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Saadh MJ, Ahmed HH, Kareem RA, Chandra M, Monsi M, Walia C, Prasad GVS, Taher WM, Alwan M, Jawad MJ, Hamad AK. From Motor Proteins to Oncogenic Factors: The Evolving Role of Kinesin Superfamily Proteins in Breast Cancer Development. Mol Biotechnol 2025:10.1007/s12033-025-01428-2. [PMID: 40146390 DOI: 10.1007/s12033-025-01428-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 02/24/2025] [Indexed: 03/28/2025]
Abstract
The kinesin family of proteins (KIFs), known for their role as motor proteins, is integral to transporting cargo within cells along microtubule tracks, which is crucial for processes, such as cell division, differentiation, and intracellular communication. Increasing evidence shows that specific KIFs are overexpressed in breast cancer, a change linked to higher tumor aggression and poorer outcomes in patients. KIFs contribute to the cancerous characteristics of breast tumor cells through several mechanisms, including disruptions in spindle assembly during cell division, altered cell motility, and accelerated proliferation. This review summarizes current insights into KIFs' functions in breast cancer pathology and assesses their viability as therapeutic targets. By unraveling the complex involvement of KIFs, the article aims to open pathways for new therapeutic approaches in breast cancer and to promote further study into the cellular pathways that these proteins regulate.
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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, Gujarat, 360003, India
| | - Mekha Monsi
- Department of Pharmacy Practice, NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, 302131, India
| | - Chakshu Walia
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, 140307, India
| | - G V Siva Prasad
- Department of Basic Sciences and Humanities, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | - Waam Mohammed Taher
- College of Nursing, National University of Science and Technology, Nasiriyah, Dhi Qar, Iraq
| | - Mariem Alwan
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
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Fernández-Ramos D, Lopitz-Otsoa F, Lu SC, Mato JM. S-Adenosylmethionine: A Multifaceted Regulator in Cancer Pathogenesis and Therapy. Cancers (Basel) 2025; 17:535. [PMID: 39941901 PMCID: PMC11816870 DOI: 10.3390/cancers17030535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 01/30/2025] [Accepted: 02/03/2025] [Indexed: 02/16/2025] Open
Abstract
S-adenosylmethionine (SAMe) is a key methyl donor that plays a critical role in a variety of cellular processes, such as DNA, RNA and protein methylation, essential for maintaining genomic stability, regulating gene expression and maintaining cellular homeostasis. The involvement of SAMe in cancer pathogenesis is multifaceted, as through its multiple cellular functions, it can influence tumor initiation, progression and therapeutic resistance. In addition, the connection of SAMe with polyamine synthesis and oxidative stress management further underscores its importance in cancer biology. Recent studies have highlighted the potential of SAMe as a biomarker for cancer diagnosis and prognosis. Furthermore, the therapeutic implications of SAMe are promising, with evidence suggesting that SAMe supplementation or modulation could improve the efficacy of existing cancer treatments by restoring proper methylation patterns and mitigating oxidative damage and protect against damage induced by chemotherapeutic drugs. Moreover, targeting methionine cycle enzymes to both regulate SAMe availability and SAMe-independent regulatory effects, particularly in methionine-dependent cancers such as colorectal and lung cancer, presents a promising therapeutic approach. Additionally, exploring epitranscriptomic regulations, such as m6A modifications, and their interaction with non-coding RNAs could enhance our understanding of tumor progression and resistance mechanisms. Precision medicine approaches integrating patient subtyping and combination therapies with chemotherapeutics, such as decitabine or doxorubicin, together with SAMe, can enhance chemosensitivity and modulate epigenomics, showing promising results that may improve treatment outcomes. This review comprehensively examines the various roles of SAMe in cancer pathogenesis, its potential as a diagnostic and prognostic marker, and its emerging therapeutic applications. While SAMe modulation holds significant promise, challenges such as bioavailability, patient stratification and context-dependent effects must be addressed before clinical implementation. In addition, better validation of the obtained results into specific cancer animal models would also help to bridge the gap between research and clinical practice.
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Affiliation(s)
- David Fernández-Ramos
- Precision Medicine and Metabolism Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain; (D.F.-R.); (F.L.-O.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Fernando Lopitz-Otsoa
- Precision Medicine and Metabolism Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain; (D.F.-R.); (F.L.-O.)
| | - Shelly C. Lu
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - José M. Mato
- Precision Medicine and Metabolism Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain; (D.F.-R.); (F.L.-O.)
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Ma Q, Chen L, Feng K, Guo W, Huang T, Cai YD. Exploring Prognostic Gene Factors in Breast Cancer via Machine Learning. Biochem Genet 2024; 62:5022-5050. [PMID: 38383836 DOI: 10.1007/s10528-024-10712-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 01/21/2024] [Indexed: 02/23/2024]
Abstract
Breast cancer remains the most prevalent cancer in women. To date, its underlying molecular mechanisms have not been fully uncovered. The determination of gene factors is important to improve our understanding on breast cancer, which can correlate the specific gene expression and tumor staging. However, the knowledge in this regard is still far from complete. Thus, this study aimed to explore these knowledge gaps by analyzing existing gene expression profile data from 3149 breast cancer samples, where each sample was represented by the expression of 19,644 genes and classified into Nottingham histological grade (NHG) classes (Grade 1, 2, and 3). To this end, a machine learning-based framework was designed. First, the profile data were analyzed by using seven feature ranking algorithms to evaluate the importance of features (genes). Seven feature lists were generated, each of which sorted features in accordance with feature importance evaluated from a special aspect. Then, the incremental feature selection method was applied to each list to determine essential features for classification and building efficient classifiers. Consequently, overlapping genes, such as AURKA, CBX2, and MYBL2, were deemed as potentially related to breast cancer malignancy and prognosis, indicating that such genes were identified to be important by multiple feature ranking algorithms. In addition, the study formulated classification rules to reflect special gene expression patterns for three NHG classes. Some genes and rules were analyzed and supported by recent literature, providing new references for studying breast cancer.
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Affiliation(s)
- QingLan Ma
- School of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Lei Chen
- College of Information Engineering, Shanghai Maritime University, Shanghai, 201306, China
| | - KaiYan Feng
- Department of Computer Science, Guangdong AIB Polytechnic College, Guangzhou, 510507, China
| | - Wei Guo
- Key Laboratory of Stem Cell Biology, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, 200030, China
| | - Tao Huang
- Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Yu-Dong Cai
- School of Life Sciences, Shanghai University, Shanghai, 200444, China.
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Zhou Q, Yang M, Fu J, Sun X, Wang J, Zhang H, Hu J, Han B. KIF1A promotes neuroendocrine differentiation in prostate cancer by regulating the OGT-mediated O-GlcNAcylation. Cell Death Dis 2024; 15:796. [PMID: 39505875 PMCID: PMC11542072 DOI: 10.1038/s41419-024-07142-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 09/27/2024] [Accepted: 10/07/2024] [Indexed: 11/08/2024]
Abstract
Neuroendocrine prostate cancer (NEPC) arises from prostate adenocarcinoma after endocrine treatment failure and implies lethality and limited therapeutic options. Deciphering the molecular mechanisms underlying transdifferentiation from adenocarcinoma to NEPC may provide valuable therapeutic strategies. We performed a pan-cancer differential mRNA abundance analysis and identified that Kinesin-like protein (KIF1A) was highly expressed in NEPC. KIF1A knockdown impaired neuroendocrine(NE) features, including NE marker gene expression, stemness, and epithelial-mesenchymal transition (EMT), whereas KIF1A overexpression promoted these processes. Targeting KIF1A inhibited the growth of NE differentiated prostate cancer (PCa) cells in vitro and in vivo. Mechanistically, KIF1A bound with O-linked N-acetylglucosamine transferase (OGT) and regulated its protein expression and activity. Nuclear accumulation of OGT induced by KIF1A overexpression promoted intranuclear O-GlcNAcylation of β-catenin and OCT4 in nucleus. More importantly, our data revealed that OGT was critical for KIF1A induced NE differentiation and aggressive tumor growth. An OGT inhibitor, OSMI-1, can significantly inhibited NE differentiated PCa cell proliferation in vitro and tumor growth in vivo. Our findings showed that KIF1A promotes NE differentiation to NEPC by regulating the OGT-mediated O-GlcNAcylation. Targeting O-GlcNAcylation may impede the development of NEPC for a group of PCa patients with elevated KIF1A expression.
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Affiliation(s)
- Qianqian Zhou
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250000, P R China
| | - Muyi Yang
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
| | - Jiawei Fu
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250000, P R China
| | - Xinyu Sun
- Jinan Central Hospital, Shandong University, Jinan, Shandong, 250000, P R China
| | - Jiajia Wang
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250000, P R China
| | - Hanwen Zhang
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250000, P R China
| | - Jing Hu
- Department of Pathology, Shandong University Qilu Hospital, Jinan, Shandong, 250000, P R China
| | - Bo Han
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250000, P R China.
- Department of Pathology, Shandong University Qilu Hospital, Jinan, Shandong, 250000, P R China.
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Shen J, He Y, Li S, Chen H. Crosstalk of methylation and tamoxifen in breast cancer (Review). Mol Med Rep 2024; 30:180. [PMID: 39129315 PMCID: PMC11338244 DOI: 10.3892/mmr.2024.13304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 07/23/2024] [Indexed: 08/13/2024] Open
Abstract
Tamoxifen is a widely used anti‑estrogen drug in the endocrine therapy of breast cancer (BC). It blocks estrogen signaling by competitively binding to estrogen receptor α (ERα), thereby inhibiting the growth of BC cells. However, with the long‑term application of tamoxifen, a subset of patients with BC have shown resistance to tamoxifen, which leads to low overall survival and progression‑free survival. The molecular mechanism of resistance is mainly due to downregulation of ERα expression and abnormal activation of the PI3K/AKT/mTOR signaling pathway. Moreover, the downregulation of targeted gene expression mediated by DNA methylation is an important regulatory mode to control protein expression. In the present review, methylation and tamoxifen are briefly introduced, followed by a focus on the effect of methylation on tamoxifen resistance and sensitivity. Finally, the clinical application of methylation for tamoxifen is described, including its use as a prognostic indicator. Finally, it is hypothesized that when methylation is used in combination with tamoxifen, it could recover the resistance of tamoxifen.
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Affiliation(s)
- Jin Shen
- Department of Rehabilitation, The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, P.R. China
| | - Yan He
- Department of Neurology, The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, P.R. China
| | - Shengpeng Li
- Department of Rehabilitation, The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, P.R. China
| | - Huimin Chen
- Department of Rehabilitation, The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, P.R. China
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Chen Q, Le X, Li Q, Liu S, Chen Z. Exploration of inhibitors targeting KIF18A with ploidy-specific lethality. Drug Discov Today 2024; 29:104142. [PMID: 39168405 DOI: 10.1016/j.drudis.2024.104142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 08/06/2024] [Accepted: 08/14/2024] [Indexed: 08/23/2024]
Abstract
Currently, various antimitotic inhibitors applied in tumor therapy. However, these inhibitors exhibit targeted toxicity to some extent. As a motor protein, kinesin family member 18A (KIF18A) is crucial to spindle formation and is associated with tumors exhibiting ploidy-specific characteristics such as chromosomal aneuploidy, whole-genome doubling (WGD), and chromosomal instability (CIN). Differing from traditional antimitotic targets, KIF18A exhibits tumor-specific selectivity. The functional loss or attenuation of KIF18A results in vulnerability of tumor cells with ploidy-specific characteristics, with lesser effects on diploid cells. Research on inhibitors targeting KIF18A with ploidy-specific lethality holds significant importance. This review provides a brief overview of the regulatory mechanisms of the ploidy-specific lethality target KIF18A and the research advancements in its inhibitors, aiming to facilitate the development of KIF18A inhibitors.
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Affiliation(s)
- Qingsong Chen
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, China; Hunan Key Laboratory of Small Molecules for Diagnosis and Treatment of Chronic Disease, Changsha 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha 410013, Hunan, China
| | - Xiangyang Le
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, China; Hunan Key Laboratory of Small Molecules for Diagnosis and Treatment of Chronic Disease, Changsha 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha 410013, Hunan, China
| | - Qianbin Li
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, China; Hunan Key Laboratory of Small Molecules for Diagnosis and Treatment of Chronic Disease, Changsha 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha 410013, Hunan, China
| | - Suyou Liu
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, China; Hunan Key Laboratory of Small Molecules for Diagnosis and Treatment of Chronic Disease, Changsha 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha 410013, Hunan, China
| | - Zhuo Chen
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, China; Hunan Key Laboratory of Small Molecules for Diagnosis and Treatment of Chronic Disease, Changsha 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha 410013, Hunan, China.
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Lukacova E, Hanzlikova Z, Podlesnyi P, Sedlackova T, Szemes T, Grendar M, Samec M, Hurtova T, Malicherova B, Leskova K, Budis J, Burjanivova T. Novel liquid biopsy CNV biomarkers in malignant melanoma. Sci Rep 2024; 14:15786. [PMID: 38982214 PMCID: PMC11233564 DOI: 10.1038/s41598-024-65928-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 06/25/2024] [Indexed: 07/11/2024] Open
Abstract
Malignant melanoma (MM) is known for its abundance of genetic alterations and a tendency for rapid metastasizing. Identification of novel plasma biomarkers may enhance non-invasive diagnostics and disease monitoring. Initially, we examined copy number variations (CNV) in CDK genes (CDKN2A, CDKN2B, CDK4) using MLPA (gDNA) and ddPCR (ctDNA) analysis. Subsequently, low-coverage whole genome sequencing (lcWGS) was used to identify the most common CNV in plasma samples, followed by ddPCR verification of chosen biomarkers. CNV alterations in CDK genes were identified in 33.3% of FFPE samples (Clark IV, V only). Detection of the same genes in MM plasma showed no significance, neither compared to healthy plasmas nor between pre- versus post-surgery plasma. Sequencing data showed the most common CNV occurring in 6q27, 4p16.1, 10p15.3, 10q22.3, 13q34, 18q23, 20q11.21-q13.12 and 22q13.33. CNV in four chosen genes (KIF25, E2F1, DIP2C and TFG) were verified by ddPCR using 2 models of interpretation. Model 1 was concordant with lcWGS results in 54% of samples, for model 2 it was 46%. Although CDK genes have not been proven to be suitable CNV liquid biopsy biomarkers, lcWGS defined the most frequently affected chromosomal regions by CNV. Among chosen genes, DIP2C demonstrated a potential for further analysis.
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Affiliation(s)
- E Lukacova
- Department of Molecular Biology and Genomics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Martin, Slovakia
| | | | - P Podlesnyi
- Instituto de Investigaciones Biomedicas de Barcelona (IIBB), CSIC /Centro Investigacion Biomedica en Red Enfermedades Neurodegenerativas (CiberNed), Barcelona, Spain
| | - T Sedlackova
- Geneton Ltd., Bratislava, Slovakia
- Science Park, Comenius University in Bratislava, Bratislava, Slovakia
| | - T Szemes
- Geneton Ltd., Bratislava, Slovakia
- Science Park, Comenius University in Bratislava, Bratislava, Slovakia
| | - M Grendar
- Laboratory of Bioinformatics and Biostatistics, Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Martin, Slovakia
| | - M Samec
- Department of Medical Biology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - T Hurtova
- Department of Dermatovenereology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - B Malicherova
- Department of Clinical Biochemistry, University Hospital in Martin and Jessenius Faculty of Medicine, Comenius University, Martin, Slovakia
| | - K Leskova
- Department of Pathological Anatomy, Jessenius Faculty of Medicine and University Hospital in Martin, Comenius University, Martin, Slovakia
| | - J Budis
- Geneton Ltd., Bratislava, Slovakia
- Science Park, Comenius University in Bratislava, Bratislava, Slovakia
| | - T Burjanivova
- Department of Molecular Biology and Genomics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Martin, Slovakia.
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Wang JM, Zhang FH, Liu ZX, Tang YJ, Li JF, Xie LP. Cancer on motors: How kinesins drive prostate cancer progression? Biochem Pharmacol 2024; 224:116229. [PMID: 38643904 DOI: 10.1016/j.bcp.2024.116229] [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: 01/02/2024] [Revised: 04/02/2024] [Accepted: 04/18/2024] [Indexed: 04/23/2024]
Abstract
Prostate cancer causes numerous male deaths annually. Although great progress has been made in the diagnosis and treatment of prostate cancer during the past several decades, much about this disease remains unknown, especially its pathobiology. The kinesin superfamily is a pivotal group of motor proteins, that contains a microtubule-based motor domain and features an adenosine triphosphatase activity and motility characteristics. Large-scale sequencing analyses based on clinical samples and animal models have shown that several members of the kinesin family are dysregulated in prostate cancer. Abnormal expression of kinesins could be linked to uncontrolled cell growth, inhibited apoptosis and increased metastasis ability. Additionally, kinesins may be implicated in chemotherapy resistance and escape immunologic cytotoxicity, which creates a barrier to cancer treatment. Here we cover the recent advances in understanding how kinesins may drive prostate cancer progression and how targeting their function may be a therapeutic strategy. A better understanding of kinesins in prostate cancer tumorigenesis may be pivotal for improving disease outcomes in prostate cancer patients.
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Affiliation(s)
- Jia-Ming Wang
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Feng-Hao Zhang
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Zi-Xiang Liu
- Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, People's Republic of China
| | - Yi-Jie Tang
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Jiang-Feng Li
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
| | - Li-Ping Xie
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
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Di Y, Zhang H, Zhang B, Li T, Li D. CCNA2 and KIF23 are molecular targets for the prognosis of adenoid cystic carcinoma. Aging (Albany NY) 2024; 16:205703. [PMID: 38568110 DOI: 10.18632/aging.205703] [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: 06/02/2023] [Accepted: 12/12/2023] [Indexed: 01/07/2025]
Abstract
OBJECTIVE Adenoid cystic carcinoma (ACC) is a tumor type derived from glands. However, relationship between CCNA2 and KIF23, and adenoid cystic carcinoma remains unclear. METHODS GSE36820 and GSE88804 profiles for ACC were obtained from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified, and Weighted Gene Co-expression Network Analysis (WGCNA) was conducted. Subsequently, the construction and analysis of protein-protein interaction (PPI) network, functional enrichment analysis, and Gene Set Enrichment Analysis (GSEA) were performed. A gene expression heat map was generated to visually depict the expression difference of core genes between adenoid cystic carcinoma and normal samples. TargetScan was employed to identify miRNAs that regulated central DEGs. Western blotting (WB) was conducted for cell verification. RESULTS A total of 885 DEGs were identified. GO and KEGG analyses revealed their main enrichment in responses to chemical stimuli, cell proliferation, tissue development, and regulation of cell proliferation. The GO and KEGG results indicated significant enrichment in aldosterone-regulated sodium reabsorption, the cell cycle, and the PPAR signaling pathway. Notably, core genes (CCNA2 and KIF23) were found to be highly expressed in Adenoid Cystic Carcinoma samples and expressed at low levels in normal samples. WB validated the overexpression of CCNA2 and KIF23 in the Adenoid Cystic Carcinoma group, confirming the protein-level changes associated with cell cycle, metastasis, apoptosis, and inflammatory factors in Adenoid Cystic Carcinoma groups with gene overexpression and knockout. CONCLUSIONS CCNA2 and KIF23 exhibit high expression levels in ACC, suggesting their potential role as molecular targets for this malignancy.
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Affiliation(s)
- Yongbin Di
- Department of Stomatology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050030, P.R. China
| | - Haolei Zhang
- Department of Otolaryngology, Head and Neck Surgery, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050030, P.R. China
| | - Bohao Zhang
- Department of Otolaryngology, Head and Neck Surgery, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050030, P.R. China
| | - Tianke Li
- Department of Stomatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Dan Li
- Department of Otolaryngology, Head and Neck Surgery, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050030, P.R. China
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Li L, Qin Y, Chen Y. The enzymes of serine synthesis pathway in cancer metastasis. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119697. [PMID: 38382845 DOI: 10.1016/j.bbamcr.2024.119697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 02/05/2024] [Accepted: 02/14/2024] [Indexed: 02/23/2024]
Abstract
Metastasis, the major cause of cancer mortality, requires cancer cells to reprogram their metabolism to adapt to and thrive in different environments, thereby leaving metastatic cells metabolic characteristics different from their parental cells. Mounting research has revealed that the de novo serine synthesis pathway (SSP), a glycolytic branching pathway that consumes glucose carbons for serine makeup and α-ketoglutarate generation and thus supports the proliferation, survival, and motility of cancer cells, is one such reprogrammed metabolic pathway. During different metastatic cascades, the SSP enzyme proteins or their enzymatic activity are both dynamically altered; manipulating their expression or catalytic activity could effectively prevent the progression of cancer metastasis; and the SSP enzymatic proteins could even conduce to metastasis via their nonenzymatic functions. In this article we overview the SSP dynamics during cancer metastasis and put the focuses on the regulatory role of the SSP in metastasis and the underlying mechanisms that mainly involve cellular anabolism/catabolism, redox balance, and epigenetics, aiming to provide a theoretical basis for the development of therapeutic strategies for targeting metastatic lesions.
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Affiliation(s)
- Lei Li
- Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Yuting Qin
- School of Pharmaceutical Sciences, University of South China, Hengyang, Hunan 421001, China
| | - Yuping Chen
- Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; School of Pharmaceutical Sciences, University of South China, Hengyang, Hunan 421001, China.
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Ali SI, Najaf-Panah MJ, Pyper KB, Lujan FE, Sena J, Ashley AK. Comparative analysis of basal and etoposide-induced alterations in gene expression by DNA-PKcs kinase activity. Front Genet 2024; 15:1276365. [PMID: 38577247 PMCID: PMC10991847 DOI: 10.3389/fgene.2024.1276365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 01/29/2024] [Indexed: 04/06/2024] Open
Abstract
Background: Maintenance of the genome is essential for cell survival, and impairment of the DNA damage response is associated with multiple pathologies including cancer and neurological abnormalities. DNA-PKcs is a DNA repair protein and a core component of the classical nonhomologous end-joining pathway, but it also has roles in modulating gene expression and thus, the overall cellular response to DNA damage. Methods: Using cells producing either wild-type (WT) or kinase-inactive (KR) DNA-PKcs, we assessed global alterations in gene expression in the absence or presence of DNA damage. We evaluated differential gene expression in untreated cells and observed differences in genes associated with cellular adhesion, cell cycle regulation, and inflammation-related pathways. Following exposure to etoposide, we compared how KR versus WT cells responded transcriptionally to DNA damage. Results: Downregulated genes were mostly involved in protein, sugar, and nucleic acid biosynthesis pathways in both genotypes, but enriched biological pathways were divergent, again with KR cells manifesting a more robust inflammatory response compared to WT cells. To determine what major transcriptional regulators are controlling the differences in gene expression noted, we used pathway analysis and found that many master regulators of histone modifications, proinflammatory pathways, cell cycle regulation, Wnt/β-catenin signaling, and cellular development and differentiation were impacted by DNA-PKcs status. Finally, we have used qPCR to validate selected genes among the differentially regulated pathways to validate RNA sequence data. Conclusion: Overall, our results indicate that DNA-PKcs, in a kinase-dependent fashion, decreases proinflammatory signaling following genotoxic insult. As multiple DNA-PK kinase inhibitors are in clinical trials as cancer therapeutics utilized in combination with DNA damaging agents, understanding the transcriptional response when DNA-PKcs cannot phosphorylate downstream targets will inform the overall patient response to combined treatment.
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Affiliation(s)
- Sk Imran Ali
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM, United States
| | - Mohammad J. Najaf-Panah
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM, United States
| | - Kennedi B. Pyper
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM, United States
| | - F. Ester Lujan
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM, United States
| | - Johnny Sena
- National Center for Genome Resources, Santa Fe, NM, United States
| | - Amanda K. Ashley
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM, United States
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12
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Zhuang R, Liu H. Mechanism of regulation of KIF23 on endometrial cancer cell growth and apoptosis. Discov Oncol 2024; 15:83. [PMID: 38514510 PMCID: PMC10957832 DOI: 10.1007/s12672-024-00937-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 03/14/2024] [Indexed: 03/23/2024] Open
Abstract
OBJECTIVE The global incidence of endometrial cancer, a malignant tumor in females, is on the rise. It is one of the most common gynecological cancers. Early-stage endometrial cancers can often be treated successfully with uterine extirpation. However, those diagnosed at a later stage have a poor prognosis and encounter treatment challenges. Therefore, additional research is necessary to develop primary prevention strategies for high-risk women and improve survival rates among patients with endometrial cancer. Hence, gene therapy targeting KIF23 shows promise as an advanced strategy for the treatment of endometrial cancer. METHODS Immunohistochemistry, Western blotting, and PCR were used to examine the expression of KIF23 and its associated pathway factors in endometrial cancer tissue (specifically Ishikawa and SNGM cells, respectively). We investigated the functional roles of KIF23 using CCK-8, colony-forming proliferation assays, Transwell migration assays, and xenotransplantation in mice. RESULTS Immunohistochemistry analysis showed variations in the expression levels of KIF23 between endometrial cancer tissue and normal endometrium tissue. KIF23 downregulated BAX and caspase-3 protein expression while upregulating BCL-2 protein expression. Additionally, knocking out KIF23 inhibits endometrial cancer cell proliferation and migration while promoting cell death. Mechanistically, our study provides evidence that KIF23 promotes endometrial cancer cell proliferation by activating the ERK and AKT/PI3K pathways, while simultaneously inhibiting programmed cell death in endometrial cancer. CONCLUSION Our study provides evidence to support the inhibition of endometrial cancer by KIF23 knockdown. This offers valuable insights for future research on potential therapeutic strategies for this type of cancer.
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Affiliation(s)
- Ruiying Zhuang
- Jinzhou Medical University, Jinzhou, Liaoning Province, China
| | - Haiyan Liu
- The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning Province, China.
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13
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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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14
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Gharpure M, Chen J, Nerella R, Vyavahare S, Kumar S, Isales CM, Hamrick M, Adusumilli S, Fulzele S. Sex-specific alteration in human muscle transcriptome with age. GeroScience 2023:10.1007/s11357-023-00795-5. [PMID: 37106281 PMCID: PMC10400750 DOI: 10.1007/s11357-023-00795-5] [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: 01/24/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
Sarcopenia is a medical condition that progressively develops with age and results in reduced skeletal muscle mass, alteration in muscle composition, and decreased muscle strength. Several clinical studies suggested that sarcopenia disproportionally affects males and females with age. Despite this knowledge, the molecular mechanism governing the pathophysiology is not well understood in a sex-specific manner. In this study, we utilized human gastrocnemius muscles from males and females to identify differentially regulated genes with age. We found 269 genes with at least a twofold expression difference in the aged muscle transcriptome. Among the female muscle samples, there were 239 differentially regulated genes, and the novel protein-coding genes include KIF20A, PIMREG, MTRNR2L6, TRPV6, EFNA2, RNF24, and SFN. In aged male skeletal muscle, there were 166 differentially regulated genes, and the novel-protein coding genes are CENPK, CDKN2A, BHLHA15, and EPHA. Gene Ontology (GO) enrichment revealed glucose catabolism, NAD metabolic processes, and muscle fiber transition pathways that are involved in aged female skeletal muscle, whereas replicative senescence, cytochrome C release, and muscle composition pathways are disrupted in aged male skeletal muscle. Targeting these novels, differentially regulated genes, and signaling pathways could serve as sex-specific therapeutic targets to combat the age-related onset of sarcopenia and promote healthy aging.
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Affiliation(s)
- Mohini Gharpure
- Department of Medicine, Medical College of Georgia, Augusta University, GA, Augusta, USA
| | - Jie Chen
- Division of Biostatistics and Data Science, Department of Population Health Sciences, Augusta University, Augusta, GA, USA
- Center for Healthy Aging, Augusta University, Augusta, GA, USA
| | - Resheek Nerella
- Department of Medicine, Medical College of Georgia, Augusta University, GA, Augusta, USA
- Augusta University, Augusta, GA, 30912, USA
| | - Sagar Vyavahare
- Department of Medicine, Medical College of Georgia, Augusta University, GA, Augusta, USA
| | - Sandeep Kumar
- Department of Medicine, Medical College of Georgia, Augusta University, GA, Augusta, USA
| | - Carlos M Isales
- Department of Medicine, Medical College of Georgia, Augusta University, GA, Augusta, USA
- Center for Healthy Aging, Augusta University, Augusta, GA, USA
| | - Mark Hamrick
- Center for Healthy Aging, Augusta University, Augusta, GA, USA
- Department of Cell Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | | | - Sadanand Fulzele
- Department of Medicine, Medical College of Georgia, Augusta University, GA, Augusta, USA.
- Center for Healthy Aging, Augusta University, Augusta, GA, USA.
- Department of Cell Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA.
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15
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A Novel Four Mitochondrial Respiration-Related Signature for Predicting Biochemical Recurrence of Prostate Cancer. J Clin Med 2023; 12:jcm12020654. [PMID: 36675580 PMCID: PMC9866444 DOI: 10.3390/jcm12020654] [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: 12/09/2022] [Revised: 01/09/2023] [Accepted: 01/10/2023] [Indexed: 01/18/2023] Open
Abstract
The biochemical recurrence (BCR) of patients with prostate cancer (PCa) after radical prostatectomy is high, and mitochondrial respiration is reported to be associated with the metabolism in PCa development. This study aimed to establish a mitochondrial respiratory gene-based risk model to predict the BCR of PCa. RNA sequencing data of PCa were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and mitochondrial respiratory-related genes (MRGs) were sourced via GeneCards. The differentially expressed mitochondrial respiratory and BCR-related genes (DE-MR-BCRGs) were acquired through overlapping BCR-related differentially expressed genes (BCR-DEGs) and differentially expressed MRGs (DE-MRGs) between PCa samples and controls. Further, univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox analyses were performed to construct a DE-MRGs-based risk model. Then, a nomogram was established by analyzing the independent prognostic factor of five clinical features and risk scores. Moreover, Gene Set Enrichment Analysis (GSEA), tumor microenvironment, and drug susceptibility analyses were employed between high- and low-risk groups of PCa patients with BCR. Finally, qRT-PCR was utilized to validate the expression of prognostic genes. We identified 11 DE-MR-BCRGs by overlapping 132 DE-MRGs and 13 BCR-DEGs and constructed a risk model consisting of 4 genes (APOE, DNAH8, EME2, and KIF5A). Furthermore, we established an accurate nomogram, including a risk score and a Gleason score, for the BCR prediction of PCa patients. The GSEA result suggested the risk model was related to the PPAR signaling pathway, the cholesterol catabolic process, the organic hydroxy compound biosynthetic process, the small molecule catabolic process, and the steroid catabolic process. Simultaneously, we found six immune cell types relevant to the risk model: resting memory CD4+ T cells, monocytes, resting mast cells, activated memory CD4+ T cells, regulatory T cells (Tregs), and macrophages M2. Moreover, the risk model could affect the IC50 of 12 cancer drugs, including Lapatinib, Bicalutamide, and Embelin. Finally, qRT-PCR showed that APOE, EME2, and DNAH8 were highly expressed in PCa, while KIF5A was downregulated in PCa. Collectively, a mitochondrial respiratory gene-based nomogram including four genes and one clinical feature was established for BCR prediction in patients with PCa, which could provide novel strategies for further studies.
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16
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Liu Q, Liu YY, Chen XM, Tao BY, Chen K, Li WM, Xu CT, Shi Y, Li H, Liu HR. KIF5A upregulation in hepatocellular carcinoma: A novel prognostic biomarker associated with unique tumor microenvironment status. Front Oncol 2023; 12:1071722. [PMID: 36686769 PMCID: PMC9853384 DOI: 10.3389/fonc.2022.1071722] [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: 10/16/2022] [Accepted: 12/05/2022] [Indexed: 01/09/2023] Open
Abstract
Liver hepatocellular carcinoma (LIHC) is one of the most common liver malignancies with high mortality and morbidity. Thus, it is crucial to identify potential biomarker that is capable of accurately predicting the prognosis and therapeutic response of LIHC. Kinesin family member 5A (KIF5A) is a microtubule-based motor protein involved in the transport of macromolecules such as organelle proteins in cells. Recent studies have illustrated that the high expression of KIF5A was related to poor prognosis of solid tumors, including bladder cancer, prostate cancer, and breast cancer. However, little is currently known concerning the clinical significance of KIF5A expression in LIHC. Herein, by adopting multi-omics bioinformatics analysis, we comprehensively uncovered the potential function and the predictive value of KIF5A in stratifying clinical features among patients with LIHC, for which a high KIF5A level predicted an unfavorable clinical outcome. Results from KIF5A-related network and enrichment analyses illustrated that KIF5A might involve in microtubule-based process, antigen processing and presentation of exogenous peptide antigen via MHC class II. Furthermore, immune infiltration and immune function analyses revealed upregulated KIF5A could predict a unique tumor microenvironment with more CD8+T cells and a higher level of anti-tumor immune response. Evidence provided by immunohistochemistry staining (IHC) further validated our findings at the protein level. Taken together, KIF5A might serve as a novel prognostic biomarker for predicting immunotherapy response and could be a potential target for anti-cancer strategies for LIHC.
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Affiliation(s)
- Qi Liu
- Faculty of Hepato-Pancreato-Biliary Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China,Department of Hepatobiliary, The Eighth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yu-yang Liu
- Medical School of Chinese PLA, Beijing, China
| | - Xue-min Chen
- Medical School of Chinese PLA, Beijing, China,Senior Department of Otolaryngology-Head & Neck Surgery, Chinese PLA General Hospital, Beijing, China
| | | | - Kuang Chen
- Faculty of Hepato-Pancreato-Biliary Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Wei-min Li
- Faculty of Hepato-Pancreato-Biliary Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China,Department of Hepatobiliary, The Eighth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Chang-tao Xu
- Faculty of Hepato-Pancreato-Biliary Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China,Department of Hepatobiliary, The Eighth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Ying Shi
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Hao Li
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Hao-run Liu
- Faculty of Hepato-Pancreato-Biliary Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China,Department of Hepatobiliary, The Eighth Medical Center, Chinese PLA General Hospital, Beijing, China,*Correspondence: Hao-run Liu,
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17
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Fu J, Zhang J, Chen X, Liu Z, Yang X, He Z, Hao Y, Liu B, Yao D. ATPase family AAA domain-containing protein 2 (ATAD2): From an epigenetic modulator to cancer therapeutic target. Theranostics 2023; 13:787-809. [PMID: 36632213 PMCID: PMC9830439 DOI: 10.7150/thno.78840] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 12/22/2022] [Indexed: 01/06/2023] Open
Abstract
ATPase family AAA domain-containing protein 2 (ATAD2) has been widely reported to be a new emerging oncogene that is closely associated with epigenetic modifications in human cancers. As a coactivator of transcription factors, ATAD2 can participate in epigenetic modifications and regulate the expression of downstream oncogenes or tumor suppressors, which may be supported by the enhancer of zeste homologue 2. Moreover, the dominant structure (AAA + ATPase and bromine domains) can make ATAD2 a potential therapeutic target in cancer, and some relevant small-molecule inhibitors, such as GSK8814 and AZ13824374, have also been discovered. Thus, in this review, we focus on summarizing the structural features and biological functions of ATAD2 from an epigenetic modulator to a cancer therapeutic target, and further discuss the existing small-molecule inhibitors targeting ATAD2 to improve potential cancer therapy. Together, these inspiring findings would shed new light on ATAD2 as a promising druggable target in cancer and provide a clue on the development of candidate anticancer drugs.
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Affiliation(s)
- Jiahui Fu
- School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, 518118, China.,State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jin Zhang
- School of Pharmaceutical Sciences, Medical School, Shenzhen University, Shenzhen 518060, China
| | - Xiya Chen
- School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, 518118, China.,School of Pharmaceutical Sciences, Medical School, Shenzhen University, Shenzhen 518060, China
| | - Zhiying Liu
- School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, 518118, China.,School of Pharmaceutical Sciences, Medical School, Shenzhen University, Shenzhen 518060, China
| | - Xuetao Yang
- School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, 518118, China
| | - Zhendan He
- School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, 518118, China
| | - Yue Hao
- School of Pharmaceutical Sciences, Medical School, Shenzhen University, Shenzhen 518060, China.,✉ Corresponding authors: E-mail addresses: (Yue Hao); (Bo Liu), or (Dahong Yao). Tel./Fax. (+86)-28-85164063
| | - Bo Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.,✉ Corresponding authors: E-mail addresses: (Yue Hao); (Bo Liu), or (Dahong Yao). Tel./Fax. (+86)-28-85164063
| | - Dahong Yao
- School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, 518118, China.,✉ Corresponding authors: E-mail addresses: (Yue Hao); (Bo Liu), or (Dahong Yao). Tel./Fax. (+86)-28-85164063
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18
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A targetable MYBL2-ATAD2 axis governs cell proliferation in ovarian cancer. Cancer Gene Ther 2023; 30:192-208. [PMID: 36151333 DOI: 10.1038/s41417-022-00538-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/25/2022] [Accepted: 09/12/2022] [Indexed: 01/19/2023]
Abstract
The chromatin-modifying enzyme ATAD2 confers oncogenic competence and proliferative advantage in malignances. We previously identified ATAD2 as a marker and driver of cell proliferation in ovarian cancer (OC); however, the mechanisms whereby ATAD2 is regulated and involved in cell proliferation are still unclear. Here, we disclose that ATAD2 displays a classical G2/M gene signature, functioning to facilitate mitotic progression. ATAD2 ablation caused mitotic arrest and decreased the ability of OC cells to pass through nocodazole-arrested mitosis. ChIP-seq data analyses demonstrated that DREAM and MYBL2-MuvB (MMB), two switchable MuvB-based complexes, bind the CHR elements in the ATAD2 promoter, representing a typical feature and principle mechanism of the periodic regulation of G2/M genes. As a downstream target of MYBL2, ATAD2 deletion significantly impaired MYBL2-driven cell proliferation. Intriguingly, ATAD2 silencing also fed back to destabilize the MYBL2 protein. The significant coexpression of MYBL2 and ATAD2 at both the bulk tissue and single-cell levels highlights the existence of the MYBL2-ATAD2 signaling in OC patients. This signaling is activated during tumorigenesis and correlated with TP53 mutation, and its hyperactivation was found especially in high-grade serous and drug-resistant OCs. Disrupting this signaling by CRISPR/Cas9-mediated ATAD2 ablation inhibited the in vivo growth of OC in a subcutaneous tumor xenograft mouse model, while pharmacologically targeting this signaling with an ATAD2 inhibitor demonstrated high therapeutic efficacy in both drug-sensitive and drug-resistant OC cells. Collectively, we identified a novel MYBL2-ATAD2 proliferative signaling axis and highlighted its potential application in developing new therapeutic strategies, especially for high-grade serous and drug-resistant OCs.
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19
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Zhang H, Li C, Liao S, Tu Y, Sun S, Yao F, Li Z, Wang Z. PSMD12 promotes the activation of the MEK-ERK pathway by upregulating KIF15 to promote the malignant progression of liver cancer. Cancer Biol Ther 2022; 23:1-11. [PMID: 36137220 PMCID: PMC9519003 DOI: 10.1080/15384047.2022.2125260] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The tumor recurrence and drug resistance of hepatocellular carcinoma (HCC) threatened patients a lot. The mechanism should be further explored. The information of expression status and survival were available in public databases. The Western blot and immunohistochemistry staining displayed the level of related proteins. CCK-8, colony-formation assays, transwell assay and wound healing assay were performed to illustrate the ability of tumor growth, invasion and migration. In vivo model was established to verify our cell experiments. In our study, we revealed that proteasome 26S subunit, non-ATPase 12 (PSMD12) was high expressed in HCC tissues and positive related to the survival. In vitro experiments suggested that PSMD12 knockdown attenuated tumor cell growth, invasion and migration. Moreover, PSMD12 interference blocked the activation of MEK-ERK pathway. The ERK inhibitor could alleviate the tumor-promoting effect in PSMD12-overexpression cells. In addition, kinesin family member 15 (KIF15) was also observed to be highly expressed in HCC and be harmful to the survival. The public database, the images of immunohistochemistry and the western blot illustrated that PSMD12 and KIF15 was positive correlated. KIF15 knockdown impaired tumor progression and tumor-promoting effect of PSMD12. The xenograft models supported the results of cell experiments. In conclusion, PSMD12 could activated MEK-ERK pathway via KIF15 upregulation, thereby promoting tumor progression.
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Affiliation(s)
- Hanpu Zhang
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, P. R. China.,Department of Colorectal Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chenyuan Li
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, P. R. China
| | - Shichong Liao
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, P. R. China
| | - Yi Tu
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, P. R. China
| | - Shengrong Sun
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, P. R. China
| | - Feng Yao
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, P. R. China
| | - Zhiyu Li
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, P. R. China
| | - Zhong Wang
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, P. R. China
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Dutta M, Mohapatra D, Mohapatra AP, Senapati S, Roychowdhury A. ATAD2 suppression enhances the combinatorial effect of gemcitabine and radiation in pancreatic cancer cells. Biochem Biophys Res Commun 2022; 635:179-186. [DOI: 10.1016/j.bbrc.2022.10.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 09/22/2022] [Accepted: 10/05/2022] [Indexed: 11/25/2022]
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21
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Hassan Ibrahim I, Balah A, Gomaa Abd Elfattah Hassan A, Gamal Abd El-Aziz H. Role of motor proteins in human cancers. Saudi J Biol Sci 2022; 29:103436. [PMID: 36131778 PMCID: PMC9483653 DOI: 10.1016/j.sjbs.2022.103436] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 08/04/2022] [Accepted: 09/01/2022] [Indexed: 11/30/2022] Open
Abstract
Motor proteins include several protein families (Kinesin, Dynein and Myosin) responsible for intracellular transport, intercellular communication, among other functions. In cancer cells, motor proteins along with microtubules (MT) and other tubulin and actin structures, are crucial for cell proliferation and invasion. The cBioPortal platform for Cancer Genomics database was queried for solid cancers in a combined cohort of 9204 patients with complete cancer genomics data. To assess the importance of motor proteins in cancer, copy number alterations (CNAs) and survival rates were analyzed in the combined dataset. Kinesin, Dynein, and Myosin families showed CNAs in 47%, 49%, and 57 % of patients, respectively, in at least one of their members. Survival analysis showed that CNAs in Kinesin and Dynein, families' genes in the same patients were significantly correlated to decreased overall survival. These results added more evidence to previous literature highlighting the importance of motor proteins as a target in cancer therapy. Kinesin inhibitors could act by several mechanisms such as inhibiting spindle assembly or centrosome separation during mitosis, leading to cell cycle arrest and eventually apoptosis. Dynein inhibitors modulate Dynein's activity and MT binding, inhibiting cell proliferation and invasion. Myosin inhibitors act by stabilizing MT, inducing cell cycle arrest and inhibiting invasiveness. Increasing the specificity of motor proteins targeting drugs could improve cancer therapy and patient survival.
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Affiliation(s)
- Iman Hassan Ibrahim
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Postal code 11765, Egypt
| | - Amany Balah
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al- Azhar University, Postal code 11765, Egypt
| | - Abrar Gomaa Abd Elfattah Hassan
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Postal code 11765, Egypt
| | - Heba Gamal Abd El-Aziz
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Postal code 11765, Egypt
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22
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Zhang H, Meng S, Chu K, Chu S, Fan YC, Bai J, Yu ZQ. KIF4A drives gliomas growth by transcriptional repression of Rac1/Cdc42 to induce cytoskeletal remodeling in glioma cells. J Cancer 2022; 13:3640-3651. [PMID: 36606197 PMCID: PMC9809311 DOI: 10.7150/jca.77238] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 11/02/2022] [Indexed: 12/03/2022] Open
Abstract
Glioma is one of the most prevalent cancers diseases in the worldwide. Kinesin superfamily protein 4 (KIF4), a KIF member classified in Kinesin 4 has been indicated as a mediator acted in tumorigenesis of human cancer. However, the mechanism of KIF4A on glioma is yet to be investigated. This study aimed to explore the potential function and mechanism of KIF4A in gliomas. We analyzed the KIF4A expression and the prognosis in gliomas patients using The Cancer Genome Atlas (TCGA) databases. KIF4A level in normal human astrocyte cell (NHA) and glioma cell lines were examined by Western blot. We studied the function of KIF4A on proliferation, migration, invasion, cell cycle in glioma cell lines using a series of in vitro and in vivo experiments. Chromatin Immunoprecipitation (ChIP) analysis was applied to searching potential KIF4A related downstream in glioma. We identified the significant up-regulated expression of KIF4A both in glioma tissues and cell. Glioma patients with elevated KIF4A expression have shorter survival. Down-regulation of KIF4A exerted inhibitory effect on cell proliferation, invasion and migration. We crucially identified that KIF4A drives gliomas growth by transcriptional repression of Rac1/Cdc42 to induce cytoskeletal remodeling in glioma cells. Knockdown of KIF4A decreased RohA, Rac1, Cdc42, Pak1 and Pak2 expression level. Our study provided a prospect that KIF4A functions as an oncogene in glioma.
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Affiliation(s)
- Hui Zhang
- Department of Neurosurgery, the first Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.,Department of Neurosurgery, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Seng Meng
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Kun Chu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Sufang Chu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yue-Chao Fan
- Department of Neurosurgery, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.,✉ Corresponding authors: Zheng-Quan Yu, Department of Neurosurgery, The first Affiliated Hospital of Soochow University, Suzhou, China. E-mail: ; Jin Bai, Cancer Institute, Xuzhou Medical University. 84 West Huaihai Road, Xuzhou, 221002, Jiangsu Province, China. E-mail: ; Yue-Chao Fan, Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, Jiangsu Province, China. E-mail:
| | - Jin Bai
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Center of Clinical Oncology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.,✉ Corresponding authors: Zheng-Quan Yu, Department of Neurosurgery, The first Affiliated Hospital of Soochow University, Suzhou, China. E-mail: ; Jin Bai, Cancer Institute, Xuzhou Medical University. 84 West Huaihai Road, Xuzhou, 221002, Jiangsu Province, China. E-mail: ; Yue-Chao Fan, Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, Jiangsu Province, China. E-mail:
| | - Zheng-Quan Yu
- Department of Neurosurgery, the first Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.,✉ Corresponding authors: Zheng-Quan Yu, Department of Neurosurgery, The first Affiliated Hospital of Soochow University, Suzhou, China. E-mail: ; Jin Bai, Cancer Institute, Xuzhou Medical University. 84 West Huaihai Road, Xuzhou, 221002, Jiangsu Province, China. E-mail: ; Yue-Chao Fan, Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, Jiangsu Province, China. E-mail:
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miR-302 Suppresses the Proliferation, Migration, and Invasion of Breast Cancer Cells by Downregulating ATAD2. Cancers (Basel) 2022; 14:cancers14184345. [PMID: 36139505 PMCID: PMC9497224 DOI: 10.3390/cancers14184345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/01/2022] [Accepted: 09/02/2022] [Indexed: 11/18/2022] Open
Abstract
Simple Summary ATPase family AAA domain-containing protein 2 (ATAD2) overexpression is associated with poor survival and disease recurrence in multiple cancers. The current study aimed to investigate the expression and function of ATAD2 in breast cancer. Our results showed that ATAD2 expression was upregulated in human breast cancer tissues and cell lines, while ATAD2 knockdown inhibited the proliferation, migration, and invasion of breast cancer cells. Moreover, we provide evidence suggesting that miR-302 directly targets ATAD2 and thus modulates cancer cell proliferation, migration, and invasion in vitro. Moreover, ATAD2 overexpression rescued the inhibition of tumor growth caused by miR-302 in xenograft mice. These findings indicate that miR-302 plays a crucial role in inhibiting the malignant phenotypes of breast cancer cells by targeting ATAD2. Abstract Breast cancer is the most common malignant tumor in women. The ATPase family AAA domain-containing protein 2 (ATAD2) contains an ATPase domain and a bromodomain, and is abnormally expressed in various human cancers, including breast cancer. However, the molecular mechanisms underlying the regulation of ATAD2 expression in breast cancer remain unclear. This study aimed to investigate the expression and function of ATAD2 in breast cancer. We found that ATAD2 was highly expressed in human breast cancer tissues and cell lines. ATAD2 depletion via RNA interference inhibited the proliferation, migration, and invasive ability of the SKBR3 and T47D breast cancer cell lines. Furthermore, Western blot analysis and luciferase assay results revealed that ATAD2 is a putative target of miR-302. Transfection with miR-302 mimics markedly reduced cell migration and invasion. These inhibitory effects of miR-302 were restored by ATAD2 overexpression. Moreover, miR-302 overexpression in SKBR3 and T47D cells suppressed tumor growth in the xenograft mouse model. However, ATAD2 overexpression rescued the decreased tumor growth seen after miR-302 overexpression. Our findings indicate that miR-302 plays a prominent role in inhibiting the cancer cell behavior associated with tumor progression by targeting ATAD2, and could thus be a valuable target for breast cancer therapy.
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Aspirin Exerts Its Antitumor Effect in Esophageal Squamous Cell Carcinoma by Downregulating the Expression of ATAD2 and KIF4A. Anal Cell Pathol (Amst) 2022; 2022:7005328. [PMID: 36046597 PMCID: PMC9420644 DOI: 10.1155/2022/7005328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 08/03/2022] [Accepted: 08/05/2022] [Indexed: 12/24/2022] Open
Abstract
Objective To investigate the expression of ATPase family AAA domain-containing protein 2 (ATAD2) and kinesin family member 4A (KIF4A) in esophageal squamous cell carcinoma (ESCC) tissues and their association with clinicopathological features and to explore the role of ATAD2 in regulating KIF4A expression and biological functions in ESCC cells and the effect of aspirin on their expression. Methods The mRNA and protein expression of ATAD2 and KIF4A in the tissues of patients with ESCC were measured by RT-qPCR and immunohistochemistry, and the correlation between the expression of mRNA and clinicopathological characteristics was analyzed. Western blot and RT-qPCR were used to detect the interference efficiency and KIF4A expression after si-ATAD2 transfection in EC109 and KYSE30 cells. CCK-8 and Transwell assay were performed to investigate the effects of ATAD2 and aspirin on proliferation, migration, and invasion of ESCC cells. The effect of aspirin on the expression of ATAD2 and KIF4A in ESCC cells was measured by RT-qPCR and Western blot. Results The expression of ATAD2 and KIF4A was upregulated in ESCC tissues, and both were correlated with the differentiation grades and lymph node metastasis. Knockdown of ATAD2 in ESCC cells significantly inhibited cell proliferation, migration, and invasion. Compared to the negative control group, the proliferation, migration, and invasion ability of ESCC cells in the aspirin-treated groups were decreased, and the expression of ATAD2 and KIF4A in ESCC cells was decreased after treating with aspirin for 48 h. Conclusion The expression levels of ATAD2 and KIF4A are elevated in ESCC. ATAD2 promotes proliferation, migration, and invasion of ESCC cells by regulating KIF4A. Aspirin can inhibit the malignant behavior of ESCC cells by downregulating ATAD2 and KIF4A.
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Tumor-Promoting ATAD2 and Its Preclinical Challenges. Biomolecules 2022; 12:biom12081040. [PMID: 36008934 PMCID: PMC9405547 DOI: 10.3390/biom12081040] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/15/2022] [Accepted: 07/19/2022] [Indexed: 02/06/2023] Open
Abstract
ATAD2 has received extensive attention in recent years as one prospective oncogene with tumor-promoting features in many malignancies. ATAD2 is a highly conserved bromodomain family protein that exerts its biological functions by mainly AAA ATPase and bromodomain. ATAD2 acts as an epigenetic decoder and transcription factor or co-activator, which is engaged in cellular activities, such as transcriptional regulation, DNA replication, and protein modification. ATAD2 has been reported to be highly expressed in a variety of human malignancies, including gastrointestinal malignancies, reproductive malignancies, urological malignancies, lung cancer, and other types of malignancies. ATAD2 is involved in the activation of multiple oncogenic signaling pathways and is closely associated with tumorigenesis, progression, chemoresistance, and poor prognosis, but the oncogenic mechanisms vary in different cancer types. Moreover, the direct targeting of ATAD2’s bromodomain may be a very challenging task. In this review, we summarized the role of ATAD2 in various types of malignancies and pointed out the pharmacological direction.
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Hao WW, Xu F. KIFC3 promotes proliferation, migration and invasion of esophageal squamous cell carcinoma cells by activating EMT and β-catenin signaling. World J Gastrointest Oncol 2022; 14:1239-1251. [PMID: 36051093 PMCID: PMC9305573 DOI: 10.4251/wjgo.v14.i7.1239] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/26/2022] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies. A total of 45 kinesin superfamily proteins (KIFs) have been identified in humans, among which several family members have demonstrated varied functions in tumor pathobiology via different mechanisms, including regulation of cell cycle progression and metastasis. KIFC3 has microtubule motor activity and is involved in cancer cell invasion and migration, as well as survival. However, the role of KIFC3 in ESCC is still unknown.
AIM To evaluate the role of KIFC3 in ESCC and the underlying mechanisms.
METHODS Expression of KIFC3 was evaluated in ESCC tissues and adjacent normal esophageal tissues. The prognostic value of KIFC3 was analyzed using Kaplan–Meier Plotter. Colony formation, EdU assays, cell cycle analysis, Transwell assay, immunofluorescence, and western blotting were performed in ESCC cell lines after transfection with pLVX-Puro-KIFC3-shRNA- and pLVX-Puro-KIFC3-expressing lentiviruses. A xenograft tumor model in nude mice was used to evaluate the role of KIFC3 in tumorigenesis. Inhibitor of β-catenin, XAV-939, was used to clarify the mechanism of KIFC3 in ESCC. To analyze the differences between groups, t test and nonparametric tests were used. P < 0.05 was considered statistically significant.
RESULTS Immunohistochemical staining indicated that KIFC3 was upregulated in ESCC tissues compared with adjacent normal tissues. Kaplan–Meier Plotter revealed that overexpressed KIFC3 was associated with poor prognosis in ESCC patients. Colony formation and EdU assay showed that KIFC3 overexpression promoted cell proliferation, while KIFC3 knockdown inhibited cell proliferation in ESCC cell lines. In addition, cell cycle analysis showed that KIFC3 overexpression promoted cell cycle progression. KIFC3 knockdown suppressed ESCC tumorigenesis in vivo. Transwell assay and western blotting revealed that KIFC3 overexpression promoted cell migration and invasion, as well as epithelial–mesenchymal transition (EMT), while KIFC3 knockdown showed the opposite results. Mechanistically, KIFC3 overexpression promoted β-catenin signaling in KYSE450 cells; however, the role of KIFC3 was abolished by XAV-939, the inhibitor of β-catenin signaling.
CONCLUSION KIFC3 was overexpressed in ESCC and was associated with poor prognosis. Furthermore, KIFC3 promoted proliferation, migration and invasion of ESCC via β-catenin signaling and EMT.
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Affiliation(s)
- Wei-Wei Hao
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Feng Xu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
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Bai X, Cao Y, Yan X, Tuoheti K, Du G, Chen Z, Wu H, Guo L, Liu T. Systematic Pan-Cancer Analysis of KIF23 and a Prediction Model Based on KIF23 in Clear Cell Renal Cell Carcinoma (ccRCC). Pharmgenomics Pers Med 2022; 14:1717-1729. [PMID: 35002290 PMCID: PMC8725058 DOI: 10.2147/pgpm.s337695] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 12/02/2021] [Indexed: 12/04/2022] Open
Abstract
Purpose This study aims to carry out a pan-cancer analysis of kinesin family member 23 (KIF23) and construct a predictive model for the prognosis of clear cell renal cell carcinoma (ccRCC) patients. Methods We evaluated the differential expression of KIF23 in pan-cancer by The Cancer Genome Atlas (TCGA) and Oncomine database. Then, the correlation between KIF23 with prognosis, clinical grade, stage, immune subtype, tumor mutation burden (TMB), microsatellite instability (MSI) and immune microenvironment was explored by TCGA, an integrated repository portal for tumor-immune system interactions (TISIDB) and cBioPortal. Subsequently, we screened out ferroptosis-related genes (FRGs) related to KIF23 and constructed a risk score model. Univariate Cox analysis was used to determine independent prognostic factors for ccRCC overall survival (OS), and a nomogram was established. Furthermore, gene set enrichment analysis (GSEA) was applied to study the biological functions and pathways of KIF23. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to evaluate the expression of KIF23. Results KIF23 was highly expressed in most tumors. Further, KIF23 was strongly correlated with prognosis, clinical grade, stage, immune subtype, TMB, MSI and immune microenvironment in different tumors. We found that KIF23 was significantly associated with all aspects of ccRCC. Then, 8 FRGs were identified to construct a risk score model together with KIF23. And a prognostic nomogram prediction model of OS was established. After GSEA analysis, cell cycle, condensed chromosome and other physiological processes were screened out. Finally, qRT-PCR verified the high expression of KIF23 in ccRCC cell lines than normal kidney cell line. Conclusion KIF23 may act as a pivotal part in occurrence and progression of different tumors. In ccRCC, KIF23 can be a great prognostic biomarker, and the nomogram based on KIF23 may contribute to better treatment plans for ccRCC patients.
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Affiliation(s)
- Xiaojie Bai
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Yuanfei Cao
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Xin Yan
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Kurerban Tuoheti
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Guowei Du
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Zhao Chen
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Huahui Wu
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Linfa Guo
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Tongzu Liu
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
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Fritz AJ, El Dika M, Toor RH, Rodriguez PD, Foley SJ, Ullah R, Nie D, Banerjee B, Lohese D, Glass KC, Frietze S, Ghule PN, Heath JL, Imbalzano AN, van Wijnen A, Gordon J, Lian JB, Stein JL, Stein GS, Stein GS. Epigenetic-Mediated Regulation of Gene Expression for Biological Control and Cancer: Cell and Tissue Structure, Function, and Phenotype. Results Probl Cell Differ 2022; 70:339-373. [PMID: 36348114 PMCID: PMC9753575 DOI: 10.1007/978-3-031-06573-6_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Epigenetic gene regulatory mechanisms play a central role in the biological control of cell and tissue structure, function, and phenotype. Identification of epigenetic dysregulation in cancer provides mechanistic into tumor initiation and progression and may prove valuable for a variety of clinical applications. We present an overview of epigenetically driven mechanisms that are obligatory for physiological regulation and parameters of epigenetic control that are modified in tumor cells. The interrelationship between nuclear structure and function is not mutually exclusive but synergistic. We explore concepts influencing the maintenance of chromatin structures, including phase separation, recognition signals, factors that mediate enhancer-promoter looping, and insulation and how these are altered during the cell cycle and in cancer. Understanding how these processes are altered in cancer provides a potential for advancing capabilities for the diagnosis and identification of novel therapeutic targets.
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Affiliation(s)
- Andrew J. Fritz
- University of Vermont, UVM Cancer Center, Larner College of Medicine, Department of Biochemistry, Burlington, VT 05405
| | - Mohammed El Dika
- University of Vermont, UVM Cancer Center, Larner College of Medicine, Department of Biochemistry, Burlington, VT 05405
| | - Rabail H. Toor
- University of Vermont, UVM Cancer Center, Larner College of Medicine, Department of Biochemistry, Burlington, VT 05405
| | | | - Stephen J. Foley
- University of Vermont, UVM Cancer Center, Larner College of Medicine, Department of Biochemistry, Burlington, VT 05405
| | - Rahim Ullah
- University of Vermont, UVM Cancer Center, Larner College of Medicine, Department of Biochemistry, Burlington, VT 05405
| | - Daijing Nie
- University of Vermont, UVM Cancer Center, Larner College of Medicine, Department of Biochemistry, Burlington, VT 05405
| | - Bodhisattwa Banerjee
- University of Vermont, UVM Cancer Center, Larner College of Medicine, Department of Biochemistry, Burlington, VT 05405
| | - Dorcas Lohese
- University of Vermont, UVM Cancer Center, Larner College of Medicine, Department of Biochemistry, Burlington, VT 05405
| | - Karen C. Glass
- University of Vermont, UVM Cancer Center, Larner College of Medicine, Department of Pharmacology, Burlington, VT 05405
| | - Seth Frietze
- University of Vermont, College of Nursing and Health Sciences, Burlington, VT 05405
| | - Prachi N. Ghule
- University of Vermont, UVM Cancer Center, Larner College of Medicine, Department of Biochemistry, Burlington, VT 05405
| | - Jessica L. Heath
- University of Vermont, UVM Cancer Center, Larner College of Medicine, Department of Biochemistry, Burlington, VT 05405,University of Vermont, Larner College of Medicine, Department of Pediatrics, Burlington, VT 05405
| | - Anthony N. Imbalzano
- UMass Chan Medical School, Department of Biochemistry and Molecular Biotechnology, Worcester, MA 01605
| | - Andre van Wijnen
- University of Vermont, UVM Cancer Center, Larner College of Medicine, Department of Biochemistry, Burlington, VT 05405
| | - Jonathan Gordon
- University of Vermont, UVM Cancer Center, Larner College of Medicine, Department of Biochemistry, Burlington, VT 05405
| | - Jane B. Lian
- University of Vermont, UVM Cancer Center, Larner College of Medicine, Department of Biochemistry, Burlington, VT 05405
| | - Janet L. Stein
- University of Vermont, UVM Cancer Center, Larner College of Medicine, Department of Biochemistry, Burlington, VT 05405
| | - Gary S. Stein
- University of Vermont, UVM Cancer Center, Larner College of Medicine, Department of Biochemistry, Burlington, VT 05405
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Gao L, Zhao R, Liu J, Zhang W, Sun F, Yin Q, Wang X, Wang M, Feng T, Qin Y, Cai W, Li Q, Dong H, Chen X, Xiong X, Liu H, Hu J, Chen W, Han B. KIF15 Promotes Progression of Castration Resistant Prostate Cancer by Activating EGFR Signaling Pathway. Front Oncol 2021; 11:679173. [PMID: 34804913 PMCID: PMC8599584 DOI: 10.3389/fonc.2021.679173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 10/18/2021] [Indexed: 11/29/2022] Open
Abstract
Castration-resistant prostate cancer (CRPC) continues to be a major clinical problem and its underlying mechanisms are still not fully understood. The epidermal growth factor receptor (EGFR) activation is an important event that regulates mitogenic signaling. EGFR signaling plays an important role in the transition from androgen dependence to castration-resistant state in prostate cancer (PCa). Kinesin family member 15 (KIF15) has been suggested to be overexpressed in multiple malignancies. Here, we demonstrate that KIF15 expression is elevated in CRPC. We show that KIF15 contributes to CRPC progression by enhancing the EGFR signaling pathway, which includes complex network intermediates such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. In CRPC tumors, increased expression of KIF15 is positively correlated with EGFR protein level. KIF15 binds to EGFR, and prevents EGFR proteins from degradation in a Cdc42-dependent manner. These findings highlight the key role of KIF15 in the development of CRPC and rationalize KIF15 as a potential therapeutic target.
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Affiliation(s)
- Lin Gao
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ru Zhao
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Junmei Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wenbo Zhang
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Feifei Sun
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qianshuo Yin
- School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Xin Wang
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Meng Wang
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tingting Feng
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yiming Qin
- College of Chemical Engineering and Materials Science, Shandong Normal University, Jinan, China
| | - Wenjie Cai
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qianni Li
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Hanchen Dong
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xueqing Chen
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xueting Xiong
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Hui Liu
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jing Hu
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Weiwen Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Bo Han
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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KIF4A Regulates the Progression of Pancreatic Ductal Adenocarcinoma through Proliferation and Invasion. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8249293. [PMID: 34805404 PMCID: PMC8601854 DOI: 10.1155/2021/8249293] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 10/28/2021] [Indexed: 12/18/2022]
Abstract
Background Pancreatic cancer is a malignant tumor of the digestive tract, which is difficult to diagnose and treat due to bad early diagnosis. We aimed to explore the role of kinesin superfamily 4A (KIF4A) in pancreatic ductal adenocarcinoma (PDAC). Methods We first used the bioinformatic website to screen the data of pancreatic cancer in TCGA, and KIF4A protein was detected among the 86 specimens of patients in our hospital combined with clinic-pathological characteristics and survival analysis. KIF4A loss-expression cell lines were established by RNA interference (RNAi). In addition, we performed in vitro cell assays to detect the changes in cell proliferation, migration, and invasion. The proteins involved in the proliferation and metastasis of cancer cells were also detected by western blot. The above results could be proved in vivo. Further, the correlation between KIF4A and CDC5L was analyzed by TCGA and IHC data. Results We first found a high expression of KIF4A in pancreatic cancer, suggesting a role of KIF4A in the development of pancreatic cancer. KIF4A was found to be differentially expressed (P < 0.05) among the 86 specimens of patients in our hospital and was significantly associated with PDAC TNM stages and tumor size. High KIF4A expression also significantly worsened overall survival (OS) and disease-free survival rate (DFS) (P < 0.05, respectively). In addition, cell proliferation, migration, and invasion were inhibited by the KIF4A-shRNA group compared with the control (P < 0.05, respectively). In the end, knockdown of KIF4A could inhibit tumor development and metastasis in vivo. Further, the positive correlation between KIF4A and CDC5L existed, and KIF4A might promote pancreatic cancer proliferation by affecting CDC5L expression. Conclusion In conclusion, the high expression level of KIF4A in PDAC was closely related to poor clinical and pathological status, lymphatic metastasis, and vascular invasion. KIF4A might be involved in promoting the development of PDAC in vitro and in vivo, which might be a new therapeutic target of PDAC.
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Lucanus AJ, Thike AA, Tan XF, Lee KW, Guo S, King VPC, Yap VB, Bay BH, Tan PH, Yip GW. KIF21A regulates breast cancer aggressiveness and is prognostic of patient survival and tumor recurrence. Breast Cancer Res Treat 2021; 191:63-75. [PMID: 34698969 DOI: 10.1007/s10549-021-06426-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 10/14/2021] [Indexed: 12/24/2022]
Abstract
PURPOSE Invasion of carcinoma cells into surrounding tissue affects breast cancer staging, influences choice of treatment, and impacts on patient outcome. KIF21A is a member of the kinesin superfamily that has been well-studied in congenital extraocular muscle fibrosis. However, its biological relevance in breast cancer is unknown. This study investigated the functional roles of KIF21A in this malignancy and examined its expression pattern in breast cancer tissue. METHODS The function of KIF21A in breast carcinoma was studied in vitro by silencing its expression in breast cancer cells and examining the changes in cellular activities. Immunohistochemical staining of breast cancer tissue microarrays was performed to determine the expression patterns of KIF21A. RESULTS Knocking down the expression of KIF21A using siRNA in MDA-MB-231 and MCF7 human breast cancer cells resulted in significant decreases in tumor cell migration and invasiveness. This was associated with reduced Patched 1 expression and F-actin microfilaments. Additionally, the number of focal adhesion kinase- and paxillin-associated focal adhesions was increased. Immunohistochemical staining of breast cancer tissue microarrays showed that KIF21A was expressed in both the cytoplasmic and nuclear compartments of carcinoma cells. Predominance of cytoplasmic KIF21A was significantly associated with larger tumors and high grade cancer, and prognostic of cause-specific overall patient survival and breast cancer recurrence. CONCLUSION The data demonstrates that KIF21A is an important regulator of breast cancer aggressiveness and may be useful in refining prognostication of this malignant disease.
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Affiliation(s)
- Anton J Lucanus
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore.,School of Anatomy, Human Biology and Physiology, University of Western Australia, Crawley, WA, 6009, Australia
| | - Aye Aye Thike
- Division of Pathology, Singapore General Hospital, Singapore, 169856, Singapore
| | - Xing Fei Tan
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore
| | - Kee Wah Lee
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore
| | - Shiyuan Guo
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore
| | - Victoria P C King
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore
| | - Von Bing Yap
- Department of Statistics and Applied Probability, National University of Singapore, Singapore, 117546, Singapore
| | - Boon Huat Bay
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore
| | - Puay Hoon Tan
- Division of Pathology, Singapore General Hospital, Singapore, 169856, Singapore
| | - George W Yip
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore.
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Qureshi Z, Ahmad M, Yang WX, Tan FQ. Kinesin 12 (KIF15) contributes to the development and tumorigenicity of prostate cancer. Biochem Biophys Res Commun 2021; 576:7-14. [PMID: 34474246 DOI: 10.1016/j.bbrc.2021.08.072] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 08/25/2021] [Indexed: 02/05/2023]
Abstract
In Asia, prostate cancer is becoming a growing concern, impacting both socially and economically, compared with what is seen in western countries. Hence, it is essential to know the mechanisms associated with the development and tumorigenesis of PCa for primary diagnosis, risk management, and development of therapy strategies against PCa. Kinesin family member 15 (KIF15), a kinesin family member, is a plus-end-directed kinesin that functions to form bipolar spindles. There is emerging evidence indicating that KIF15 plays a significant role in several malignancies, such as pancreatic cancer, hepatocellular carcinoma, lung adenocarcinoma, and breast cancer. Still, the function of KIF15 remains unclear in prostate cancer. Here, we study the functional importance of KIF15 in the tumorigenesis of PCa. The bioinformatic analysis from PCa patients revealed high KIF15 expression compared to normal prostate tissues. High expression hinting at a possible functional role of KIF15 in regulating cell proliferation of PCa, which was demonstrated by both in vitro and in vivo assays. Downregulation of KIF15 silenced the expression of CDK2, p-RB, and Cyclin D1 and likewise blocked the cells at the G1 stage of the cell cycle. In addition, KIF15 downregulation inhibited MEK-ERK signaling by significantly silencing p-ERK and p-MEK levels. In conclusion, this study confirmed the functional significance of KIF15 in the growth and development of prostate cancer and could be a novel therapeutic target for the treatment of PCa.
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Affiliation(s)
- Zeeshan Qureshi
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Mashaal Ahmad
- Department of Biochemistry and Cancer Institute of Second Affiliated Hospital, Key Laboratory of Cancer Prevention and Intervention of China National MOE, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Wan-Xi Yang
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, 310058, China.
| | - Fu-Qing Tan
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
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Zhu D, Xu X, Zhang M, Wang T. Enhanced expression of KIF4A in osteosarcoma predicts a poor prognosis and facilitates tumor growth by activation of the MAPK pathway. Exp Ther Med 2021; 22:1339. [PMID: 34630693 PMCID: PMC8495555 DOI: 10.3892/etm.2021.10774] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 08/13/2021] [Indexed: 12/24/2022] Open
Abstract
The present study aimed to explore the prognostic value and role of kinesin family member 4A (KIF4A) expression in human osteosarcoma. KIF4A expression was evaluated in human osteosarcoma tissues from The Cancer Genome Atlas and Gene Expression Omnibus datasets. Reverse transcription-quantitative PCR was then applied to assess KIF4A level in both osteosarcoma cell lines and tissues. The association between KIF4A expression and clinical results in patients with osteosarcoma was detected by survival analysis. MTT assays and colony formation assays were used to evaluate the effects of KIF4A on osteosarcoma cell proliferation. The results indicated that the level of KIF4A was increased and associated with a poor prognosis in osteosarcoma tissues. Knockdown of KIF4A was shown to inhibit osteosarcoma cellular proliferation by affecting the MAPK pathway. The level of KIF4A was high in the human osteosarcoma tissues and this could be considered as a tumor induction gene, which may be used as an indicator of prognosis.
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Affiliation(s)
- Dongsheng Zhu
- Department of Pediatric Orthopedic Surgery, Lianyungang No. 1 People's Hospital Affiliated to Xuzhou Medical University, Lianyungang, Jiangsu 222000, P.R. China
| | - Xiangfei Xu
- Department of Pediatric Orthopedic Surgery, Lianyungang No. 1 People's Hospital Affiliated to Xuzhou Medical University, Lianyungang, Jiangsu 222000, P.R. China
| | - Ming Zhang
- Department of Pediatric Orthopedic Surgery, Lianyungang No. 1 People's Hospital Affiliated to Xuzhou Medical University, Lianyungang, Jiangsu 222000, P.R. China
| | - Tong Wang
- Department of Pediatric Orthopedic Surgery, Lianyungang No. 1 People's Hospital Affiliated to Xuzhou Medical University, Lianyungang, Jiangsu 222000, P.R. China
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Shi X, Wang X, Neuwald AF, Halakivi-Clarke L, Clarke R, Xuan J. A Bayesian approach for accurate de novo transcriptome assembly. Sci Rep 2021; 11:17663. [PMID: 34480063 PMCID: PMC8417280 DOI: 10.1038/s41598-021-97015-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 05/17/2021] [Indexed: 11/09/2022] Open
Abstract
De novo transcriptome assembly from billions of RNA-seq reads is very challenging due to alternative splicing and various levels of expression, which often leads to incorrect, mis-assembled transcripts. BayesDenovo addresses this problem by using both a read-guided strategy to accurately reconstruct splicing graphs from the RNA-seq data and a Bayesian strategy to estimate, from these graphs, the probability of transcript expression without penalizing poorly expressed transcripts. Simulation and cell line benchmark studies demonstrate that BayesDenovo is very effective in reducing false positives and achieves much higher accuracy than other assemblers, especially for alternatively spliced genes and for highly or poorly expressed transcripts. Moreover, BayesDenovo is more robust on multiple replicates by assembling a larger portion of common transcripts. When applied to breast cancer data, BayesDenovo identifies phenotype-specific transcripts associated with breast cancer recurrence.
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Affiliation(s)
- Xu Shi
- Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, 900 North Glebe Road, Arlington, VA, 22203, USA
| | - Xiao Wang
- Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, 900 North Glebe Road, Arlington, VA, 22203, USA
| | - Andrew F Neuwald
- Institute for Genome Sciences and Department Biochemistry and Molecular Biology, University of Maryland School of Medicine, 670 W. Baltimore Street, Baltimore, MD, 21201, USA
| | | | - Robert Clarke
- Hormel Institute, University of Minnesota, 16th Street N, Austin, MN, 55912, USA
| | - Jianhua Xuan
- Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, 900 North Glebe Road, Arlington, VA, 22203, USA.
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Qin Z, Wang W, Ali MA, Wang Y, Zhang Y, Zhang M, Zhou G, Yang JD, Zeng C. Transcriptome-wide m 6A profiling reveals mRNA post-transcriptional modification of boar sperm during cryopreservation. BMC Genomics 2021; 22:588. [PMID: 34344298 PMCID: PMC8335898 DOI: 10.1186/s12864-021-07904-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 07/21/2021] [Indexed: 12/12/2022] Open
Abstract
Background Cryopreservation induces transcriptomic and epigenetic modifications that strongly impairs sperm quality and function, and thus decrease reproductive performance. N6-methyladenosine (m6A) RNA methylation varies in response to stress and has been implicated in multiple important biological processes, including post-transcriptional fate of mRNA, metabolism, and apoptosis. This study aimed to explore whether cryopreservation induces m6A modification of mRNAs associated with sperm energy metabolism, cryoinjuries, and freezability. Results The mRNA and protein expression of m6A modification enzymes were significantly dysregulated in sperm after cryopreservation. Furthermore, m6A peaks were mainly enriched in coding regions and near stop codons with classical RRACH motifs. The mRNAs containing highly methylated m6A peaks (fts vs. fs) were significantly associated with metabolism and gene expression, while the genes with less methylated m6A peaks were primarily involved in processes regulating RNA metabolism and transcription. Furthermore, the joint analysis of DMMGs and differentially expressed genes indicated that both of these play a vital role in sperm energy metabolism and apoptosis. Conclusions Our study is the first to reveal the dynamic m6A modification of mRNAs in boar sperm during cryopreservation. These epigenetic modifications may affect mRNA expression and are closely related to sperm motility, apoptosis, and metabolism, which will provide novel insights into understanding of the cryoinjuries or freezability of boar sperm during cryopreservation. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-021-07904-8.
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Affiliation(s)
- Ziyue Qin
- College of Animal Sciences and Technology, Sichuan Agricultural University, 611130, Chengdu, Sichuan, China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, 611130, Chengdu, Sichuan Province, China
| | - Wencan Wang
- College of Animal Sciences and Technology, Sichuan Agricultural University, 611130, Chengdu, Sichuan, China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, 611130, Chengdu, Sichuan Province, China
| | - Malik Ahsan Ali
- College of Animal Sciences and Technology, Sichuan Agricultural University, 611130, Chengdu, Sichuan, China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, 611130, Chengdu, Sichuan Province, China.,Department of Theriogenology, Riphah College of Veterinary Sciences, 54000, Lahore, Pakistan
| | - Yihan Wang
- College of Animal Sciences and Technology, Sichuan Agricultural University, 611130, Chengdu, Sichuan, China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, 611130, Chengdu, Sichuan Province, China
| | - Yan Zhang
- College of Animal Sciences and Technology, Sichuan Agricultural University, 611130, Chengdu, Sichuan, China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, 611130, Chengdu, Sichuan Province, China
| | - Ming Zhang
- College of Animal Sciences and Technology, Sichuan Agricultural University, 611130, Chengdu, Sichuan, China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, 611130, Chengdu, Sichuan Province, China
| | - Guangbin Zhou
- College of Animal Sciences and Technology, Sichuan Agricultural University, 611130, Chengdu, Sichuan, China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, 611130, Chengdu, Sichuan Province, China
| | - Jian-Dong Yang
- College of Animal Sciences and Technology, Sichuan Agricultural University, 611130, Chengdu, Sichuan, China.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, 611130, Chengdu, Sichuan Province, China
| | - Changjun Zeng
- College of Animal Sciences and Technology, Sichuan Agricultural University, 611130, Chengdu, Sichuan, China. .,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, 611130, Chengdu, Sichuan Province, China.
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Li LX, Li X. Epigenetically Mediated Ciliogenesis and Cell Cycle Regulation, and Their Translational Potential. Cells 2021; 10:cells10071662. [PMID: 34359832 PMCID: PMC8307023 DOI: 10.3390/cells10071662] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/24/2021] [Accepted: 06/29/2021] [Indexed: 12/13/2022] Open
Abstract
Primary cilia biogenesis has been closely associated with cell cycle progression. Cilia assemble when cells exit the cell cycle and enter a quiescent stage at the post-mitosis phase, and disassemble before cells re-enter a new cell cycle. Studies have focused on how the cell cycle coordinates with the cilia assembly/disassembly process, and whether and how cilia biogenesis affects the cell cycle. Appropriate regulation of the functions and/or expressions of ciliary and cell-cycle-associated proteins is pivotal to maintaining bodily homeostasis. Epigenetic mechanisms, including DNA methylation and histone/chromatin modifications, are involved in the regulation of cell cycle progression and cilia biogenesis. In this review, first, we discuss how epigenetic mechanisms regulate cell cycle progression and cilia biogenesis through the regulation of DNA methylation and chromatin structures, to either promote or repress the transcription of genes associated with those processes and the modification of cytoskeleton network, including microtubule and actin. Next, we discuss the crosstalk between the cell cycle and ciliogenesis, and the involvement of epigenetic regulators in this process. In addition, we discuss cilia-dependent signaling pathways in cell cycle regulation. Understanding the mechanisms of how epigenetic regulators contribute to abnormal cell cycle regulation and ciliogenesis defects would lead to developing therapeutic strategies for the treatment of a wide variety of diseases, such as cancers, polycystic kidney disease (PKD), and other ciliopathy-associated disorders.
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Affiliation(s)
- Linda Xiaoyan Li
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA;
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Xiaogang Li
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA;
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
- Correspondence: ; Tel.: +1-507-266-0110
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37
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Sun X, Ding S, Lu S, Wang Z, Chen X, Shen K. Identification of Ten Mitosis Genes Associated with Tamoxifen Resistance in Breast Cancer. Onco Targets Ther 2021; 14:3611-3624. [PMID: 34113127 PMCID: PMC8187086 DOI: 10.2147/ott.s290426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 05/10/2021] [Indexed: 11/23/2022] Open
Abstract
Background Endocrine therapy is the backbone therapy in estrogen receptor α (ER)-positive breast cancer, and tamoxifen resistance is a great challenge for endocrine therapy. Tamoxifen-resistant and sensitive samples from the international public repository, the Gene Expression Omnibus (GEO) database, were used to identify therapeutic biomarkers associated with tamoxifen resistance. Materials and Methods In this study, integrated analysis was used to identify tamoxifen resistance-associated genes. Differentially expressed genes (DEGs) were identified. Gene ontology and pathway analysis were then analyzed. Weighted correlation network analysis (WGCNA) was performed to find modules correlated with tamoxifen resistance. Protein–protein interaction (PPI) network was used to find hub genes. Genes of prognostic significance were further validated in another GEO dataset and cohort from Shanghai Ruijin Hospital using RT-PCR. Results A total of 441 genes were down-regulated and 123 genes were up-regulated in tamoxifen-resistant samples. Those up-regulated genes were mostly enriched in the cell cycle pathway. Then, WGCNA was performed, and the brown module was correlated with tamoxifen resistance. An overlap of 81 genes was identified between differentially expressed genes (DEGs) and genes in the brown module. These genes were also enriched in the cell cycle. Twelve hub genes were identified using PPI network, which were involved in the mitosis phase of the cell cycle. Finally, 10 of these 12 genes were validated to be up-regulated in tamoxifen-resistant patients and were associated with poor prognosis in ER-positive patients. Conclusion Our study suggested mitosis-related genes are mainly involved in tamoxifen resistance, and high expression of these genes could predict poor prognosis of patients receiving tamoxifen. These genes may be potential targets to improve efficacy of endocrine therapy in breast cancer, and inhibitors targeted these genes could be used in endocrine-resistant patients.
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Affiliation(s)
- Xi Sun
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Shuning Ding
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Shuangshuang Lu
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Zheng Wang
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Xiaosong Chen
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Kunwei Shen
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
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38
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Rabie EM, Zhang SX, Dunn CE, Nelson CM. Substratum stiffness signals through integrin-linked kinase and β1-integrin to regulate midbody proteins and abscission during EMT. Mol Biol Cell 2021; 32:1664-1676. [PMID: 34038147 PMCID: PMC8684726 DOI: 10.1091/mbc.e21-02-0072] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Abscission is the final stage of cytokinesis during which the parent cell physically separates to yield two identical daughters. Failure of abscission results in multinucleation (MNC), a sign of genomic instability and a precursor to aneuploidy, enabling characteristics of neoplastic progression. Induction of epithelial-mesenchymal transition (EMT) causes MNC in mammary epithelial cells cultured on stiff microenvironments that have mechanical properties similar to those found in breast tumors, but not on soft microenvironments reminiscent of the normal mammary gland. Here we report that on stiff microenvironments, EMT signaling through Snail up-regulates the midbody-associated proteins septin-6, Mklp1, and anillin, leading to abscission failure and MNC. To uncover the mechanism by which stiff microenvironments promote MNC in cells undergoing EMT, we investigated the role of cell-matrix adhesion through β1-integrin and integrin-linked kinase (ILK). We found that ILK expression, but not kinase activity, is required for EMT-associated MNC in cells on stiff microenvironments. Conversely, increasing focal adhesions by expressing an autoclustering mutant of β1-integrin promotes MNC in cells on soft microenvironments. Our data suggest that signaling through focal adhesions causes failure of cytokinesis in cells actively undergoing EMT. These results highlight the importance of tissue mechanics and adhesion in regulating the cellular response to EMT inducers.
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Affiliation(s)
- Emann M Rabie
- Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854.,Departments of Molecular Biology, Princeton University, Princeton, NJ 08544
| | - Sherry X Zhang
- Chemical & Biological Engineering, Princeton University, Princeton, NJ 08544
| | - Connor E Dunn
- Departments of Molecular Biology, Princeton University, Princeton, NJ 08544
| | - Celeste M Nelson
- Departments of Molecular Biology, Princeton University, Princeton, NJ 08544.,Chemical & Biological Engineering, Princeton University, Princeton, NJ 08544
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Wang Z, Chen M, Fang X, Hong H, Yao Y, Huang H. KIF15 is involved in development and progression of Burkitt lymphoma. Cancer Cell Int 2021; 21:261. [PMID: 33985517 PMCID: PMC8117549 DOI: 10.1186/s12935-021-01967-z] [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: 01/14/2020] [Accepted: 04/30/2021] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Burkitt lymphoma (BL) is a highly aggressive, fast-growing B-cell non-Hodgkin's lymphoma, manifested in several subtypes, including sporadic, endemic, and immunodeficiency-related forms, the mechanism of which is still not clear. Abundant evidence reported that KIF15 was involved in the progression of human cancer. The emphasis of this study is to explore the functions of KIF15 in the development of BL. METHODS Firstly, tumor and normal tissues were collected for detecting expression of KIF15 in BL. Lentivirus-mediated shRNA knockdown of KIF15 was used to construct BL cell model, which was verified by qRT-PCR and Western Blot. The cell proliferation was detected by CCK8 assay, cell apoptosis and cell cycle were measured through flow cytometry. Transwell assay was conducted to detect the migration. RESULTS We first found that KIF15 is highly expressed in BL. Knockdown of KIF15 can inhibit proliferation and migration, promote apoptosis and arrest the cell cycle. Moreover, KIF15 is involved in BL cell activity through regulating expression of apoptosis-related proteins (Caspase3, Caspase8, HTRA, IGFBP-6, p53, SMAC, sTNF-R1, TNF-β and Bcl-2) and downstream pathways, such as p-Akt, CCND1, CDK6 and PIK3CA. CONCLUSIONS These findings justify the search for small molecule inhibitors targeting KIF15 as a novel therapeutic strategy in BL.
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Affiliation(s)
- Zhao Wang
- Department of Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, and Collaborative Innovation Center of Cancer Medicine, 651 Dong feng East Road, Guangzhou, 510060, Guangdong, China
| | - Meiting Chen
- Department of Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, and Collaborative Innovation Center of Cancer Medicine, 651 Dong feng East Road, Guangzhou, 510060, Guangdong, China
| | - Xiaojie Fang
- Department of Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, and Collaborative Innovation Center of Cancer Medicine, 651 Dong feng East Road, Guangzhou, 510060, Guangdong, China
| | - Huangming Hong
- Department of Medical Oncology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, 510120, Guangdong, China
| | - Yuyi Yao
- Department of Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, and Collaborative Innovation Center of Cancer Medicine, 651 Dong feng East Road, Guangzhou, 510060, Guangdong, China
| | - He Huang
- Department of Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, and Collaborative Innovation Center of Cancer Medicine, 651 Dong feng East Road, Guangzhou, 510060, Guangdong, China.
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40
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Zhou Y, Yang L, Xiong L, Wang K, Hou X, Li Q, Kong F, Liu X, He J. KIF11 is upregulated in colorectal cancer and silencing of it impairs tumor growth and sensitizes colorectal cancer cells to oxaliplatin via p53/GSK3β signaling. J Cancer 2021; 12:3741-3753. [PMID: 33995648 PMCID: PMC8120193 DOI: 10.7150/jca.52103] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 04/21/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is the most frequently diagnosed cancer of the digestive tract. Chemotherapy drugs such as oxaliplatin are frequently administered to CRC patients diagnosed with advanced or metastatic disease. A deep understanding of the molecular mechanism underlying CRC tumorigenesis and identification of optimal biomarkers for estimating chemotherapy sensitivity are essential for the treatment of CRC. Numerous members of the kinesin family are dysregulated in cancers, contributing to tumorigenesis, metastasis and drug resistance. KIF11 is a key component of the bipolar spindle and is highly expressed in several cancer types. We analyzed KIF11 expression in clinical samples by Western blotting and qRT-PCR and explored its role and mechanism in CRC growth and sensitivity to oxaliplatin via detection of the phosphorylation profile of kinases and gain-and-loss-of-function assays. We found that KIF11 was upregulated in CRC tissues and was associated with advanced clinical stage and vessel invasion and that knockdown of KIF11 led to tumor growth arrest and increased sensitivity to oxaliplatin via enhanced DNA damage and apoptosis. Mechanistically, aberrantly activated p53 signaling or possibly deactivated GSK3β signaling was responsible for KIF11 knockdown-mediated effects in CRC cells. Thus, our data firmly demonstrated that KIF11 could serve as a potential oncogene and proper biomarker for assessing oxaliplatin sensitivity in CRC.
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Affiliation(s)
- Yan Zhou
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Leping Yang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Li Xiong
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Kunpeng Wang
- Department of General Surgery, Taizhou Central Hospital, Taizhou University Hospital, Taizhou, Zhejiang 318000, China
| | - Xuyang Hou
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Qinglong Li
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Fanhua Kong
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Xi Liu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Jun He
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, 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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Sanchez-Lopez JM, Mandujano-Tinoco EA, Garcia-Venzor A, Lozada-Rodriguez LF, Zampedri C, Uribe-Carvajal S, Melendez-Zajgla J, Maldonado V, Lizarraga F. Integrative analysis of transcriptional profile reveals LINC00052 as a suppressor of breast cancer cell migration. Cancer Biomark 2021; 30:365-379. [PMID: 33361583 DOI: 10.3233/cbm-200337] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Long-non-coding RNAs, a class of transcripts with lengths > 200 nt, play key roles in tumour progression. Previous reports revealed that LINC00052 (long intergenic non-coding RNA 00052) was strongly downregulated during breast cancer multicellular spheroids formation and suggested a role in cell migration and oxidative metabolism. OBJECTIVE To examine the function of LINC00052 in MCF-7 breast cancer cells. METHODS Loss-of-function studies were performed to evaluate LINC00052 role on MCF-7 breast cancer cells. Microarray expression assays were performed to determine genes and cellular functions modified after LINC00052 knockdown. Next, the impact of LINC00052 depletion on MCF-7 cell respiration and migration was evaluated. RESULTS 1,081 genes were differentially expressed upon LINC00052 inhibition. Gene set enrichment analysis, Gene Ontology and Key Pathway Advisor analysis showed that signalling networks related to cell migration and oxidative phosphorylation were enriched. However, whereas LINC00052 knockdown in MCF-7 cells revealed marginal difference in oxygen consumption rates when compared with control cells, LINC00052 inhibition enhanced cell migration in vitro and in vivo, as observed using a Zebrafish embryo xenotransplant model. CONCLUSION Our data show that LINC00052 modulates MCF-7 cell migration. Genome-wide microarray experiments suggest that cancer cell migration is affected by LINC00052 through cytoskeleton modulation and Notch/β-catenin/NF-κB signalling pathways.
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Affiliation(s)
- Jose Manuel Sanchez-Lopez
- Epigenetics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, Mexico.,Postgraduate Program in Biological Sciences, Faculty of Medicine, Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Edna Ayerim Mandujano-Tinoco
- Epigenetics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, Mexico.,Laboratory of Connective Tissue, Centro Nacional de Investigación y Atención de Quemados, Instituto Nacional de Rehabilitación Luís Guillermo Ibarra Ibarra, Mexico City, Mexico
| | - Alfredo Garcia-Venzor
- Epigenetics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | | | - Cecilia Zampedri
- Epigenetics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Salvador Uribe-Carvajal
- Department of Molecular Genetics, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Jorge Melendez-Zajgla
- Functional Genomics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Vilma Maldonado
- Epigenetics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Floria Lizarraga
- Epigenetics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
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Ma RR, Zhang H, Chen HF, Zhang GH, Tian YR, Gao P. MiR-19a/miR-96-mediated low expression of KIF26A suppresses metastasis by regulating FAK pathway in gastric cancer. Oncogene 2021; 40:2524-2538. [PMID: 33674746 DOI: 10.1038/s41388-020-01610-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 11/27/2020] [Accepted: 12/09/2020] [Indexed: 01/31/2023]
Abstract
Gastric cancer (GC) is one of the most common malignant neoplasms. Invasion and metastasis are the main causes of GC-related deaths. Recently, kinesins were discovered to be involved in tumor development. The aim of this study was to elucidate the roles of kinesin superfamily protein 26A (KIF26A) in GC and its underlying molecular mechanism in regulating tumor invasion and metastasis. Using real-time quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC), we showed that KIF26A expression was lower in GC tissues without lymph node metastasis (LNM) than in nontumorous gastric mucosa, and even lower in GC tissues with LNM than in GC tissues without LNM. Functional experiments showed that KIF26A inhibited migration and invasion of GC cells. We further identified focal-adhesion kinase (FAK), phosphatidylinositol 3-kinase regulatory subunit alpha (PI3KR1), VAV3, Rac1 and p21-activated kinase 2, and β-PAK (PAK3) as downstream effectors of KIF26A in the focal-adhesion pathway, and we found that KIF26A could regulate FAK mRNA expression through inhibiting c-MYC by MAPK pathway. c-MYC could bind to the promoter of FAK and activate FAK transcription. Moreover, we found that KIF26A-mediated inactivation of the focal-adhesion pathway could reduce the occurrence of the epithelial-to-mesenchymal transition (EMT) by increasing expression of E-cadherin and reducing that of Snail. Luciferase assays and Western blotting revealed that miR-19a and miR-96 negatively regulate KIF26A. Finally, we found that decreased expression of KIF26A has been positively correlated with histological differentiation, Lauren classification, LNM, distal metastasis, and clinical stage, as well as poor survival in patients with GC. These data indicate that KIF26A could inhibit GC migration and invasion by regulating the focal-adhesion pathway and repressing the occurrence of EMT.
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Affiliation(s)
- Ran-Ran Ma
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China.,Department of Pathology, Qilu Hospital, Shandong University, Jinan, PR China
| | - Hui Zhang
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China.,Department of Pathology, Qilu Hospital, Shandong University, Jinan, PR China
| | - Hong-Fang Chen
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China.,Department of Pathology, Yidu Central Hospital of Weifang, Weifang, PR China
| | - Guo-Hao Zhang
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China
| | - Ya-Ru Tian
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China
| | - Peng Gao
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China. .,Department of Pathology, Qilu Hospital, Shandong University, Jinan, PR China.
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Nayak A, Dutta M, Roychowdhury A. Emerging oncogene ATAD2: Signaling cascades and therapeutic initiatives. Life Sci 2021; 276:119322. [PMID: 33711386 DOI: 10.1016/j.lfs.2021.119322] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 02/12/2021] [Accepted: 02/27/2021] [Indexed: 12/11/2022]
Abstract
ATAD2 is a promising oncoprotein with tumor-promoting functions in many cancers. It is a valid cancer drug-target and a potential cancer-biomarker for multiple malignancies. As a cancer/testis antigen (CTA), ATAD2 could also be a probable candidate for immunotherapy. It is a unique CTA that belongs to both AAA+ ATPase and bromodomain family proteins. Since 2007, several research groups have been reported on the pleiotropic oncogenic functions of ATAD2 in diverse signaling pathways, including Rb/E2F-cMyc pathway, steroid hormone signaling pathway, p53 and p38-MAPK-mediated apoptotic pathway, AKT pathway, hedgehog signaling pathway, HIF1α signaling pathway, and Epithelial to Mesenchymal Transition (EMT) pathway in various cancers. In all these pathways, ATAD2 participates in chromatin dynamics, DNA replication, and gene transcription, demonstrating its role as an epigenetic reader and transcription factor or coactivator to promote tumorigenesis. However, despite the progress, an overall mechanism of ATAD2-mediated oncogenesis in diverse origin is elusive. In this review, we summarize the accumulated evidence to envision the overall ATAD2 signaling networks during carcinogenesis and highlight the area where missing links await further research. Besides, the structure-function aspect of ATAD2 is also discussed. Since the efforts have already been initiated to explore targeted drug molecules and RNA-based therapeutic alternatives against ATAD2, their potency and prospects have been elucidated. Together, we believe this is a well-rounded review on ATAD2, facilitating a new drift in ATAD2 research, essential for its clinical implication as a biomarker and/or cancer drug-target.
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Affiliation(s)
- Aditi Nayak
- Biochemistry and Cell Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Odisha 752050, India
| | - Madhuri Dutta
- Biochemistry and Cell Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Odisha 752050, India
| | - Anasuya Roychowdhury
- Biochemistry and Cell Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Odisha 752050, India.
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Morani F, Bisceglia L, Rosini G, Mutti L, Melaiu O, Landi S, Gemignani F. Identification of Overexpressed Genes in Malignant Pleural Mesothelioma. Int J Mol Sci 2021; 22:ijms22052738. [PMID: 33800494 PMCID: PMC7962966 DOI: 10.3390/ijms22052738] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/03/2021] [Accepted: 03/05/2021] [Indexed: 02/07/2023] Open
Abstract
Malignant pleural mesothelioma (MPM) is a fatal tumor lacking effective therapies. The characterization of overexpressed genes could constitute a strategy for identifying drivers of tumor progression as targets for novel therapies. Thus, we performed an integrated gene-expression analysis on RNAseq data of 85 MPM patients from TCGA dataset and reference samples from the GEO. The gene list was further refined by using published studies, a functional enrichment analysis, and the correlation between expression and patients' overall survival. Three molecular signatures defined by 15 genes were detected. Seven genes were involved in cell adhesion and extracellular matrix organization, with the others in control of the mitotic cell division or apoptosis inhibition. Using Western blot analyses, we found that ADAMTS1, PODXL, CIT, KIF23, MAD2L1, TNNT1, and TRAF2 were overexpressed in a limited number of cell lines. On the other hand, interestingly, CTHRC1, E-selectin, SPARC, UHRF1, PRSS23, BAG2, and MDK were abundantly expressed in over 50% of the six MPM cell lines analyzed. Thus, these proteins are candidates as drivers for sustaining the tumorigenic process. More studies with small-molecule inhibitors or silencing RNAs are fully justified and need to be undertaken to better evaluate the cancer-driving role of the targets herewith identified.
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Affiliation(s)
- Federica Morani
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (F.M.); (L.B.); (G.R.); (O.M.); (F.G.)
| | - Luisa Bisceglia
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (F.M.); (L.B.); (G.R.); (O.M.); (F.G.)
| | - Giulia Rosini
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (F.M.); (L.B.); (G.R.); (O.M.); (F.G.)
| | - Luciano Mutti
- Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA;
| | - Ombretta Melaiu
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (F.M.); (L.B.); (G.R.); (O.M.); (F.G.)
- Paediatric Haematology/Oncology Department, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy
| | - Stefano Landi
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (F.M.); (L.B.); (G.R.); (O.M.); (F.G.)
- Correspondence: ; Tel.: +39-050-221-1528
| | - Federica Gemignani
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (F.M.); (L.B.); (G.R.); (O.M.); (F.G.)
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Ji Z, Mi A, Li M, Li Q, Qin C. Aberrant KIF23 expression is associated with adverse clinical outcome and promotes cellular malignant behavior through the Wnt/β-catenin signaling pathway in Colorectal Cancer. J Cancer 2021; 12:2030-2040. [PMID: 33754001 PMCID: PMC7974518 DOI: 10.7150/jca.51565] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 12/29/2020] [Indexed: 01/11/2023] Open
Abstract
Purpose: The aim of the present study was to reveal the clinicopathological significance and prognostic role of kinesin family member 23 (KIF23) in colorectal cancer (CRC) and characterize its biological function and the underlying mechanisms. Methods: Bioinformatics analysis, immunohistochemistry, Western blot and qRT-PCR were utilized to investigate the expression of KIF23 in CRC tissues. The CCK-8 assay, wound healing assay and Matrigel assay were used to detect cell proliferation, migration and invasion in vitro. Western blot, immunofluorescence staining and cell function experiment were performed to explore the underlying mechanism. Results: The overexpression of KIF23 was associated with T stage, N stage, M stage and TNM stage, and CRC patients with high KIF23 expression had a worse prognosis. KIF23 knockdown inhibits CRC cells proliferation, migration and invasion in vitro. The mechanism study determined that KIF23 activates the Wnt/β-catenin signaling pathway by promoting the nuclear translocation of β-catenin to regulate the malignant behavior of CRC cells. Conclusion: These results suggest that KIF23 may act as a putative oncogene and a potential therapeutic target in CRC.
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Affiliation(s)
- Zhiyu Ji
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, China
| | - Aoning Mi
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, China
| | - Mengmeng Li
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, China
| | - Quanying Li
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, China
| | - Changjiang Qin
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, China
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Zheng L, Li L, Xie J, Jin H, Zhu N. Six Novel Biomarkers for Diagnosis and Prognosis of Esophageal squamous cell carcinoma: validated by scRNA-seq and qPCR. J Cancer 2021; 12:899-911. [PMID: 33403046 PMCID: PMC7778544 DOI: 10.7150/jca.50443] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 11/16/2020] [Indexed: 12/24/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide. ESCC has a generally poor prognosis and there is a lack of available biomarkers for diagnosis and prognosis. The aim of the study was to identify novel biomarkers for ESCC. We screened the overlapping differentially expressed genes (DEGs) acquired from six Gene Expression Omnibus (GEO) ESCC datasets and The Cancer Genome Atlas (TCGA) ESCC datasets. Subsequently, protein-protein interaction network analysis was performed to identify the key hub genes. Then, Kaplan Meier survival and receiver operating curve (ROC) analysis were utilized to clarify the diagnostic and prognostic role of these hub genes. The UALCAN database, single cell RNA sequencing (scRNA-seq) and real-time quantitative PCR (qPCR) were performed to confirm the expression levels of identified hub genes. Finally, immune infiltration analysis was conducted to investigate the role of these genes in the pathogenesis of ESCC. The results showed that PBK, KIF2C, NUF2, KIF20A, RAD51AP1, and DEPDC1 effectively distinguish ESCC tissues from normal samples, and all of them were significantly correlated with overall survival. The results of scRNA-seq and qPCR indicated that the expression levels of hub genes in ESCC were significantly higher than in normal cells or tissues. Further immune infiltration analysis showed that infiltration of dendritic cells was significantly negatively correlated with PBK, KIF2C, NUF2, RAD51AP1, and DEPDC1 expression levels. In conclusion, our results suggest that PBK, KIF2C, NUF2, KIF20A, RAD51AP1 and DEPDC1 are all potential biomarkers for ESCC diagnosis and prognosis may also be potential therapeutic targets for ESCC.
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Affiliation(s)
- Liuhai Zheng
- Laboratory of Molecular Immunology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Linzhi Li
- Laboratory of Molecular Immunology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Jun Xie
- Laboratory of Molecular Immunology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Hai Jin
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Naishuo Zhu
- Laboratory of Molecular Immunology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
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Kader A, Brangsch J, Kaufmann JO, Zhao J, Mangarova DB, Moeckel J, Adams LC, Sack I, Taupitz M, Hamm B, Makowski MR. Molecular MR Imaging of Prostate Cancer. Biomedicines 2020; 9:1. [PMID: 33375045 PMCID: PMC7822017 DOI: 10.3390/biomedicines9010001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 12/18/2020] [Accepted: 12/19/2020] [Indexed: 02/06/2023] Open
Abstract
This review summarizes recent developments regarding molecular imaging markers for magnetic resonance imaging (MRI) of prostate cancer (PCa). Currently, the clinical standard includes MR imaging using unspecific gadolinium-based contrast agents. Specific molecular probes for the diagnosis of PCa could improve the molecular characterization of the tumor in a non-invasive examination. Furthermore, molecular probes could enable targeted therapies to suppress tumor growth or reduce the tumor size.
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Affiliation(s)
- Avan Kader
- Department of Radiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.B.); (J.O.K.); (J.Z.); (D.B.M.); (J.M.); (L.C.A.); (I.S.); (M.T.); (B.H.); (M.R.M.)
- Department of Biology, Chemistry and Pharmacy, Institute of Biology, Freie Universität Berlin, Königin-Luise-Str. 1-3, 14195 Berlin, Germany
| | - Julia Brangsch
- Department of Radiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.B.); (J.O.K.); (J.Z.); (D.B.M.); (J.M.); (L.C.A.); (I.S.); (M.T.); (B.H.); (M.R.M.)
- Department of Veterinary Medicine, Institute of Animal Welfare, Animal Behavior and Laboratory Animal Science, Freie Universität Berlin, Königsweg 67, Building 21, 14163 Berlin, Germany
| | - Jan O. Kaufmann
- Department of Radiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.B.); (J.O.K.); (J.Z.); (D.B.M.); (J.M.); (L.C.A.); (I.S.); (M.T.); (B.H.); (M.R.M.)
- Division 1.5 Protein Analysis, Federal Institute for Materials Research and Testing (BAM), Richard-Willstätter-Str. 11, 12489 Berlin, Germany
- Department of Chemistry, Humboldt-Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
| | - Jing Zhao
- Department of Radiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.B.); (J.O.K.); (J.Z.); (D.B.M.); (J.M.); (L.C.A.); (I.S.); (M.T.); (B.H.); (M.R.M.)
| | - Dilyana B. Mangarova
- Department of Radiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.B.); (J.O.K.); (J.Z.); (D.B.M.); (J.M.); (L.C.A.); (I.S.); (M.T.); (B.H.); (M.R.M.)
- Department of Veterinary Medicine, Institute of Veterinary Pathology, Freie Universität Berlin, Robert-von-Ostertag-Str. 15, Building 12, 14163 Berlin, Germany
| | - Jana Moeckel
- Department of Radiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.B.); (J.O.K.); (J.Z.); (D.B.M.); (J.M.); (L.C.A.); (I.S.); (M.T.); (B.H.); (M.R.M.)
| | - Lisa C. Adams
- Department of Radiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.B.); (J.O.K.); (J.Z.); (D.B.M.); (J.M.); (L.C.A.); (I.S.); (M.T.); (B.H.); (M.R.M.)
| | - Ingolf Sack
- Department of Radiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.B.); (J.O.K.); (J.Z.); (D.B.M.); (J.M.); (L.C.A.); (I.S.); (M.T.); (B.H.); (M.R.M.)
| | - Matthias Taupitz
- Department of Radiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.B.); (J.O.K.); (J.Z.); (D.B.M.); (J.M.); (L.C.A.); (I.S.); (M.T.); (B.H.); (M.R.M.)
| | - Bernd Hamm
- Department of Radiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.B.); (J.O.K.); (J.Z.); (D.B.M.); (J.M.); (L.C.A.); (I.S.); (M.T.); (B.H.); (M.R.M.)
| | - Marcus R. Makowski
- Department of Radiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany; (J.B.); (J.O.K.); (J.Z.); (D.B.M.); (J.M.); (L.C.A.); (I.S.); (M.T.); (B.H.); (M.R.M.)
- School of Biomedical Engineering and Imaging Sciences, King’s College London, St Thomas’ Hospital Westminster Bridge Road, London SE1 7EH, UK
- Department of Diagnostic and Interventional Radiology, School of Medicine & Klinikum Rechts der Isar, Technical University of Munich, Munich (TUM), Ismaninger Str. 22, 81675 München, Germany
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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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Gao L, Zhang W, Zhang J, Liu J, Sun F, Liu H, Hu J, Wang X, Wang X, Su P, Chen S, Qu S, Shi B, Xiong X, Chen W, Dong X, Han B. KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer. Cancer Res 2020; 81:1026-1039. [PMID: 33277366 DOI: 10.1158/0008-5472.can-20-1965] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 09/10/2020] [Accepted: 11/30/2020] [Indexed: 11/16/2022]
Abstract
The new generation androgen receptor (AR) pathway inhibitor enzalutamide can prolong the survival of patients with metastatic prostate cancer. However, resistance to enzalutamide inevitably develops in these patients, and the underlying mechanisms of this resistance are not fully defined. Here we demonstrate that the kinesin family member 15 (KIF15) contributes to enzalutamide resistance by enhancing the AR signaling in prostate cancer cells. KIF15 directly bound the N-terminus of AR/AR-V7 and prevented AR/AR-V7 proteins from degradation by increasing the protein association of ubiquitin-specific protease 14 (USP14) with AR/AR-V7. In turn, the transcriptionally active AR stimulated KIF15 expression. KIF15 inhibitors alone or in combination with enzalutamide significantly suppressed enzalutamide-resistant prostate cancer cell growth and xenograft progression. These findings highlight a key role of KIF15 in enabling prostate cancer cells to develop therapy resistance to enzalutamide and rationalize KIF15 as a potential therapeutic target. SIGNIFICANCE: These findings demonstrate how reciprocal activation between KIF15 and AR contributes to enzalutamide resistance in prostate cancer and highlights cotargeting KIF15 and AR as a therapeutic strategy for these tumors.
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Affiliation(s)
- Lin Gao
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Wenbo Zhang
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jing Zhang
- Department of Pharmacy, Shandong Provincial Hospital, Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Junmei Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Feifei Sun
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Hui Liu
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jing Hu
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xin Wang
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xueli Wang
- Department of Pathology, Binzhou City Central Hospital, Binzhou, China
| | - Peng Su
- Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Shouzhen Chen
- Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Sifeng Qu
- Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Benkang Shi
- Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xueting Xiong
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Weiwen Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xuesen Dong
- Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada. .,Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Bo Han
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. .,Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
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