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Jawwad T, Kamkaew M, Phongkitkarun K, Chusorn P, Jamnongsong S, Lam EWF, Sampattavanich S. Exploring the Single-Cell Dynamics of FOXM1 Under Cell Cycle Perturbations. Cell Prolif 2025:e70019. [PMID: 40091487 DOI: 10.1111/cpr.70019] [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: 07/11/2024] [Revised: 02/18/2025] [Accepted: 02/21/2025] [Indexed: 03/19/2025] Open
Abstract
The cell cycle is crucial for maintaining normal cellular functions and preventing replication errors. FOXM1, a key transcription factor, plays a pivotal role in regulating cell cycle progression and is implicated in various physiological and pathological processes, including cancers like liver, prostate, breast, lung and colon cancer. Despite previous research, our understanding of FOXM1 dynamics under different cell cycle perturbations and its connection to heterogeneous cell fate decisions remains limited. In this study, we investigated FOXM1 behaviour in individual cells exposed to various perturbagens. We found that different drugs induce diverse responses due to heterogeneous FOXM1 dynamics at the single-cell level. Single-cell analysis identified six distinct cellular phenotypes: on-time cytokinesis, cytokinesis delay, cell cycle delay, G1 arrest, G2 arrest and cell death, observed across different drug types and doses. Specifically, treatments with PLK1, CDK1, CDK1/2 and Aurora kinase inhibitors revealed varied FOXM1 dynamics leading to heterogeneous cellular outcomes. Our findings affirm that the dynamics of FOXM1 are essential in shaping cellular outcomes, influencing the signals that dictate responses to various stimuli. Our results gave insights into how FOXM1 dynamics contribute to cell cycle fate decisions, especially under different cell cycle perturbations.
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Affiliation(s)
- Tooba Jawwad
- Siriraj Center of Research Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Maliwan Kamkaew
- Siriraj Center of Research Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Kriengkrai Phongkitkarun
- Siriraj Center of Research Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Department of Biomedical Engineering, Faculty of Engineering, Mahidol University, Nakhon Pathom, Thailand
| | - Porncheera Chusorn
- Siriraj Center of Research Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Faculty of Liberal Arts and Science, Roi Et Rajabhat University, Roi Et, Thailand
| | - Supawan Jamnongsong
- Siriraj Center of Research Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Eric W-F Lam
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Somponnat Sampattavanich
- Siriraj Center of Research Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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2
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Li J, Wang Y, Wei S, Xu S, Dai S, Zhang L, Tian Z, Zhao L, Lv H. NEK2 Promotes ESCC Malignant Progression by Inhibiting Cellular Senescence via the FOXM1/c-Myc/p27 Signaling Pathway. Mol Carcinog 2025; 64:244-259. [PMID: 39503194 DOI: 10.1002/mc.23839] [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: 10/15/2024] [Accepted: 10/20/2024] [Indexed: 01/15/2025]
Abstract
Never in mitosis gene A (NIMA)-related kinase 2 (NEK2) is a crucial serine-threonine kinase involved in the process of cell mitosis. However, the precise relationship between NEK2 and esophageal squamous cell carcinoma (ESCC) remains inadequately understood. NEK2 expression in ESCC tissues was assessed through bioinformatics analysis, reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemistry, revealing a correlation with ESCC patient prognosis. Cultured ESCC cells and human normal esophageal epithelial cells (HEEC) were used to investigate the effects of NEK2 knockdown on the development and progression of ESCC by integrated confluence algorithm, colony formation, wound-healing, transwell, and ESCC xenograft tumor model, in vitro and in vivo. In ESCC tissues, NEK2 was found to be significantly upregulated, and its expression correlated with poor prognosis in ESCC patients. NEK2 may facilitate ESCC development by regulating cell proliferation, migration, and invasion. Additionally, results from in vivo experiments suggested that NEK2 knockdown can inhibit tumor growth. Moreover, forkhead box M1 (FOXM1) was identified as a potential downstream target of NEK2 in the regulation of ESCC, with its overexpression reversing the effects of NEK2 knockdown on ESCC. Mechanistic studies also indicated that NEK2 may promote the malignant progression of ESCC by inhibiting cellular senescence through the activation of the FOXM1/c-Myc/p27 signaling pathways, which may provide a novel perspective for the management of ESCC.
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Affiliation(s)
- Jiachen Li
- Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yaojie Wang
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Key Laboratory of Tumor Gene Diagnosis, Prevention, and Therapy of Hebei Province, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Sisi Wei
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Key Laboratory of Tumor Gene Diagnosis, Prevention, and Therapy of Hebei Province, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Shi Xu
- Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Suli Dai
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Key Laboratory of Tumor Gene Diagnosis, Prevention, and Therapy of Hebei Province, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Li Zhang
- Department of Geriatric, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Ziqiang Tian
- Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Lianmei Zhao
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Key Laboratory of Tumor Gene Diagnosis, Prevention, and Therapy of Hebei Province, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Huilai Lv
- Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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Hsu CC, Yao X, Chen SY, Tsuo TC, Wang IC. The conformation of FOXM1 homodimers in vivo is crucial for regulating transcriptional activities. Nucleic Acids Res 2024; 52:13625-13643. [PMID: 39535028 DOI: 10.1093/nar/gkae988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 09/24/2024] [Accepted: 10/15/2024] [Indexed: 11/16/2024] Open
Abstract
Conformational changes in a transcription factor can significantly affect its transcriptional activity. The activated form of the FOXM1 transcription factor regulates the transcriptional network of genes essential for cell cycle progression and carcinogenesis. However, the mechanism and impact of FOXM1 conformational change on its transcriptional activity in vivo throughout the cell cycle progression remain unexplored. Here, we demonstrate that FOXM1 proteins form novel intermolecular homodimerizations in vivo, and these conformational changes in FOXM1 homodimers impact activity during the cell cycle. Specifically, during the G1 phase, FOXM1 undergoes autorepressive homodimerization, wherein the αβα motif in the C-terminal transcriptional activation domain interacts with the ββαβ motif in the N-terminal repression domain, as evidenced by FRET imaging. Phosphorylation of the αβα motif by PLK1 at S715/S724 disrupts ββαβ-αβα hydrophobic interactions, thereby facilitating a conserved αβα motif switch binding partner to the novel intrinsically disordered regions, leading to FOXM1 autostimulatory homodimerization persisting from the S phase to the G2/M phase in vivo. Furthermore, we identified a minimal ββαβ motif peptide that effectively inhibits cancer cell proliferation both in cell culture and in a mouse tumor model, suggesting a promising autorepression approach for targeting FOXM1 in cancer therapy.
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Affiliation(s)
- Chia-Chan Hsu
- Institute of Biotechnology, National Tsing Hua University, No. 101, Sec. 2, Kuang-Fu Road, Hsinchu 300044, Taiwan
| | - Xiang Yao
- Institute of Biotechnology, National Tsing Hua University, No. 101, Sec. 2, Kuang-Fu Road, Hsinchu 300044, Taiwan
| | - Shang-Yao Chen
- Institute of Biotechnology, National Tsing Hua University, No. 101, Sec. 2, Kuang-Fu Road, Hsinchu 300044, Taiwan
| | - Tsui-Chun Tsuo
- National Institute of Environmental Health Sciences, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli 350401, Taiwan
| | - I-Ching Wang
- Institute of Biotechnology, National Tsing Hua University, No. 101, Sec. 2, Kuang-Fu Road, Hsinchu 300044, Taiwan
- Department of Life Sciences, National Tsing Hua University, No. 101, Sec. 2, Kuang-Fu Road, Hsinchu 300044, Taiwan
- Brain Research Center, National Tsing Hua University, No. 101, Sec. 2, Kuang-Fu Road, Hsinchu 300044, Taiwan
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Shi Y, Men X, Wang F, Li X, Zhang B. Role of long non-coding RNAs (lncRNAs) in gastric cancer metastasis: A comprehensive review. Pathol Res Pract 2024; 262:155484. [PMID: 39180802 DOI: 10.1016/j.prp.2024.155484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 07/17/2024] [Accepted: 07/22/2024] [Indexed: 08/27/2024]
Abstract
One of the greatest frequent types of malignancy is gastric cancer (GC). Metastasis, an essential feature of stomach cancer, results in a high rate of mortality and a poor prognosis. However, metastasis biological procedures are not well recognized. Long non-coding RNAs (lncRNAs) have a role in numerous gene regulation pathways via epigenetic modification as well as transcriptional and post-transcriptional control. LncRNAs have a role in a variety of disorders, such as cardiovascular disease, Alzheimer's, and cancer. LncRNAs are substantially related to GC incidence, progression, metastasis and drug resistance. Several research released information on the molecular processes of lncRNAs in GC pathogenesis. By interacting with a gene's promoter or enhancer region to influence gene expression, lncRNAs can operate as an oncogene or a tumor suppressor. This review includes the lncRNAs associated with metastasis of GC, which may give insights into the processes as well as potential clues for GC predicting and tracking.
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Affiliation(s)
- Yue Shi
- Department of Microbiology and Immunology, Changchun University of Chinese Medicine, Jilin 130117, PR China.
| | - Xiaoping Men
- Department of Clinical Laboratory, The First Affiliated Hospital to Changchun University of Chinese Medicine, Jilin 130021, PR China.
| | - Fang Wang
- Department of Microbiology and Immunology, Changchun University of Chinese Medicine, Jilin 130117, PR China.
| | - Xueting Li
- Experimental Center, Changchun University of Chinese Medicine, Jilin 130021, PR China.
| | - Biao Zhang
- School of Health Management, Changchun University of Chinese Medicine, Jilin 130117, PR China.
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Chu S, Zhao T, Li M, Sun Y, Yang Y, Yang Z. Long non-coding RNA (CMR) involved in autoprotection in S. aureus mastitis in dairy cows by regulating miR-877/FOXM1. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 278:116456. [PMID: 38744067 DOI: 10.1016/j.ecoenv.2024.116456] [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: 09/20/2023] [Revised: 04/30/2024] [Accepted: 05/09/2024] [Indexed: 05/16/2024]
Abstract
Long non-coding RNAs (LncRNAs) are dysregulated in a variety of human diseases and are highly involved in the development and progression of tumors. Studies on lncRNAs associated with cow mastitis have been lagging behind compared to humans or model animals, therefore, the aim of this study was to explore the mechanism of LncRNAs (CMR) involved in autoprotection against S. aureus mastitis in Bovine Mammary Epithelial Cells (BMECs). First, qRT-PCR was used to examine the relative expression of CMR in a S. aureus mastitis model of BMECs. Then, cell proliferation and apoptosis were detected by EdU and apoptosis assay. Finally, the targeting relationship between miRNAs and mRNA/LncRNAs was determined by dual luciferase reporter gene, qRT-PCR and western blotting techniques. The results showed that CMR was upregulated in the S. aureus mastitis model of BMECs and promoted the expression of inflammatory factors, and SiRNA-mediated CMR inhibited the proliferation of mammary epithelial cells and induced apoptosis. Mechanistically, CMR acts as a competitive endogenous RNA (ceRNA) sponge miR-877, leading to upregulation of FOXM1, a target of miR-877. Importantly, either miR-877 overexpression or FOXM1 inhibition abrogated CMR knockdown-induced apoptosis promoting cell proliferation and reducing inflammatory factor expression levels. In summary, CMR is involved in the regulation of autoprotection against S. aureus mastitis through the miR-877/FOXM1 axis in BMECs and induces immune responses in mammary tissues and cells of dairy cows, providing an important reference for subsequent prevention and control of cow mastitis and the development of targeted drugs.
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Affiliation(s)
- Shuangfeng Chu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture & Agri-Product Safety, Ministry of Education, Yangzhou University, Yangzhou 225009, China
| | - Tianqi Zhao
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture & Agri-Product Safety, Ministry of Education, Yangzhou University, Yangzhou 225009, China
| | - Mingxun Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture & Agri-Product Safety, Ministry of Education, Yangzhou University, Yangzhou 225009, China
| | - Yujia Sun
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture & Agri-Product Safety, Ministry of Education, Yangzhou University, Yangzhou 225009, China
| | - Yi Yang
- Joint International Research Laboratory of Agriculture & Agri-Product Safety, Ministry of Education, Yangzhou University, Yangzhou 225009, China; Yangzhou University, College of Veterinary Medicine, Yangzhou 225009, China
| | - Zhangping Yang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture & Agri-Product Safety, Ministry of Education, Yangzhou University, Yangzhou 225009, China.
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6
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Yang L, Wu X, Bian S, Zhao D, Fang S, Yuan H. SIRT6-mediated vascular smooth muscle cells senescence participates in the pathogenesis of abdominal aortic aneurysm. Atherosclerosis 2024; 392:117483. [PMID: 38490134 DOI: 10.1016/j.atherosclerosis.2024.117483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 02/09/2024] [Accepted: 02/15/2024] [Indexed: 03/17/2024]
Abstract
BACKGROUND AND AIMS In this study, we carried out a clinical sample study, and in vivo and in vitro studies to evaluate the effect of SIRT6 and SIRT6-mediated vascular smooth muscle senescence on the development of abdominal aortic aneurysm (AAA). METHOD AND RESULTS AAA specimen showed an increased P16, P21 level and a decreased SIRT6 level compared with control aorta. Time curve study of Ang II infusion AAA model showed similar P16, P21 and SIRT6 changes at the early phase of AAA induction. The in vivo overexpression of SIRT6 significantly prevented AAA formation in Ang II infusion model. The expression of P16 and P21 was significantly reduced after SIRT6 overexpression. SIRT6 overexpression also attenuated chronic inflammation and neo-angiogenesis in Ang II infusion model. The overexpression of SIRT6 could attenuate premature senescence, inflammatory response and neo-angiogenesis in human aortic smooth muscle cells (HASMC) under Ang II stimulation. CONCLUSIONS SIRT6 overexpression could limit AAA formation via attenuation of vascular smooth muscle senescence, chronic inflammation and neovascularity.
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MESH Headings
- Aged
- Animals
- Humans
- Male
- Middle Aged
- Angiotensin II
- Aorta, Abdominal/pathology
- Aorta, Abdominal/metabolism
- Aortic Aneurysm, Abdominal/metabolism
- Aortic Aneurysm, Abdominal/pathology
- Cells, Cultured
- Cellular Senescence/genetics
- Cyclin-Dependent Kinase Inhibitor p16/metabolism
- Cyclin-Dependent Kinase Inhibitor p21/metabolism
- Disease Models, Animal
- Inflammation
- Mice, Inbred C57BL
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/metabolism
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Neovascularization, Pathologic
- Sirtuins/metabolism
- Sirtuins/genetics
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Affiliation(s)
- Le Yang
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China; Department of Vascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China
| | - Xuejun Wu
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China; Department of Vascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China
| | - Shuai Bian
- Department of Invasive Therapy, Anqing Municipal Hospital (Anqing Hospital Affiliated to Anhui Medical University), Anqing, China
| | - Dongfang Zhao
- Jinan Third Hospital of Jining Medical University, Jinan, China
| | - Sheng Fang
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China; Department of Vascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China
| | - Hai Yuan
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China; Department of Vascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China.
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7
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Lunger C, Shen Z, Holcombe H, Mannion AJ, Dzink-Fox J, Kurnick S, Feng Y, Muthupalani S, Carrasco SE, Wilson KT, Peek RM, Piazuelo MB, Morgan DR, Armijo AL, Mammoliti M, Wang TC, Fox JG. Gastric coinfection with thiopeptide-positive Cutibacterium acnes decreases FOXM1 and pro-inflammatory biomarker expression in a murine model of Helicobacter pylori-induced gastric cancer. Microbiol Spectr 2024; 12:e0345023. [PMID: 38014984 PMCID: PMC10783005 DOI: 10.1128/spectrum.03450-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 10/19/2023] [Indexed: 11/29/2023] Open
Abstract
IMPORTANCE H. pylori infects half of the world population and is the leading cause of gastric cancer. We previously demonstrated that gastric cancer risk is associated with gastric microbiota. Specifically, gastric urease-positive Staphylococcus epidermidis and Streptococcus salivarius had contrasting effects on H. pylori-associated gastric pathology and immune responses in germ-free INS-GAS mice. As gastritis progresses to gastric cancer, the oncogenic transcription factor Foxm1 becomes increasingly expressed. In this study, we evaluated the gastric commensal C. acnes, certain strains of which produce thiopeptides that directly inhibit FOXM1. Thiopeptide-positive C. acnes was isolated from Nicaraguan patient gastric biopsies and inoculated into germ-free INS-GAS mice with H. pylori. We, therefore, asked whether coinfection with C. acnes expressing thiopeptide and H. pylori would decrease gastric Foxm1 expression and pro-inflammatory cytokine mRNA and protein levels. Our study supports the growing literature that specific non-H. pylori gastric bacteria affect inflammatory and cancer biomarkers in H. pylori pathogenesis.
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Affiliation(s)
- Courtney Lunger
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Zeli Shen
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Hilda Holcombe
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Anthony J. Mannion
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - JoAnn Dzink-Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Susanna Kurnick
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Yan Feng
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Sureshkumar Muthupalani
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Sebastian E. Carrasco
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Keith T. Wilson
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Richard M. Peek
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M. Blanca Piazuelo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Douglas R. Morgan
- Division of Gastroenterology and Hepatology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Amanda L. Armijo
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Melissa Mammoliti
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Timothy C. Wang
- Division of Gastroenterology and Irvine Cancer Research Center, Columbia University, New York, New York, USA
| | - James G. Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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8
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Zhang C, Pan G, Qin JJ. Role of F-box proteins in human upper gastrointestinal tumors. Biochim Biophys Acta Rev Cancer 2024; 1879:189035. [PMID: 38049014 DOI: 10.1016/j.bbcan.2023.189035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 11/22/2023] [Accepted: 11/25/2023] [Indexed: 12/06/2023]
Abstract
Protein ubiquitination and degradation is an essential physiological process in almost all organisms. As the key participants in this process, the E3 ubiquitin ligases have been widely studied and recognized. F-box proteins, a crucial component of E3 ubiquitin ligases that regulates diverse biological functions, including cell differentiation, proliferation, migration, and apoptosis by facilitating the degradation of substrate proteins. Currently, there is an increasing focus on studying the role of F-box proteins in cancer. In this review, we present a comprehensive overview of the significant contributions of F-box proteins to the development of upper gastrointestinal tumors, highlighting their dual roles as both carcinogens and tumor suppressors. We delve into the molecular mechanisms underlying the involvement of F-box proteins in upper gastrointestinal tumors, exploring their interactions with specific substrates and their cross-talks with other key signaling pathways. Furthermore, we discuss the implications of F-box proteins in radiotherapy resistance in the upper gastrointestinal tract, emphasizing their potential as clinical therapeutic and prognostic targets. Overall, this review provides an up-to-date understanding of the intricate involvement of F-box proteins in human upper gastrointestinal tumors, offering valuable insights for the identification of prognostic markers and the development of targeted therapeutic strategies.
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Affiliation(s)
- Che Zhang
- School of Molecular Medicine, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Guangzhao Pan
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China
| | - Jiang-Jiang Qin
- School of Molecular Medicine, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou 310022, China.
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9
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Akhlaghipour I, Fanoodi A, Zangouei AS, Taghehchian N, Khalili-Tanha G, Moghbeli M. MicroRNAs as the Critical Regulators of Forkhead Box Protein Family in Pancreatic, Thyroid, and Liver Cancers. Biochem Genet 2023; 61:1645-1674. [PMID: 36781813 DOI: 10.1007/s10528-023-10346-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 02/02/2023] [Indexed: 02/15/2023]
Abstract
The metabolism of human body is mainly regulated by the pancreas, liver, and thyroid using the hormones or exocrine secretions that affect the metabolic processes from food digestion to intracellular metabolism. Therefore, metabolic organ disorders have wide clinical symptoms that severely affect the quality of patient's life. The pancreatic, liver, and thyroid cancers as the main malignancies of the metabolic system have always been considered as one of the serious health challenges worldwide. Despite the novel therapeutic modalities, there are still significant high mortality and recurrence rates, especially in liver and pancreatic cancer patients which are mainly related to the late diagnosis. Therefore, it is required to assess the molecular bases of tumor progressions to introduce novel early detection and therapeutic markers in these malignancies. Forkhead box (FOX) protein family is a group of transcription factors that have pivotal roles in regulation of cell proliferation, migration, and apoptosis. They function as oncogene or tumor suppressor during tumor progression. MicroRNAs (miRNAs) are also involved in regulation of cellular processes. Therefore, in the present review, we discussed the role of miRNAs during pancreatic, thyroid, and liver tumor progressions through FOX regulation. It has been shown that miRNAs were mainly involved in tumor progression via FOXM and FOXO targeting. This review paves the way for the introduction of miR/FOX axis as an efficient early detection marker and therapeutic target in pancreatic, thyroid, and liver tumors.
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Affiliation(s)
- Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Fanoodi
- Student Research Committee, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negin Taghehchian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ghazaleh Khalili-Tanha
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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10
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Takada H, Sasagawa Y, Yoshimura M, Tanaka K, Iwayama Y, Hayashi T, Isomura-Matoba A, Nikaido I, Kurisaki A. Single-cell transcriptomics uncovers EGFR signaling-mediated gastric progenitor cell differentiation in stomach homeostasis. Nat Commun 2023; 14:3750. [PMID: 37386010 PMCID: PMC10310803 DOI: 10.1038/s41467-023-39113-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/30/2023] [Indexed: 07/01/2023] Open
Abstract
Defects in gastric progenitor cell differentiation are associated with various gastric disorders, including atrophic gastritis, intestinal metaplasia, and gastric cancer. However, the mechanisms underlying the multilineage differentiation of gastric progenitor cells during healthy homeostasis remain poorly understood. Here, using a single-cell RNA sequencing method, Quartz-Seq2, we analyzed the gene expression dynamics of progenitor cell differentiation toward pit cell, neck cell, and parietal cell lineages in healthy adult mouse corpus tissues. Enrichment analysis of pseudotime-dependent genes and a gastric organoid assay revealed that EGFR-ERK signaling promotes pit cell differentiation, whereas NF-κB signaling maintains gastric progenitor cells in an undifferentiated state. In addition, pharmacological inhibition of EGFR in vivo resulted in a decreased number of pit cells. Although activation of EGFR signaling in gastric progenitor cells has been suggested as one of the major inducers of gastric cancers, our findings unexpectedly identified that EGFR signaling exerts a differentiation-promoting function, not a mitogenic function, in normal gastric homeostasis.
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Affiliation(s)
- Hitomi Takada
- Laboratory of Stem Cell Technologies, Graduate School of Science and Technology, Nara Institute of Science and Technology, Takayama-cho, Ikoma, Nara, Japan
| | - Yohei Sasagawa
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
- Department of Functional Genome Informatics, Biological Data Science, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan
| | - Mika Yoshimura
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
| | - Kaori Tanaka
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
| | - Yoshimi Iwayama
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
- Department of Functional Genome Informatics, Biological Data Science, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan
| | - Tetsutaro Hayashi
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
| | - Ayako Isomura-Matoba
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
| | - Itoshi Nikaido
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan.
- Department of Functional Genome Informatics, Biological Data Science, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan.
- Master's/Doctoral Program in Life Science Innovation (Bioinformatics), Degree Programs in Systems and Information Engineering, Graduate School of Science and Technology, University of Tsukuba, Tsukuba, Ibaraki, Japan.
| | - Akira Kurisaki
- Laboratory of Stem Cell Technologies, Graduate School of Science and Technology, Nara Institute of Science and Technology, Takayama-cho, Ikoma, Nara, Japan.
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11
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MicroRNA-370 as a negative regulator of signaling pathways in tumor cells. Process Biochem 2023. [DOI: 10.1016/j.procbio.2023.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
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12
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FOXM1 increases hTERT protein stability and indicates poor prognosis in gastric cancer. Neoplasia 2022; 36:100863. [PMID: 36528911 PMCID: PMC9792884 DOI: 10.1016/j.neo.2022.100863] [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: 05/31/2022] [Revised: 11/29/2022] [Accepted: 12/02/2022] [Indexed: 12/23/2022] Open
Abstract
Gastric cancer is one of most lethal diseases across the world. However, the underlying mechanism of gastric cancer carcinogenesis and development is still not fully known. Forkhead box M1 (FOXM1) belongs to the FOX family and has crucial roles in transactivation of multiple oncogenes in several cancer types, including gastric cancer. Recent studies have also shown the non-transcriptional function of FOXM1 via protein-protein interactions. Human telomerase reverse transcriptase (hTERT) is the core subunit of telomerase that facilitates cancer initiation and progression by maintaining cell immortalization, promoting cell proliferation and inhibiting cell apoptosis. However, the relationship between FOXM1 and hTERT in gastric cancer is still unclear. In our study, we found that FOXM1 and hTERT were convergent to the cell cycle-related pathways and they were positively related with advanced gastric cancer stages and poor outcomes. Simultaneous high levels of FOXM1 and hTERT predicted the worst prognosis. FOXM1 could increase hTERT protein rather than mRNA levels in a non-transcriptional manner. Mechanistically, FOXM1 interrupted the interaction between the E3 ligase MKRN1 and hTERT and decreased hTERT protein degradation. Further studies revealed that FOXM1 interacted with hTERT through its DNA-binding domain (DBD) region. Finally, we found that hTERT played important roles in FOXM1-mediated activation of the Wnt/β-catenin pathway to promote gastric cancer cell proliferation. Taken together, we found a novel non-classical function of FOXM1 to increase hTERT protein stability. Targeting the FOXM1-hTERT pathway may be a potential therapeutic strategy in treating gastric cancer.
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13
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Guo Z, Zou K, Li X, Duan X, Fan Y, Liu X, Wang W. Relationship between miRNAs polymorphisms and peripheral blood leukocyte DNA telomere length in coke oven workers: A cross-sectional study. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2022; 95:103941. [PMID: 35931358 DOI: 10.1016/j.etap.2022.103941] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 07/23/2022] [Accepted: 08/01/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVE The purpose of this study was to investigate the factors affecting telomere length (TL) in coke oven workers by analyzing the interaction between miRNAs polymorphisms and coke oven emissions (COEs) exposure. METHODS A total of 544 coke oven workers and 238 healthy controls were recruited. Peripheral blood was collected from the subjects, genomic DNA was extracted, leukocyte TL was detected by real-time quantitative polymerase chain reaction, and fifteen polymorphisms of eight miRNAs were genotyped by flight mass spectrometry. RESULTS Statistical analysis showed that the peripheral blood DNA TL in the exposure group was shorter than that in the control group (P < 0.001). Generalized linear model found that COEs-exposure [β (95%CI) = -0.427 (-0.556, -0.299), P < 0.001], genotype CC+CT for miR-612 rs1144925 [β (95%CI) = -0.367 (-0.630, -0.104), P = 0.006], and the interaction of miR-181B1 rs12039395 TT genotype and COEs-exposure [β (95% CI) = 0.564 (0.108, 1.020), P = 0.015] were associated with the shortened TL. CONCLUSION COEs-exposure and miR-612 rs1144925 TT could promote telomere shortening in coke oven workers. The interaction of miR-181B1 rs12039395 TT genotype and COEs-exposure could protect telomere. This provides clues for further mechanistic studies between miRNA and telomere damage.
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Affiliation(s)
- Zhifeng Guo
- Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China; The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou 450001, Henan, China
| | - Kaili Zou
- Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China; The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou 450001, Henan, China
| | - Xinling Li
- Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China; The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou 450001, Henan, China
| | - Xiaoran Duan
- Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China; Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Yahui Fan
- Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China; The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou 450001, Henan, China
| | - Xiaohua Liu
- Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China; The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou 450001, Henan, China
| | - Wei Wang
- Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China; The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou 450001, Henan, China.
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14
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Zhang N, Gao Y, Bian Q, Wang Q, Shi Y, Zhao Z, Yu H. The role of fascin-1 in the pathogenesis, diagnosis and management of respiratory related cancers. Front Oncol 2022; 12:948110. [PMID: 36033434 PMCID: PMC9404296 DOI: 10.3389/fonc.2022.948110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/25/2022] [Indexed: 11/15/2022] Open
Abstract
Human cancer statistics report that respiratory related cancers such as lung, laryngeal, oral and nasopharyngeal cancers account for a large proportion of tumors, and tumor metastasis remains the major reason for patient death. The metastasis of tumor cells requires actin cytoskeleton remodeling, in which fascin-1 plays an important role. Fascin-1 can cross-link F-actin microfilaments into bundles and form finger-like cell protrusions. Some studies have shown that fascin-1 is overexpressed in human tumors and is associated with tumor growth, migration and invasion. The role of fascin-1 in respiratory related cancers is not very clear. The main purpose of this study was to provide an updated literature review on the role of fascin-1 in the pathogenesis, diagnosis and management of respiratory related cancers. These studies suggested that fascin-1 can serve as an emerging biomarker and potential therapeutic target, and has attracted widespread attention.
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Affiliation(s)
- Naibin Zhang
- Department of biochemistry, Jining Medical University, Jining, China
| | - Yankun Gao
- Department of biochemistry, Jining Medical University, Jining, China
| | - Qiang Bian
- Collaborative Innovation Center, Jining Medical University, Jining, China
- Department of Pathophysiology, Weifang Medical University, Weifang, China
| | - Qianqian Wang
- Department of biochemistry, Jining Medical University, Jining, China
| | - Ying Shi
- Department of biochemistry, Jining Medical University, Jining, China
| | - Zhankui Zhao
- The Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Honglian Yu
- Department of biochemistry, Jining Medical University, Jining, China
- Collaborative Innovation Center, Jining Medical University, Jining, China
- *Correspondence: Honglian Yu,
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15
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Kuttikrishnan S, Prabhu KS, Khan AQ, Alali FQ, Ahmad A, Uddin S. Thiostrepton inhibits growth and induces apoptosis by targeting FoxM1/SKP2/MTH1 axis in B-precursor acute lymphoblastic leukemia cells. Leuk Lymphoma 2021; 62:3170-3180. [PMID: 34369229 DOI: 10.1080/10428194.2021.1957873] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/19/2021] [Accepted: 07/10/2021] [Indexed: 12/15/2022]
Abstract
Forkhead box M1 (FoxM1) is a transcription factor that plays an important role in the etiology of many cancers, however, its role has not been elucidated in B-precursor acute lymphoblastic leukemia (B-pre-ALL). In the current study, we showed that the downregulation of FoxM1 by its inhibitor thiostrepton inhibited cell viability and induced caspase-dependent apoptosis in a panel of B-pre-ALL cell lines. Thiostrepton led downregulation of FoxM1 accompanied by decreased expression of Aurora kinase A, B, matrix metalloproteinases, and oncogene SKP2 as well as MTH1. Downregulation of the FoxM1/SKP2/MTH1 axis led to increase in the Bax/Bcl2 ratio and suppression of antiapoptotic proteins. Thiostrepton-mediated apoptosis was prevented by N-acetyl cysteine, a scavenger of reactive oxygen species. Co-treatment of B-pre-ALL with subtoxic doses of thiostrepton and bortezomib potentiated the proapoptotic action. Altogether, our results suggest that targeting FoxM1expression could be an attractive strategy for the treatment of B-pre-ALL.
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Affiliation(s)
- Shilpa Kuttikrishnan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- College of Pharmacy, Qatar University, Doha, Qatar
| | - Kirti S Prabhu
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Feras Q Alali
- College of Pharmacy, Qatar University, Doha, Qatar
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University
| | - Aamir Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Laboratory of Animal Research Center, Qatar University, Doha, Qatar
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16
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Barberis M. Quantitative model of eukaryotic Cdk control through the Forkhead CONTROLLER. NPJ Syst Biol Appl 2021; 7:28. [PMID: 34117265 PMCID: PMC8196193 DOI: 10.1038/s41540-021-00187-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 05/07/2021] [Indexed: 12/20/2022] Open
Abstract
In budding yeast, synchronization of waves of mitotic cyclins that activate the Cdk1 kinase occur through Forkhead transcription factors. These molecules act as controllers of their sequential order and may account for the separation in time of incompatible processes. Here, a Forkhead-mediated design principle underlying the quantitative model of Cdk control is proposed for budding yeast. This design rationalizes timing of cell division, through progressive and coordinated cyclin/Cdk-mediated phosphorylation of Forkhead, and autonomous cyclin/Cdk oscillations. A "clock unit" incorporating this design that regulates timing of cell division is proposed for both yeast and mammals, and has a DRIVER operating the incompatible processes that is instructed by multiple CLOCKS. TIMERS determine whether the clocks are active, whereas CONTROLLERS determine how quickly the clocks shall function depending on external MODULATORS. This "clock unit" may coordinate temporal waves of cyclin/Cdk concentration/activity in the eukaryotic cell cycle making the driver operate the incompatible processes, at separate times.
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Affiliation(s)
- Matteo Barberis
- Systems Biology, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
- Centre for Mathematical and Computational Biology, CMCB, University of Surrey, Guildford, UK.
- Synthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
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17
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Lee NR, Kim DY, Jin H, Meng R, Chai OH, Kim SH, Park BH, Kim SM. Inactivation of the Akt/FOXM1 Signaling Pathway by Panobinostat Suppresses the Proliferation and Metastasis of Gastric Cancer Cells. Int J Mol Sci 2021; 22:5955. [PMID: 34073071 PMCID: PMC8199011 DOI: 10.3390/ijms22115955] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/28/2021] [Accepted: 05/28/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Histone deacetylase (HDAC) inhibitors are a new class of cytostatic agents available for the treatment of various cancers and diseases. Although numerous clinical and pre-clinical trials on the anticancer effects of panobinostat have been conducted, only a few reports have investigated its efficacy in gastric cancer. The present study aimed to investigate the effects of panobinostat in gastric cancer cells. Panobinostat significantly inhibited the cell viability and proliferation of the gastric cancer cell lines SNU484 and SNU638 in a dose-dependent manner; it reduced the colony-forming ability of these cells. Moreover, it induced apoptosis as indicated by increased protein levels of cleaved poly ADP-ribose polymerase and cleaved caspase-3. Panobinostat induced the G2/M cell cycle arrest in SNU484 and SNU638 cells and subsequently decreased the G2/M phase regulatory-associated protein expression of p-Wee1, Myt1, and Cdc2. Furthermore, panobinostat significantly inhibited the metastasis of SNU484 and SNU638 cells by regulating the expression of MMP-9 and E-cadherin. Further, it decreased the protein levels of p-Akt and forkhead box protein M1 (FOXM1). These effects were reversed by the Akt agonist SC79 and were accelerated by the Akt inhibitor LY2940002. Moreover, tumor growth in xenograft animal experiments was suppressed by panobinostat. These results indicated that panobinostat inhibits the proliferation, metastasis, and cell cycle progression of gastric cancer cells by promoting apoptosis and inactivating Akt/FOXM1 signaling. Cumulatively, our present study suggests that panobinostat is a potential drug for the treatment of gastric cancer.
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Affiliation(s)
- Na-Ri Lee
- Division of Hematology/Oncology, Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju 54907, Korea;
- Research Institute of Clinical Medicine, Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Korea
| | - Da-Yeah Kim
- Department of Physiology, Institute of Medical Science, Jeonbuk National University Medical School, Jeonju 54907, Korea; (D.-Y.K.); (R.M.)
| | - Hua Jin
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China;
| | - Ruoyu Meng
- Department of Physiology, Institute of Medical Science, Jeonbuk National University Medical School, Jeonju 54907, Korea; (D.-Y.K.); (R.M.)
| | - Ok Hee Chai
- Department of Anatomy, Institute of Medical Science, Jeonbuk National University Medical School, Jeonju 54907, Korea;
| | - Seong-Hun Kim
- Research Institute of Clinical Medicine, Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Korea
- Department of Internal Medicine, Division of Gastroentrology, Jeonbuk National University Medical School, Jeonbuk National University Hospital, Jeonju 54907, Korea;
| | - Byung-Hyun Park
- Department of Biochemistry, Jeonbuk National University Medical School, Jeonju 54907, Korea;
| | - Soo Mi Kim
- Department of Physiology, Institute of Medical Science, Jeonbuk National University Medical School, Jeonju 54907, Korea; (D.-Y.K.); (R.M.)
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18
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Xiao H, Jiang Z, Fu X, Kuang Y, Lin S, Cai Y, Zhang Q, Zheng F. High expression of forkhead box M1 (FOXM1) is a poor prognostic biomarker in lung adenocarcinoma. Transl Cancer Res 2020; 9:6331-6343. [PMID: 35117241 PMCID: PMC8799027 DOI: 10.21037/tcr-20-1103] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 09/02/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Forkhead box M1 (FOXM1) is closely related to the formation and development of cancer. Because of differences in cellular origin, lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SCC) usually exhibit different signatures. Therefore, it is essential to investigate the abnormalities of FOXM1 in the two subtypes separately. METHODS Through the Oncomine and TCGA databases, we investigated the expression of FOXM1 mRNA, its prognostic value and possible mechanisms leading to its dysregulation. Furthermore, networks involving FOXM1 and its significantly altered neighboring genes were identified using the cBioPortal database. GO and KEGG enrichment analyses were performed using DAVID. RESULTS Expression of FOXM1 mRNA was higher in lung tumor tissues than in normal tissues, and higher in SCC tissues than in ADC tissues. FOXM1 mRNA expression was correlated with N stage, TNM stage, age, sex and smoking history in ADC, but only correlated with N stage, age and sex in SCC. Survival analysis indicated that high expression of FOXM1 mRNA resulted to poor overall survival (OS) for ADC patients, but not for SCC patients. Cox regression analysis confirmed that FOXM1 mRNA expression was an independent prognostic indicator for ADC patients, and regression analysis identified a moderately positive correlation between FOXM1 mRNA levels and copy number alterations (CNAs), but a weakly negative association with DNA methylation. FOXM1 was mainly involved in cell cycle regulation, G2/M transition, G1/S transition and p53, PI3K-Akt and TGF-beta signaling pathway. CONCLUSIONS High expression of FOXM1 mRNA might be an independent biomarker of poor OS in ADC patients.
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Affiliation(s)
- Hong Xiao
- Department of Clinical Laboratory, the First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Zebin Jiang
- Department of Clinical Pharmacology Laboratory, the First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Xian Fu
- Department of Clinical Pharmacology Laboratory, the First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Yongjun Kuang
- Department of Clinical Laboratory, the First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Sheng Lin
- Department of Pharmacology, Shantou University Medical College, Shantou, China
| | - Yingmu Cai
- Department of Clinical Laboratory, the First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Qiaoxin Zhang
- Department of Clinical Laboratory, the First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Fuchun Zheng
- Department of Clinical Pharmacology Laboratory, the First Affiliated Hospital of Shantou University Medical College, Shantou, China
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Abstract
Forkhead box O (FOXO) transcription factors regulate diverse biological processes, affecting development, metabolism, stem cell maintenance and longevity. They have also been increasingly recognised as tumour suppressors through their ability to regulate genes essential for cell proliferation, cell death, senescence, angiogenesis, cell migration and metastasis. Mechanistically, FOXO proteins serve as key connection points to allow diverse proliferative, nutrient and stress signals to converge and integrate with distinct gene networks to control cell fate, metabolism and cancer development. In consequence, deregulation of FOXO expression and function can promote genetic disorders, metabolic diseases, deregulated ageing and cancer. Metastasis is the process by which cancer cells spread from the primary tumour often via the bloodstream or the lymphatic system and is the major cause of cancer death. The regulation and deregulation of FOXO transcription factors occur predominantly at the post-transcriptional and post-translational levels mediated by regulatory non-coding RNAs, their interactions with other protein partners and co-factors and a combination of post-translational modifications (PTMs), including phosphorylation, acetylation, methylation and ubiquitination. This review discusses the role and regulation of FOXO proteins in tumour initiation and progression, with a particular emphasis on cancer metastasis. An understanding of how signalling networks integrate with the FOXO transcription factors to modulate their developmental, metabolic and tumour-suppressive functions in normal tissues and in cancer will offer a new perspective on tumorigenesis and metastasis, and open up therapeutic opportunities for malignant diseases.
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Affiliation(s)
- Yannasittha Jiramongkol
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Eric W-F Lam
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK.
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20
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A Driver Never Works Alone-Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer. Cancers (Basel) 2020; 12:cancers12061532. [PMID: 32545208 PMCID: PMC7353041 DOI: 10.3390/cancers12061532] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/03/2020] [Accepted: 06/05/2020] [Indexed: 12/12/2022] Open
Abstract
The knowledge accumulating on the occurrence and mechanisms of the activation of oncogenes in human neoplasia necessitates an increasingly detailed understanding of their systemic interactions. None of the known oncogenic drivers work in isolation from the other oncogenic pathways. The cooperation between these pathways is an indispensable element of a multistep carcinogenesis, which apart from inactivation of tumor suppressors, always includes the activation of two or more proto-oncogenes. In this review we focus on representative examples of the interaction of major oncogenic drivers with one another. The drivers are selected according to the following criteria: (1) the highest frequency of known activation in human neoplasia (by mutations or otherwise), (2) activation in a wide range of neoplasia types (universality) and (3) as a part of a distinguishable pathway, (4) being a known cause of phenotypic addiction of neoplastic cells and thus a promising therapeutic target. Each of these universal oncogenic factors—mutant p53, KRAS and CMYC proteins, telomerase ribonucleoprotein, proteasome machinery, HSP molecular chaperones, NF-κB and WNT pathways, AP-1 and YAP/TAZ transcription factors and non-coding RNAs—has a vast network of molecular interrelations and common partners. Understanding this network allows for the hunt for novel therapeutic targets and protocols to counteract drug resistance in a clinical neoplasia treatment.
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21
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Li R, Wang X, Zhao X, Zhang X, Chen H, Ma Y, Liu Y. Centromere protein F and Forkhead box M1 correlation with prognosis of non-small cell lung cancer. Oncol Lett 2020; 19:1368-1374. [PMID: 31966068 PMCID: PMC6956421 DOI: 10.3892/ol.2019.11232] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 10/15/2019] [Indexed: 12/13/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer. Altered expression of centromere protein F (CENPF), a transient kinetochore protein, has been found in a variety of human cancers. However, its clinical significance in NSCLC remains unknown. In the present study the results of quantitative PCR and western blot analyses demonstrated that CENPF and Forkhead box M1 (FOXM1) were significantly higher in NSCLC tissues than in the non-cancerous controls at both transcriptional and translational levels. Immunohistochemical staining results showed 58.7% (44/75) and 64.0% (48/75) of NSCLC tissues displayed high expression of CENPF and FOXM1, respectively. CENPF protein expression showed a positive correlation with tumor size (P=0.0179), vital status (P=0.0008) and FOXM1 expression (P=0.0013) in NSCLC. Poor overall survival was correlated with high levels of CENPF and FOXM1 in NSCLC patients as evaluated by Kaplan-Meier and log rank test. Multivariate analyses showed that CENPF expression was an independent prognostic factor for NSCLC. In conclusion, our study provides evidence of the prognostic function of CENPF in NSCLC.
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Affiliation(s)
- Rui Li
- Department of Clinical Laboratory, Shenyang Fifth People's Hospital, Shenyang, Liaoning 110021, P.R. China
| | - Xia Wang
- Department of Clinical Laboratory, Shenyang Fifth People's Hospital, Shenyang, Liaoning 110021, P.R. China
| | - Xiaoqian Zhao
- Department of Clinical Laboratory, Shenyang Fifth People's Hospital, Shenyang, Liaoning 110021, P.R. China
| | - Xiaohong Zhang
- Department of Clinical Laboratory, Shenyang Fifth People's Hospital, Shenyang, Liaoning 110021, P.R. China
| | - Honghai Chen
- Department of Clinical Laboratory, Shenyang Fifth People's Hospital, Shenyang, Liaoning 110021, P.R. China
| | - Yue Ma
- Department of Clinical Laboratory, Shenyang Fifth People's Hospital, Shenyang, Liaoning 110021, P.R. China
| | - Yandong Liu
- Admin Office, Shenyang Fifth People's Hospital, Shenyang, Liaoning 110021, P.R. China
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22
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Yu Y, Lu W, Zhou X, Huang H, Shen S, Guo L. MicroRNA-132 suppresses migration and invasion of renal carcinoma cells. J Clin Lab Anal 2020; 34:e22969. [PMID: 31625200 PMCID: PMC6977305 DOI: 10.1002/jcla.22969] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 06/03/2019] [Accepted: 06/12/2019] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND The aim of this study was to explain the effects of microRNA-132 in renal cell carcinoma by regulating FOXM1 expression. METHODS Thirty patients with renal cell carcinoma admitted to our hospital were enrolled, and their adjacent normal tissues and cancer tissues were taken. The expression of microRNA-132 was measured by in situ hybridization (ISH) and RT-PCR, and the expression of FOXM1 was evaluated by RT-PCR and immunohistochemistry (IHC), and the correlation between microRNA-132 and FOXM1 was analyzed. In the cell experiment, the KETR-3 cells were divided into three groups: Negative control (NC) group were treated with nothing; blank (BL) group were transfected with empty vector; and microRNA-132 (miRNA) group were transfected with microRNA-132. The cell invasion and migration abilities among groups were assessed by transwell and wound healing assays. The expression levels of related proteins (FOXM1, MMP-2, MMP-9, VEGF-alpha, and uPAR) were determined by Western blot. RESULTS Depending on clinical data, we found that FOXM1 protein expression of renal cell carcinoma tissues was higher than that in adjacent normal tissues. MiRNA-132 was negative correlation with FOXM1. In vitro, the number of invasive cells and wound healing rate in the microRNA group were significantly suppressed than those in the NC group (P < 0.05, respectively). In the Western blot assay, the results showed that the protein expression levels of FOXM1, MMP-2, MMP-9, VEGF-α, and uPAR were significantly inhibited in the miRNA group compared with the NC group (P < 0.05, respectively). CONCLUSION miRNA-132 had anti-tumor effects in renal cell carcinoma by suppressing FOXM1 expression.
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Affiliation(s)
- Yi Yu
- Department of UrologyThe Second Affiliated Hospital of Nanchang UniversityNanchangJiangxi ProvinceChina
| | - Wenbao Lu
- Department of UrologyThe Affiliated Hospital of Jiujiang University Clinical Medical CollegeJiujiangJiangxi ProvinceChina
| | - Xinmin Zhou
- Department of UrologyDuchang County Hospital of Traditional Chinese MedicineDuchangJiangxi ProvinceChina
| | - Hua Huang
- Department of UrologyThe Second Affiliated Hospital of Nanchang UniversityNanchangJiangxi ProvinceChina
| | - Shaochen Shen
- Department of UrologyThe Second Affiliated Hospital of Nanchang UniversityNanchangJiangxi ProvinceChina
| | - Lian Guo
- Department of AnesthesiaThe Second Affiliated Hospital of Nanchang UniversityNanchangJiangxi ProvinceChina
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Hamzehlou S, Momeny M, Zandi Z, Kashani B, Yousefi H, Dehpour AR, Tavakkoly-Bazzaz J, Ghaffari SH. Anti-tumor activity of neratinib, a pan-HER inhibitor, in gastric adenocarcinoma cells. Eur J Pharmacol 2019; 863:172705. [DOI: 10.1016/j.ejphar.2019.172705] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 09/25/2019] [Accepted: 09/26/2019] [Indexed: 12/24/2022]
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Based on Integrated Bioinformatics Analysis Identification of Biomarkers in Hepatocellular Carcinoma Patients from Different Regions. BIOMED RESEARCH INTERNATIONAL 2019; 2019:1742341. [PMID: 31886176 PMCID: PMC6925735 DOI: 10.1155/2019/1742341] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 09/24/2019] [Indexed: 02/07/2023]
Abstract
Accumulating statistics have shown that liver cancer causes the second highest mortality rate of cancer-related deaths worldwide, of which 80% is hepatocellular carcinoma (HCC). Given the underlying molecular mechanism of HCC pathology is not fully understood yet, identification of reliable predictive biomarkers is more applicable to improve patients' outcomes. The results of principal component analysis (PCA) showed that the grouped data from 1557 samples in Gene Expression Omnibus (GEO) came from different populations, and the mean tumor purity of tumor tissues was 0.765 through the estimate package in R software. After integrating the differentially expressed genes (DEGs), we finally got 266 genes. Then, the protein-protein interaction (PPI) network was established based on these DEGs, which contained 240 nodes and 1747 edges. FOXM1 was the core gene in module 1 and highly associated with FOXM1 transcription factor network pathway, while FTCD was the core gene in module 2 and was enriched in the metabolism of amino acids and derivatives. The expression levels of hub genes were in line with The Cancer Genome Atlas (TCGA) database. Meanwhile, there were certain correlations among the top ten genes in the up- and downregulated DEGs. Finally, Kaplan–Meier curves and receiver operating characteristic (ROC) curves were plotted for the top five genes in PPI. Apart from CDKN3, the others were closely concerned with overall survival. In this study, we detected the potential biomarkers and their involved biological processes, which would provide a new train of thought for clinical diagnosis and treatment.
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Yuan X, Larsson C, Xu D. Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players. Oncogene 2019; 38:6172-6183. [PMID: 31285550 PMCID: PMC6756069 DOI: 10.1038/s41388-019-0872-9] [Citation(s) in RCA: 303] [Impact Index Per Article: 50.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 06/20/2019] [Accepted: 06/20/2019] [Indexed: 12/25/2022]
Abstract
Long-lived species Homo sapiens have evolved robust protection mechanisms against cancer by repressing telomerase and maintaining short telomeres, thereby delaying the onset of the majority of cancer types until post-reproductive age. Indeed, telomerase is silent in most differentiated human cells, predominantly due to the transcriptional repression of its catalytic component telomerase reverse transcriptase (TERT) gene. The lack of telomerase/TERT expression leads to progressive telomere erosion in dividing human cells, whereas critically shortened telomere length induces a permanent growth arrest stage named replicative senescence. TERT/telomerase activation has been experimentally shown to be essential to cellular immortalization and malignant transformation by stabilizing telomere length and erasing the senescence barrier. Consistently, TERT expression/telomerase activity is detectable in up to 90% of human primary cancers. Compelling evidence has also accumulated that TERT contributes to cancer development and progression via multiple activities beyond its canonical telomere-lengthening function. Given these key roles of telomerase and TERT in oncogenesis, great efforts have been made to decipher mechanisms underlying telomerase activation and TERT induction. In the last two decades since the TERT gene and promoter were cloned, the derepression of the TERT gene has been shown to be achieved typically at a transcriptional level through dysregulation of oncogenic factors or signaling, post-transcriptional/translational regulation and genomic amplification. However, advances in high-throughput next-generation sequencing technologies have prompted a revolution in cancer genomics, which leads to the recent discovery that genomic alterations take center stage in activating the TERT gene. In this review article, we summarize critical mechanisms activating TERT transcription, with special emphases on the contribution of TERT promoter mutations and structural alterations at the TERT locus, and briefly discuss the underlying implications of these genomic events-driven TERT hyperactivity in cancer initiation/progression and potential clinical applications as well.
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Affiliation(s)
- Xiaotian Yuan
- School of Medicine, Shandong University, 250012, Jinan, People's Republic of China. .,Department of Medicine, Center for Molecular Medicine (CMM) and Bioclinicum, Karolinska Institutet and Karolinska University Hospital Solna, 171 64, Solna, Sweden.
| | - Catharina Larsson
- Department of Oncology-Pathology and Bioclinicum, Karolinska Institutet and Karolinska University Hospital Solna, 171 64, Solna, Sweden
| | - Dawei Xu
- Department of Medicine, Center for Molecular Medicine (CMM) and Bioclinicum, Karolinska Institutet and Karolinska University Hospital Solna, 171 64, Solna, Sweden.
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Zhi Y, Abudoureyimu M, Zhou H, Wang T, Feng B, Wang R, Chu X. FOXM1-Mediated LINC-ROR Regulates the Proliferation and Sensitivity to Sorafenib in Hepatocellular Carcinoma. MOLECULAR THERAPY. NUCLEIC ACIDS 2019; 16:576-588. [PMID: 31082791 PMCID: PMC6514537 DOI: 10.1016/j.omtn.2019.04.008] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 04/03/2019] [Accepted: 04/03/2019] [Indexed: 01/04/2023]
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-associated death worldwide. Indeed, despite the benefit of sorafenib in the treatment of some patients with HCC, the majority of these patients have a poor response to or intolerance of sorafenib, resulting in further tumor progression. Exploring the mechanisms underlying sorafenib resistance is essential to the treatment of HCC. Long noncoding RNAs (lncRNAs) are known as participants in tumorigenesis. In this study, we identified that long intergenic non-protein coding RNA, regulator of reprogramming (LINC-ROR), was upregulated in HCC cell lines, which was transcriptionally activated by FOXM1. Furthermore, the sponging of miR-876-5p by LINC-ROR released FOXM1, thereby forming a positive-feedback loop. Additionally, we demonstrated that upregulation of both FOXM1 and LINC-ROR impaired the sensitivity to sorafenib in HCC cells. The role of this feedback loop was demonstrated by rescue assays. These results revealed a novel molecular feedback loop between LINC-ROR and FOXM1 and elucidated their functions in sorafenib sensitivity of HCC cell lines.
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Affiliation(s)
- Yingru Zhi
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, People's Republic of China
| | - Mubalake Abudoureyimu
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, People's Republic of China
| | - Hao Zhou
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Ting Wang
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, People's Republic of China
| | - Bing Feng
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, People's Republic of China
| | - Rui Wang
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, People's Republic of China.
| | - Xiaoyuan Chu
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, People's Republic of China
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ASF1a inhibition induces p53-dependent growth arrest and senescence of cancer cells. Cell Death Dis 2019; 10:76. [PMID: 30692519 PMCID: PMC6349940 DOI: 10.1038/s41419-019-1357-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 01/07/2019] [Accepted: 01/11/2019] [Indexed: 12/13/2022]
Abstract
Anti-silencing function 1a (ASF1a) is a histone H3-H4 chaperone isoform involved in chromatin assembling and transcription regulation. Recently, ASF1a has been shown to be up-regulated in certain human malignancies and required for the expression of telomerase reverse transcriptase (TERT), a factor essential for the immortal phenotype of cancer cells; however, its role in oncogenesis remains poorly defined. In the present study, we determine whether ASF1a is required for the unlimited proliferation of cancer cells, a key cancer hallmark. Elevated ASF1a mRNA expression was observed in hepatocellular carcinoma (HCC) tumors. The overexpression of ASF1a was similarly found in 20 cancer types contained in TCGA and GTEx datasets. ASF1a knockdown led to growth arrest and senescence of wild-type (wt) p53-carrying HCC and prostate cancer cells. Cellular senescence mediated by ASF1a inhibition resulted from the robust up-regulation of p53 and p21cip1 expression, but without detectable changes in TERT expression. p53 inhibition attenuated p21cip1 induction caused by ASF1a depletion. Mechanistically, ASF1a-knocked down cells displayed widespread DNA damage. The TCGA dataset analysis revealed a negative correlation between ASF1a and p21cip1 expression in multiple types of primary tumors, including HCC, prostate, gastric, and breast cancer. Higher ASF1a and lower p21cip1 expression predicted a poor outcome in patients with HCC. Our results reveal that ASF1a overexpression is widespread in human malignancies and is required for the infinite proliferation of cancer cells, whereas its inhibition induces DNA damage and subsequent up-regulation of p53-p21cip1 expression, thereby triggering cellular senescence. Thus, ASF1a may serve as a potential target in cancer therapy.
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Gu C, Jing X, Holman C, Sompallae R, Zhan F, Tricot G, Yang Y, Janz S. Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma. BMC Cancer 2018; 18:1152. [PMID: 30463534 PMCID: PMC6249818 DOI: 10.1186/s12885-018-5015-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 10/30/2018] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Following up on previous work demonstrating the involvement of the transcription factor forkhead box M1 (FOXM1) in the biology and outcome of a high-risk subset of newly diagnosed multiple myeloma (nMM), this study evaluated whether FOXM1 gene expression may be further upregulated upon tumor recurrence in patients with relapsed multiple myeloma (rMM). Also assessed was the hypothesis that increased levels of FOXM1 diminish the sensitivity of myeloma cells to commonly used myeloma drugs, such as the proteasome inhibitor bortezomib (Bz) and the DNA intercalator doxorubicin (Dox). METHODS FOXM1 message was evaluated in 88 paired myeloma samples from patients with nMM and rMM, using gene expression microarrays as measurement tool. Sources of differential gene expression were identified and outlier analyses were performed using statistical methods. Two independent human myeloma cell lines (HMCLs) containing normal levels of FOXM1 (FOXM1N) or elevated levels of lentivirus-encoded FOXM1 (FOXM1Hi) were employed to determine FOXM1-dependent changes in cell proliferation, survival, efflux-pump activity, and drug sensitivity. Levels of retinoblastoma (Rb) protein were determined with the assistance of Western blotting. RESULTS Upregulation of FOXM1 occurred in 61 of 88 (69%) patients with rMM, including 4 patients that exhibited > 20-fold elevated expression peaks. Increased FOXM1 levels in FOXM1Hi myeloma cells caused partial resistance to Bz (1.9-5.6 fold) and Dox (1.5-2.9 fold) in vitro, using FOXM1N myeloma as control. Reduced sensitivity of FOXM1Hi cells to Bz was confirmed in vivo using myeloma-in-mouse xenografts. FOXM1-dependent regulation of total and phosphorylated Rb agreed with a working model of myeloma suggesting that FOXM1 governs both chromosomal instability (CIN) and E2F-dependent proliferation, using a mechanism that involves interaction with NIMA related kinase 2 (NEK2) and cyclin dependent kinase 6 (CDK6), respectively. CONCLUSIONS These findings enhanced our understanding of the emerging FOXM1 genetic network in myeloma and provided preclinical support for the therapeutic targeting of the FOXM1-NEK2 and CDK4/6-Rb-E2F pathways using small-drug CDK and NEK2 inhibitors. Clinical research is warranted to assess whether this approach may overcome drug resistance in FOXM1Hi myeloma and, thereby, improve the outcome of patients in which the transcription factor is expressed at high levels.
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Affiliation(s)
- Chunyan Gu
- The Third Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, 210023 China
- Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242 USA
| | - Xuefang Jing
- Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242 USA
| | - Carol Holman
- Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242 USA
| | - Ramakrishna Sompallae
- Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242 USA
- Iowa Institute for Genetics, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242 USA
| | - Fenghuang Zhan
- Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242 USA
- Holden Comprehensive Cancer Center, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242 USA
| | - Guido Tricot
- Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242 USA
- Holden Comprehensive Cancer Center, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242 USA
| | - Ye Yang
- The Third Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, 210023 China
- Key Laboratory of Acupuncture and Medicine Research, Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, 210023 China
| | - Siegfried Janz
- Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242 USA
- Holden Comprehensive Cancer Center, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242 USA
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53213 USA
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Zhang HP, Li SY, Wang JP, Lin J. Clinical significance and biological roles of cyclins in gastric cancer. Onco Targets Ther 2018; 11:6673-6685. [PMID: 30349301 PMCID: PMC6186297 DOI: 10.2147/ott.s171716] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background and aim Cyclins have been reported to be overexpressed with poor prognosis in several human cancers. However, limited numbers of studies evaluated the expressions and prognostic roles of cyclins in gastric cancer (GC). We aim to evaluate the expressions and prognostic roles of cyclins. Also, further efforts were made to explore biological function of the differentially expressed cyclins. Methods Cyclins expressions were analyzed by Oncomine and The Cancer Genome Atlas datasets, and the prognostic roles of cyclins in GC patients were investigated by the Kaplan–Meier Plotter database. Then, a comprehensive PubMed literature search was performed to identify expression and prognosis of cyclins in GC. Biological functions of the differentially expressed cyclins were explored through Enrich R platform, and KEGG and transcription factor were analyzed. Results The expression levels of CCNA2 (cyclin A2), CCNB1 (cyclin B1), CCNB2 (cyclin B2), and CCNE1 (cyclin E1) mRNAs were identified to be significantly higher in GC tissues than in normal tissues in both Oncomine and The Cancer Genome Atlas datasets. High expressions of CCNA2, CCNB1, and CCNB2 mRNAs were identified to be related with poor overall survival in Kaplan–Meier Plotter dataset. Evidence from clinical studies showed that CCNB1 was related with overall survival in GC patients. Cyclins were associated with several biological pathways, including cell cycle, p53 signaling pathway, FoxO signaling pathway, viral carcinogenesis, and AMPK signaling pathway. Enrichment analysis also showed that cyclins interacted with some certain transcription factors, such as FOXM1, SIN3A, NFYA, and E2F4. Conclusion Based on our results, high expressions of cyclins were related with poor prognosis in GC patients. The above information might be useful for better understanding the clinical and biological roles of cyclins mRNA and guiding individualized treatments for GC patients.
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Affiliation(s)
- Hai-Ping Zhang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan City, Hubei Province 430071, China,
| | - Shu-Yu Li
- Department of Gastroenterology, Zhongshan Hospital of Hubei Province, Wuhan City, Hubei Province 430071, China
| | - Jian-Ping Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan City, Hubei Province 430071, China,
| | - Jun Lin
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan City, Hubei Province 430071, China,
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Wu J, Qin W, Wang Y, Sadik A, Liu J, Wang Y, Song P, Wang X, Sun K, Zeng J, Wang L. SPDEF is overexpressed in gastric cancer and triggers cell proliferation by forming a positive regulation loop with FoxM1. J Cell Biochem 2018; 119:9042-9054. [PMID: 30076647 DOI: 10.1002/jcb.27161] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Accepted: 05/14/2018] [Indexed: 12/20/2022]
Abstract
The SAM-pointed domain-containing ETS transcription factor (SPDEF) is an epithelial-specific transcription factor of the E26 transformation-specific (ETS) family, which binds the target gene through the high-affinity sequence of GGAT. It is suggested that SPDEF targets the promoter activity of Forkhead Box M1 (FoxM1), which has been proven to be highly expressed in gastric cancer. We found that SPDEF was overexpressed both at the messenger RNA (mRNA) and at the protein level in human gastric cancer species. The gastric cancer cells transfected with the SPDEF expression plasmid or SPDEF small interfering RNA (siRNA) led to observations on the clone genetics assay that indicated the promotion or the inhibition of gastric cancer cell proliferation, respectively. Both mRNA and protein levels of FoxM1 were regulated by SPDEF in gastric cancer cells and FoxM1 was also overexpressed in the corresponding human gastric cancer species. The overexpression and inhibition of FoxM1 could upregulate and downregulate the mRNA and protein levels of SPDEF expression, respectively. The recovery experiments verified that the overexpression of FoxM1 could at least partially revert both the expression of SPDEF and the proliferation of the cell lines even with the siRNA inhibition of SPDEF. The result of the dual luciferase activity assay showed that SPDEF bound to the promoter of FoxM1 and activated it. FoxM1 might also bind to the promoter of SPDEF to affect its expression. The results were checked in vivo. In conclusion, SPDEF is overexpressed in gastric cancer, which can form a positive regulation loop with FoxM1 to promote gastric carcinogenesis.
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Affiliation(s)
- Jing Wu
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Wen Qin
- Department of Medical Administration, Shandong University Hospital, Shandong University, Jinan, China
| | - Ying Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Arsil Sadik
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Jilan Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Yangyang Wang
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Ping Song
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Xiaoyun Wang
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Kaiyue Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Jiping Zeng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Lixiang Wang
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
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Pan H, Zhu Y, Wei W, Shao S, Rui X. Transcription factor FoxM1 is the downstream target of c-Myc and contributes to the development of prostate cancer. World J Surg Oncol 2018; 16:59. [PMID: 29554906 PMCID: PMC5859725 DOI: 10.1186/s12957-018-1352-3] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 02/27/2018] [Indexed: 12/21/2022] Open
Abstract
Background Prostate cancer is a common malignancy and the second leading cause of cancer death in men. Elevated expression of the transcription factor FoxM1 and c-Myc has been identified in prostate cancer. However, the potential mechanism of elevated FoxM1 and c-Myc to the development of prostate cancer has not been identified. Methods In this report, the mRNA level of FoxM1 and c-Myc was detected in 30 prostate cancer and para-cancer tissues. Then, we detected the expression level of FoxM1 by real-time PCR and Western blot after disturbance of the expression level of c-Myc in PC-3 cells. Whether c-Myc could bind to FoxM1 promoter was identified by ChIP assay. Finally, the migratory, invasive, and proliferative abilities in FoxM1 overexpressing and silencing PC-3 cells were detected by wound healing, transwell assay, CCK-8 assays, and Ki-67 protein level. Results We found that the expression level of FoxM1 and c-Myc were both increased in prostate cancer samples compared with para-cancer samples. The expression level of FoxM1 was changed consistent with the protein level of c-Myc. ChIP assay detected the direct binding of c-Myc in FoxM1 gene promoter. Lastly, overexpression of FoxM1 increased the migratory, invasive, and proliferative abilities of PC-3 cells, and its downregulation significantly decreased the migratory, invasive, and proliferative abilities. Conclusions In conclusion, FoxM1 was significantly increased in prostate cancer samples, and it could regulate the proliferative and invasive ability of prostate cancer cells which might be a new target for prostate cancer. Besides, c-Myc could regulate the expression level of FoxM1 by directly binding to its gene promoter.
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Affiliation(s)
- Huafeng Pan
- Department of Urology, Ningbo No.2 Hospital, No.41 Xibei Street, Ningbo, 315010, Zhejiang Province, People's Republic of China
| | - Yudi Zhu
- Department of Urology, Ningbo No.2 Hospital, No.41 Xibei Street, Ningbo, 315010, Zhejiang Province, People's Republic of China
| | - Wei Wei
- Department of Urology, Ningbo No.2 Hospital, No.41 Xibei Street, Ningbo, 315010, Zhejiang Province, People's Republic of China
| | - Siliang Shao
- Department of Urology, Ningbo No.2 Hospital, No.41 Xibei Street, Ningbo, 315010, Zhejiang Province, People's Republic of China
| | - Xin Rui
- Department of Urology, Ningbo No.2 Hospital, No.41 Xibei Street, Ningbo, 315010, Zhejiang Province, People's Republic of China.
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Wang Y, Zeng J, Pan J, Geng X, Li L, Wu J, Song P, Wang Y, Liu J, Wang L. MiR-320a inhibits gastric carcinoma by targeting activity in the FoxM1-P27KIP1 axis. Oncotarget 2017; 7:29275-86. [PMID: 27086911 PMCID: PMC5045395 DOI: 10.18632/oncotarget.8676] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 03/18/2016] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) regulate tumorigenesis by inhibiting gene expression. In this study, we showed that miR-320a expression is decreased in human gastric cancer tissues and correlates inversely with expression of FoxM1, a key cell cycle regulator involved in gastric carcinoma. By contrast, the expression of P27KIP1, a downstream effector of FoxM1, correlates positively with miR-320a levels. Luciferase assays indicate that miR-320a suppresses FoxM1 expression, and in vitro recovery tests using FoxM1 siRNA indicate miR-320a inhibits gastric cancer cell proliferation by suppressing activity in the FoxM1-P27KIP1 axis. In vivo, nude mice injected with BGC-823 gastric cancer cells expressing a miR-320a inhibitor exhibit faster tumor growth than mice injected with control cells. Analysis of FoxM1 and P27KIP1 expression in tumor tissues indicates that miR-320a suppression increases the tumor growth by enhancing FoxM1-P27KIP1 signaling. These results thus reveal the crucial role played by miR-320a in limiting gastric carcinoma by directly targeting FoxM1- P27KIP1 axis.
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Affiliation(s)
- Yangyang Wang
- Department of Pharmacology, Shandong University School of Medicine, Jinan 250012, P.R.China
| | - Jiping Zeng
- Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, P.R. China
| | - Jianyong Pan
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, P.R. China
| | - Xue Geng
- Department of Pharmacology, Shandong University School of Medicine, Jinan 250012, P.R.China
| | - Lupeng Li
- Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, P.R. China
| | - Jing Wu
- Department of Pharmacology, Shandong University School of Medicine, Jinan 250012, P.R.China
| | - Ping Song
- Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, P.R. China
| | - Ying Wang
- Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, P.R. China
| | - Jilan Liu
- Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, P.R. China
| | - Lixiang Wang
- Department of Pharmacology, Shandong University School of Medicine, Jinan 250012, P.R.China
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Pratheeshkumar P, Divya SP, Parvathareddy SK, Alhoshani NM, Al-Badawi IA, Tulbah A, Al-Dayel F, Siraj AK, Al-Kuraya KS. FoxM1 and β-catenin predicts aggressiveness in Middle Eastern ovarian cancer and their co-targeting impairs the growth of ovarian cancer cells. Oncotarget 2017; 9:3590-3604. [PMID: 29423068 PMCID: PMC5790485 DOI: 10.18632/oncotarget.23338] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 11/26/2017] [Indexed: 01/12/2023] Open
Abstract
Epithelial ovarian cancer (EOC) is a highly lethal disease with poor prognosis especially in advanced stage tumor. Emerging evidence has reported that aberrant upregulation of FoxM1 and β-catenin are closely associated with aggressiveness of human cancer. However, interplay between these factors in the aggressiveness of EOC is not fully illustrated. In this study, we show that FoxM1 is frequently increased in Middle Eastern EOC and associated with high proliferative index (p = 0.0007) and high grade tumor (p = 0.0024). Interestingly, FoxM1 is significantly associated with elevated nuclear β-catenin and the concomitant increase of FoxM1 and β-catenin is associated with advanced stage of EOC by immunohistochemical analysis of 261 samples of Saudi patients with EOC. Functional analysis showed that β-catenin is a direct transcriptional target of FoxM1 in EOC cell lines. FoxM1 inhibition either by specific inhibitor, thiostrepton or siRNA suppressed β-catenin expression, whereas overexpression of FoxM1 increased nuclear β-catenin expression. We identified two FoxM1 binding sites in the β-catenin promoter that specifically bound to FoxM1 protein. Down-regulation of FoxM1 using thiostrepton induced apoptosis and inhibited cell migration/invasion in EOC cells. Moreover, co-inhibition of FoxM1 by thiostrepton and β-catenin by FH535 significantly and synergistically inhibited EOC cell growth in vitro and in vivo. Collectively, our findings confer that co-targeting FoxM1/β-catenin signaling cascade may be a promising molecular therapeutic choice in advanced EOC.
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Affiliation(s)
- Poyil Pratheeshkumar
- Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Sasidharan Padmaja Divya
- Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | | | - Norah M Alhoshani
- Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Ismail A Al-Badawi
- Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Asma Tulbah
- Department of Pathology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Fouad Al-Dayel
- Department of Pathology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Abdul K Siraj
- Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Khawla S Al-Kuraya
- Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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Inoue Y, Moriwaki K, Ueda Y, Takeuchi T, Higuchi K, Asahi M. Elevated O-GlcNAcylation stabilizes FOXM1 by its reduced degradation through GSK-3β inactivation in a human gastric carcinoma cell line, MKN45 cells. Biochem Biophys Res Commun 2017; 495:1681-1687. [PMID: 29196265 DOI: 10.1016/j.bbrc.2017.11.179] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 11/28/2017] [Indexed: 01/12/2023]
Abstract
O-GlcNAcylation is a dynamic post-translational modification of cytonuclear proteins for intracellular signaling. Elevated O-GlcNAcylation is a general feature of cancer and contributes to cancer progression, and recent studies indicate the contribution to increasing incidence of various types of cancer in diabetic patients. However, the role of O-GlcNAcylation in tumor progression is not fully elucidated. Forkhead box M1 (FOXM1), a master mitotic transcription factor, has been implicated in all major hallmarks of cancer, and is wildly expressed in solid tumors. Given that FOXM1 expression was reported to be elevated in gastric cancer, we examined the effect of high glucose or an inhibitor of O-GlcNAc hydrolase, Thiamet G (TMG), on FOXM1 protein expression in a human gastric cancer cell line, MKN45 cells, and confirmed that FOXM1 protein level and the cell proliferation were upregulated. To investigate the molecular mechanisms by which FOXM1 protein expression is regulated by O-GlcNAcylation, the effect of high glucose and TMG on FOXM1 ubiquitination was examined in MKN45 cells. As a result, the ubiquitination and degradation of FOXM1 protein were both suppressed by high glucose and TMG treatment. However, the O-GlcNAcylation was not detected on FOXM1 but not on GSK-3β. High glucose and TMG treatment increased phospho-serine 9 GSK-3β, an inactive form, and the degradation of FOXM1 protein was suppressed by treatment of GSK-3β inhibitors in MKN45 cells. Taken together, we suggest that high glucose and elevated O-GlcNAcylation stabilize FOXM1 protein by its reduced degradation via GSK-3β inactivation in MKN45 cells, suggesting that the higher risk of gastric cancer in diabetic patients could be partially due to O-GlcNAcylation-mediated FOXM1 stabilization.
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Affiliation(s)
- Yosuke Inoue
- Department of Internal Medicine II, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan
| | - Kazumasa Moriwaki
- Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan
| | - Yasuhiro Ueda
- Department of Internal Medicine II, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan
| | - Toshihisa Takeuchi
- Department of Internal Medicine II, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan
| | - Kazuhide Higuchi
- Department of Internal Medicine II, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan
| | - Michio Asahi
- Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan.
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Fang W, Qian J, Wu Q, Chen Y, Yu G. ADAM-17 expression is enhanced by FoxM1 and is a poor prognostic sign in gastric carcinoma. J Surg Res 2017; 220:223-233. [DOI: 10.1016/j.jss.2017.06.032] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 05/15/2017] [Accepted: 06/15/2017] [Indexed: 12/30/2022]
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Ma J, Qi G, Xu J, Ni H, Xu W, Ru G, Zhao Z, Xu W, He X. Overexpression of forkhead box M1 and urokinase-type plasminogen activator in gastric cancer is associated with cancer progression and poor prognosis. Oncol Lett 2017; 14:7288-7296. [PMID: 29344165 PMCID: PMC5754915 DOI: 10.3892/ol.2017.7136] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Accepted: 07/03/2017] [Indexed: 01/26/2023] Open
Abstract
Forkhead box M1 (FOXM1) and urokinase-type plasminogen activator (uPA) are overexpressed and associated with the pathogenesis of multiple types of human malignancy. The aims of the present study were to investigate FOXM1 and uPA expression levels in human gastric cancer using tissue microarray techniques; determining their association with clinicopathological characteristics as well as their prognostic value. Tissue microarray blocks, comprising 436 gastric cancer cases and 92 non-cancerous adjacent normal gastric tissues, were analyzed for FOXM1 and uPA protein expression levels using immunohistochemistry. The results were analyzed statistically in association with various clinicopathological characteristics and overall survival rates. FOXM1 and uPA were detected in 78.67 (343/436) and 83.26% (363/436) of cancer samples, respectively. FOXM1 and uPA were not expressed in the 92 normal gastric tissue samples. In gastric cancer, FOXM1 and uPA levels were associated with tumor size, depth of invasion, tumor-node-metastasis (TNM) stage, lymph node metastasis, vessel invasion and distant metastases. The overall survival rate was significantly decreased in patients expressing FOXM1 and uPA compared with FOXM1- and uPA-negative patients. Coxs multivariate analysis revealed that age, depth of invasion and expression levels of FOXM1 and uPA are independent predictors of survival in patients with gastric cancer. These results indicated that increased FOXM1 and uPA expression levels are associated with the invasive and metastatic processes in human gastric cancer, and inversely associated with patient prognosis. Therefore, FOXM1 and uPA may serve as novel prognostic markers independent of, but supplementing, the TNM staging system.
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Affiliation(s)
- Jie Ma
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Guangwei Qi
- Department of Pathology, Hangzhou Children's Hospital, Hangzhou, Zhejiang 310014, P.R. China
| | - Ji Xu
- Department of Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Haibing Ni
- Department of Surgery, Tongde Hospital of Zhejiang, Hangzhou, Zhejiang 310012, P.R. China
| | - Wulin Xu
- Department of Respiratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Guoqing Ru
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Zhongsheng Zhao
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Wenjuan Xu
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Xujun He
- Key Laboratory of Gastroenterology of Zhejiang, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
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Yao S, Fan LYN, Lam EWF. The FOXO3-FOXM1 axis: A key cancer drug target and a modulator of cancer drug resistance. Semin Cancer Biol 2017; 50:77-89. [PMID: 29180117 PMCID: PMC6565931 DOI: 10.1016/j.semcancer.2017.11.018] [Citation(s) in RCA: 167] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 10/30/2017] [Accepted: 11/23/2017] [Indexed: 12/11/2022]
Abstract
The FOXO3 and FOXM1 forkhead box transcription factors, functioning downstream of the essential PI3K-Akt, Ras-ERK and JNK/p38MAPK signalling cascades, are crucial for cell proliferation, differentiation, cell survival, senescence, DNA damage repair and cell cycle control. The development of resistance to both conventional and newly emerged molecularly targeted therapies is a major challenge confronting current cancer treatment in the clinic. Intriguingly, the mechanisms of resistance to ‘classical’ cytotoxic chemotherapeutics and to molecularly targeted therapies are invariably linked to deregulated signalling through the FOXO3 and FOXM1 transcription factors. This is owing to the involvement of FOXO3 and FOXM1 in the regulation of genes linked to crucial drug action-related cellular processes, including stem cell renewal, DNA repair, cell survival, drug efflux, and deregulated mitosis. A better understanding of the mechanisms regulating the FOXO3-FOXM1 axis, as well as their downstream transcriptional targets and functions, may render these proteins reliable and early diagnostic/prognostic factors as well as crucial therapeutic targets for cancer treatment and importantly, for overcoming chemotherapeutic drug resistance.
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Affiliation(s)
- Shang Yao
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
| | - Lavender Yuen-Nam Fan
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
| | - Eric Wing-Fai Lam
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
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Egawa M, Yoshida Y, Ogura S, Kurahashi T, Kizu T, Furuta K, Kamada Y, Chatani N, Hamano M, Kiso S, Hikita H, Tatsumi T, Eguchi H, Nagano H, Doki Y, Mori M, Takehara T. Increased expression of Forkhead box M1 transcription factor is associated with clinicopathological features and confers a poor prognosis in human hepatocellular carcinoma. Hepatol Res 2017; 47:1196-1205. [PMID: 28002884 DOI: 10.1111/hepr.12854] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Revised: 09/29/2016] [Accepted: 12/19/2016] [Indexed: 02/08/2023]
Abstract
AIM Forkhead Box M1 (FoxM1) is a proliferation-specific transcription factor. In this study, we aimed to elucidate the clinicopathological and prognostic values of FoxM1 expression in human hepatocellular carcinoma (HCC) and correlate FoxM1 expression with various etiologies of liver diseases. We also investigated its therapeutic value in HCC. METHODS We investigated the expression of FoxM1 in tumor tissues and adjacent non-tumor tissues of 79 Japanese HCC patients by quantitative real-time reverse transcription-polymerase chain reaction analysis. Depletion by siRNA or specific inhibition by siomycin A were also used to investigate the effect of FoxM1 inhibition on stem-like features of human HCC cells. RESULTS Quantitative real-time reverse transcription-polymerase chain reaction analysis showed that tumor tissues displayed an approximately 14-fold increase in FoxM1 expression compared with adjacent non-tumor tissues. Interestingly, the expression levels of FoxM1in tumor tissues did not depend on the etiology of liver disease. The expression of FoxM1 in tumor tissues was associated with serum α-fetoprotein level, maximum tumor size, histological grade, TNM staging, and portal involvement. Kaplan-Meier analysis indicated that the high FoxM1 expression (≥median) group had a poor prognosis compared with the low FoxM1 expression (<median) group. Using multivariate analysis, the expression of FoxM1 in tumor tissues was shown to be an independent prognostic factor that affected overall survival and disease-free survival. Furthermore, FoxM1 inhibition by siRNA or siomycin A reduced spheroid colony formation of HCC cells in vitro. CONCLUSION Our data suggest that FoxM1 might be a prognostic biomarker and a promising therapeutic target for HCC.
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Affiliation(s)
- Mayumi Egawa
- Department of Gastroenterology and Hepatology, Osaka, Japan
| | - Yuichi Yoshida
- Department of Gastroenterology and Hepatology, Osaka, Japan
| | - Satoshi Ogura
- Department of Gastroenterology and Hepatology, Osaka, Japan
| | | | - Takashi Kizu
- Department of Gastroenterology and Hepatology, Osaka, Japan
| | | | - Yoshihiro Kamada
- Department of Gastroenterology and Hepatology, Osaka, Japan.,Department of Molecular Biochemistry and Clinical Investigation, Osaka, Japan
| | | | - Mina Hamano
- Department of Gastroenterology and Hepatology, Osaka, Japan
| | - Shinichi Kiso
- Department of Gastroenterology and Hepatology, Osaka, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka, Japan
| | | | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Nagano
- Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
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Nandi D, Cheema PS, Jaiswal N, Nag A. FoxM1: Repurposing an oncogene as a biomarker. Semin Cancer Biol 2017; 52:74-84. [PMID: 28855104 DOI: 10.1016/j.semcancer.2017.08.009] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Revised: 08/08/2017] [Accepted: 08/23/2017] [Indexed: 12/16/2022]
Abstract
The past few decades have witnessed a tremendous progress in understanding the biology of cancer, which has led to more comprehensive approaches for global gene expression profiling and genome-wide analysis. This has helped to determine more sophisticated prognostic and predictive signature markers for the prompt diagnosis and precise screening of cancer patients. In the search for novel biomarkers, there has been increased interest in FoxM1, an extensively studied transcription factor that encompasses most of the hallmarks of malignancy. Considering the attractive potential of this multifarious oncogene, FoxM1 has emerged as an important molecule implicated in initiation, development and progression of cancer. Bolstered with the skill to maneuver the proliferation signals, FoxM1 bestows resistance to contemporary anti-cancer therapy as well. This review sheds light on the large body of literature that has accumulated in recent years that implies that FoxM1 neoplastic functions can be used as a novel predictive, prognostic and therapeutic marker for different cancers. This assessment also highlights the key features of FoxM1 that can be effectively harnessed to establish FoxM1 as a strong biomarker in diagnosis and treatment of cancer.
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Affiliation(s)
- Deeptashree Nandi
- Department of Biochemistry, University of Delhi South Campus, New Delhi, 110021, India
| | - Pradeep Singh Cheema
- Department of Biochemistry, University of Delhi South Campus, New Delhi, 110021, India
| | - Neha Jaiswal
- Department of Biochemistry, University of Delhi South Campus, New Delhi, 110021, India
| | - Alo Nag
- Department of Biochemistry, University of Delhi South Campus, New Delhi, 110021, India.
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40
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Xu MD, Wang Y, Weng W, Wei P, Qi P, Zhang Q, Tan C, Ni SJ, Dong L, Yang Y, Lin W, Xu Q, Huang D, Huang Z, Ma Y, Zhang W, Sheng W, Du X. A Positive Feedback Loop of lncRNA- PVT1 and FOXM1 Facilitates Gastric Cancer Growth and Invasion. Clin Cancer Res 2017; 23:2071-2080. [PMID: 27756785 DOI: 10.1158/1078-0432.ccr-16-0742] [Citation(s) in RCA: 204] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 09/16/2016] [Accepted: 09/20/2016] [Indexed: 02/07/2023]
Abstract
Purpose: The long, noncoding RNA (lncRNA) PVT1 is an important epigenetic regulator with a critical role in human tumors. Here, we aimed to investigate the clinical application and the potential molecular mechanisms of PVT1 in gastric cancer tumorigenesis and progression.Experimental Design: The expression level of PVT1 was determined by RT-qPCR analysis in 190 pairs of gastric cancer tissues and adjacent normal gastric mucosa tissues (ANT). The biologic functions of PVT1 were assessed by in vitro and in vivo functional experiments. RNA protein pull-down assays and LS/MS mass spectrometry analysis were performed to detect and identify the PVT1- interacting protein FOXM1. Protein-RNA immunoprecipitation assays were conducted to examine the interaction of FOXM1 and PVT1 Chromatin immunoprecipitation (ChIP) and luciferase analyses were utilized to identify the binding site of FOXM1 on the PVT1 promoter.Results: The lncRNA PVT1 was significantly upregulated in gastric cancer tissues compared with ANTs. High expression of PVT1 predicted poor prognosis in patients with gastric cancer. PVT1 enhanced gastric cancer cell proliferation and invasion in vitro and in vivoPVT1 directly bound FOXM1 protein and increased FOXM1 posttranslationally. Moreover, PVT1 is also a FOXM1-responsive lncRNA, and FOXM1 directly binds to the PVT1 promoter to activate its transcription. Finally, PVT1 fulfilled its oncogenic functions in a FOXM1-mediated manner.Conclusions: Our study suggests that PVT1 promotes tumor progression by interacting with FOXM1. PVT1 may be a valuable prognostic predictor for gastric cancer, and the positive feedback loop of PVT1-FOXM1 could be a therapeutic target in pharmacologic strategies. Clin Cancer Res; 23(8); 2071-80. ©2016 AACR.
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Affiliation(s)
- Mi-Die Xu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Yiqin Wang
- Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Weiwei Weng
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Ping Wei
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Peng Qi
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Qiongyan Zhang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Cong Tan
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Shu-Juan Ni
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Lei Dong
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Yusi Yang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Wanrun Lin
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Qinghua Xu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Hangzhou Canhelp Genomics Company Limited, Hangzhou, Zhejiang, China
| | - Dan Huang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Zhaohui Huang
- Wuxi Oncology Institute, the Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
| | - Yuqing Ma
- Department of Pathology, First Hospital Affiliated to Xinjiang Medical University, Urumqi, China
| | - Wei Zhang
- Department of Pathology, First Hospital Affiliated to Xinjiang Medical University, Urumqi, China
| | - Weiqi Sheng
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Xiang Du
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
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Tang H, Fan X, Xing J, Liu Z, Jiang B, Dou Y, Gorospe M, Wang W. NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation. Aging (Albany NY) 2016; 7:1143-58. [PMID: 26687548 PMCID: PMC4712338 DOI: 10.18632/aging.100860] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
A rise in the levels of the cyclin-dependent kinase (CDK) inhibitor p27KIP1 is important for the growth arrest of senescent cells, but the mechanisms responsible for this increase are poorly understood. Here, we show that the tRNA methyltransferase NSun2 represses the expression of p27 in replicative senescence. NSun2 methylated the 5′-untranslated region (UTR) of p27 mRNA at cytosine C64 in vitro and in cells, thereby repressing the translation of p27. During replicative senescence, increased p27 protein levels were accompanied by decreased NSun2 protein levels. Knockdown of NSun2 in human diploid fibroblasts (HDFs) elevated p27 levels and reduced the expression of CDK1 (encoded by CDK1 mRNA, a previously reported target of NSun2), which in turn further repressed cell proliferation and accelerated replicative senescence, while overexpression of NSun2 exerted the opposite effect. Ectopic overexpression of the p27 5′UTR fragment rescued the effect of NSun2 overexpression in lowering p27, increasing CDK1, promoting cell proliferation, and delaying replicative senescence. Our findings indicate that NSun2-mediated mRNA methylation regulates p27 and CDK1 levels during replicative senescence.
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Affiliation(s)
- Hao Tang
- Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Xiuqin Fan
- Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Junyue Xing
- Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Zhenyun Liu
- Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Bin Jiang
- Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Yali Dou
- Department of Pathology and Biological Chemistry, University of Michigan, Ann Arbor, MI 48105, USA
| | - Myriam Gorospe
- Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Wengong Wang
- Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
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Wang Y, Zeng J, Pan J, Geng X, Liu Y, Wu J, Song P, Wang Y, Jia J, Wang L. MicroRNA-200c is involved in proliferation of gastric cancer by directly repressing p27 Kip1. Biochem Biophys Rep 2016; 8:227-233. [PMID: 28955960 PMCID: PMC5613965 DOI: 10.1016/j.bbrep.2016.09.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 08/10/2016] [Accepted: 09/06/2016] [Indexed: 12/21/2022] Open
Abstract
P27Kip1, also known as Cyclin-dependent kinase inhibitor 1B, is an important check-point protein in the cell cycle. It has been identified that although as a tumor suppressor, P27Kip1 is expressed in different cancer cell types, which shows the therapeutic potential in tumor genesis. In this study, we examined the upstream regulatory mechanism of P27Kip1 at the microRNA (miRNA) level in gastric carcinogenesis. We used bioinformatics to predict that microRNA-200c (miR-200c) might be a direct upstream regulator of P27Kip1. It was also verified in gastric epithelial-derived cell lines that overexpression of miR-200c significantly inhibited the expression levels of P27Kip1, whereas knockdown of miR-200c promoted P27Kip1 expression in AGS and BGC-823 cells. Furthermore, we identified the direct binding of miR-200c on the P27Kip1 3′ -UTR sequence by luciferase assay. MiR-200c could enhance the colony formation of cells by repressing P27Kip1 expression. In addition, the negative correlation between P27Kip1 and miR-200c in human gastric cancer tissues and matched normal tissues further supported the tumor-promoting action of miR-200c in vivo. Our finding suggested that miR-200c directly regulates the expression of P27Kip1 and promotes cell growth in gastric cancer as an oncogene, which may provide new clues to treatment.
miR-200c is involved in the proliferation of gastric cancer cell lines. P27Kip1 is a direct downstream target of miR-200c. miR-200c is determined an oncogene in human gastric cancer tissue species.
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Affiliation(s)
- Yangyang Wang
- Department of Pharmocology, Shandong University School of Medicine, Jinan 250012, PR China
| | - Jiping Zeng
- Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, PR China
| | - Jianyong Pan
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, PR China
| | - Xue Geng
- Department of Pharmocology, Shandong University School of Medicine, Jinan 250012, PR China
| | - Yansong Liu
- Shandong Tumor's Hospital and Institute, Jinan 250117, PR China
| | - Jing Wu
- Department of Pharmocology, Shandong University School of Medicine, Jinan 250012, PR China
| | - Ping Song
- Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, PR China
| | - Ying Wang
- Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, PR China
| | - Jihui Jia
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, Shandong University School of Medicine, Jinan 250012, PR China
| | - Lixiang Wang
- Department of Pharmocology, Shandong University School of Medicine, Jinan 250012, PR China
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DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling. Oncogene 2016; 36:1404-1416. [PMID: 27593933 PMCID: PMC5348575 DOI: 10.1038/onc.2016.307] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 07/11/2016] [Accepted: 07/25/2016] [Indexed: 12/26/2022]
Abstract
Recent evidence from a comprehensive genome analysis and functional studies have revealed that FOXM1 is a crucial metastatic regulator that drives cancer progression. However, the regulatory mechanism by which FOXM1 exerts its metastatic functions in cancer cells remains obscure. Here, we report that DLX1 acts as a FOXM1 downstream target, exerting pro-metastatic function in ovarian cancers. Both FOXM1 isoforms (FOXM1B or FOXM1C) could transcriptionally upregulate DLX1 through two conserved binding sites, located at +61 to +69bp downstream (TFBS1) and −675 to −667bp upstream (TFBS2) of the DLX1 promoter, respectively. This regulation was further accentuated by the significant correlation between the nuclear expression of FOXM1 and DLX1 in high-grade serous ovarian cancers. Functionally, the ectopic expression of DLX1 promoted ovarian cancer cell growth, cell migration/invasion and intraperitoneal dissemination of ovarian cancer in mice, whereas small interfering RNA-mediated DLX1 knockdown in FOXM1-overexpressing ovarian cancer cells abrogated these oncogenic capacities. In contrast, depletion of FOXM1 by shRNAi only partially attenuated tumor growth and exerted almost no effect on cell migration/invasion and the intraperitoneal dissemination of DLX1-overexpressing ovarian cancer cells. Furthermore, the mechanistic studies showed that DLX1 positively modulates transforming growth factor-β (TGF-β) signaling by upregulating PAI-1 and JUNB through direct interaction with SMAD4 in the nucleus upon TGF-β1 induction. Taken together, these data strongly suggest that DLX1 has a pivotal role in FOXM1 signaling to promote cancer aggressiveness through intensifying TGF-β/SMAD4 signaling in high-grade serous ovarian cancer cells.
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Cancer-Specific Telomerase Reverse Transcriptase (TERT) Promoter Mutations: Biological and Clinical Implications. Genes (Basel) 2016; 7:genes7070038. [PMID: 27438857 PMCID: PMC4962008 DOI: 10.3390/genes7070038] [Citation(s) in RCA: 105] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 07/05/2016] [Accepted: 07/11/2016] [Indexed: 12/11/2022] Open
Abstract
The accumulated evidence has pointed to a key role of telomerase in carcinogenesis. As a RNA-dependent DNA polymerase, telomerase synthesizes telomeric DNA at the end of linear chromosomes, and attenuates or prevents telomere erosion associated with cell divisions. By lengthening telomeres, telomerase extends cellular life-span or even induces immortalization. Consistent with its functional activity, telomerase is silent in most human normal somatic cells while active only in germ-line, stem and other highly proliferative cells. In contrast, telomerase activation widely occurs in human cancer and the enzymatic activity is detectable in up to 90% of malignancies. Recently, hotspot point mutations in the regulatory region of the telomerase reverse transcriptase (TERT) gene, encoding the core catalytic component of telomerase, was identified as a novel mechanism to activate telomerase in cancer. This review discusses the cancer-specific TERT promoter mutations and potential biological and clinical significances.
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Cao X, Ren K, Song Z, Li D, Quan M, Zheng Y, Cao J, Zeng W, Zou H. 7-Difluoromethoxyl-5,4′-di-n-octyl genistein inhibits the stem-like characteristics of gastric cancer stem-like cells and reverses the phenotype of epithelial-mesenchymal transition in gastric cancer cells. Oncol Rep 2016; 36:1157-65. [DOI: 10.3892/or.2016.4848] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 03/02/2016] [Indexed: 11/06/2022] Open
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Francica P, Nisa L, Aebersold DM, Langer R, Bladt F, Blaukat A, Stroka D, Martínez MR, Zimmer Y, Medová M. Depletion of FOXM1 via MET Targeting Underlies Establishment of a DNA Damage-Induced Senescence Program in Gastric Cancer. Clin Cancer Res 2016; 22:5322-5336. [PMID: 27185371 DOI: 10.1158/1078-0432.ccr-15-2987] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 04/20/2016] [Indexed: 11/16/2022]
Abstract
PURPOSE Deregulated signaling via the MET receptor tyrosine kinase is abundant in gastric tumors, with up to 80% of cases displaying aberrant MET expression. A growing body of evidence suggests MET as a potential target for tumor radiosensitization. EXPERIMENTAL DESIGN Cellular proliferation and DNA damage-induced senescence were studied in a panel of MET-overexpressing human gastric cancer cell lines as well as in xenograft models after MET inhibition and/or ionizing radiation. Pathways activation and protein expression were assessed by immunoblotting and immunohistochemistry. Tumor tissue microarrays (91 gastric cancer patients) were generated and copy number alteration (178 patients) and gene expression (373 patients) data available at The Cancer Genome Atlas were analyzed to assess the coalterations of MET and FOXM1. RESULTS MET targeting administered before ionizing radiation instigates DNA damage-induced senescence (∼80%, P < 0.001) rather than cell death. MET inhibition-associated senescence is linked to the blockade of MAPK pathway, correlates with downregulation of FOXM1, and can be abrogated (11.8% vs. 95.3%, P < 0.001) by ectopic expression of FOXM1 in the corresponding gastric tumor cells. Cells with ectopic FOXM1 expression demonstrate considerable (∼20%, P < 0.001) growth advantage despite MET targeting, suggesting a novel clinically relevant resistance mechanism to MET inhibition as the copresence of both MET and FOXM1 protein (33%) and mRNA (30%) overexpression as well as gene amplification (24,7%) are common in patients with gastric cancer. CONCLUSIONS FOXM1, a negative regulator of senescence, has been identified as a key downstream effector and potential clinical biomarker that mediates MET signaling following infliction of DNA damage in gastric tumors. Clin Cancer Res; 22(21); 5322-36. ©2016 AACR.
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Affiliation(s)
- Paola Francica
- Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.,Department of Clinical Research, University of Bern, Bern, Switzerland
| | - Lluís Nisa
- Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.,Department of Clinical Research, University of Bern, Bern, Switzerland
| | - Daniel M Aebersold
- Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.,Department of Clinical Research, University of Bern, Bern, Switzerland
| | - Rupert Langer
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Friedhelm Bladt
- Merck Serono Research & Development, Merck KGaA, Darmstadt, Germany
| | - Andree Blaukat
- Merck Serono Research & Development, Merck KGaA, Darmstadt, Germany
| | - Deborah Stroka
- Department of Clinical Research, University of Bern, Bern, Switzerland.,Department of Visceral Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | | | - Yitzhak Zimmer
- Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.,Department of Clinical Research, University of Bern, Bern, Switzerland
| | - Michaela Medová
- Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland. .,Department of Clinical Research, University of Bern, Bern, Switzerland
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FoxM1 promotes breast tumorigenesis by activating PDGF-A and forming a positive feedback loop with the PDGF/AKT signaling pathway. Oncotarget 2016; 6:11281-94. [PMID: 25869208 PMCID: PMC4484456 DOI: 10.18632/oncotarget.3596] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 02/20/2015] [Indexed: 11/25/2022] Open
Abstract
The autocrine platelet-derived growth factor (PDGF)/PDGF receptor (PDGFR) signaling pathway promotes breast cancer tumorigenesis, but the mechanisms for its dysregulation in breast cancer are largely unknown. In the study, we identified PDGF-A as a novel transcriptional target of FoxM1. FoxM1 directly binds to two sites in the promoter of PDGF-A and activates its transcription. Mutation of these FoxM1-binding sites diminished PDGF-A promoter activity. Increased FoxM1 resulted in the upregulation of PDGF-A, which led to activation of the AKT pathway and increased breast cancer cell proliferation and tumorigenesis, whereas knockdown of FoxM1 does the opposite. Blocking AKT activation with a phosphoinositide 3-kinase/AKT inhibitor decreased FoxM1-induced cell proliferation. Moreover, PDGF/AKT pathway upregulates the expression of FoxM1 in breast cancer cells. Knockdown of PDGF-A or blockade of AKT activation inhibited the expression of FoxM1 in breast cancer cells. Furthermore, expression of FoxM1 significantly correlated with the expression of PDGF-A and the activated AKT signaling pathway in human breast cancer specimens. Our study demonstrates a novel positive regulatory feedback loop between FoxM1 and the PDGF/AKT signaling pathway; this loop contributes to breast cancer cell growth and tumorigenesis.
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48
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miR-34a induces cellular senescence via modulation of telomerase activity in human hepatocellular carcinoma by targeting FoxM1/c-Myc pathway. Oncotarget 2016; 6:3988-4004. [PMID: 25686834 PMCID: PMC4414168 DOI: 10.18632/oncotarget.2905] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Accepted: 12/11/2014] [Indexed: 12/21/2022] Open
Abstract
Increasing evidence suggests that miRNAs can act as either tumor suppressors or oncogenes in carcinogenesis. In the present study, we identified the role of miR-34a in regulating telomerase activity, with subsequent effect on cellular senescence and viability. We found the higher expression of miR-34a was significantly correlated with the advanced clinicopathologic parameters in hepatocellular carcinoma. Furthermore, tumor tissues of 75 HCC patients demonstrated an inverse correlation between the miR-34a level and telomere indices (telomere length and telomerase activity). Transient introduction of miR-34a into HCC cell lines inhibited the telomerase activity and telomere length, which induced senescence-like phenotypes and affected cellular viability. We discovered that miR-34a potently targeted c-Myc and FoxM1, both of which were involved in the activation of telomerase reverse transcriptase (hTERT) transcription, essential for the sustaining activity of telomerase to avoid senescence. Taken together, our results demonstrate that miR-34a functions as a potent tumor suppressor through the modulation of telomere pathway in cellular senescence.
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Dibb M, Han N, Choudhury J, Hayes S, Valentine H, West C, Sharrocks AD, Ang YS. FOXM1 and polo-like kinase 1 are co-ordinately overexpressed in patients with gastric adenocarcinomas. BMC Res Notes 2015; 8:676. [PMID: 26576650 PMCID: PMC4650505 DOI: 10.1186/s13104-015-1658-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 11/02/2015] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Gastric cancers present late in life with advanced disease and carry a poor prognosis. Polo-like Kinase 1 (PLK1) is a mitotic kinase with regulatory functions during G2/M and mitosis in the cell cycle. In mammalian cells, there is an intricate co-regulatory relationship between PLK1 and the forkhead transcription factor FOXM1. It has been demonstrated that individually either PLK1 or FOXM1 expression predicts poorer survival. However, the co-expression of both of these markers in gastric adenocarcinomas has not been reported previously. METHODS We aimed to assess the expression of PLK1 and FOXM1 in Gastric adenocarcinomas in a Western Population, to examine whether there is a relationship of PLK1 to FOXM1 in cancer samples. We assess both the protein and mRNA expression in this patient population by Tissue Microarray immunohistochemistry and RT-PCR. RESULTS Immunohistochemistry was performed on biopsy samples from 79 patients with gastric cancer. Paired normal controls were available in 47 patients. FOXM1 expression was significantly associated with gastric adenocarcinoma (p = 0.001). PLK1 and FOXM1 co-expression was demonstrated in 6/8 (75 %) tumours when analysed by RT-PCR. FOXM1 is overexpressed in a large proportion of gastric carcinomas at the protein level and FOXM1 and PLK1 are concomitantly overexpressed at the mRNA level in this cancer type. CONCLUSIONS This study has demonstrated that FOXM1 and its target gene PLK1 are coordinately overexpressed in a proportion of gastric adenocarcinomas. This suggests that chemotherapeutic treatments that target this pathway may be of clinical utility.
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Affiliation(s)
- M Dibb
- Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
- Faculty of Medical and Human Sciences, University of Manchester, Oxford Road, Manchester, UK.
| | - N Han
- Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
| | - J Choudhury
- Department of Histopathology, Salford Royal Foundation Trust, Stott Lane, Salford, M6 8HD, UK.
| | - S Hayes
- Faculty of Medical and Human Sciences, University of Manchester, Oxford Road, Manchester, UK.
- Department of Histopathology, Salford Royal Foundation Trust, Stott Lane, Salford, M6 8HD, UK.
| | - H Valentine
- School of Cancer and Enabling Sciences, Christie Hospital, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
| | - C West
- School of Cancer and Enabling Sciences, Christie Hospital, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
| | - A D Sharrocks
- Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
| | - Yeng S Ang
- Faculty of Medical and Human Sciences, University of Manchester, Oxford Road, Manchester, UK.
- GI Science Centre, Salford Royal NHS FT, University of Manchester, Stott Lane, Salford, M6 8HD, UK.
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Prognostic Value of FOXM1 in Patients with Malignant Solid Tumor: A Meta-Analysis and System Review. DISEASE MARKERS 2015; 2015:352478. [PMID: 26451068 PMCID: PMC4584221 DOI: 10.1155/2015/352478] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 06/23/2015] [Indexed: 01/18/2023]
Abstract
Forkhead box M1 (FOXM1), a member of the Fox transcription factors family, was closely related with cell cycle. FOXM1 played an important role in MST and prompted a poor prognosis for MST patients. However, there were also some studies revealing no significant association between the FOXM1 expression and prognosis of patients. Therefore, we conducted meta-analysis to investigate whether the expression of FOXM1 was associated with MST prognosis. We collected 36 relevant studies through PubMed database and obtained research data of 4946 patients. Stata 12.0 was used to express the results as hazard ratio (HR) for time-to-event outcomes with 95% confidence intervals (95% CI). It was shown that overexpression of FOXM1 was relevant to worse survival of MST patients (HR = 1.99, 95% CI = 1.79–2.21, P < 0.001; I2 = 26.4%, Ph = 0.076). Subgroup analysis suggested that overexpression of FOXM1 in breast cancer (BC), gastric cancer (GC), hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDA), and non-small-cell lung cancer (NSCLC) all predicted a worse survival (P < 0.05), in addition to ovarian cancer (OC) (P = 0.084). In conclusion, our research indicated that overexpression of FOXM1 was to the disadvantage of the prognosis for majority of MST and therefore can be used as an evaluation index of prognosis.
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