed genes (DEGs) were detected. The DEG-tan module intersection yielded seven hub genes [BUB1, kinesin family member (KIF)2C, RACGAP1, CENPE, KIF11, TTK and KIF20A]. Using univariate and multivariate logistic regression analyses for independent risk factors of bone metastasis, KIF11 and VEGF were found to be significantly associated with a higher T stage, prostate-specific antigen level and Gleason score. In addition, KIF11 and VEGF expression levels were positively correlated (P<0.001). Using univariate Cox analysis, KIF11 and VEGF were found to exhibit a significant association with poor MFS (P<0.05). However, only KIF11 was significantly associated with MFS upon multivariate analysis (P=0.007; hazard ratio, 2.776; 95% confidence interval, 1.315-5.859). Markers of bone metastasis in PCa were identified. Overall, KIF11 is an independent indicator that can predict bone metastasis for patients with PCa, which could be used to guide clinical practice.
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Affiliation(s)
- Haoyuan Wang
- Department of Urology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Sijie Li
- Department of Urology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Bin Liu
- Department of Urology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Shufei Wei
- Department of Urology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Tianyi Wang
- Department of Urology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Tao Li
- Department of Urology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Jiahu Lin
- Department of Urology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Xiaochen Ni
- Department of Urology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
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Sarafidis M, Lambrou GI, Zoumpourlis V, Koutsouris D. An Integrated Bioinformatics Analysis towards the Identification of Diagnostic, Prognostic, and Predictive Key Biomarkers for Urinary Bladder Cancer. Cancers (Basel) 2022; 14:cancers14143358. [PMID: 35884419 PMCID: PMC9319344 DOI: 10.3390/cancers14143358] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/03/2022] [Accepted: 07/06/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Bladder cancer is evidently a challenge as far as its prognosis and treatment are concerned. The investigation of potential biomarkers and therapeutic targets is indispensable and still in progress. Most studies attempt to identify differential signatures between distinct molecular tumor subtypes. Therefore, keeping in mind the heterogeneity of urinary bladder tumors, we attempted to identify a consensus gene-related signature between the common expression profile of bladder cancer and control samples. In the quest for substantive features, we were able to identify key hub genes, whose signatures could hold diagnostic, prognostic, or therapeutic significance, but, primarily, could contribute to a better understanding of urinary bladder cancer biology. Abstract Bladder cancer (BCa) is one of the most prevalent cancers worldwide and accounts for high morbidity and mortality. This study intended to elucidate potential key biomarkers related to the occurrence, development, and prognosis of BCa through an integrated bioinformatics analysis. In this context, a systematic meta-analysis, integrating 18 microarray gene expression datasets from the GEO repository into a merged meta-dataset, identified 815 robust differentially expressed genes (DEGs). The key hub genes resulted from DEG-based protein–protein interaction and weighted gene co-expression network analyses were screened for their differential expression in urine and blood plasma samples of BCa patients. Subsequently, they were tested for their prognostic value, and a three-gene signature model, including COL3A1, FOXM1, and PLK4, was built. In addition, they were tested for their predictive value regarding muscle-invasive BCa patients’ response to neoadjuvant chemotherapy. A six-gene signature model, including ANXA5, CD44, NCAM1, SPP1, CDCA8, and KIF14, was developed. In conclusion, this study identified nine key biomarker genes, namely ANXA5, CDT1, COL3A1, SPP1, VEGFA, CDCA8, HJURP, TOP2A, and COL6A1, which were differentially expressed in urine or blood of BCa patients, held a prognostic or predictive value, and were immunohistochemically validated. These biomarkers may be of significance as prognostic and therapeutic targets for BCa.
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Affiliation(s)
- Michail Sarafidis
- Biomedical Engineering Laboratory, School of Electrical and Computer Engineering, National Technical University of Athens, 9 Iroon Polytechniou Str., 15780 Athens, Greece;
- Correspondence: ; Tel.: +30-210-772-2430
| | - George I. Lambrou
- Choremeio Research Laboratory, First Department of Pediatrics, National and Kapodistrian University of Athens, 8 Thivon & Levadeias Str., 11527 Athens, Greece;
- University Research Institute of Maternal and Child Health and Precision Medicine, National and Kapodistrian University of Athens, 8 Thivon & Levadeias Str., 11527 Athens, Greece
| | - Vassilis Zoumpourlis
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation, 48 Vas. Konstantinou Ave., 11635 Athens, Greece;
| | - Dimitrios Koutsouris
- Biomedical Engineering Laboratory, School of Electrical and Computer Engineering, National Technical University of Athens, 9 Iroon Polytechniou Str., 15780 Athens, Greece;
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Liu B, Sun Y, Zhang Y, Xing Y, Suo J. DEK modulates both expression and alternative splicing of cancer‑related genes. Oncol Rep 2022; 47:111. [PMID: 35475534 PMCID: PMC9073418 DOI: 10.3892/or.2022.8322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 04/11/2022] [Indexed: 11/05/2022] Open
Abstract
DEK is known to be a potential proto‑oncogene and is highly expressed in gastric cancer (GC); thus, DEK is considered to contribute to the malignant progression of GC. DEK is an RNA‑binding protein involved in transcription, DNA repair, and selection of splicing sites during mRNA processing; however, its precise function remains elusive due to the lack of clarification of the overall profiles of gene transcription and post‑transcriptional splicing that are regulated by DEK. We performed our original whole‑genomic RNA‑Seq data to analyze the global transcription and alternative splicing profiles in a human GC cell line by comparing DEK siRNA‑treated and control conditions, dissecting both differential gene expression and potential alternative splicing events regulated by DEK. The siRNA‑mediated knockdown of DEK in a GC cell line led to significant changes in gene expression of multiple cancer‑related genes including both oncogenes and tumor suppressors. Moreover, it was revealed that DEK regulated a number of alternative splicing in genes which were significantly enriched in various cancer‑related pathways including apoptosis and cell cycle processes. This study clarified for the first time that DEK has a regulatory effect on the alternative splicing, as well as on the expression, of numerous cancer‑related genes, which is consistent with the role of DEK as a possible oncogene. Our results further expand the importance and feasibility of DEK as a clinical therapeutic target for human malignancies including GC.
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Affiliation(s)
- Bin Liu
- Department of Gastrocolorectal Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yuanlin Sun
- Department of Gastrocolorectal Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yang Zhang
- Department of Gastrocolorectal Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yanpeng Xing
- Department of Gastrocolorectal Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Jian Suo
- Department of Gastrocolorectal Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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KIF26B in the Prognosis and Immune Biomarking of Various Cancers: A Pan-Cancer Study. JOURNAL OF ONCOLOGY 2022; 2022:4829697. [PMID: 35359341 PMCID: PMC8964195 DOI: 10.1155/2022/4829697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 01/08/2022] [Accepted: 01/12/2022] [Indexed: 11/26/2022]
Abstract
KIF26B has been identified as an oncogene in several tumors; however, its utility as a prognostic indicator for various cancers has not yet been comprehensively evaluated. Here, we first examined how KIF26B intervenes in thirty-three cancers within the TCGA database, including potential immunological functions, and how it affects the prognosis. Based on the open databases TCGA, TIMER2, GEPIA2, GTEx, CPTAC, and HPA, we found that, when compared with normal tissues, KIF26B is overexpressed in 22 tumor tissues. Following a survival analysis, a relationship between the expression of KIF26B and the prognosis of various cancers was observed. Among the genetic alterations assessed, mutations were the most frequent. On the contrary, high phosphorylation levels of S977 were detected in breast cancer, KIRC, LUAD, and UCEC. We also found positive or negative correlations between KIF26B and the immune infiltration of endothelial cells and cancer-associated fibroblast infiltration. This could imply that patients may benefit from immunotherapy. Finally, KEGG pathways and GO enrichment analyses were implemented to identify the molecular mechanisms of KIF26B. This study illustrates the function of KIF26B from a pan-cancer perspective and offers a new horizon for cancer prognostic and immunotherapeutic investigations.
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Liu K, Chen Y, Feng P, Wang Y, Sun M, Song T, Tan J, Li C, Liu S, Kong Q, Zhang J. Identification of Pathologic and Prognostic Genes in Prostate Cancer Based on Database Mining. Front Genet 2022; 13:854531. [PMID: 35360870 PMCID: PMC8963346 DOI: 10.3389/fgene.2022.854531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 02/14/2022] [Indexed: 12/24/2022] Open
Abstract
Background: Prostate cancer (PCa) is an epithelial malignant tumor that occurs in the urinary system with high incidence and is the second most common cancer among men in the world. Thus, it is important to screen out potential key biomarkers for the pathogenesis and prognosis of PCa. The present study aimed to identify potential biomarkers to reveal the underlying molecular mechanisms. Methods: Differentially expressed genes (DEGs) between PCa tissues and matched normal tissues from The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) dataset were screened out by R software. Weighted gene co-expression network analysis was performed primarily to identify statistically significant genes for clinical manifestations. Protein–protein interaction (PPI) network analysis and network screening were performed based on the STRING database in conjunction with Cytoscape software. Hub genes were then screened out by Cytoscape in conjunction with stepwise algorithm and multivariate Cox regression analysis to construct a risk model. Gene expression in different clinical manifestations and survival analysis correlated with the expression of hub genes were performed. Moreover, the protein expression of hub genes was validated by the Human Protein Atlas database. Results: A total of 1,621 DEGs (870 downregulated genes and 751 upregulated genes) were identified from the TCGA-PRAD dataset. Eight prognostic genes [BUB1, KIF2C, CCNA2, CDC20, CCNB2, PBK, RRM2, and CDC45] and four hub genes (BUB1, KIF2C, CDC20, and PBK) potentially correlated with the pathogenesis of PCa were identified. A prognostic model with good predictive power for survival was constructed and was validated by the dataset in GSE21032. The survival analysis demonstrated that the expression of RRM2 was statistically significant to the prognosis of PCa, indicating that RRM2 may potentially play an important role in the PCa progression. Conclusion: The present study implied that RRM2 was associated with prognosis and could be used as a potential therapeutic target for PCa clinical treatment.
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Affiliation(s)
- Kun Liu
- Department of Immunology, Zunyi Medical University, Zunyi, China
| | - Yijun Chen
- Department of Immunology, Zunyi Medical University, Zunyi, China
| | - Pengmian Feng
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yucheng Wang
- Department of Immunology, Zunyi Medical University, Zunyi, China
| | - Mengdi Sun
- Department of Immunology, Zunyi Medical University, Zunyi, China
| | - Tao Song
- Department of Immunology, Zunyi Medical University, Zunyi, China
| | - Jun Tan
- Department of Histology and Embryology, Zunyi Medical University, Zunyi, China
| | - Chunyang Li
- Department of Immunology, Zunyi Medical University, Zunyi, China
| | - Songpo Liu
- Department of Immunology, Zunyi Medical University, Zunyi, China
| | - Qinghong Kong
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, China
- *Correspondence: Qinghong Kong, ; Jidong Zhang,
| | - Jidong Zhang
- Department of Immunology, Zunyi Medical University, Zunyi, China
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China
- *Correspondence: Qinghong Kong, ; Jidong Zhang,
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Yang J, Wu Z, Yang L, Jeong JH, Zhu Y, Lu J, Wang B, Wang N, Wang Y, Shen K, Li R. Characterization of Kinesin Family Member 2C as a Proto-Oncogene in Cervical Cancer. Front Pharmacol 2022; 12:785981. [PMID: 35153749 PMCID: PMC8828917 DOI: 10.3389/fphar.2021.785981] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 12/21/2021] [Indexed: 12/20/2022] Open
Abstract
Kinesin family member 2C (KIF2C) is known as an oncogenic gene to regulate tumor progression and metastasis. However, its pan-cancer analysis has not been reported. In this study, we comprehensively analyzed the characteristics of KIF2C in various cancers. We found that KIF2C was highly expressed and corresponded to a poor prognosis in various cancers. We also found a significant correlation between KIF2C and clinicopathological characteristics, particularly in cervical cancer, which is the most common gynecological malignancy and is the second leading cause of cancer-related deaths among women worldwide. KIF2C mutation is strongly associated with the survival rate of cervical cancer, and KIF2C expression was significantly upregulated in cervical cancer tissues and cervical cancer cells. Moreover, KIF2C promoted cervical cancer cells proliferation, invasion, and migration in vitro and as well increased tumor growth in vivo. KIF2C knockdown promotes the activation of the p53 signaling pathway by regulating the expression of related proteins. The rescue assay with KIF2C and p53 double knockdown partially reversed the inhibitory influence of KIF2C silencing on cervical cancer processes. In summary, our study provided a relatively comprehensive description of KIF2C as an oncogenic gene and suggested KIF2C as a therapeutic target for cervical cancer.
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Affiliation(s)
- Jing Yang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zimeng Wu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Li Yang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan International Joint Laboratory of Ovarian Malignancies, Zhengzhou, China.,Zhengzhou Key Laboratory of Endometrial Disease Prevention and Treatment, Zhengzhou, China
| | - Ji-Hak Jeong
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, South Korea
| | - Yuanhang Zhu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jie Lu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Baojin Wang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan International Joint Laboratory of Ovarian Malignancies, Zhengzhou, China
| | - Nannan Wang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yan Wang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ke Shen
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ruiqing Li
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Liu H, Chen C, Fehm T, Cheng Z, Neubauer H. Identifying Mitotic Kinesins as Potential Prognostic Biomarkers in Ovarian Cancer Using Bioinformatic Analyses. Diagnostics (Basel) 2022; 12:470. [PMID: 35204562 PMCID: PMC8871464 DOI: 10.3390/diagnostics12020470] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/03/2022] [Accepted: 02/08/2022] [Indexed: 02/01/2023] Open
Abstract
Ovarian cancer (OC) is characterized by late-stage presentation, chemoresistance, and poor survival. Evaluating the prognosis of OC patients via effective biomarkers is essential to manage OC progression and to improve survival; however, it has been barely established. Here, we intend to identify differentially expressed genes (DEGs) as potential prognostic biomarkers of OC via bioinformatic analyses. Initially, a total of thirteen DEGs were extracted from different public databases as candidates. The expression of KIF20A, one of the DEGs, was correlated with a worse outcome of OC patients. The functional correlation of the DEGs with mitosis and the prognostic value of KIF20A imply a high correlation between mitotic kinesins (KIFs) and OC development. Finally, we found that KIF20A, together with the other nine mitotic KIFs (4A, 11, 14, 15, 18A, 18B, 23, C1, and2C) were upregulated and activated in OC tissues. Among the ten, seven overexpressed mitotic KIFs (11, 14, 18B, 20A, 23, and C1) were correlated with unfavorable clinical prognosis. Moreover, KIF20A and KIF23 overexpression was associated with worse prognosis in OC patients treated with platinum/taxol chemotherapy, while OCs overexpressing mitotic KIFs (11, 15, 18B, and C1) were resistant to MAPK pathway inhibitors. In conclusion, worse outcomes of OC patients were correlated with overexpression of several mitotic KIFs, which may serve both as prognostic biomarkers and therapeutic targets for OC.
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Affiliation(s)
- Hailun Liu
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Universitaetsstr, 1, 40225 Duesseldorf, Germany; (H.L.); (C.C.); (T.F.)
- Department of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Chen Chen
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Universitaetsstr, 1, 40225 Duesseldorf, Germany; (H.L.); (C.C.); (T.F.)
- Breast and Thyroid Center, The First People’s Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi 563000, China
| | - Tanja Fehm
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Universitaetsstr, 1, 40225 Duesseldorf, Germany; (H.L.); (C.C.); (T.F.)
| | - Zhongping Cheng
- Department of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
- Institute of Gynecological Minimally Invasive Medicine, Tongji University School of Medicine, Shanghai 200072, China
| | - Hans Neubauer
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Universitaetsstr, 1, 40225 Duesseldorf, Germany; (H.L.); (C.C.); (T.F.)
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Stelcer E, Komarowska H, Jopek K, Żok A, Iżycki D, Malińska A, Szczepaniak B, Komekbai Z, Karczewski M, Wierzbicki T, Suchorska W, Ruchała M, Ruciński M. Biological response of adrenal carcinoma and melanoma cells to mitotane treatment. Oncol Lett 2022; 23:120. [PMID: 35261634 PMCID: PMC8855164 DOI: 10.3892/ol.2022.13240] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 12/02/2021] [Indexed: 11/09/2022] Open
Abstract
A previous case report described an adrenal incidentaloma initially misdiagnosed as adrenocortical carcinoma (ACC), which was treated with mitotane. The final diagnosis was metastatic melanoma of unknown primary origin. However, the patient developed rapid disease progression after mitotane withdrawal, suggesting a protective role for mitotane in a non-adrenal-derived tumor. The aim of the present study was to determine the biological response of primary melanoma cells obtained from that patient, and that of other established melanoma and ACC cell lines, to mitotane treatment using a proliferation assay, flow cytometry, quantitative PCR and microarrays. Although mitotane inhibited the proliferation of both ACC and melanoma cells, its role in melanoma treatment appears to be limited. Flow cytometry analysis and transcriptomic studies indicated that the ACC cell line was highly responsive to mitotane treatment, while the primary melanoma cells showed a moderate response in vitro. Mitotane modified the activity of several key biological processes, including ‘mitotic nuclear division’, ‘DNA repair’, ‘angiogenesis’ and ‘negative regulation of ERK1 and ERK2 cascade’. Mitotane administration led to elevated levels of DNA double-strand breaks, necrosis and apoptosis. The present study provides a comprehensive insight into the biological response of mitotane-treated cells at the molecular level. Notably, the present findings offer new knowledge on the effects of mitotane on ACC and melanoma cells.
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Affiliation(s)
- Ewelina Stelcer
- Department of Histology and Embryology, Poznan University of Medical Sciences, 61‑001 Poznan, Poland
| | - Hanna Komarowska
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 60‑355 Poznan, Poland
| | - Karol Jopek
- Department of Histology and Embryology, Poznan University of Medical Sciences, 61‑001 Poznan, Poland
| | - Agnieszka Żok
- Division of Philosophy of Medicine and Bioethics, Department of Social Sciences and Humanities, Poznan University of Medical Sciences, 60‑806 Poznan, Poland
| | - Dariusz Iżycki
- Department of Cancer Immunology, Poznan University of Medical Sciences, 61‑866 Poznan, Poland
| | - Agnieszka Malińska
- Department of Histology and Embryology, Poznan University of Medical Sciences, 61‑001 Poznan, Poland
| | - Beata Szczepaniak
- Department of Histology and Embryology, Poznan University of Medical Sciences, 61‑001 Poznan, Poland
| | - Zhanat Komekbai
- Department of Histology, West Kazakhstan Marat Ospanov Medical University, Aktobe 030019, Kazakhstan
| | - Marek Karczewski
- Department of General and Transplantation Surgery, Poznan University of Medical Sciences, 60‑355 Poznan, Poland
| | - Tomasz Wierzbicki
- Department of General, Endocrinological and Gastroenterological Surgery, Poznan University of Medical Sciences, 60‑355 Poznan, Poland
| | - Wiktoria Suchorska
- Radiobiology Laboratory, Greater Poland Cancer Centre, 61‑866 Poznan, Poland
| | - Marek Ruchała
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 60‑355 Poznan, Poland
| | - Marcin Ruciński
- Department of Histology and Embryology, Poznan University of Medical Sciences, 61‑001 Poznan, Poland
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48
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Liu L, Zhang Z, Xia X, Lei J. KIF18B promotes breast cancer cell proliferation, migration and invasion by targeting TRIP13 and activating the Wnt/β‑catenin signaling pathway. Oncol Lett 2022; 23:112. [PMID: 35251343 PMCID: PMC8850966 DOI: 10.3892/ol.2022.13232] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 12/08/2021] [Indexed: 11/28/2022] Open
Abstract
Kinesin superfamily member 18B (KIF18B) has previously been reported to be upregulated in breast cancer (BC) and is involved in BC tumorigenesis. Therefore, the present study aimed to investigate the effects and underlying mechanisms of KIF18B in BC. Comprehensive bioinformatics analysis was performed, using data from The Cancer Genome Atlas. KIF18B knockdown and thyroid hormone receptor-interacting protein 13 (TRIP13) overexpression in BC cells were induced via transfection, by using the short hairpin RNA-KIF18B and overexpression-TRIP13 vectors, respectively. Cellular processes, including proliferation, migration and invasion were assessed using colony formation, wound healing and Transwell assays, respectively. mRNA and protein expression levels were determined using reverse transcription-quantitative PCR and western blot analysis, respectively. Protein-protein interactions were determined using co-immunoprecipitation. The results demonstrated that the KIF18B expression levels were upregulated in BC, particularly in triple-negative BC (TNBC) tissues and cell lines. KIF18B knockdown inhibited the proliferation, migration and invasion of HCC-1937 TNBC cells. Furthermore, MMP12 and MMP9 protein expression levels were decreased by KIF18B knockdown. TRIP13 expression was also demonstrated to be upregulated in BC, particularly in TNBC tissues and cell lines. TRIP13 expression levels positively correlated with those of KIF18B in BC tissues and cells, and further analysis verified that TRIP13 and KIF14B were able to directly bind to each other. However, TRIP13 overexpression abolished the effects of KIF18B knockdown on HCC-1937 cells. Furthermore, KIF18B knockdown decreased β-catenin, c-Myc and cyclin D1 protein expression levels; however, TRIP13 overexpression resulted in the recovery of all respective protein expression levels. On the whole, the present study demonstrates that KIF18B promotes BC malignant events, including the proliferation, migration and invasion of TNBC cells. These results indicate that KIF18B may play an oncogenic role in BC by upregulating TRIP13 expression, thereby activating the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Lan Liu
- Department of Mammary Glands, Baoji Maternal and Child Health Hospital, Baoji, Shaanxi 721000, P.R. China
| | - Zhaofeng Zhang
- Department of Mammary Glands, Baoji Maternal and Child Health Hospital, Baoji, Shaanxi 721000, P.R. China
| | - Xiulin Xia
- Department of Mammary Glands, Baoji Maternal and Child Health Hospital, Baoji, Shaanxi 721000, P.R. China
| | - Jing Lei
- Department of Women's Healthcare, Baoji Maternal and Child Health Hospital, Baoji, Shaanxi 721000, P.R. China
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49
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Jiang S, Bu X, Tang D, Yan C, Huang Y, Fang K. A Tumor Suppressor Gene-Based Prognostic Classifier Predicts Prognosis, Tumor Immune Infiltration, and Small Molecule Compounds in Breast Cancer. Front Genet 2022; 12:783026. [PMID: 35186006 PMCID: PMC8850650 DOI: 10.3389/fgene.2021.783026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 12/14/2021] [Indexed: 11/30/2022] Open
Abstract
Objective: Tumor suppressor genes (TSGs) play critical roles in the cell cycle checkpoints and in modulating genomic stability. Here, we aimed to develop a TSG-based prognostic classifier for breast cancer. Methods: Gene expression profiles and clinical information of breast cancer were curated from TCGA (discovery set) and Gene Expression Omnibus (GEO) repository (GSE12093 and GSE17705 datasets as testing sets). Univariate cox regression analysis and random forest machine learning method were presented for screening characteristic TSGs. After multivariate cox regression analyses, a TSG-based prognostic classifier was constructed. The predictive efficacy was verified by C-index and receiver operating characteristic (ROC) curves. Meanwhile, the predictive independency was assessed through uni- and multivariate cox regression analyses and stratified analyses. Tumor immune infiltration was estimated via ESTIMATE and CIBERSORT algorithms. Small molecule agents were predicted through CMap method. Molecular subtypes were clustered based on the top 100 TSGs with the most variance. Results: A prognostic classifier including nine TSGs was established. High-risk patients were predictive of undesirable prognosis. C-index and ROC curves demonstrated its excellent predictive performance in prognosis. Also, this prognostic classifier was independent of conventional clinicopathological parameters. Low-risk patients exhibited increased infiltration levels of immune cells like T cells CD8. Totally, 48 small molecule compounds were predicted to potentially treat breast cancer. Five TSG-based molecular subtypes were finally constructed, with distinct prognosis and clinicopathological features. Conclusion: Collectively, this study provided a TSG-based prognostic classifier with the potential to predict clinical outcomes and immune infiltration in breast cancer and identified potential small molecule agents against breast cancer.
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Affiliation(s)
- Suxiao Jiang
- Department of Surgery, Yinchuan Maternal and Child Health Hospital, Yinchuan, China
| | - Xiangjing Bu
- Department of Surgery, Yinchuan Maternal and Child Health Hospital, Yinchuan, China
| | - Desheng Tang
- Department of Surgery, The First Affiliated Hospital of Harbin Medical University, Heilongjiang, China
| | - Changsheng Yan
- Department of Surgery, The First Affiliated Hospital of Harbin Medical University, Heilongjiang, China
| | - Yan Huang
- Department of Surgery, Affiliated Hospital of Ningxia Medical University, Ningxia, China
| | - Kun Fang
- Department of Surgery, Yinchuan Maternal and Child Health Hospital, Yinchuan, China
- *Correspondence: Kun Fang,
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50
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Deshpande N, Wilkins MR, Khachigian LM. RNA sequencing identifies genes reliant upon Ser26 in early growth response-1 in vascular endothelial cells exposed to fibroblast growth factor-2. Vascul Pharmacol 2022; 143:106952. [PMID: 35041980 DOI: 10.1016/j.vph.2022.106952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 01/08/2022] [Indexed: 11/25/2022]
Abstract
Early growth response-1 (Egr-1) is an inducible master regulatory transcription factor that orchestrates gene expression in vascular endothelial cells. We recently determined that Ser26 in Egr-1 undergoes phosphorylation and plays a critical functional role in a range of pro-angiogenic processes. To better understand the effect of Ser26 on Egr-1-dependent gene expression, in this study, we performed RNA-seq and bioinformatics analysis on human microvascular endothelial cells bearing a germline mutation (M) in Ser26 to Ala (M26 cells) exposed to the mitogen and chemoattractant fibroblast growth factor-2 (FGF2) as compared with wildtype (WT) cells. In WT cells, FGF2 increased the expression of numerous growth factors and hormones cytokines, signaling molecules and transcriptional regulators. Comparison of FGF2-inducible WT and M26 cells enabled identification of differentially expressed genes, including genes reliant or not reliant upon Ser26. For example, Ser26 in Egr-1 was required for FGF2 inducible LIF expression but not for FGF2 inducible IL11. Ser26 was also required for FGF2 inducible NKX2-8 and RIPK2 expression but not for FGF2 inducible CREB5 or ALPK2 expression. Conversely, FGF2 inhibited genes such as TIE1, GPR146 and EPHB3, and Ser26 was required for FGF2's effect on TIE1 and GPR146 but not for EPHB3. Enrichment analysis also identified a range of gene ontologies upregulated and downregulated by FGF2. These findings demonstrate the importance of Ser26 in Egr-1 in programs of endothelial gene expression modulated by FGF2.
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Affiliation(s)
- Nandan Deshpande
- Systems Biology Initiative, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Marc R Wilkins
- Systems Biology Initiative, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Levon M Khachigian
- Vascular Biology and Translational Research, School of Medical Sciences & UNSW Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
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