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Li Y, Zhou M, Hu X, Xie T, Peng W, Zhang L, Tang M, Hu R, He Y. Cancer-associated fibroblast-derived exosomal FAM83F regulates KIF23 expression to promote the malignant progression and reduce radiosensitivity in non-small cell lung cancer. Cytotechnology 2025; 77:50. [PMID: 39867833 PMCID: PMC11759729 DOI: 10.1007/s10616-025-00713-x] [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: 08/26/2024] [Accepted: 01/08/2025] [Indexed: 01/28/2025] Open
Abstract
Cancer-associated fibroblasts (CAFs) have been shown to play a crucial role in the progression of non-small cell lung cancer (NSCLC). Exosomes derived from CAFs have emerged as important mediators of intercellular communication in the tumor microenvironment, contributing to cancer progression. Therefore, it is essential to further investigate the mechanisms by which CAF-derived exosomes regulate NSCLC. CAFs promoted NSCLC cell proliferation, invasion, and migration, while also suppressing radiosensitivity. We observed an upregulation of FAM83F expression in both NSCLC cells and NSCLC cells treated with conditioned medium from CAFs. Notably, CAF-derived exosomes were found to transfer FAM83F to NSCLC cells, thereby enhancing the malignant properties of the cancer cells. In contrast, FAM83F-deficient CAF-derived exosomes exerted inhibitory effects on NSCLC cell proliferation, invasion, and migration, while also sensitizing the cells to radiotherapy. FAM83F was found to interact with KIF23 in NSCLC cells, and the overexpression of KIF23 attenuated the effects induced by FAM83F-deficient exosomes in NSCLC cells. Moreover, FAM83F-deficient CAF-derived exosomes were effective in inhibiting tumor formation in vivo. Our findings highlight the crucial role of CAF-derived exosomal FAM83F in promoting NSCLC progression and conferring resistance to radiotherapy. Targeting this signaling pathway may offer promising therapeutic strategies for combating NSCLC progression and improving patient outcomes. Supplementary Information The online version contains supplementary material available at 10.1007/s10616-025-00713-x.
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Affiliation(s)
- Yi Li
- Department of Thoracic Surgery, Suining Central Hospital, Suining, 629099 China
| | - Mingming Zhou
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing Cancer Institute, Chongqing Cancer Hospital, Chongqing University Cancer Hospital, Chongqing, 400030 China
| | - Xiaogang Hu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing Cancer Institute, Chongqing Cancer Hospital, Chongqing University Cancer Hospital, Chongqing, 400030 China
| | - Tingting Xie
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing Cancer Institute, Chongqing Cancer Hospital, Chongqing University Cancer Hospital, Chongqing, 400030 China
| | - Wenli Peng
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing Cancer Institute, Chongqing Cancer Hospital, Chongqing University Cancer Hospital, Chongqing, 400030 China
| | - Lina Zhang
- Department Radiotherapy, Affiliated Hospital of Hebei University, Hebei, 071000 China
| | - Minxin Tang
- Department of Medical Laboratory, Chongqing Institute of Orthopedics of Traditional Chinese Medicine, Chongqing Orthopedic Hospital of Traditional Chinese Medicine, The People’s Hospital of Chongqing Yuzhong District, Chongqing, 400039 China
| | - Rui Hu
- Department of Medical Laboratory, Chongqing Institute of Orthopedics of Traditional Chinese Medicine, Chongqing Orthopedic Hospital of Traditional Chinese Medicine, The People’s Hospital of Chongqing Yuzhong District, Chongqing, 400039 China
| | - Yongpeng He
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing Cancer Institute, Chongqing Cancer Hospital, Chongqing University Cancer Hospital, Chongqing, 400030 China
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Price KL, Tharakan DM, Salvenmoser W, Ayers K, Mah J, Dunn C, Hobmayer B, Cooley L. Examination of germline and somatic intercellular bridges in Hydra vulgaris reveals insights into the evolutionarily conserved mechanism of intercellular bridge formation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.19.639158. [PMID: 40027827 PMCID: PMC11870534 DOI: 10.1101/2025.02.19.639158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Incomplete cytokinesis results in the formation of stable intercellular bridges that have been extensively studied in bilaterians, where they play essential roles in cell-cell communication and coordination of differentiation. However, little is known about their structure and molecular composition in non-bilaterian animals. This study characterizes germline and somatic intercellular bridges in the cnidarian Hydra vulgaris , providing insights into their evolutionary origins and functional significance. We identified key conserved components, including KIF23, F-actin, and phosphotyrosine. Notably, we observed microtubule localization within Hydra ring canals, suggesting previously unrecognized functions for this cytoskeletal component in intercellular bridge formation. Bioinformatic analyses confirmed the conserved expression of Kif23 and suggested its role as a molecular marker for identifying ring canal-associated components. EdU incorporation during DNA replication demonstrated that cells connected by ring canals exhibit synchronized cell cycles, which may be critical for the coordination of division and differentiation. Our findings reveal that the molecular and structural features of intercellular bridges in Hydra are conserved across evolutionary lineages, highlighting their ancient origins and functional significance in cellular connectivity. The presence of synchronized cell cycles in ring canal-connected cells underscores their role in promoting coordinated cellular behaviors, processes fundamental to multicellular organization. This study provides new perspectives on the evolution of incomplete cytokinesis and establishes a framework for comparative investigations into the diversity and conservation of intercellular bridge mechanisms across metazoans.
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Affiliation(s)
- Kari L. Price
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- UC Davis Comprehensive Cancer Center, Sacramento, CA, USA
| | - Dyuthi M. Tharakan
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Willi Salvenmoser
- Institute of Zoology and Centre for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria
| | - Kathleen Ayers
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
| | - Jasmine Mah
- Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA
| | - Casey Dunn
- Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA
| | - Bert Hobmayer
- Institute of Zoology and Centre for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria
| | - Lynn Cooley
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, USA
- Lead contact
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Zhang C, Wu BZ, Thu KL. Targeting Kinesins for Therapeutic Exploitation of Chromosomal Instability in Lung Cancer. Cancers (Basel) 2025; 17:685. [PMID: 40002279 PMCID: PMC11853690 DOI: 10.3390/cancers17040685] [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: 01/22/2025] [Revised: 02/13/2025] [Accepted: 02/14/2025] [Indexed: 02/27/2025] Open
Abstract
New therapeutic approaches that antagonize tumour-promoting phenotypes in lung cancer are needed to improve patient outcomes. Chromosomal instability (CIN) is a hallmark of lung cancer characterized by the ongoing acquisition of genetic alterations that include the gain and loss of whole chromosomes or segments of chromosomes as well as chromosomal rearrangements during cell division. Although it provides genetic diversity that fuels tumour evolution and enables the acquisition of aggressive phenotypes like immune evasion, metastasis, and drug resistance, too much CIN can be lethal because it creates genetic imbalances that disrupt essential genes and induce severe proteotoxic and metabolic stress. As such, sustaining advantageous levels of CIN that are compatible with survival is a fine balance in cancer cells, and potentiating CIN to levels that exceed a tolerable threshold is a promising treatment strategy for inherently unstable tumours like lung cancer. Kinesins are a superfamily of motor proteins with many members having functions in mitosis that are critical for the correct segregation of chromosomes and, consequently, maintaining genomic integrity. Accordingly, inhibition of such kinesins has been shown to exacerbate CIN. Therefore, inhibiting mitotic kinesins represents a promising strategy for amplifying CIN to lethal levels in vulnerable cancer cells. In this review, we describe the concept of CIN as a therapeutic vulnerability and comprehensively summarize studies reporting the clinical and functional relevance of kinesins in lung cancer, with the goal of outlining how kinesin inhibition, or "targeting kinesins", holds great potential as an effective strategy for treating lung cancer.
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Affiliation(s)
- Christopher Zhang
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON M5B 1T8, Canada
| | - Benson Z. Wu
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON M5B 1T8, Canada
| | - Kelsie L. Thu
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON M5B 1T8, Canada
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Saadh MJ, Ghnim ZS, Mahdi MS, Chandra M, Ballal S, Bareja L, Chaudhary K, Sharma RSK, Gupta S, Taher WM, Alwan M, Jawad MJ, Hamad AK. Decoding the Role of Kinesin Superfamily Proteins in Glioma Progression. J Mol Neurosci 2025; 75:10. [PMID: 39847238 DOI: 10.1007/s12031-025-02308-9] [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: 12/05/2024] [Accepted: 01/04/2025] [Indexed: 01/24/2025]
Abstract
Glioma is a highly aggressive and invasive brain tumor with limited treatment options, highlighting the need for novel therapeutic approaches. Kinesin superfamily proteins (KIFs) are a diverse group of motor proteins that play essential roles in cellular processes such as mitosis, intracellular transport, and signal transduction, all of which are crucial for tumorigenesis. This review focuses on the multifaceted role of KIFs in glioma, examining their clinical relevance, contribution to tumor progression, and potential as therapeutic targets. We discuss how KIFs influence key aspects of glioma biology, including cell proliferation, invasion, migration, and metastasis. Furthermore, we explore the regulation of the cell cycle and critical signaling pathways associated with glioma, such as PI3K-Akt, Wnt/β-catenin, and Hedgehog signaling by KIFs. The review also addresses the emerging interplay between KIFs and non-coding RNAs, including circular RNAs (circRNAs) and microRNAs (miRNAs), in glioma progression. Finally, we examine current therapeutic strategies targeting KIFs, including immunotherapy, chemotherapy, and small-molecule inhibitors, and their potential to improve treatment outcomes for glioma patients. By synthesizing these insights, this review underscores the significance of KIFs in glioma pathogenesis and their promise as novel therapeutic targets in the fight against glioma.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan.
| | | | | | - Muktesh Chandra
- Department of Microbiology, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, 360003, Gujarat, India
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Lakshay Bareja
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - Kamlesh Chaudhary
- Department of Neurology, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - R S K Sharma
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | - Sofia Gupta
- Department of Applied Sciences, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - Waam Mohammed Taher
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
| | - Mariem Alwan
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
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Xiao Z, Nian Z, Zhang M, Liu Z, Zhang P, Zhang Z. Single-cell and bulk RNA-sequencing reveal SPP1 and CXCL12 as cell-to-cell communication markers to predict prognosis in lung adenocarcinoma. ENVIRONMENTAL TOXICOLOGY 2024; 39:4610-4622. [PMID: 38622884 DOI: 10.1002/tox.24297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 03/22/2024] [Accepted: 04/09/2024] [Indexed: 04/17/2024]
Abstract
Lung adenocarcinoma (LUAD) generally presents as an immunosuppressive microenvironment. The characteristics of cell-to-cell communication in the LUAD microenvironment has been unclear. In this study, the LUAD bulk RNA-seq data and single-cell RNA-seq data were retrieved from public dataset. Differential expression genes (DEGs) between LUAD tumor and adjacent non-tumor tissues were calculated by limma algorithm, and then detected by PPI, KEGG, and GO analysis. Cell-cell interactions were explored using the single-cell RNA-seq data. Finally, the first 15 CytoHubba genes were used to establish related pathways and these pathways were used to characterize the immune-related ligands and their receptors in LUAD. Our analyses showed that monocytes or macrophages interact with tissue stem cells and NK cells via SPP1 signaling pathway and tissue stem cells interact with T and B cells via CXCL signaling pathway in different states. Hub genes of SPP1 participated in SPP1 signaling pathway, which was negatively correlated with CD4+ T cell and CD8+ T cell. The expression of SPP1 in LUAD tumor tissues was negatively correlated with the prognosis. While CXCL12 participated in CXCL signaling pathway, which was positively correlated with CD4+ T cell and CD8+ T cell. The role of CXCL12 in LUAD tumor tissues exhibits an opposite effect to that of SPP1. This study reveals that tumor-associated monocytes or macrophages may affect tumor progression. Moreover, the SPP1 and CXCL12 may be the critic genes of cell-to-cell communication in LUAD, and targeting these pathways may provide a new molecular mechanism for the treatment of LUAD.
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Affiliation(s)
- Zengtuan Xiao
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin, China
- Department of Immunology, Biochemistry and Molecular Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, State Key Laboratory of Experimental Hematology, Tianjin Medical University, Tianjin, China
| | - Zhe Nian
- Department of Immunology, Biochemistry and Molecular Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, State Key Laboratory of Experimental Hematology, Tianjin Medical University, Tianjin, China
| | - Mengzhe Zhang
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin, China
| | - Zuo Liu
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin, China
| | - Pengpeng Zhang
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin, China
| | - Zhenfa Zhang
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin, China
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Sun-Zhang A, Juhlin CC, Carling T, Scholl U, Schott M, Larsson C, Bajalica-Lagercrantz S. Comprehensive genomic analysis of adrenocortical carcinoma reveals genetic profiles associated with patient survival. ESMO Open 2024; 9:103617. [PMID: 38935991 PMCID: PMC11260375 DOI: 10.1016/j.esmoop.2024.103617] [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: 04/22/2024] [Accepted: 05/16/2024] [Indexed: 06/29/2024] Open
Abstract
BACKGROUND Adrenocortical carcinoma (ACC) is one of the most lethal endocrine malignancies and there is a lack of clinically useful markers for prognosis and patient stratification. Therefore our aim was to identify clinical and genetic markers that predict outcome in patients with ACC. METHODS Clinical and genetic data from a total of 162 patients with ACC were analyzed by combining an independent cohort consisting of tumors from Yale School of Medicine, Karolinska Institutet, and Düsseldorf University (YKD) with two public databases [The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO)]. We used a novel bioinformatical pipeline combining differential expression and messenger RNA (mRNA)- and DNA-dependent survival. Data included reanalysis of previously conducted whole-exome sequencing (WES) for the YKD cohort, WES and RNA data for the TCGA cohort, and RNA data for the GEO cohort. RESULTS We identified 3903 significant differentially expressed genes when comparing ACC and adrenocortical adenoma, and the mRNA expression levels of 461/3903 genes significantly impacted survival. Subsequent analysis revealed 45 of these genes to be mutated in patients with significantly worse survival. The relationship was significant even after adjusting for stage and age. Protein-protein interaction showed previously unexplored interactions among many of the 45 proteins, including the cancer-related proteins DNA polymerase delta 1 (POLD1), aurora kinase A (AURKA), and kinesin family member 23 (KIF23). Furthermore 14 of the proteins had significant interactions with TP53 which is the most frequently mutated gene in the germline of patients with ACC. CONCLUSIONS Using a multiparameter approach, we identified 45 genes that significantly influenced survival. Notably, many of these genes have protein interactions not previously implicated in ACC. These findings may lay the foundation for improved prognostication and future targeted therapies.
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Affiliation(s)
- A Sun-Zhang
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm.
| | - C C Juhlin
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm; Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden. https://twitter.com/DrJuhlin
| | - T Carling
- Carling Adrenal Center & Hospital for Endocrine Surgery, Tampa; Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, USA
| | - U Scholl
- Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin
| | - M Schott
- Division for Specific Endocrinology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
| | - C Larsson
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm
| | - S Bajalica-Lagercrantz
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
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7
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Liu X, Xie X, Li Q, Xie X, Xiong M, Han W, Xie W. KIF23 promotes cervical cancer progression via inhibiting NLRP3-mediated pyroptosis. FASEB J 2024; 38:e23685. [PMID: 38780518 DOI: 10.1096/fj.202400281r] [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: 02/05/2024] [Revised: 04/25/2024] [Accepted: 05/08/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND Cervical cancer (CC), closely linked to persistent human papillomavirus infection, represents a major health problem for women worldwide. The objective of this study is to elucidate KIF23's role in the development of CC and its regulatory mechanism. METHODS The bioinformatics methods were utilized to extract pyroptosis-associated differentially expressed genes (DEGs) and pivot genes from the GSE9750 and GSE63678 datasets, followed by immune infiltration analysis and quantification of these genes' expression. The effects of kinesin family member 23 (KIF23) were verified through functional experiments in vitro and a mouse xenograft model. The NLPR3 activator, nigericin, was applied for further analyzing the potential regulatory mechanism of KIF23 in CC. RESULTS A total of 8 pyroptosis-related DEGs were screened out, among which 4 candidate core genes were identified as candidate hub genes and confirmed upregulation in CC tissues and cells. These genes respectively showed a positive correlation with the infiltration of distinct immune cells or tumor purity. Downregulation of KIF23 could suppress the proliferation, migration, and invasion abilities in CC cells and tumorigenesis through enhancing pyroptosis. Conversely, KIF23 overexpression accelerated the malignant phenotypes of CC cells and inhibited pyroptosis activation, which was blocked by nigericin treatment. CONCLUSIONS KIF23 may play an oncogenic role in CC progression via inhibition of the NLRP3-mediated pyroptosis pathway.
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Affiliation(s)
- Xiaoyan Liu
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China
| | - Xiaoqing Xie
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China
| | - Qiulian Li
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China
| | - Xiaohong Xie
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China
| | - Min Xiong
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China
| | - Wenling Han
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China
| | - Wei Xie
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China
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Wang T, Peng X, Liu W, Ji M, Sun J. Identification and validation of KIF23 as a hypoxia-regulated lactate metabolism-related oncogene in uterine corpus endometrial carcinoma. Life Sci 2024; 341:122490. [PMID: 38336274 DOI: 10.1016/j.lfs.2024.122490] [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: 11/15/2023] [Revised: 02/01/2024] [Accepted: 02/04/2024] [Indexed: 02/12/2024]
Abstract
AIMS The "Warburg effect" has been developed from the discovery that hypoxia-inducible factor 1α (HIF-1α) could promote the conversion of pyruvate to lactate. However, no studies have linked hypoxia and lactate metabolism to uterine corpus endometrial carcinoma (UCEC). MAIN METHODS Sequencing and clinical data of patients with UCEC were extracted from The Cancer Genome Atlas (TCGA) database. Hypoxia-related lactate metabolism genes (HRLGs) were screened using Spearman's correlation analysis. A prognostic signature based on HRLGs was developed using the least absolute shrinkage and selection operator (LASSO) algorithm. A comprehensive analysis was conducted on the molecular features, immune environment, mutation patterns, and response to drugs between different risk groups. In vitro and in vivo experiments were performed to verify the function of KIF23. KEY FINDINGS A five HRLG-based prognostic signature was identified. The prognostic outcome was unfavorable for the high-risk subgroup. Observation of increased pathway activities associated with cell proliferation and DNA damage repair was noted in the high-risk subgroup. Additionally, notable correlations were observed between risk score and immune microenvironment, mutational features, and drug responsiveness. Further, we confirmed KIF23 as a novel oncogene in UCEC, whose silencing decreased proliferation and promoted apoptosis of cancer cells. KIF23 knockdown reduced tumor growth in nude mice. We demonstrated that KIF23 was upregulated under hypoxic stress in a HIF-1α dependent manner. Moreover, KIF23 regulated lactate dehydrogenase A expression. SIGNIFICANCE The developed HRLG-related signature was associated with prognosis, immune microenvironment, and drug sensitivity in UCEC. We also revealed KIF23 as a hypoxia-regulated lactate metabolism-related oncogene.
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Affiliation(s)
- Tao Wang
- The Gynecology Department, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Xiaotong Peng
- The Gynecology Department, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Wenwen Liu
- The Gynecology Department, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Mei Ji
- The Gynecology Department, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Jing Sun
- The Gynecology Department, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
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Zhao K, Li X, Feng Y, Wang J, Yao W. The role of kinesin family members in hepatobiliary carcinomas: from bench to bedside. Biomark Res 2024; 12:30. [PMID: 38433242 PMCID: PMC10910842 DOI: 10.1186/s40364-024-00559-z] [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: 10/06/2023] [Accepted: 01/03/2024] [Indexed: 03/05/2024] Open
Abstract
As a major component of the digestive system malignancies, tumors originating from the hepatic and biliary ducts seriously endanger public health. The kinesins (KIFs) are molecular motors that enable the microtubule-dependent intracellular trafficking necessary for mitosis and meiosis. Normally, the stability of KIFs is essential to maintain cell proliferation and genetic homeostasis. However, aberrant KIFs activity may destroy this dynamic stability, leading to uncontrolled cell division and tumor initiation. In this work, we have made an integral summarization of the specific roles of KIFs in hepatocellular and biliary duct carcinogenesis, referring to aberrant signal transduction and the potential for prognostic evaluation. Additionally, current clinical applications of KIFs-targeted inhibitors have also been discussed, including their efficacy advantages, relationship with drug sensitivity or resistance, the feasibility of combination chemotherapy or other targeted agents, as well as the corresponding clinical trials. In conclusion, the abnormally activated KIFs participate in the regulation of tumor progression via a diverse range of mechanisms and are closely associated with tumor prognosis. Meanwhile, KIFs-aimed inhibitors also carry out a promising tumor-targeted therapeutic strategy that deserves to be further investigated in hepatobiliary carcinoma (HBC).
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Affiliation(s)
- Kai Zhao
- Department of Biliary and Pancreatic Surgery, Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Xiangyu Li
- Department of Thoracic Surgery Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Yunxiang Feng
- Department of Biliary and Pancreatic Surgery, Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Jianming Wang
- Department of Biliary and Pancreatic Surgery, Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China.
- Affiliated Tianyou Hospital, Wuhan University of Science & Technology, 430064, Wuhan, China.
| | - Wei Yao
- Department of Oncology Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China.
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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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Bai M, Liu X. Diagnostic biomarker KIF23 is associated with immune infiltration and immunotherapy response in gastric cancer. Front Oncol 2023; 13:1191009. [PMID: 37483517 PMCID: PMC10361780 DOI: 10.3389/fonc.2023.1191009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 06/12/2023] [Indexed: 07/25/2023] Open
Abstract
Kinesin family member 23 (KIF23), an index of tumor proliferation, can serve as a prognostic marker in numerous tumors. However, the relationship between KIF23 expression and diagnostic value, immune infiltration, and immunotherapy response remains unclear in gastric cancer(GC). We primarily demonstrated that GC tissue had higher levels of KIF23 expression than the adjacent normal tissue on mRNA and protein levels. The ROC analysis revealed KIF23 had an outstanding diagnostic value of GC in the training and validation set (AUC = 0.958, and AUC = 0.86793, respectively). We discovered that KIF23 was positively associated with age, histological type, and H. pylori infection of GC. Subsequently, the KIF23 expression level was correlated with the gene mutation, function enrichment, immune cell infiltration, and immune cell marker of GC based on multiple online websites and R software. KIF23 expression was related to the infiltration of CD8+ T cells, CD4+T cells, macrophages, and dendritic cells in GC. Especially, KIF23 expression was positively significantly associated with the Th1 cell marker STAT1 (Signal transducer and activator of transcription 1). Patients with high KIF23 expression exhibited greater immune cell infiltrates, including T cell CD4+ memory helper, Treg, and M1 cells, which indicated that high KIF23 expression is more conducive to immunosuppression. Finally, KIF23 expression had a positive relationship with TMB and MSI, and affected the immune microenvironment in GC tissues by increased expression of ICPs such as CD274(PD-L1), CTLA4, HAVCR2, and LAG3. Our study uncovered that KIF23 can serve as an immune-related biomarker for diagnosis and immunotherapy response of GC.
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Affiliation(s)
- Maoshu Bai
- Department of Oncology, Dazhou Integrated Traditional Chinese Medicine and Western Medicine Hospital, Dazhou Second People’s Hospital, Dazhou, Sichuan, China
| | - Xin Liu
- Molecular Diagnosis Center, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, Yunnan, China
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Tang W, Zhang L, Li J, Guan Y. KCNQ1OT1 promotes retinoblastoma progression by targeting miR-339-3p that suppresses KIF23. Int Ophthalmol 2023:10.1007/s10792-023-02641-1. [PMID: 37198502 DOI: 10.1007/s10792-023-02641-1] [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: 08/20/2021] [Accepted: 01/19/2023] [Indexed: 05/19/2023]
Abstract
BACKGROUND Long noncoding RNAs (lncRNAs) are involved in tumor formation and development. KCNQ1OT1 regulates the malignant proliferation of retinoblastoma (RB), but the specific mechanism remains to be further investigated. METHODS The KCNQ1OT1, miR-339-3p and KIF23 expression levels in RB were detected by qRT-PCR and western blotting. The cell viability, proliferation, migration ability and caspase-3 activity of RB cells were evaluated by CCK-8, BrdU, transwell and caspase-3 activity analysis. Western blot was used to detect the Bax and Bcl-2 protein expression in RB cells. The binding relationship between KCNQ1OT1, miR-339-3p and KIF23 was detected by luciferase, RIP and RNA pull-down assay. RESULTS KCNQ1OT1 and KIF23 were up-regulated frequently in RB, and miR-339-3p was down-regulated. Functional studies showed that downregulation of KCNQ1OT1 or KIF23 inhibited the survival and migration of RB cells, and facilitated apoptosis. Interference with miR-339-3p showed the opposite effect. Mechanisms suggested that KCNQ1OT1 exited its oncogenic activity by positively regulating the expression of KIF23 and sponging miR-339-3p. CONCLUSION KCNQ1OT1/miR-339-3p/KIF23 may be a new biomarker for the diagnosis and treatment of RB.
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Affiliation(s)
- Wenting Tang
- Department of Ophthalmology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, Sichuan, China
| | - Li Zhang
- Department of Ophthalmology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, Sichuan, China
| | - Jing Li
- Department of Ophthalmology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, Sichuan, China
| | - Yu Guan
- Department of Ophthalmology, The 2nd Affiliated Hospital of Chengdu Medical College, Nuclear Industry 416 Hospital, No. 4, North 4th Erhuan Street, Chengdu, 610051, Sichuan, China.
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Xu Q, Li X, Li Y, Yu J, Yang A. Kinesin family member 23 knockdown inhibits cell proliferation and epithelial-mesenchymal transition in esophageal carcinoma by inactivating the Wnt/β-catenin pathway. Funct Integr Genomics 2023; 23:154. [PMID: 37162618 DOI: 10.1007/s10142-023-01088-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 05/03/2023] [Accepted: 05/05/2023] [Indexed: 05/11/2023]
Abstract
Kinesin family member 23 (KIF23) serves as a tumor-promoting gene with prognostic values in various tumors. However, the role of KIF23 in esophageal carcinoma (ESCA) progression is largely unknown. The overlapping differentially expressed genes (DEGs) in GSE12452, GSE17351, and GSE20347 datasets were identified via GEO2R tool and Venn diagram software. KIF23 expression was analyzed using GSE12452, GSE17351, and GSE20347 datasets, GEPIA database, and qRT-PCR. Cell proliferation was assessed by CCK-8 and EdU incorporation assays. Gene set enrichment analysis (GSEA) analysis was performed to investigate the pathways associated with the regulatory mechanisms of KIF23 in ESCA. The expression of E-cadherin, vimentin, N-cadherin, and matrix metalloproteinase-9 (MMP-9) and alternation of Wnt/β-catenin pathway were detected by western blot analysis. We identified two overlapping upregulated DEGs, among which KIF23 was selected for subsequent experiments. KIF23 was overexpressed in ESCA samples and cells, and knockdown of KIF23 retarded cell proliferation in ESCA cells. Besides, KIF23 knockdown suppressed epithelial-mesenchymal transition (EMT) process in ESCA cells, as evidenced by the increase of E-cadherin expression and the reduction of vimentin, N-cadherin, and MMP-9 expression. GSEA analysis suggested that Wnt signaling pathway was the significant pathway related to KIF23. Moreover, we demonstrated that KIF23 silencing inhibited the Wnt/β-catenin pathway in ESCA cells. Activation of Wnt/β-catenin pathway by SKL2001 reversed the effects of KIF23 silencing on cell proliferation and EMT in ESCA cells. In conclusion, KIF23 knockdown inhibited the proliferation and EMT in ESCA cells through blockage of Wnt/β-catenin pathway.
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Affiliation(s)
- Quanxiao Xu
- Department of Oncology, Nanyang First People's Hospital Affiliated to Henan University, Nanyang, 473012, China
| | - Xianzhe Li
- Department of General Surgery, Nanshi Hospital Affiliated to Henan University, Nanyang, 473000, China
| | - Yan Li
- Department of General Surgery, Nanyang First People's Hospital Affiliated to Henan University, Nanyang, 473012, China
| | - Jinsong Yu
- Department of General Surgery, Nanyang First People's Hospital Affiliated to Henan University, Nanyang, 473012, China
| | - Aimin Yang
- Department of Radiotherapy, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an Second People's Hospital, 62 South Huaihai Road, Huai'an, 223022, China.
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Qiao S, Jiang Y, Li N, Zhu X. The kinesin light chain-2, a target of mRNA stabilizing protein HuR, inhibits p53 protein phosphorylation to promote radioresistance in NSCLC. Thorac Cancer 2023. [PMID: 37055376 DOI: 10.1111/1759-7714.14886] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/23/2023] [Accepted: 03/24/2023] [Indexed: 04/15/2023] Open
Abstract
BACKGROUND Radioresistance hinders radiotherapy for the treatment of lung cancer. Kinesin light chain-2 (KLC2) has been found to be upregulated in lung cancer and also to be associated with poor prognosis. This study aimed to investigate the effect of KLC2 on radiosensitivity in lung cancer. METHODS The radioresistant role of KLC2 was determined by colony formation, neutral comet assay, and γH2AX immunofluorescent staining assay. We further verified the function of KLC2 in a xenograft tumor model. The downstream of KLC2 was identified through gene set enrichment analysis and validated by western blot. Finally, we analyzed clinical data from the TCGA database to reveal the upstream transcription factor of KLC2, which was validated by RNA binding protein immunoprecipitation assay. RESULTS Here, we found that downregulation of KLC2 could significantly reduce colony formation, increase γH2AX level, and double-stranded DNA breaks in vitro. Meanwhile, overexpressed KLC2 significantly increased the proportion of the S phase in lung cancer cells. KLC2 knockdown could activate P53 pathway, and ultimately promoting radiosensitivity. The mRNA of KLC2 was observed to bind with Hu-antigen R (HuR). The mRNA and protein expression of KLC2 in lung cancer cells was significantly reduced when combined with siRNA-HuR. Interestingly, KLC2 overexpression significantly increased the expression of HuR in lung cancer cells. CONCLUSION Taken together, these results indicated that HuR-KLC2 forms a positive feedback loop, which decreases the phosphorylation of p53 and thereby weaken the radiosensitivity of lung cancer cells. Our findings highlight the potential prognosis and therapeutic target value of KLC2 in lung cancer patients treated with radiotherapy.
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Affiliation(s)
- Simiao Qiao
- Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yuhang Jiang
- Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Na Li
- Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoxia Zhu
- Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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Xu H, Liu J, Zhang Y, Zhou Y, Zhang L, Kang J, Ning C, He Z, Song S. KIF23, under regulation by androgen receptor, contributes to nasopharyngeal carcinoma deterioration by activating the Wnt/β-catenin signaling pathway. Funct Integr Genomics 2023; 23:116. [PMID: 37010644 DOI: 10.1007/s10142-023-01044-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 03/22/2023] [Accepted: 03/27/2023] [Indexed: 04/04/2023]
Abstract
Our study aimed to explore the potential mechanisms of KIF23 regulating function in the progression of nasopharyngeal carcinoma and pinpoint novel therapeutic targets for the clinical treatment of nasopharyngeal carcinoma patients. Firstly, the mRNA and protein level of KIF23 in nasopharyngeal carcinoma was measured using quantitative real-time PCR and western blot. Then, the influence of KIF23 on tumor metastasis and growth in nasopharyngeal carcinoma was determined through the in vivo and in vitro experiments. Lastly, the regulatory mechanisms of KIF23 in nasopharyngeal carcinoma were illustrated in the chromatin immunoprecipitation assay. KIF23 was first found to be overexpressed in nasopharyngeal carcinoma samples, and its expression was associated with poor prognosis. Then, the nasopharyngeal carcinoma cell's proliferation, migration, and invasion potential could be improved by inducing KIF23 expression both in vivo and in vitro. Furthermore, androgen receptor (AR) was found to bind to the KIF23 promoter region directly and enhance KIF23 transcription. At last, KIF23 could accelerate nasopharyngeal carcinoma deterioration via activating the Wnt/β-catenin signaling pathway. AR/KIF23/Wnt/β-catenin pathway promotes nasopharyngeal carcinoma deterioration. Our findings could serve as a new therapeutic strategy for nasopharyngeal carcinoma in the clinical practice.
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Affiliation(s)
- Hongbo Xu
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
- Anhui Province Key Laboratory of Translational Cancer Research Affiliated to Bengbu Medical College, Bengbu, Anhui, China
| | - Jingjing Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Yajun Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Yan Zhou
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Lei Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Jia Kang
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Can Ning
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Zelai He
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China.
- Anhui Province Key Laboratory of Translational Cancer Research Affiliated to Bengbu Medical College, Bengbu, Anhui, China.
| | - Shilong Song
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China.
- Anhui Province Key Laboratory of Translational Cancer Research Affiliated to Bengbu Medical College, Bengbu, Anhui, China.
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Rashid MU, Lorzadeh S, Gao A, Ghavami S, Coombs KM. PSMA2 knockdown impacts expression of proteins involved in immune and cellular stress responses in human lung cells. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166617. [PMID: 36481484 DOI: 10.1016/j.bbadis.2022.166617] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 11/21/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022]
Abstract
Proteasome subunit alpha type-2 (PSMA2) is a critical component of the 20S proteasome, which is the core particle of the 26S proteasome complex and is involved in cellular protein quality control by recognizing and recycling defective proteins. PSMA2 expression dysregulation has been detected in different human diseases and viral infections. No study yet has reported PSMA2 knockdown (KD) effects on the cellular proteome. METHODS We used SOMAScan, an aptamer-based multiplexed technique, to measure >1300 human proteins to determine the impact of PSMA2 KD on A549 human lung epithelial cells. RESULTS PSMA2 KD resulted in significant dysregulation of 52 cellular proteins involved in different bio-functions, including cellular movement and development, cell death and survival, and cancer. The immune system and signal transduction were the most affected cellular functions. PSMA2 KD caused dysregulation of several signaling pathways involved in immune response, cytokine signaling, organismal growth and development, cellular stress and injury (including autophagy and unfolded protein response), and cancer responses. CONCLUSIONS In summary, this study helps us better understand the importance of PSMA2 in different cellular functions, signaling pathways, and human diseases.
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Affiliation(s)
- Mahamud-Ur Rashid
- University of Manitoba, Department of Medical Microbiology & Infectious Diseases, Room 543 Basic Medical Sciences Building, 745 Bannatyne Ave., Winnipeg, MB R3E 0J9, Canada; Manitoba Centre for Proteomics & Systems Biology, Room 799, 715 McDermot Ave., Winnipeg, MB R3E 3P4, Canada
| | - Shahrokh Lorzadeh
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
| | - Ang Gao
- Manitoba Centre for Proteomics & Systems Biology, Room 799, 715 McDermot Ave., Winnipeg, MB R3E 3P4, Canada
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada; Research Institutes of Oncology and Hematology, Cancer Care Manitoba-University of Manitoba, Winnipeg, MB R3E 0V9, Canada; Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
| | - Kevin M Coombs
- University of Manitoba, Department of Medical Microbiology & Infectious Diseases, Room 543 Basic Medical Sciences Building, 745 Bannatyne Ave., Winnipeg, MB R3E 0J9, Canada; Manitoba Centre for Proteomics & Systems Biology, Room 799, 715 McDermot Ave., Winnipeg, MB R3E 3P4, Canada; Children's Hospital Research Institute of Manitoba, Room 513, 715 McDermot Ave., Winnipeg, MB R3E 3P4, Canada.
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In Silico Pan-Cancer Analysis Reveals Prognostic Role of the Erythroferrone (ERFE) Gene in Human Malignancies. Int J Mol Sci 2023; 24:ijms24021725. [PMID: 36675239 PMCID: PMC9864255 DOI: 10.3390/ijms24021725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/12/2023] [Accepted: 01/13/2023] [Indexed: 01/19/2023] Open
Abstract
The erythroferrone gene (ERFE), also termed CTRP15, belongs to the C1q tumor necrosis factor-related protein (CTRP) family. Despite multiple reports about the involvement of CTRPs in cancer, the role of ERFE in cancer progression is largely unknown. We previously found that ERFE was upregulated in erythroid progenitors in myelodysplastic syndromes and strongly predicted overall survival. To understand the potential molecular interactions and identify cues for further functional investigation and the prognostic impact of ERFE in other malignancies, we performed a pan-cancer in silico analysis utilizing the Cancer Genome Atlas datasets. Our analysis shows that the ERFE mRNA is significantly overexpressed in 22 tumors and affects the prognosis in 11 cancer types. In certain tumors such as breast cancer and adrenocortical carcinoma, ERFE overexpression has been associated with the presence of oncogenic mutations and a higher tumor mutational burden. The expression of ERFE is co-regulated with the factors and pathways involved in cancer progression and metastasis, including activated pathways of the cell cycle, extracellular matrix/tumor microenvironment, G protein-coupled receptor, NOTCH, WNT, and PI3 kinase-AKT. Moreover, ERFE expression influences intratumoral immune cell infiltration. Conclusively, ERFE is aberrantly expressed in pan-cancer and can potentially function as a prognostic biomarker based on its putative functions during tumorigenesis and tumor development.
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Antitumor Effects of Poplar Propolis on DLBCL SU-DHL-2 Cells. Foods 2023; 12:foods12020283. [PMID: 36673375 PMCID: PMC9857396 DOI: 10.3390/foods12020283] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/27/2022] [Accepted: 01/02/2023] [Indexed: 01/11/2023] Open
Abstract
Propolis is resinous natural product produced by Western honeybees using beeswax and plant and bud exudates, which has a wide range of biological activities, including antioxidation, antibacterial, anti-inflammation, immune regulation, antitumor, and so on. Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer, and accounts for about 30% of all lymphomas. The effect of poplar propolis on DLBCL has not been reported. The IC50 of propolis on the proliferation of DLBCL SU-DHL-2 cell line and its proteins and gene expressions were detected by CCK-8 kit, label-free proteomic, and RT-PCR. The results showed that the IC50 of propolis at the 5 × l05/mL cell for 24 h was 5.729 μg/mL. Label-free-based proteomics analysis showed that there were 115 differentially expressed proteins (61 up-regulated and 54 down-regulated proteins) between IC50 dose-treated and solvent control groups. There were 32.47% differential proteins located in the nucleus, 20.78% in the cytoplasm, and 14.29% in mitochondria. The most significant different pathway (p = 0.0016) of protein enrichment was ferroptosis (including glutamate-cysteine ligase regulatory subunit, ferritin, and heme oxygenase). The relative expression trend of 17 of the total 22 genes selected according to proteomics results was in line with their encoded protein. The highest protein-protein interaction was serine/threonine-protein kinase PLK, which interacted with 16 differential proteins. In conclusion, poplar propolis inhibited SU-DHL-2 cells via ferroptosis pathway, accelerating cell death and down-regulated serine/threonine-protein kinase PLK1, affecting apoptosis of cell. This result provides a theoretical basis for the treatment of DLBCL using propolis.
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Li Z, Yang HY, Zhang XL, Zhang X, Huang YZ, Dai XY, Shi L, Zhou GR, Wei JF, Ding Q. Kinesin family member 23, regulated by FOXM1, promotes triple negative breast cancer progression via activating Wnt/β-catenin pathway. J Exp Clin Cancer Res 2022; 41:168. [PMID: 35524313 PMCID: PMC9077852 DOI: 10.1186/s13046-022-02373-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
Background Triple negative breast cancer (TNBC) is highly malignant and has a worse prognosis, compared with other subtypes of breast cancer due to the absence of therapeutic targets. KIF23 plays a crucial role in the tumorigenesis and cancer progression. However, the role of KIF23 in development of TNBC and the underlying mechanism remain unknown. The study aimed to elucidate the biological function and regulatory mechanism of KIF23 in TNBC. Methods Quantitative real-time PCR and Western blot were used to determine the KIF23 expression in breast cancer tissues and cell lines. Then, functional experiments in vitro and in vivo were performed to investigate the effects of KIF23 on tumor growth and metastasis in TNBC. Chromatin immunoprecipitation assay was conducted to illustrate the potential regulatory mechanisms of KIF23 in TNBC. Results We found that KIF23 was significantly up-regulated and associated with poor prognosis in TNBC. KIF23 could promote TNBC proliferation, migration and invasion in vitro and in vivo. KIF23 could activate Wnt/β-catenin pathway and promote EMT progression in TNBC. In addition, FOXM1, upregulated by WDR5 via H3K4me3 modification, directly bound to the promoter of KIF23 gene to promote its transcription and accelerated TNBC progression via Wnt/β-catenin pathway. Both of small inhibitor of FOXM1 and WDR5 could inhibit TNBC progression. Conclusions Our findings elucidate WDR5/FOXM1/KIF23/Wnt/β-catenin axis is associated with TNBC progression and may provide a novel and promising therapeutic target for TNBC treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02373-7.
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Zhang L, Fan S, Vera J, Lai X. A network medicine approach for identifying diagnostic and prognostic biomarkers and exploring drug repurposing in human cancer. Comput Struct Biotechnol J 2022; 21:34-45. [PMID: 36514340 PMCID: PMC9732137 DOI: 10.1016/j.csbj.2022.11.037] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 11/18/2022] [Accepted: 11/18/2022] [Indexed: 12/03/2022] Open
Abstract
Cancer is a heterogeneous disease mainly driven by abnormal gene perturbations in regulatory networks. Therefore, it is appealing to identify the common and specific perturbed genes from multiple cancer networks. We developed an integrative network medicine approach to identify novel biomarkers and investigate drug repurposing across cancer types. We used a network-based method to prioritize genes in cancer-specific networks reconstructed using human transcriptome and interactome data. The prioritized genes show extensive perturbation and strong regulatory interaction with other highly perturbed genes, suggesting their vital contribution to tumorigenesis and tumor progression, and are therefore regarded as cancer genes. The cancer genes detected show remarkable performances in discriminating tumors from normal tissues and predicting survival times of cancer patients. Finally, we developed a network proximity approach to systematically screen drugs and identified dozens of candidates with repurposable potential in several cancer types. Taken together, we demonstrated the power of the network medicine approach to identify novel biomarkers and repurposable drugs in multiple cancer types. We have also made the data and code freely accessible to ensure reproducibility and reusability of the developed computational workflow.
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Affiliation(s)
- Le Zhang
- College of Computer Science, Sichuan University, Chengdu, China
| | - Shiwei Fan
- College of Computer Science, Sichuan University, Chengdu, China
| | - Julio Vera
- Laboratory of Systems Tumor Immunology, Department of Dermatology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie, Erlangen, Germany,Comprehensive Cancer Center Erlangen, Erlangen, Germany
| | - Xin Lai
- Laboratory of Systems Tumor Immunology, Department of Dermatology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie, Erlangen, Germany,Comprehensive Cancer Center Erlangen, Erlangen, Germany,BioMediTech, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland,Corresponding author at: Universitätsklinikum Erlangen, Erlangen, Germany; Tampere University, Tampere, Finland.
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Li J, Du Q, Sun J, Xiang L, Wang S. Identification and validation of a novel phagocytosis regulators-related signature with potential prognostic and immunotherapeutic value in patients with lung adenocarcinoma. Front Oncol 2022; 12:988332. [PMID: 36408131 PMCID: PMC9666737 DOI: 10.3389/fonc.2022.988332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 10/21/2022] [Indexed: 02/22/2024] Open
Abstract
BACKGROUND Lung adenocarcinoma (LUAD) is a malignant tumor that seriously affects the prognosis of patients. Tumor-associated macrophages (TAMs) play a vital role in the tumor microenvironment and can be used as a potential target for tumor therapy, and phagocytosis regulators (PRs) are particularly important in this process. However, the PRs-related signature that can predict the potential prognostic and immunotherapeutic value in patients with LUAD has not been discovered. METHODS In this study, we mainly analyzed the effect of phagocytosis regulators on the prognosis of LUAD, and based on multiple screening analyses including differential analysis, univariate Cox analysis, and Lasso analysis, we constructed a prognostic risk model consisting of five genes. To verify the stability of the model, survival analysis and ROC curve verification were carried out through multiple data sets. In addition, we also combined many factors, such as immune infiltrating cells, clinical grouping characteristics, immune examination sites, pro-inflammatory factors, and other factors as well as in vitro cell experiments and clinical tissue samples for further validation analysis. RESULTS After identifying 29 differentially expressed PRs in LUAD samples, we further constructed a prognostic model consisting of five prognostic signatures (FURIN, KIF23, SASH3, GNPNAT1, and ITGAL). Further survival analysis tests, ROC verification, as well as univariate and multivariate Cox regression analysis showed that the risk score of the model could well predict the prognosis of LUAD patients and could be used as an independent prognostic factor. In addition, we further found that these phagocytic regulators-related signatures were closely related to the immune microenvironment and immunotherapy in LUAD patients, and could well predict the efficacy of immunotherapy in patients. In vitro cell experiments and Immunohistochemistry of clinical tissues showed that the expressions of FURIN, KIF23, SASH3, GNPNAT1 and ITGAL in normal lung cells/tissues and LUAD cells/tissues were consistent with bioinformatics results, and 3 of them had significant differences. CONCLUSION Our study identified a novel PRs-related signature that has potential application value in predicting the prognosis of LUAD patients and predicting the efficacy of immunotherapy. This provides a new basis for the prognosis assessment of LUAD patients and provides a novel target for immunotherapy of LUAD patients.
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Affiliation(s)
- Jingyang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qinyun Du
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiayi Sun
- State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li Xiang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shaohui Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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22
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Identifying General Tumor and Specific Lung Cancer Biomarkers by Transcriptomic Analysis. BIOLOGY 2022; 11:biology11071082. [PMID: 36101460 PMCID: PMC9313083 DOI: 10.3390/biology11071082] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/25/2022] [Accepted: 07/03/2022] [Indexed: 11/17/2022]
Abstract
The bioinformatic pipeline previously developed in our research laboratory is used to identify potential general and specific deregulated tumor genes and transcription factors related to the establishment and progression of tumoral diseases, now comparing lung cancer with other two types of cancer. Twenty microarray datasets were selected and analyzed separately to identify hub differentiated expressed genes and compared to identify all the deregulated genes and transcription factors in common between the three types of cancer and those unique to lung cancer. The winning DEGs analysis allowed to identify an important number of TFs deregulated in the majority of microarray datasets, which can become key biomarkers of general tumors and specific to lung cancer. A coexpression network was constructed for every dataset with all deregulated genes associated with lung cancer, according to DAVID’s tool enrichment analysis, and transcription factors capable of regulating them, according to oPOSSUM´s tool. Several genes and transcription factors are coexpressed in the networks, suggesting that they could be related to the establishment or progression of the tumoral pathology in any tissue and specifically in the lung. The comparison of the coexpression networks of lung cancer and other types of cancer allowed the identification of common connectivity patterns with deregulated genes and transcription factors correlated to important tumoral processes and signaling pathways that have not been studied yet to experimentally validate their role in lung cancer. The Kaplan–Meier estimator determined the association of thirteen deregulated top winning transcription factors with the survival of lung cancer patients. The coregulatory analysis identified two top winning transcription factors networks related to the regulatory control of gene expression in lung and breast cancer. Our transcriptomic analysis suggests that cancer has an important coregulatory network of transcription factors related to the acquisition of the hallmarks of cancer. Moreover, lung cancer has a group of genes and transcription factors unique to pulmonary tissue that are coexpressed during tumorigenesis and must be studied experimentally to fully understand their role in the pathogenesis within its very complex transcriptomic scenario. Therefore, the downstream bioinformatic analysis developed was able to identify a coregulatory metafirm of cancer in general and specific to lung cancer taking into account the great heterogeneity of the tumoral process at cellular and population levels.
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Gong Y, Zhou L, Ding L, Zhao J, Wang Z, Ren G, Zhang J, Mao Z, Zhou R. KIF23 is a potential biomarker of diffuse large B cell lymphoma: Analysis based on bioinformatics and immunohistochemistry. Medicine (Baltimore) 2022; 101:e29312. [PMID: 35713434 PMCID: PMC9276187 DOI: 10.1097/md.0000000000029312] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Accepted: 05/04/2022] [Indexed: 11/26/2022] Open
Abstract
Diffuse Large B Cell Lymphoma (DLBCL), the most common form of blood cancer. The genetic and clinical heterogeneity of DLBCL poses a major barrier to diagnosis and treatment. Hence, we aim to identify potential biomarkers for DLBCL.Differentially expressed genes were screened between DLBCL and the corresponding normal tissues. Kyoto Encyclopedia of Genes and Genomes and Gene oncology analyses were performed to obtain an insight into these differentially expressed genes. PPI network was constructed to identify hub genes. survival analysis was applied to evaluate the prognostic value of those hub genes. DNA methylation analysis was implemented to explore the epigenetic dysregulation of genes in DLBCL.In this study, Kinesin family member 23 (KIF23) showed higher expression in DLBCL and was identified as a risk factor in DLBCL. The immunohistochemistry experiment further confirmed this finding. Subsequently, the univariate and multivariate analysis indicated that KIF23 might be an independent adverse factor in DLBCL. Upregulation of KIF23 might be a risk factor for the overall survival of patients who received an R-CHOP regimen, in late-stage, whatever with or without extranodal sites. Higher expression of KIF23 also significantly reduced 3, 5, 10-year overall survival. Furthermore, functional enrichment analyses (Kyoto Encyclopedia of Genes and Genomes, Gene oncology, and Gene Set Enrichment Analysis) showed that KIF23 was mainly involved in cell cycle, nuclear division, PI3K/AKT/mTOR, TGF-beta, and Wnt/beta-catenin pathway in DLBCL. Finally, results of DNA methylation analysis indicated that hypomethylation in KIF23's promoter region might be the result of its higher expression in DLBCL.The findings of this study suggested that KIF23 is a potential biomarker for the diagnosis and prognosis of DLBCL. However, further studies were needed to validate these findings.
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Affiliation(s)
- Yuqi Gong
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Lingna Zhou
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Liya Ding
- Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jing Zhao
- Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhe Wang
- Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Guoping Ren
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Jing Zhang
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhengrong Mao
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Ren Zhou
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China
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Xu J, Sang N, Zhao J, He W, Zhang N, Li X. Knockdown of circ_0067934 inhibits gastric cancer cell proliferation, migration and invasion via the miR‑1301‑3p/KIF23 axis. Mol Med Rep 2022; 25:202. [PMID: 35475447 PMCID: PMC9073844 DOI: 10.3892/mmr.2022.12718] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 07/28/2021] [Indexed: 11/24/2022] Open
Abstract
In recent years, circular RNAs (circRNAs/circs) have attracted significant attention due to their potentially important functions in a variety of human cancer types. circ_0067934 is a newly identified circRNA, the role of which in gastric cancer (GC) has yet to be reported, to the best of our knowledge. In the present study, the expression levels of circ_0067934, microRNA (miR)‑1301‑3p and kinesin family member 23 (KIF23) in GC cells were detected via reverse transcription‑quantitative PCR. Cell proliferation was measured using Cell Counting Kit‑8 assays and EdU staining. Wound healing and Transwell assays were performed to assess cell migration and invasion, respectively. Western blotting was performed to measure the protein expression levels of Ki67, proliferating cell nuclear antigen, MMP2, MMP9 and KIF23. The starBase database and luciferase reporter assays were used to predict and verify the binding between circ_0067934 and miR‑1301‑3p, as well as KIF23, in GC cells. The results demonstrated that circ_0067934 expression was upregulated in GC cells, and circ_0067934 silencing significantly inhibited GC cell proliferation, migration and invasion. In addition, miR‑1301‑3p was regulated by circ_0067934, and miR‑1301‑3p overexpression suppressed GC cell migration, invasion and proliferation. miR‑1301‑3p was found to target KIF23, and KIF23 overexpression reversed the effects of circ_0067934 silencing and miR‑1301‑3p overexpression on cell proliferation, migration and invasion. In conclusion, circ_0067934 may regulate the proliferation, invasion and migration of GC cells via the miR‑1301‑3p/KIF23 signaling axis, which may represent a novel therapeutic target for GC metastasis.
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Affiliation(s)
- Jin Xu
- Department of Gastroenterology, Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu 210024, P.R. China
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Nan Sang
- Department of Gastroenterology, Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu 210024, P.R. China
| | - Junning Zhao
- Department of Gastroenterology, Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu 210024, P.R. China
| | - Wei He
- Department of Gastroenterology, Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu 210024, P.R. China
| | - Nannan Zhang
- Department of Gastroenterology, Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu 210024, P.R. China
| | - Xueliang Li
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
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Zhang Y, Xu W, Wang Y, Li J, He G, Guan M, Zeng X, Bian W, Song Y, Liu J. Oncogenic lncRNA ZNFX1 antisense RNA 1 promotes osteosarcoma cells proliferation and metastasis by stabilizing serine and arginine‑rich splicing factor 3. Bioengineered 2022; 13:5962-5974. [PMID: 35184675 PMCID: PMC8974064 DOI: 10.1080/21655979.2022.2036900] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Recent studies have demonstrated that lncRNAs play an important role in cancers, particularly osteosarcoma. ZFAS1 is a newly identified and characterized lncRNA linked to a variety of cancers. The role of ZFAS1 in osteosarcoma is mainly unknown. This study discovered that ZFAS1 was upregulated in osteosarcoma patient tissues, which correlates with elevated SRSF3 protein levels. Higher levels of ZFAS1 or SRSF3 were linked to a poor prognosis of osteosarcoma. ZFAS1 knockdown decreased SRSF3 protein levels but had a negligible effect on SRSF3 mRNA expression. Further research indicated that ZFAS1 could bind to the SRSF3 protein directly and prevent degrading. Functional studies revealed that ZFAS1 knockdown inhibited osteosarcoma cell proliferation as measured by the CCK-8 assay, colony formation assay, and Ki-67 immunofluorescence staining. Furthermore, ZFAS1 knockdown reduced the expression of PCNA, CDK1, CDK4, and CDK6, increasing p53 and p16. IT has also been observed that ZFAS1 knockdown inhibited osteosarcoma cell migration and invasion as measured by the wound healing assay and the trans-well assay with or without Matrigel. Furthermore, exogenous SRSF3 expression in ZFAS1-depleted osteosarcoma cells restored SRSF3 expression while simultaneously inhibiting cell proliferation and metastasis. Our findings show that ZFAS1 plays an essential role in osteosarcoma progression by stabilizing the SRSF3 protein. Our study provides novel insight into the role of ZFAS1 in osteosarcoma. ZFAS1 has the potential to be used as a prognostic biomarker as well as a therapeutic target in the treatment of osteosarcoma.
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Affiliation(s)
- Yang Zhang
- Department of Orthopaedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, P. R. China
| | - Wenbo Xu
- Department of Orthopaedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, P. R. China
| | - Yanlong Wang
- Department of Orthopaedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, P. R. China
| | - Jianming Li
- Department of Orthopaedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, P. R. China
| | - Guanyi He
- Department of Orthopaedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, P. R. China
| | - Mingyan Guan
- Department of Orthopaedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, P. R. China
| | - Xiangyu Zeng
- Department of Orthopaedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, P. R. China
| | - Wei Bian
- Department of Orthopaedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, P. R. China
| | - Yan Song
- Department of Operating Room, The Second Affiliated Hospital of Harbin Medical University, Harbin, P. R. China
| | - Jianyu Liu
- Department of Orthopaedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, P. R. China
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Duan L, Perez RE, Calhoun S, Maki CG. RBL2/DREAM-mediated repression of the Aurora kinase A/B pathway determines therapy responsiveness and outcome in p53 WT NSCLC. Sci Rep 2022; 12:1049. [PMID: 35058503 PMCID: PMC8776870 DOI: 10.1038/s41598-022-05013-4] [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: 09/16/2021] [Accepted: 12/28/2021] [Indexed: 01/03/2023] Open
Abstract
Wild-type p53 is a stress-responsive transcription factor and potent tumor suppressor. P53 activates or represses genes involved in cell cycle progression or apoptosis in order to arrest the cell cycle or induce cell death. Transcription repression by p53 is indirect and requires repressive members of the RB-family (RB1, RBL1, RBL2) and formation of repressor complexes of RB1-E2F and RBL1/RBL2-DREAM. Many aurora kinase A/B (AURKA/B) pathway genes are repressed in a p53-DREAM-dependent manner. We found heightened expression of RBL2 and reduced expression of AURKA/B pathway genes is associated with improved outcomes in p53 wild-type but not p53 mutant non-small cell lung cancer (NSCLC) patients. Knockdown of p53, RBL2, or the DREAM component LIN37 increased AURKA/B pathway gene expression and reduced paclitaxel and radiation toxicity in NSCLC cells. In contrast, pharmacologic inhibition of AURKA/B or knockdown of AURKA/B pathway components increased paclitaxel and IR sensitivity. The results support a model in which p53-RBL2-DREAM-mediated repression of the AURKA/B pathway contributes to tumor suppression, improved tumor therapy responses, and better outcomes in p53 wild-type NSCLCs.
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Affiliation(s)
- Lei Duan
- Department of Anatomy and Cell Biology, Rush University Medical Center, 600 S. Paulina Ave, AcFac 507, Chicago, IL, 60612, USA. .,Rush University Medical Center, Chicago, IL, 60612, USA.
| | - Ricardo E Perez
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Sarah Calhoun
- Department of Anatomy and Cell Biology, Rush University Medical Center, 600 S. Paulina Ave, AcFac 507, Chicago, IL, 60612, USA.,Rush University Medical Center, Chicago, IL, 60612, USA
| | - Carl G Maki
- Department of Anatomy and Cell Biology, Rush University Medical Center, 600 S. Paulina Ave, AcFac 507, Chicago, IL, 60612, USA. .,Rush University Medical Center, Chicago, IL, 60612, USA.
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Shen E, Zhang J, Lu Y. DEP domain containing 1B (DEPDC1B) exerts the tumor promoter in hepatocellular carcinoma through activating p53 signaling pathway via kinesin family member 23 (KIF23). Bioengineered 2022; 13:1103-1114. [PMID: 34983303 PMCID: PMC8805966 DOI: 10.1080/21655979.2021.2017629] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/07/2021] [Accepted: 12/07/2021] [Indexed: 12/28/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is closely associated with chronic liver disease and possesses a high incidence. DEP domain containing 1B (DEPDC1B) expression has been found to be upregulated in HCC according to bioinformatics analysis. This paper sought to study the specific role of DEPDC1B in HCC. The data of DEPDC1B expression and individual overall survival in HCC and normal liver tissues were acquired from UALCAN database. The association between DEPDC1B and the downstream signal, kinesin family member 23 (KIF23), was determined using LinkedOmics and STRING database, and subsequently confirmed by co-immunoprecipitation assay. The expression levels of DEPDC1B and KIF23 in normal hepatic epithelial cells and HCC cell lines were assessed by RT-qPCR and Western blotting, respectively. Following transfection with small interference RNA-DEPDC1B, the influences of DEPDC1B knockdown on cell proliferation, colony formation, cell cycle, cell invasion, migration, and KIF23 expression were evaluated. In addition, the effects of KIF23 overexpression on the above aspects of HCC cells were also determined, as well as the expression level of p53 signaling-related proteins. The results indicated that DEPDC1B was highly expressed in HCC cells. DEPDC1B knockdown inhibited the proliferation, migration, invasion, cycle, and KIF23 expression in HCC cells. Moreover, KIF23 overexpression reversed the inhibitory effect of DEPDC1B knockdown in HCC cells and the activation of the p53 signaling. In conclusion, DEPDC1B knockdown exerts anti-cancer role in HCC by activating the p53 signaling through KIF23.
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Affiliation(s)
- Enhua Shen
- Department of Infectious Diseases, Jilin Province Faw General Hospital, Changchun, Jilin, China
| | - Jingzhi Zhang
- Department of Critical Care Medicine, Zibo Integrated Chinese and Western Medicine Hospital, Zibo, Shandong, China
| | - Yujuan Lu
- Department of Infectious Disease, Zibo Central Hospital, Zibo, Shandong, China
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He X, Wang J, Zhou R, Yu S, Jiang J, Zhou Q. Kinesin family member 23 exerts a protumor function in breast cancer via stimulation of the Wnt/β-catenin pathway. Toxicol Appl Pharmacol 2021; 435:115834. [PMID: 34933054 DOI: 10.1016/j.taap.2021.115834] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/14/2021] [Accepted: 12/16/2021] [Indexed: 01/22/2023]
Abstract
Kinesin family member 23 (KIF23) has been described as one of the main genes that are associated with malignant transformation in numerous cancers. However, the exact significance of KIF23 in breast cancer has not been well-addressed. The present study was dedicated to the comprehensive investigation of KIF23 in breast cancer. Initial expression analysis through The Cancer Genome Atlas (TCGA) demonstrated high KIF23 levels in breast cancer compared with normal controls. These in silico data showing high levels of KIF23 in breast cancer were verified by assessing clinical specimens using real-time quantitative PCR and immunoblot assays. Moreover, a high KIF23 level was correlated with adverse clinical outcomes in breast cancer patients. Cellular functional experiments showed that the down-regulation of KIF23 affected the malignant behaviors of breast cancer cells in vitro, whereas the forced expression of KIF23 stimulated them. Mechanistic studies revealed that KIF23 restraint down-regulated the levels of phosphorylated glycogen synthetase kinase-3β (GSK-3β), β-catenin, cyclin D1 and c-myc in breast cancer cells, showing an inhibitory effect on the Wnt/β-catenin pathway. The suppression of GSK-3β was able to reverse KIF23-silencing-induced inactivation of the Wnt/β-catenin pathway. Inhibition of the Wnt/β-catenin pathway abolished KIF23 overexpression-mediated protumor effects in breast cancer. A xenograft assay confirmed the in vivo antitumor function of KIF23 inhibition. In conclusion, these findings suggest that KIF23 may exert a protumor function in breast cancer by stimulating the Wnt/β-catenin pathway. This work suggests that KIF23 has potential values for targeted therapy and prognosis in breast cancer.
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Affiliation(s)
- Xin He
- Department of Ultrasound, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, Shaanxi 710004, PR China
| | - Juan Wang
- Department of Ultrasound, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, Shaanxi 710004, PR China
| | - Ru Zhou
- Department of Ultrasound, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, Shaanxi 710004, PR China
| | - Shanshan Yu
- Department of Ultrasound, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, Shaanxi 710004, PR China
| | - Jue Jiang
- Department of Ultrasound, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, Shaanxi 710004, PR China.
| | - Qi Zhou
- Department of Ultrasound, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, Shaanxi 710004, PR China.
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Sun Y, Pan H, He Y, Hu C, Gu Y. Functional roles of the SHCBP1 and KIF23 interaction in modulating the cell-cycle and cisplatin resistance of head and neck squamous cell carcinoma. Head Neck 2021; 44:591-605. [PMID: 34918847 DOI: 10.1002/hed.26961] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 11/08/2021] [Accepted: 12/02/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND This study aimed to explore the functional roles of Shc SH2-domain-binding protein 1 (SHCBP1) and Kinesin Family Member 23 (KIF23) in HPV-negative head and neck squamous cell carcinoma (HNSCC). METHODS Bioinformatic analysis was conducted using data from The Cancer Genome Atlas (TCGA) and GSE103322. HNSCC cell lines were used for in vitro and in vivo analysis. RESULTS SHCBP1 upregulation was associated with unfavorable survival. SHCBP1 knockdown reduced cell proliferation and increased the cisplatin sensitivity of SCC9/SCC25 cells. SHCBP1 interacted with KIF23 via its Nesd homology domain (NHD) domain, which was important for its nucleus localization. SHCBP1 positively modulated KIF23 expression and activated phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), extracellular signal regulated kinase (ERK)1/2, nuclear factor kappa B (NF/κB)-p65, and Wnt/β-catenin signaling. KIF23 knockdown abrogated cisplatin resistance induced by SHCBP1 overexpression. CONCLUSION SHCBP1 interacts with KIF23 and cooperatively regulates cell-cycle progression and cisplatin resistance of HNSCC tumor cells.
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Affiliation(s)
- Yonghong Sun
- Department of Oncology, Nanchong Central Hospital, Nanchong, China
| | - Haixia Pan
- Cancer Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yanwei He
- Department of Orthopedics, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Chunmei Hu
- Department of Otolaryngology - Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yi Gu
- Department of Vascular and Thyroid Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
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Zeng X, Shi G, He Q, Zhu P. Screening and predicted value of potential biomarkers for breast cancer using bioinformatics analysis. Sci Rep 2021; 11:20799. [PMID: 34675265 PMCID: PMC8531389 DOI: 10.1038/s41598-021-00268-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 10/08/2021] [Indexed: 12/16/2022] Open
Abstract
Breast cancer is the most common cancer and the leading cause of cancer-related deaths in women. Increasing molecular targets have been discovered for breast cancer prognosis and therapy. However, there is still an urgent need to identify new biomarkers. Therefore, we evaluated biomarkers that may aid the diagnosis and treatment of breast cancer. We searched three mRNA microarray datasets (GSE134359, GSE31448 and GSE42568) and identified differentially expressed genes (DEGs) by comparing tumor and non-tumor tissues using GEO2R. Functional and pathway enrichment analyses of the DEGs were performed using the DAVID database. The protein-protein interaction (PPI) network was plotted with STRING and visualized using Cytoscape. Module analysis of the PPI network was done using MCODE. The associations between the identified genes and overall survival (OS) were analyzed using an online Kaplan-Meier tool. The redundancy analysis was conducted by DepMap. Finally, we verified the screened HUB gene at the protein level. A total of 268 DEGs were identified, which were mostly enriched in cell division, cell proliferation, and signal transduction. The PPI network comprised 236 nodes and 2132 edges. Two significant modules were identified in the PPI network. Elevated expression of the genes Discs large-associated protein 5 (DLGAP5), aurora kinase A (AURKA), ubiquitin-conjugating enzyme E2 C (UBE2C), ribonucleotide reductase regulatory subunit M2(RRM2), kinesin family member 23(KIF23), kinesin family member 11(KIF11), non-structural maintenance of chromosome condensin 1 complex subunit G (NCAPG), ZW10 interactor (ZWINT), and denticleless E3 ubiquitin protein ligase homolog(DTL) are associated with poor OS of breast cancer patients. The enriched functions and pathways included cell cycle, oocyte meiosis and the p53 signaling pathway. The DEGs in breast cancer have the potential to become useful targets for the diagnosis and treatment of breast cancer.
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Affiliation(s)
- Xiaoyu Zeng
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Gaoli Shi
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Qiankun He
- School of Life Sciences, Zhengzhou University, Zhengzhou, China.
| | - Pingping Zhu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China.
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Jiang L, Guo T, Jiang Y, Liu P, Bai Y. Dauricine inhibits human pancreatic carcinoma cell proliferation through regulating miRNAs. Mol Omics 2021; 17:630-640. [PMID: 34184018 DOI: 10.1039/d1mo00156f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Pancreatic cancer is one of the most malignant digestive tract tumors with the worst prognosis. Dauricine (Dau) can inhibit the proliferation of the pancreatic cancer cell line, and has the potential to be used as an adjuvant drug against pancreatic cancer; however, the working mechanism of Dau has not been elucidated. To unravel the effects and mechanisms of Dau on proteins and metabolic pathways, we evaluated the mRNA and microRNA expression in BxPC3 cells treated with Dau. The differences in the gene expression were compared using principal component analysis using mRNA and miRNA data to detect and analyze the sample discrimination. 187 miRNA and 907 mRNA that were significantly differentially expressed were identified using Python programming. On comparing genes and miRNAs in the DISEASES database, 79 known miRNA and 47 mRNA were found to be affected by Dau. The up-regulated and down-regulated genes were annotated with GO biological processes to determine the functional effect. Interactions between mRNA and mRNA were analyzed using the STRING database and the miRBase database was queried to obtain experimentally verified interactions between miRNA and mRNA as edges of miRNA and mRNA in the network. Finally, 413 sites and 2125 sides of the network were obtained, including 1 up-regulated and 18 down-regulated miRNAs. The expression of 19 miRNAs was identified by qPCR. The analysis of the protein-protein interaction network, using the Molecular Complex Detection (MCODE) plug-in of cytoscape, helped in identifying 12 important sub-networks. Most subnets are indirectly or directly related to specific miRNAs. This study provides evidence for the anticancer effect of Dau as a potential anticancer compound.
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Affiliation(s)
- Ling Jiang
- School Basic Medical Science, Heilongjiang University of Chinese Medicine, Heilongjiang University of Chinese Medicine, 24 Heping Road, Harbin, 150040, P. R. China.
| | - Tianzhu Guo
- School Basic Medical Science, Heilongjiang University of Chinese Medicine, Heilongjiang University of Chinese Medicine, 24 Heping Road, Harbin, 150040, P. R. China.
| | - Ying Jiang
- School Basic Medical Science, Heilongjiang University of Chinese Medicine, Heilongjiang University of Chinese Medicine, 24 Heping Road, Harbin, 150040, P. R. China.
| | - Ping Liu
- School Basic Medical Science, Heilongjiang University of Chinese Medicine, Heilongjiang University of Chinese Medicine, 24 Heping Road, Harbin, 150040, P. R. China.
| | - Yun Bai
- School Basic Medical Science, Heilongjiang University of Chinese Medicine, Heilongjiang University of Chinese Medicine, 24 Heping Road, Harbin, 150040, P. R. China.
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Jian W, Deng XC, Munankarmy A, Borkhuu O, Ji CL, Wang XH, Zheng WF, Yu YH, Zhou XQ, Fang L. KIF23 promotes triple negative breast cancer through activating epithelial-mesenchymal transition. Gland Surg 2021; 10:1941-1950. [PMID: 34268078 DOI: 10.21037/gs-21-19] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 04/29/2021] [Indexed: 12/15/2022]
Abstract
Background KIF23 is a member of kinesin family, recent researches indicate KIF23 plays an important role in the proliferation and migration of malignant cancer cells. While the function and specific molecule mechanism of KIF23 in triple negative breast cancer remains unclear. Methods QRT-PCR and immunohistochemistry were conducted to analyze expression of KIF23 in triple negative breast cancer tissues and paired paracancer tissues. CCK-8 assay, colony formation assay, wound healing assay and transwell assay were applied for exploring phenotype changing of triple negative breast cancer cell lines MDA-MB-231 and BT549 after siRNA-induced knockdown of KIF23. Several bioinformatic databases were used for predicting miRNAs that combing with KIF23 mRNA and verified by dual luciferase reporter assay. Western blot assay was performed to explore downstream signaling pathway of KIF23. Results KIF23 was overexpressed in triple negative breast cancer, knockdown of KIF23 by siRNA inhibited proliferation and migration of TNBC cell lines MDA-MB-231 and BT549. Mechanistically, knockdown of KIF23 resulted in the suppression of Epithelial-Mesenchymal Transition. Meanwhile, miR-195-5p was downregulated in TNBC, and dual luciferase reporter assay indicated miR-195-5p could combine with 3'UTR of KIF23 thus promoting degradation of KIF23. Conclusions KIF23 is a potential oncogene in triple negative breast cancer, miR-195-5p could combine with 3'UTR of KIF23. Our study reveals a new sight into triple negative breast cancer.
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Affiliation(s)
- Wei Jian
- Department of Thyroid and Breast Surgery, Shanghai Tenth People's Hospital, Shanghai Tenth People's Hospital of Nanjing Medical University, Shanghai, China
| | - Xiao-Chong Deng
- Department of Thyroid and Breast Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Amik Munankarmy
- Department of Thyroid and Breast Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Oyungerel Borkhuu
- Department of Thyroid and Breast Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chang-Le Ji
- Department of Thyroid and Breast Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xue-Hui Wang
- Department of Thyroid and Breast Surgery, Shanghai Tenth People's Hospital, Shanghai Tenth People's Hospital of Nanjing Medical University, Shanghai, China
| | - Wen-Fang Zheng
- Department of Thyroid and Breast Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yun-He Yu
- Department of Thyroid and Breast Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xi-Qian Zhou
- Department of Thyroid and Breast Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lin Fang
- Department of Thyroid and Breast Surgery, Shanghai Tenth People's Hospital, Shanghai Tenth People's Hospital of Nanjing Medical University, Shanghai, China
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Guo C, Gao YY, Ju QQ, Zhang CX, Gong M, Li ZL. The landscape of gene co-expression modules correlating with prognostic genetic abnormalities in AML. J Transl Med 2021; 19:228. [PMID: 34051812 PMCID: PMC8164775 DOI: 10.1186/s12967-021-02914-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 05/25/2021] [Indexed: 12/15/2022] Open
Abstract
Background The heterogenous cytogenetic and molecular variations were harbored by AML patients, some of which are related with AML pathogenesis and clinical outcomes. We aimed to uncover the intrinsic expression profiles correlating with prognostic genetic abnormalities by WGCNA. Methods We downloaded the clinical and expression dataset from BeatAML, TCGA and GEO database. Using R (version 4.0.2) and ‘WGCNA’ package, the co-expression modules correlating with the ELN2017 prognostic markers were identified (R2 ≥ 0.4, p < 0.01). ORA detected the enriched pathways for the key co-expression modules. The patients in TCGA cohort were randomly assigned into the training set (50%) and testing set (50%). The LASSO penalized regression analysis was employed to build the prediction model, fitting OS to the expression level of hub genes by ‘glmnet’ package. Then the testing and 2 independent validation sets (GSE12417 and GSE37642) were used to validate the diagnostic utility and accuracy of the model. Results A total of 37 gene co-expression modules and 973 hub genes were identified for the BeatAML cohort. We found that 3 modules were significantly correlated with genetic markers (the ‘lightyellow’ module for NPM1 mutation, the ‘saddlebrown’ module for RUNX1 mutation, the ‘lightgreen’ module for TP53 mutation). ORA revealed that the ‘lightyellow’ module was mainly enriched in DNA-binding transcription factor activity and activation of HOX genes. The ‘saddlebrown’ module was enriched in immune response process. And the ‘lightgreen’ module was predominantly enriched in mitosis cell cycle process. The LASSO- regression analysis identified 6 genes (NFKB2, NEK9, HOXA7, APRC5L, FAM30A and LOC105371592) with non-zero coefficients. The risk score generated from the 6-gene model, was associated with ELN2017 risk stratification, relapsed disease, and prior MDS history. The 5-year AUC for the model was 0.822 and 0.824 in the training and testing sets, respectively. Moreover, the diagnostic utility of the model was robust when it was employed in 2 validation sets (5-year AUC 0.743–0.79). Conclusions We established the co-expression network signature correlated with the ELN2017 recommended prognostic genetic abnormalities in AML. The 6-gene prediction model for AML survival was developed and validated by multiple datasets. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-02914-2.
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Affiliation(s)
- Chao Guo
- Department of Hematology, China-Japan Friendship Hospital, Yinghua East Street, Beijing, China
| | - Ya-Yue Gao
- Department of Hematology, China-Japan Friendship Hospital, Yinghua East Street, Beijing, China
| | - Qian-Qian Ju
- Department of Hematology, China-Japan Friendship Hospital, Yinghua East Street, Beijing, China
| | - Chun-Xia Zhang
- Department of Hematology, China-Japan Friendship Hospital, Yinghua East Street, Beijing, China
| | - Ming Gong
- Department of Hematology, China-Japan Friendship Hospital, Yinghua East Street, Beijing, China
| | - Zhen-Ling Li
- Department of Hematology, China-Japan Friendship Hospital, Yinghua East Street, Beijing, China.
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Pan J, Lei X, Mao X. Identification of KIF4A as a pan-cancer diagnostic and prognostic biomarker via bioinformatics analysis and validation in osteosarcoma cell lines. PeerJ 2021; 9:e11455. [PMID: 34055488 PMCID: PMC8142929 DOI: 10.7717/peerj.11455] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 04/23/2021] [Indexed: 01/17/2023] Open
Abstract
Background Cancer is a disease of abnormal cell proliferation caused by abnormal expression of cancer-related genes. However, it is still difficult to distinguish benign and malignant lesions in many cases. KIF4A has been reported to be associated with a variety of cancer lesions. We aimed to explore whether KIF4A could be used as a biomarker of pan-cancer diagnostic. Methods We identified twenty-eight cell cycle-related genes that were overexpressed in no less than ten types of cancer. We determined KIF4A mRNA and protein expression in osteosarcoma (OS) cells. Furthermore, to determine the effect of KIF4A in OS, we silenced KIF4A in OS cells and detected cell viability, colony formation, invasion, migration, apoptosis and cell cycle parameters. Results KIF4A exhibited upregulated expression in eleven types of cancer. Cell cycle-related genes are extensively overexpressed in various types of cancers. KIF4A overexpression can serve as a diagnostic and prognostic marker in various cancers. Silencing KIF4A inhibited the viability, colony formation, invasion and migration and induced apoptosis and cell cycle arrest of OS cells. Our findings revealed that high expression of KIF4A could serve as a diagnostic and prognostic marker in OS cancers. Conclusion KIF4A could serve as a pan-cancer diagnostic and prognostic marker. KIF4A could be used as a novel therapeutic target for OS.
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Affiliation(s)
- Jiankang Pan
- Department of Orthopedics, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaohua Lei
- Department of Hepato-Biliary-Pancreatic Surgery, the First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Xinzhan Mao
- Department of Orthopedics, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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Zhao Z, Wang Z, Bao ZS, Gao WZ, Zhang YD, Ruan CJ, Lv T, Wang Y, Sun LH. Mutation and Copy Number Alterations Analysis of KIF23 in Glioma. Front Genet 2021; 12:646929. [PMID: 34017355 PMCID: PMC8129563 DOI: 10.3389/fgene.2021.646929] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 04/06/2021] [Indexed: 11/30/2022] Open
Abstract
In glioma, kinesin family member 23 (KIF23) is up-regulated and plays a vital role in oncogenesis. However, the mechanism underlying KIF23 overexpression in malignant glioma remains to be elucidated. This study aims to find potential causes of KIF23 high expression at genome level. To clarify this issue, we obtained point mutation and copy number alterations (CNAs) of KIF23 in 319 gliomas using whole-exome sequencing. Only two glioma samples with missense mutations in KIF23 coding region were identified, while 7 patients were detected with amplification of KIF23. Additional analysis showed that KIF23 amplification was significantly associated with higher expression of KIF23. Gene ontology analysis indicated that higher copy number of KIF23 was associated TNF-α signaling pathway and mitotic cell circle checkpoint, which probably caused by subsequent upregulated expression of KIF23. Moreover, pan-cancer analysis showed that gaining of copy number was significantly associated with higher expression of KIF23, consolidating our findings in glioma. Thus, it was deduced that elevated KIF23 expression in glioma tended to be caused by DNA copy number amplification, instead of mutation.
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Affiliation(s)
- Zheng Zhao
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Zheng Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Zhao-Shi Bao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Wei-Zhen Gao
- Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuan-Da Zhang
- Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ci-Jie Ruan
- Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tao Lv
- Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yong Wang
- Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li-Hua Sun
- Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Identification of novel biomarkers involved in pulmonary arterial hypertension based on multiple-microarray analysis. Biosci Rep 2021; 40:226338. [PMID: 32886110 PMCID: PMC7494994 DOI: 10.1042/bsr20202346] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/29/2020] [Accepted: 09/02/2020] [Indexed: 02/06/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a life-threatening chronic cardiopulmonary disorder. However, studies providing PAH-related gene expression profiles are scarce. To identify hub genes involved in PAH, we investigate two microarray data sets from gene expression omnibus (GEO). A total of 150 differentially expressed genes (DEGs) were identified by limma package. Enriched Gene Ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of DEGs mostly included mitotic nuclear division, ATPase activity, and Herpes simplex virus one infection. Ten hub genes from three significant modules were ascertained by Cytoscape (CytoHubba). Gene set enrichment analysis (GSEA) plots showed that transcription elongation factor complex was the most significantly enriched gene set positively correlated with the PAH group. At the same time, solute proton symporter activity was the most significantly enriched gene set positively correlated with the control group. Correlation analysis between hub genes suggested that SMC4, TOP2A, SMC2, KIF11, KIF23, ANLN, ARHGAP11A, SMC3, SMC6 and RAD50 may involve in the pathogenesis of PAH. Then, the miRNA-target genes regulation network was performed to unveil the underlying complex association among them. Finally, RNA extracted from monocrotaline (MCT)-induced Rat-PAH model lung artery tissues were to conduct quantitative real-time PCR (qRT-PCR) to validate these hub genes. In conclusion, our study offers new evidence for the underlying molecular mechanisms of PAH as well as attractive targets for diagnosis and treatment of PAH.
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Hao W, Zhao H, Li Z, Li J, Guo J, Chen Q, Gao Y, Ren M, Zhao X, Yue W. Identification of potential markers for differentiating epithelial ovarian cancer from ovarian low malignant potential tumors through integrated bioinformatics analysis. J Ovarian Res 2021; 14:46. [PMID: 33726773 PMCID: PMC7968266 DOI: 10.1186/s13048-021-00794-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 03/05/2021] [Indexed: 01/10/2023] Open
Abstract
Background Epithelial ovarian cancer (EOC), as a lethal malignancy in women, is often diagnosed as advanced stages. In contrast, intermediating between benign and malignant tumors, ovarian low malignant potential (LMP) tumors show a good prognosis. However, the differential diagnosis of the two diseases is not ideal, resulting in delays or unnecessary therapies. Therefore, unveiling the molecular differences between LMP and EOC may contribute to differential diagnosis and novel therapeutic and preventive policies development for EOC. Methods In this study, three microarray data (GSE9899, GSE57477 and GSE27651) were used to explore the differentially expressed genes (DEGs) between LMP and EOC samples. Then, 5 genes were screened by protein–protein interaction (PPI) network, receiver operating characteristic (ROC), survival and Pearson correlation analysis. Meanwhile, chemical-core gene network construction was performed to identify the potential drugs or risk factors for EOC based on 5 core genes. Finally, we also identified the potential function of the 5 genes for EOC through pathway analysis. Results Two hundred thirty-four DEGs were successfully screened, including 81 up-regulated genes and 153 down-regulated genes. Then, 5 core genes (CCNB1, KIF20A, ASPM, AURKA, and KIF23) were identified through PPI network analysis, ROC analysis, survival and Pearson correlation analysis, which show better diagnostic efficiency and higher prognostic value for EOC. Furthermore, NetworkAnalyst was used to identify top 15 chemicals that link with the 5 core genes. Among them, 11 chemicals were potential drugs and 4 chemicals were risk factors for EOC. Finally, we found that all 5 core genes mainly regulate EOC development via the cell cycle pathway by the bioinformatic analysis. Conclusion Based on an integrated bioinformatic analysis, we identified potential biomarkers, risk factors and drugs for EOC, which may help to provide new ideas for EOC diagnosis, condition appraisal, prevention and treatment in future. Supplementary Information The online version contains supplementary material available at 10.1186/s13048-021-00794-0.
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Affiliation(s)
- Wende Hao
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China
| | - Hongyu Zhao
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China
| | - Zhefeng Li
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China
| | - Jie Li
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China
| | - Jiahao Guo
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China
| | - Qi Chen
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China
| | - Yan Gao
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China
| | - Meng Ren
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China
| | - Xiaoting Zhao
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China.
| | - Wentao Yue
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China.
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Ghatnatti V, Vastrad B, Patil S, Vastrad C, Kotturshetti I. Identification of potential and novel target genes in pituitary prolactinoma by bioinformatics analysis. AIMS Neurosci 2021; 8:254-283. [PMID: 33709028 PMCID: PMC7940115 DOI: 10.3934/neuroscience.2021014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 01/29/2021] [Indexed: 02/05/2023] Open
Abstract
Pituitary prolactinoma is one of the most complicated and fatally pathogenic pituitary adenomas. Therefore, there is an urgent need to improve our understanding of the underlying molecular mechanism that drives the initiation, progression, and metastasis of pituitary prolactinoma. The aim of the present study was to identify the key genes and signaling pathways associated with pituitary prolactinoma using bioinformatics analysis. Transcriptome microarray dataset GSE119063 was downloaded from Gene Expression Omnibus (GEO) database. Limma package in R software was used to screen DEGs. Pathway and Gene ontology (GO) enrichment analysis were conducted to identify the biological role of DEGs. A protein-protein interaction (PPI) network was constructed and analyzed by using HIPPIE database and Cytoscape software. Module analyses was performed. In addition, a target gene-miRNA regulatory network and target gene-TF regulatory network were constructed by using NetworkAnalyst and Cytoscape software. Finally, validation of hub genes by receiver operating characteristic (ROC) curve analysis. A total of 989 DEGs were identified, including 461 up regulated genes and 528 down regulated genes. Pathway enrichment analysis showed that the DEGs were significantly enriched in the retinoate biosynthesis II, signaling pathways regulating pluripotency of stem cells, ALK2 signaling events, vitamin D3 biosynthesis, cell cycle and aurora B signaling. Gene Ontology (GO) enrichment analysis showed that the DEGs were significantly enriched in the sensory organ morphogenesis, extracellular matrix, hormone activity, nuclear division, condensed chromosome and microtubule binding. In the PPI network and modules, SOX2, PRSS45, CLTC, PLK1, B4GALT6, RUNX1 and GTSE1 were considered as hub genes. In the target gene-miRNA regulatory network and target gene-TF regulatory network, LINC00598, SOX4, IRX1 and UNC13A were considered as hub genes. Using integrated bioinformatics analysis, we identified candidate genes in pituitary prolactinoma, which might improve our understanding of the molecular mechanisms of pituitary prolactinoma.
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Affiliation(s)
- Vikrant Ghatnatti
- Department of Endocrinology, J N Medical College, Belagavi and KLE Academy of Higher Education & Research 590010, Karnataka, India
| | - Basavaraj Vastrad
- Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India
| | - Swetha Patil
- Department of Obstetrics and Gynaecology, J N Medical College, Belagavi and KLE Academy of Higher Education & Research 590010, Karnataka, India
| | - Chanabasayya Vastrad
- Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India
| | - Iranna Kotturshetti
- Department of Ayurveda, Rajiv Gandhi Education Society's Ayurvedic Medical College, Ron 562209, Karanataka, India
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Weed S, Armistead B, Coleman M, Liggit HD, Johnson B, Tsai J, Beyer RP, Bammler TK, Kretzer NM, Parker E, Vanderhoeven JP, Bierle CJ, Rajagopal L, Adams Waldorf KM. MicroRNA Signature of Epithelial-Mesenchymal Transition in Group B Streptococcal Infection of the Placental Chorioamniotic Membranes. J Infect Dis 2021; 222:1713-1722. [PMID: 32453818 DOI: 10.1093/infdis/jiaa280] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 05/22/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Infection-induced preterm birth is a major cause of neonatal mortality and morbidity and leads to preterm premature rupture of placental chorioamniotic membranes. The loss of amniotic epithelial cells and tensile strength preceding membrane rupture is poorly understood. We hypothesized that intrauterine bacterial infection induces changes in microRNA (miRNA) expression, leading to amniotic epithelial cell loss and membrane weakening. METHODS Ten pregnant pigtail macaques received choriodecidual inoculation of either group B Streptococcus (GBS) or saline (n = 5/group). Placental chorioamniotic membranes were studied using RNA microarray and immunohistochemistry. Chorioamniotic membranes from women with preterm premature rupture of membranes (pPROM) and normal term pregnancies were studied using transmission electron microscopy. RESULTS In our model, an experimental GBS infection was associated with changes in the miRNA profile in the chorioamniotic membranes consistent with epithelial to mesenchymal transition (EMT) with loss of epithelial (E-cadherin) and gain of mesenchymal (vimentin) markers. Similarly, loss of desmosomes (intercellular junctions) was seen in placental tissues from women with pPROM. CONCLUSIONS We describe EMT as a novel mechanism for infection-associated chorioamniotic membrane weakening, which may be a common pathway for many etiologies of pPROM. Therapy based on anti-miRNA targeting of EMT may prevent pPROM due to perinatal infection.
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Affiliation(s)
- Samantha Weed
- Department of Obstetrics and Gynecology, University of Washington, Seattle Washington, USA
| | - Blair Armistead
- Department of Global Health, University of Washington, Seattle, Washington, USA.,Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington, USA
| | - Michelle Coleman
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington, USA
| | - H Denny Liggit
- Department of Comparative Medicine, University of Washington, Seattle, Washington, USA
| | - Brian Johnson
- Department of Comparative Medicine, University of Washington, Seattle, Washington, USA
| | - Jesse Tsai
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA
| | - Richard P Beyer
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA
| | - Theodor K Bammler
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA
| | - Nicole M Kretzer
- Department of Obstetrics and Gynecology, University of Washington, Seattle Washington, USA
| | - Ed Parker
- Department of Ophthalmology, University of Washington, Seattle, Washington, USA
| | - Jeroen P Vanderhoeven
- Department of Obstetrics and Gynecology, University of Washington, Seattle Washington, USA
| | - Craig J Bierle
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington, USA.,Department of Pediatric Infectious Diseases, University of Washington, Seattle, Washington, USA
| | - Lakshmi Rajagopal
- Department of Global Health, University of Washington, Seattle, Washington, USA.,Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington, USA.,Department of Pediatric Infectious Diseases, University of Washington, Seattle, Washington, USA
| | - Kristina M Adams Waldorf
- Department of Obstetrics and Gynecology, University of Washington, Seattle Washington, USA.,Department of Global Health, University of Washington, Seattle, Washington, USA
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Sheng J, Li C, Dong M, Jiang K. Identification by Comprehensive Bioinformatics Analysis of KIF15 as a Candidate Risk Gene for Triple-Negative Breast Cancer. Cancer Manag Res 2020; 12:12337-12348. [PMID: 33293861 PMCID: PMC7718892 DOI: 10.2147/cmar.s262017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 10/29/2020] [Indexed: 11/23/2022] Open
Abstract
Background Previous studies have shown that kinesin family proteins (KIFs) play an indispensable roles in several types of cancer. However, the expression and clinical significance of KIFs in triple-negative breast cancer remain unclear. Methods In this study, the role of KIF15, including gene expression analysis, methylation characteristic, CNV characteristic, and miRNA target regulation, was evaluated using multiple bioinformatic tools based on TCGA database. Quantitative real-time PCR and Western blot were used to determine the expression level of KIF15 in triple-negative breast cancer cell lines. Then, functional experiments were employed to explore the effects of KIF15 on tumor growth and metastasis in triple-negative breast cancer. Results Our data showed that KIF15 was significantly upregulated in triple-negative breast cancer (TNBC). Functionally, downregulation of KIF15 significantly facilitated apoptosis and G2/M phase arrest, and inhibited the migration and invasion of TNBC cells. The mechanism of action of KIF15 was closely related to DNA replication checkpoint and cell cycle regulation in TNBC based on GSEA. In addition, bioinformatics analysis demonstrated that high expression of KIF15 in TNBC was correlated with copy number aberration and DNA methylation levels. Conclusion Our findings suggest that KIF15 is a novel oncogene in TNBC and provide us a strong evidence that it might be served as a potential clinical target and biomarker in triple-negative breast cancer.
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Affiliation(s)
- Jiayu Sheng
- Department of Breast Diseases, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Chunyang Li
- Department of Breast Diseases, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Mengting Dong
- Department of Breast Diseases, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Ke Jiang
- Department of Breast Diseases, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
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Differential tissue specific expression of Kif23 alternative transcripts in mice with the human mutation causing congenital dyserythropoietic anemia type III. Blood Cells Mol Dis 2020; 85:102483. [DOI: 10.1016/j.bcmd.2020.102483] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/30/2020] [Accepted: 07/30/2020] [Indexed: 01/23/2023]
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Gao CT, Ren J, Yu J, Li SN, Guo XF, Zhou YZ. KIF23 enhances cell proliferation in pancreatic ductal adenocarcinoma and is a potent therapeutic target. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1394. [PMID: 33313139 PMCID: PMC7723550 DOI: 10.21037/atm-20-1970] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Background In recent research, high expression of kinesin family member 23 (KIF23), one of the kinesin motor proteins involved in the regulation of cytokinesis, has been shown to be related to poor prognosis in glioma and paclitaxel-resistant gastric cancer, as a results of the enhancement of proliferation, migration, and invasion. In this study, we analyzed the role of KIF23 in the progression of pancreatic ductal adenocarcinoma. Methods A bioinformatic method was used to analyze the KIF23 mRNA level in pancreatic tumor tissues compared with normal pancreatic tissues and to analyze the connection between high KIF23 expression and prognosis. We examined the expression of KIF23 using immunohistochemistry and analyzed the connection between the expression of KIF23 and clinicopathological features in pancreatic ductal adenocarcinoma patients. In addition, a colony formation assay, MTT assay, and western blot assay were performed in vitro, along with a mouse xenograft model in vivo, to analyze the effect of KIF23 on proliferation. Further, the correlation between KIF23 and CDCA8 was analyzed by TCGA and immunohistochemical data. Results Bioinformatic results showed that KIF23 mRNA expression was higher in pancreatic tumor tissues than in normal pancreatic tissues and a poor prognosis has been linked to the high expression of KIF23. Immunohistochemistry revealed that KIF23 was highly expressed at the protein level and high expression of KIF23 correlated with adverse clinicopathological features. Our experimental results demonstrated that knockdown of KIF23 could inhibit the proliferation of pancreatic cells. Further, a positive correlation between KIF23 and CDCA8 expression existed, and KIF23 might promote pancreatic cancer proliferation by affecting CDCA8 expression. Conclusions Our data showed that high expression of KIF23 is associated with a poor prognosis, and KIF23 might be a potential therapeutic target for pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Chun-Tao Gao
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jin Ren
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China
| | - Jie Yu
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.,The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Sheng-Nan Li
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Xiao-Fan Guo
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yi-Zhang Zhou
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
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Liang WT, Liu XF, Huang HB, Gao ZM, Li K. Prognostic significance of KIF23 expression in gastric cancer. World J Gastrointest Oncol 2020; 12:1104-1118. [PMID: 33133380 PMCID: PMC7579732 DOI: 10.4251/wjgo.v12.i10.1104] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/29/2020] [Accepted: 08/16/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Kinesin super family 23 (KIF23) is a member of the KIF family, and it plays an important role in mitosis and cytokinesis. Loss of expression can cause mitotic arrest. The Oncomine database is one of the largest oncogene chip databases in the world, and is an integrated data mining platform for cancer gene information. By querying the database, differences in expression between tumor tissue and normal tissue can be determined.
AIM To study the expression and prognostic significance of KIF23 in gastric cancer (GC).
METHODS We used immunohistochemistry to compare the expression of KIF23 in GC and normal gastric tissues. We mined the data on the expression and prognosis of KIF23 in GC using Oncomine and Kaplan–Meier plotter database.
RESULTS Compared with normal gastric tissues, KIF23 expression was increased in GC tissues, and correlated with T, N, and tumor–node–metastasis stages. Survival analysis showed that patients with high expression of KIF23 had a poor overall survival. There were five studies in the Oncomine database in which expression of KIF23 was significantly higher in GC tissues than in normal gastric tissues (P < 0.05). Kaplan–Meier plotter database analysis showed that recurrence-free survival, overall survival, distant metastasis free survival, and post progression survival of patients with high expression of KIF23 were lower than those of patients with low expression. Further stratified analysis found that prognostic survival indicators worsened in patients with T2 and T3 poorly differentiated adenocarcinoma with high expression of KIF23.
CONCLUSION KIF23 is highly expressed in GC and is associated with a poor prognosis of patients. It may be of great significance in the diagnosis, treatment, and prognostic evaluation of GC.
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Affiliation(s)
- Wei-Tian Liang
- Department of Surgical Oncology, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Xiao-Fang Liu
- Department of Surgical Oncology, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Hai-Bo Huang
- Department of Surgical Oncology, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Zi-Ming Gao
- Department of Surgical Oncology, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Kai Li
- Department of Surgical Oncology, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Wu H, Tian X, Zhu C. Knockdown of lncRNA PVT1 inhibits prostate cancer progression in vitro and in vivo by the suppression of KIF23 through stimulating miR-15a-5p. Cancer Cell Int 2020; 20:283. [PMID: 32624708 PMCID: PMC7330980 DOI: 10.1186/s12935-020-01363-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/17/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Prostate cancer (PCa) greatly threatens men's lives, with high incidence and mortality. Recently, the research of long non-coding RNAs (lncRNAs) has made breakthroughs in the development of human cancers. This study aimed to figure out the role and action mechanism of lncRNA PVT1 (PVT1) in PCa. METHODS The expression of PVT1, microRNA-15a-5p (miR-15a-5p) and kinesin family member 23 (KIF23) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation, apoptosis, migration and invasion were assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), flow cytometry and transwell assays, respectively. The protein levels of KIF23 and proliferation, apoptosis, and epithelial-mesenchymal transition (EMT)-related markers were quantified by western blot. The relationship between miR-15a-5p and PVT1 or KIF23 was predicted by starBase v2.0 and verified by dual-luciferase reporter assay. Xenograft assay was conducted to determine the role of PVT1 in vivo. RESULTS The expression of PVT1 and KIF23 was enhanced, while miR-15a-5p expression was reduced in PCa tissues and cells. PVT1 interference inhibited proliferation, migration and invasion but promoted apoptosis of PCa cells. MiR-15a-5p was a target of PVT1, and KIF23 was a target of miR-15a-5p. The inhibition of miR-15a-5p reversed the effects of PVT1 interference and suppressed the roles of KIF23 knockdown. KIF23 expression was regulated by PVT1 through miR-15a-5p. PVT1 interference blocked PCa progression in vivo. CONCLUSION PVT1 knockdown had effects on the progression of PCa by inhibiting the expression of KIF23 via enriching miR-15a-5p in vitro and in vivo, suggesting that PVT1 might be a novel biomarker for the treatment of PCa.
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Affiliation(s)
- Huijuan Wu
- Department of Telemedicine and Internet Medical Center, The Huaihe Hospital of Henan University, No. 115 Ximen Avenue, Kaifeng, 475000 Henan China
| | - Xin Tian
- Department of Urology Surgery, The Huaihe Hospital of Henan University, Kaifeng, Henan China
| | - Chaoyang Zhu
- Department of Urology Surgery, The Huaihe Hospital of Henan University, Kaifeng, Henan China
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Liu Y, Chen H, Dong P, Xie G, Zhou Y, Ma Y, Yuan X, Yang J, Han L, Chen L, Shen L. KIF23 activated Wnt/β-catenin signaling pathway through direct interaction with Amer1 in gastric cancer. Aging (Albany NY) 2020; 12:8372-8396. [PMID: 32365332 PMCID: PMC7244035 DOI: 10.18632/aging.103146] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 03/09/2020] [Indexed: 02/07/2023]
Abstract
Increased expression of the kinesin family member 23 (KIF23) has been verified in gastric cancer (GC) and its upregulation contributes to cell proliferation. Even though, the role of KIF23 has not been fully elucidated in GC, and the mechanisms of KIF23 as an oncogene remain unknown. To further identify its potential role in GC, we analyzed gene expression data from GC patients in GEO and TCGA datasets. KIF23 was upregulated in GC, and increased expression of KIF23 correlated with poor prognosis. Importantly, KIF23 inhibition not only suppressed GC cell proliferation, tumorigenesis, but also migration and invasion, and arrested the cell cycle in the G2/M phase. Mechanistic investigations confirmed that KIF23 activated the Wnt/β-catenin signaling pathway by directly interacting with APC membrane recruitment 1 (Amer1). Furthermore, KIF23 exhibited competitive binding with Amer1 to block the association of Amer1 with adenomatous polyposis coli (APC), thus relocating Amer1 from the membrane and cytoplasm to the nucleus and attenuating the ability of Amer1 to negatively regulate Wnt/β-catenin signaling, resulting in activation of this signaling pathway. Collectively, our findings demonstrated that KIF23 promoted GC cell proliferation by directly interacting with Amer1 and activating the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Yi Liu
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Hui Chen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Ping Dong
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Guohua Xie
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yunlan Zhou
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yanhui Ma
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xiangliang Yuan
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Junyao Yang
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Li Han
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Lei Chen
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Lisong Shen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
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Wang Y, Wang F, He J, Du J, Zhang H, Shi H, Chen Y, Wei Y, Xue W, Yan J, Feng Y, Gao Y, Li D, Han J, Zhang J. miR-30a-3p Targets MAD2L1 and Regulates Proliferation of Gastric Cancer Cells. Onco Targets Ther 2019; 12:11313-11324. [PMID: 31908496 PMCID: PMC6927793 DOI: 10.2147/ott.s222854] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 11/27/2019] [Indexed: 12/24/2022] Open
Abstract
Purpose This study was done to investigate the inhibition effects of miR-30a-3p on mitotic arrest deficient 2 like 1 (MAD2L1) expression and the proliferation of gastric cancer cells. Patients and methods Cluster analysis and the TCGA database were used to screen the key genes highly expressed in gastric cancer. Based on the LinkedOmics website, the correlation between the miR-30a-3p and the cell cycle-related target gene MAD2L1 in gastric cancer was analyzed. The mRNA and protein expression levels were detected with the quantitative real-time PCR and Western blot analysis. The cell proliferation and cell cycle were also detected and analyzed. Results Bioinformatics analysis showed that MAD2L1 was highly expressed in tumor tissues compared with normal tissues. Compared with normal tissues, the miR-30a-3p was significantly decreased in the gastric cancer tissues. Moreover, MAD2L1 was significantly negatively correlated with the miR-30a-3p expression. Furthermore, over-expression of miR-30a-3p decreased the expression of MAD2L1 at the protein level, which inhibited the proliferation of AGS and BGC-823 gastric cancer cells. In addition, the cell cycles of AGS and BGC-823 cells were arrested at the G0/G1 phase. Conclusion MAD2L1 is a pro-oncogene which is up-regulated in gastric cancer. The miR-30a-3p can down-regulate the MAD2L1 expression, inhibiting the proliferation of gastric cancer cells and affect the cell cycle.
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Affiliation(s)
- Yu Wang
- Department of Clinical Medicine, Medical College of Yan'an University, Yan'an, Shaanxi 716000, People's Republic of China.,Yan'an Key Laboratory of Chronic Disease Prevention and Research, Yan'an, Shaanxi 716000, People's Republic of China
| | - Fenghui Wang
- Department of Clinical Medicine, Medical College of Yan'an University, Yan'an, Shaanxi 716000, People's Republic of China.,Yan'an Key Laboratory of Chronic Disease Prevention and Research, Yan'an, Shaanxi 716000, People's Republic of China
| | - Jing He
- Department of Clinical Medicine, Medical College of Yan'an University, Yan'an, Shaanxi 716000, People's Republic of China.,Yan'an Key Laboratory of Chronic Disease Prevention and Research, Yan'an, Shaanxi 716000, People's Republic of China
| | - Juan Du
- Department of Clinical Medicine, Medical College of Yan'an University, Yan'an, Shaanxi 716000, People's Republic of China.,Yan'an Key Laboratory of Chronic Disease Prevention and Research, Yan'an, Shaanxi 716000, People's Republic of China
| | - Huahua Zhang
- Department of Clinical Medicine, Medical College of Yan'an University, Yan'an, Shaanxi 716000, People's Republic of China.,Yan'an Key Laboratory of Chronic Disease Prevention and Research, Yan'an, Shaanxi 716000, People's Republic of China
| | - Haiyan Shi
- Department of Clinical Medicine, Medical College of Yan'an University, Yan'an, Shaanxi 716000, People's Republic of China.,Yan'an Key Laboratory of Chronic Disease Prevention and Research, Yan'an, Shaanxi 716000, People's Republic of China
| | - Yani Chen
- Department of Clinical Medicine, Medical College of Yan'an University, Yan'an, Shaanxi 716000, People's Republic of China.,Yan'an Key Laboratory of Chronic Disease Prevention and Research, Yan'an, Shaanxi 716000, People's Republic of China
| | - Yameng Wei
- Department of Clinical Medicine, Medical College of Yan'an University, Yan'an, Shaanxi 716000, People's Republic of China.,Yan'an Key Laboratory of Chronic Disease Prevention and Research, Yan'an, Shaanxi 716000, People's Republic of China
| | - Wanjuan Xue
- Department of Clinical Medicine, Medical College of Yan'an University, Yan'an, Shaanxi 716000, People's Republic of China.,Yan'an Key Laboratory of Chronic Disease Prevention and Research, Yan'an, Shaanxi 716000, People's Republic of China
| | - Jing Yan
- Department of Clinical Medicine, Medical College of Yan'an University, Yan'an, Shaanxi 716000, People's Republic of China.,Yan'an Key Laboratory of Chronic Disease Prevention and Research, Yan'an, Shaanxi 716000, People's Republic of China
| | - Yun Feng
- Department of Clinical Medicine, Medical College of Yan'an University, Yan'an, Shaanxi 716000, People's Republic of China.,Yan'an Key Laboratory of Chronic Disease Prevention and Research, Yan'an, Shaanxi 716000, People's Republic of China
| | - Yi Gao
- Department of Clinical Medicine, Medical College of Yan'an University, Yan'an, Shaanxi 716000, People's Republic of China.,Yan'an Key Laboratory of Chronic Disease Prevention and Research, Yan'an, Shaanxi 716000, People's Republic of China
| | - Dan Li
- Department of Clinical Medicine, Medical College of Yan'an University, Yan'an, Shaanxi 716000, People's Republic of China.,Yan'an Key Laboratory of Chronic Disease Prevention and Research, Yan'an, Shaanxi 716000, People's Republic of China
| | - Jiming Han
- Department of Clinical Medicine, Medical College of Yan'an University, Yan'an, Shaanxi 716000, People's Republic of China.,Yan'an Key Laboratory of Chronic Disease Prevention and Research, Yan'an, Shaanxi 716000, People's Republic of China
| | - Jing Zhang
- Department of Clinical Medicine, Medical College of Yan'an University, Yan'an, Shaanxi 716000, People's Republic of China.,Yan'an Key Laboratory of Chronic Disease Prevention and Research, Yan'an, Shaanxi 716000, People's Republic of China
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Chen T, Yang S, Xu J, Lu W, Xie X. Transcriptome sequencing profiles of cervical cancer tissues and SiHa cells. Funct Integr Genomics 2019; 20:211-221. [PMID: 31456134 DOI: 10.1007/s10142-019-00706-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 07/08/2019] [Accepted: 07/26/2019] [Indexed: 02/07/2023]
Abstract
High-risk human papillomavirus (HPV) is a causal factor for cervical cancer, of which HPV16 is the predominant genotype, but the detailed mechanism remains to be elucidated. In this study, we performed transcriptome sequencing in cervical cancer tissues with HPV16-positive and normal tissues with HPV16-negative, and SiHa cells with or without HPV16 E6/E7 knockdown, and identified 140 differential expressed genes (DEGs) in two data sets. We carried out a series of bioinformatic analyses to learn more about the 140 DEGs, and found that 140 DEGs were mostly enriched in cell cycle and DNA repair through Kyoto Encyclopedia of Genes and Genomes pathway enrichment, Gene Ontology annotation, and gene set enrichment analysis. A total of 20 genes including RMI1, MKI67, FANCB, KIF14, CENPI, RACGAP1, EXO1, KIF4A, FOXM1, C19orf57, PSRC1, NUSAP1, CIT, NDC80, MCM7, GINS2, MCM6, ORC1, TLX2, and UHRF1 were screened by co-expression analysis; of those, the expressions of 6 (CENPI, FANCB, KIF14, ORC1, RACGAP1, and RMI1) were verified by qRT-PCR. Further, we found that E2F family, NF-Y, AhR:Arnt, and KROX family may be involved in modulating DEGs by TransFind prediction. TF2DNA database and co-expression analysis suggested that 12 TFs (ZNF367, TLX2, DEPDC1B, E2F8, ZNF541, EGR2, ZMAT3, HES6, CEBPA, MYBL2, FOXM1, and RAD51) were upstream modulators of DEGs. Our findings may provide a new understanding for effects of HPV oncogenes in the maintenance of cancerous state at the transcriptional level.
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Affiliation(s)
- Tingting Chen
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shizhou Yang
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Junfen Xu
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weiguo Lu
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xing Xie
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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KIF15 plays a role in promoting the tumorigenicity of melanoma. Exp Eye Res 2019; 185:107598. [DOI: 10.1016/j.exer.2019.02.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 12/18/2018] [Accepted: 02/19/2019] [Indexed: 12/15/2022]
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Alshabi AM, Shaikh IA, Vastrad C. Exploring the Molecular Mechanism of the Drug-Treated Breast Cancer Based on Gene Expression Microarray. Biomolecules 2019; 9:biom9070282. [PMID: 31311202 PMCID: PMC6681318 DOI: 10.3390/biom9070282] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 06/24/2019] [Accepted: 07/09/2019] [Indexed: 02/07/2023] Open
Abstract
: Breast cancer (BRCA) remains the leading cause of cancer morbidity and mortality worldwide. In the present study, we identified novel biomarkers expressed during estradiol and tamoxifen treatment of BRCA. The microarray dataset of E-MTAB-4975 from Array Express database was downloaded, and the differential expressed genes (DEGs) between estradiol-treated BRCA sample and tamoxifen-treated BRCA sample were identified by limma package. The pathway and gene ontology (GO) enrichment analysis, construction of protein-protein interaction (PPI) network, module analysis, construction of target genes-miRNA interaction network and target genes-transcription factor (TF) interaction network were performed using bioinformatics tools. The expression, prognostic values, and mutation of hub genes were validated by SurvExpress database, cBioPortal, and human protein atlas (HPA) database. A total of 856 genes (421 up-regulated genes and 435 down-regulated genes) were identified in T47D (overexpressing Split Ends (SPEN) + estradiol) samples compared to T47D (overexpressing Split Ends (SPEN) + tamoxifen) samples. Pathway and GO enrichment analysis revealed that the DEGs were mainly enriched in response to lysine degradation II (pipecolate pathway), cholesterol biosynthesis pathway, cell cycle pathway, and response to cytokine pathway. DEGs (MCM2, TCF4, OLR1, HSPA5, MAP1LC3B, SQSTM1, NEU1, HIST1H1B, RAD51, RFC3, MCM10, ISG15, TNFRSF10B, GBP2, IGFBP5, SOD2, DHF and MT1H) , which were significantly up- and down-regulated in estradiol and tamoxifen-treated BRCA samples, were selected as hub genes according to the results of protein-protein interaction (PPI) network, module analysis, target genes-miRNA interaction network and target genes-TF interaction network analysis. The SurvExpress database, cBioPortal, and Human Protein Atlas (HPA) database further confirmed that patients with higher expression levels of these hub genes experienced a shorter overall survival. A comprehensive bioinformatics analysis was performed, and potential therapeutic applications of estradiol and tamoxifen were predicted in BRCA samples. The data may unravel the future molecular mechanisms of BRCA.
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Affiliation(s)
- Ali Mohamed Alshabi
- Department of Clinical Pharmacy, College of Pharmacy, Najran University, Najran, 66237, Saudi Arabia
| | - Ibrahim Ahmed Shaikh
- Department of Pharmacology, College of Pharmacy, Najran University, Najran, 66237, Saudi Arabia
| | - Chanabasayya Vastrad
- Biostatistics and Bioinformatics, ChanabasavaNilaya, Bharthinagar, Dharwad 580001, Karnataka, India.
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Li T, Li Y, Gan Y, Tian R, Wu Q, Shu G, Yin G. Methylation-mediated repression of MiR-424/503 cluster promotes proliferation and migration of ovarian cancer cells through targeting the hub gene KIF23. Cell Cycle 2019; 18:1601-1618. [PMID: 31135262 PMCID: PMC6619937 DOI: 10.1080/15384101.2019.1624112] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 05/09/2019] [Accepted: 05/10/2019] [Indexed: 12/24/2022] Open
Abstract
Ovarian cancer is one type of gynecological malignancies with extremely high lethal rate. Abnormal proliferation and metastasis are regarded to play important roles in patients' death, whereas we know little about the underlying molecular mechanisms. Under this circumstance, our current study aims to investigate the role of hub genes in ovarian cancer. Bioinformatics analysis of the data from GEO and analyses of ovarian cancer samples were performed. Then, the results showed that KIF23, a hub gene, was mainly related to cell cycle and positively associated with poor prognosis. Meanwhile, both miR-424-5p and miR-503-5p directly targeted to 3'UTR of KIF23 to suppress the expression of KIF23 and inhibit ovarian cancer cell proliferation and migration. Furthermore, we discovered that miR-424/503 was epigenetically repressed by hypermethylation in the promoter regions, which directly modulated the expression of KIF23 to improve the oncogenic performance of cancer cells in vitro. Together, our research certifies that miR-424/503 cluster is silenced by DNA hypermethylation, which promotes the expression of KIF23, thereby regulating the proliferation and migration of ovarian cancer cells. Interposing this process might be a novel approach in cancer therapy.
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Affiliation(s)
- Tong Li
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Yimin Li
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Yaqi Gan
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Ruotong Tian
- School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Qihan Wu
- NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Medical School, Fudan University, Shanghai, China
| | - Guang Shu
- School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Gang Yin
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
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