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Liu Z, Han J, Su S, Zeng Q, Wu Z, Yuan J, Yang J. Histone lactylation facilitates MCM7 expression to maintain stemness and radio-resistance in hepatocellular carcinoma. Biochem Pharmacol 2025; 236:116887. [PMID: 40118288 DOI: 10.1016/j.bcp.2025.116887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 03/17/2025] [Accepted: 03/18/2025] [Indexed: 03/23/2025]
Abstract
Cancer stem cells (CSCs) play an essential role in tumor initiation and therapy resistance. Histone lactylation as a novel epigenetic modification could regulate the gene transcription process during tumor progression. Nevertheless, researches have not well examined its role in maintaining CSC properties. Our study identified Minichromosome maintenance complex component 7 (MCM7) as a candidate gene in Hepatocellular carcinoma (HCC) with diagnostic and prognostic values, and Real-time quantitative PCR (qRT-PCR), Western blot (WB), and Immunohistochemistry (IHC) assays ascertained its obviously higher expressions in HCC cells and tissues. Ectopic of MCM7 could increase the expression of CSC-related genes and enhance spheroid both in size and in number. Suppression of MCM7 could strengthen the efficacy of radiotherapy verified by Cell counting kit-8 (CCK-8) and colony formation assays. The subcutaneous xenograft model indicated that suppression of MCM7 could inhibit CSC properties and the efficacy of radiotherapy in vivo. Mechanistically, histone lactylation could facilitate MCM7 expression, and both messenger RNA (mRNA) and protein level of MCM7 expression presented an obvious decrease due to 2-DG (glycolysis inhibitor) treatment and an obvious increase due to Rotenone (glycolysis activator) treatment. Rescue experiments verified that histone lactylation was necessary for MCM7 to promote CSC properties and radio-resistance in HCC. Arsenic trioxide (ATO) targeting MCM7 could inhibit the CSC phenotypes and enhance the efficacy of radiotherapy in vivo and in vitro. Collectively, histone lactylation could transcriptionally activate MCM7 to accelerate proliferation and radio-resistance through enhancing CSC properties. ATO targeting MCM7 could inhibit CSCs phenotypes and synergistically increase the efficacy of radiation therapy.
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Affiliation(s)
- Zijian Liu
- Laboratory of Liquid Biopsy and Single Cell Research, Department of Radiation Oncology and Department of Head and Neck Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jiaqi Han
- Laboratory of Liquid Biopsy and Single Cell Research, Department of Radiation Oncology and Department of Head and Neck Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Shitong Su
- Laboratory of Liquid Biopsy and Single Cell Research, Department of Radiation Oncology and Department of Head and Neck Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Qiwen Zeng
- Institute of Organ Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Zhenru Wu
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Jingsheng Yuan
- Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Institute of Organ Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
| | - Jian Yang
- Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Institute of Organ Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
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Panakkal N, Lekshmi A, Krishna KMJ, Saraswathy VV, Sujathan K. Expression of minichromosome maintenance proteins in the exfoliated cells supplement sputum cytology in the diagnosis of lung cancer. Cytojournal 2024; 21:81. [PMID: 39927285 PMCID: PMC11804862 DOI: 10.25259/cytojournal_115_2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 11/28/2024] [Indexed: 02/11/2025] Open
Abstract
Objective Sputum cytology is recognized as a straightforward and noninvasive way to diagnose lung cancer, although its clinical utility has not yet been investigated. The objective of the study was to detect and classify cancerous cells in sputum by examining their expression of minichromosome maintenance proteins (MCM2 and MCM7). In addition, the study attempted to evaluate these proteins' potential as biomarkers of lung cancer lesions and their relationships with clinicopathological characteristics. Material and Methods MCM2 and MCM7 expression in sputum samples was evaluated using immunocytochemistry in sputum cell blocks (n = 97), and their correlation with clinicopathological features was examined. Diagnostic performance was evaluated as a function of sensitivity and specificity. Results Immunoexpression of MCM2 and MCM7 was confined to the nuclei of malignant cells alone, suggesting its potential as a differential diagnostic marker. They showed significant correlations with tumor cytology (P < 0.001), while MCM7 alone exhibited a significant correlation with tumor stage (P = 0.014). The overexpression of these markers was notably pronounced in lung adenocarcinoma compared to other subtypes. In terms of characterizing malignant cells, MCM7 protein demonstrated the highest sensitivity at 92% with an area under the curve (AUC) of 0.961, whereas MCM2 had a sensitivity of 80% and AUC of 0.901. Conclusion This study presents the inaugural use of MCM7 immunocytochemistry on exfoliated cells in sputum samples, proposing that analyzing immunocytochemical markers in sputum could serve as a cost-effective approach for diagnosing lung cancer. Integrating these assessed markers into routine cytopathology laboratories could augment traditional morphological evaluations, thereby improving the sensitivity of sputum cytology.
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Affiliation(s)
- Neeraja Panakkal
- Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
- Manipal Academy of Higher Education, Manipal, Kerala, India
| | - Asha Lekshmi
- Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
| | | | | | - Kunjuraman Sujathan
- Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
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Fu W, Lin Y, Bai M, Yao J, Huang C, Gao L, Mi N, Ma H, Tian L, Yue P, Zhang Y, zhang J, Ren Y, Ding L, Dai L, Leung JW, Yuan J, Zhang W, Meng W. Beyond ribosomal function: RPS6 deficiency suppresses cholangiocarcinoma cell growth by disrupting alternative splicing. Acta Pharm Sin B 2024; 14:3931-3948. [PMID: 39309509 PMCID: PMC11413689 DOI: 10.1016/j.apsb.2024.06.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 05/05/2024] [Accepted: 05/23/2024] [Indexed: 09/25/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a bile duct malignancy with a dismal prognosis. This study systematically investigated the role of the ribosomal protein S6 (RPS6) gene, which is dependent in CCA. We found that RPS6 upregulation in CCA tissues was correlated with a poor prognosis. Functional investigations have shown that alterations in RPS6 expression, both gain- and loss-of function could affect the proliferation of CCA cells. In xenograft tumor models, RPS6 overexpression enhances tumorigenicity, whereas RPS6 silencing reduces it. Integration analysis using RNA-seq and proteomics elucidated downstream signaling pathways of RPS6 depletion by affecting the cell cycle, especially DNA replication. Immunoprecipitation followed by mass spectrometry has identified numerous spliceosome complex proteins associated with RPS6. Transcriptomic profiling revealed that RPS6 affects numerous alternative splicing (AS) events, and combined with RNA immunoprecipitation sequencing, revealed that minichromosome maintenance complex component 7 (MCM7) binds to RPS6, which regulates its AS and increases oncogenic activity in CCA. Targeting RPS6 with vivo phosphorodiamidate morpholino oligomer (V-PMO) significantly inhibited the growth of CCA cells, patient-derived organoids, and subcutaneous xenograft tumor. Taken together, the data demonstrate that RPS6 is an oncogenic regulator in CCA and that RPS6-V-PMO could be repositioned as a promising strategy for treating CCA.
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Affiliation(s)
- Wenkang Fu
- The First School of Clinical Medicne, Lanzhou University, Lanzhou 730030, China
| | - Yanyan Lin
- Department of General Surgery, the First Hospital of Lanzhou University, Lanzhou 730030, China
| | - Mingzhen Bai
- The First School of Clinical Medicne, Lanzhou University, Lanzhou 730030, China
| | - Jia Yao
- The First School of Clinical Medicne, Lanzhou University, Lanzhou 730030, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, the First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Chongfei Huang
- The First School of Clinical Medicne, Lanzhou University, Lanzhou 730030, China
| | - Long Gao
- The First School of Clinical Medicne, Lanzhou University, Lanzhou 730030, China
| | - Ningning Mi
- The First School of Clinical Medicne, Lanzhou University, Lanzhou 730030, China
| | - Haidong Ma
- The First School of Clinical Medicne, Lanzhou University, Lanzhou 730030, China
| | - Liang Tian
- The First School of Clinical Medicne, Lanzhou University, Lanzhou 730030, China
| | - Ping Yue
- Department of General Surgery, the First Hospital of Lanzhou University, Lanzhou 730030, China
| | - Yong Zhang
- Department of General Surgery, the First Hospital of Lanzhou University, Lanzhou 730030, China
| | - Jinduo zhang
- Department of General Surgery, the First Hospital of Lanzhou University, Lanzhou 730030, China
| | - Yanxian Ren
- Department of General Surgery, the First Hospital of Lanzhou University, Lanzhou 730030, China
| | - Liyun Ding
- School of Physical Science and Technology, Lanzhou University, Lanzhou 730000, China
| | - Lunzhi Dai
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Joseph W. Leung
- Division of Gastroenterology, UC Davis Medical Center and Sacramento VA Medical Center, Sacramento, CA 95817, USA
| | - Jinqiu Yuan
- Clinical Research Center, Big Data Center, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China
| | - Wenhua Zhang
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China
| | - Wenbo Meng
- The First School of Clinical Medicne, Lanzhou University, Lanzhou 730030, China
- Department of General Surgery, the First Hospital of Lanzhou University, Lanzhou 730030, China
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Lashen AG, Toss MS, Rutland CS, Green AR, Mongan NP, Rakha E. Prognostic and Clinical Significance of the Proliferation Marker MCM7 in Breast Cancer. Pathobiology 2024; 92:18-27. [PMID: 39191229 PMCID: PMC11797933 DOI: 10.1159/000540790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 08/05/2024] [Indexed: 08/29/2024] Open
Abstract
INTRODUCTION Minichromosome maintenance complex component 7 (MCM7) plays an essential role in proliferation and DNA replication of cancer cells. However, the expression and prognostic significance of MCM7 in breast cancer (BC) remain to be defined. In this study, we aimed to evaluate the role of MCM7 in BC. METHODS We conducted immunohistochemistry staining of MCM7 in 1,156 operable early-stage BC samples and assessed MCM7 at the transcriptomic levels using publicly available cohorts (n = 13,430). MCM7 expression was evaluated and correlated with clinicopathological parameters including Ki67 labelling index and patient outcome. RESULTS At the transcriptomic level, there was a significant association between high MCM7 mRNA levels and shorter patient survival in the whole cohort and in luminal BC class but not in the basal-like molecular subtype. High MCM7 protein expression was detected in 43% of patients and was significantly associated with parameters characteristic of aggressive tumour behaviour. MCM7 was independently associated with shorter survival, particularly in oestrogen receptor-positive (luminal) BC. MCM7 stratified luminal tumours with aggressive clinicopathological features into distinct prognostic groups. In endocrine therapy-treated BC patients, high MCM7 was associated with poor outcome, but such association disappeared with administration of adjuvant chemotherapy. Patients with high expression of Ki67 and MCM7 showed worst survival, while patients with double low expression BC showed the best outcome compared with single expression groups. CONCLUSION The current findings indicate that MCM7 expression has a prognostic value in BC and can be used to identify luminal BC patients who can benefit from adjuvant chemotherapy. INTRODUCTION Minichromosome maintenance complex component 7 (MCM7) plays an essential role in proliferation and DNA replication of cancer cells. However, the expression and prognostic significance of MCM7 in breast cancer (BC) remain to be defined. In this study, we aimed to evaluate the role of MCM7 in BC. METHODS We conducted immunohistochemistry staining of MCM7 in 1,156 operable early-stage BC samples and assessed MCM7 at the transcriptomic levels using publicly available cohorts (n = 13,430). MCM7 expression was evaluated and correlated with clinicopathological parameters including Ki67 labelling index and patient outcome. RESULTS At the transcriptomic level, there was a significant association between high MCM7 mRNA levels and shorter patient survival in the whole cohort and in luminal BC class but not in the basal-like molecular subtype. High MCM7 protein expression was detected in 43% of patients and was significantly associated with parameters characteristic of aggressive tumour behaviour. MCM7 was independently associated with shorter survival, particularly in oestrogen receptor-positive (luminal) BC. MCM7 stratified luminal tumours with aggressive clinicopathological features into distinct prognostic groups. In endocrine therapy-treated BC patients, high MCM7 was associated with poor outcome, but such association disappeared with administration of adjuvant chemotherapy. Patients with high expression of Ki67 and MCM7 showed worst survival, while patients with double low expression BC showed the best outcome compared with single expression groups. CONCLUSION The current findings indicate that MCM7 expression has a prognostic value in BC and can be used to identify luminal BC patients who can benefit from adjuvant chemotherapy.
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Affiliation(s)
- Ayat G Lashen
- Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK,
- Department of Pathology, Faculty of Medicine, Menoufia University, Shebeen El Kom, Egypt,
- Nottingham Breast Cancer Research Centre, University of Nottingham, Nottingham, UK,
| | - Michael S Toss
- Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK
- Nottingham Breast Cancer Research Centre, University of Nottingham, Nottingham, UK
- Department of Histopathology, Sheffield Teaching Hospitals NHS Foundation Trust Sheffield, Sheffield, UK
| | - Catrin S Rutland
- School of Veterinary Medicine and Sciences, University of Nottingham, Nottingham, UK
| | - Andrew R Green
- Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK
- Nottingham Breast Cancer Research Centre, University of Nottingham, Nottingham, UK
| | - Nigel P Mongan
- School of Veterinary Medicine and Sciences, University of Nottingham, Nottingham, UK
- Department of Pharmacology, Weill Cornell Medicine, New York, New York, USA
| | - Emad Rakha
- Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK
- Nottingham Breast Cancer Research Centre, University of Nottingham, Nottingham, UK
- Department of Pathology, Hamad Medical Corporation, Doha, Qatar
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Kader M, Yu YP, Liu S, Luo JH. Immuno-targeting the ectopic phosphorylation sites of PDGFRA generated by MAN2A1-FER fusion in HCC. Hepatol Commun 2024; 8:e0511. [PMID: 39082961 DOI: 10.1097/hc9.0000000000000511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 06/30/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND HCC is one of the most lethal cancers for humans. Mannosidase alpha class 2A member 1 (MAN2A1)-FER is one of the most frequent oncogenic fusion genes in HCC. In this report, we showed that MAN2A1-FER ectopically phosphorylated the extracellular domains of PDGFRA, MET, AXL, and N-cadherin. The ectopic phosphorylation of these transmembrane proteins led to the activation of their kinase activities and initiated the activation cascades of their downstream signaling molecules. METHODS A panel of mouse monoclonal antibodies was developed to recognize the ectopic phosphorylation sites of PDGFRA. RESULTS AND CONCLUSIONS The analyses showed that these antibodies bound to the specific phosphotyrosine epitopes in the extracellular domain of PDGFRA with high affinity and specificity. The treatment of MAN2A1-FER-positive cancer HUH7 with one of the antibodies called 2-3B-G8 led to the deactivation of cell growth signaling pathways and cell growth arrest while having minimal impact on HUH7ko cells where MAN2A1-FER expression was disrupted. The treatment of 2-3B-G8 antibody also led to a large number of cell deaths of MAN2A1-FER-positive cancer cells such as HUH7, HEPG2, SNU449, etc., while the same treatment had no impact on HUH7ko cells. When severe combined immunodeficiency mice xenografted with HEPG2 or HUH7 were treated with monomethyl auristatin E-conjugated 2-3B-G8 antibody, it slowed the progression of tumor growth, eliminated the metastasis, and reduced the mortality, in comparison with the controls. Targeting the cancer-specific ectopic phosphorylation sites of PDGFRA induced by MAN2A1-FER may hold promise as an effective treatment for liver cancer.
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Affiliation(s)
- Muhamuda Kader
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Yan-Ping Yu
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- High Throughput Genome Center, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Silvia Liu
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- High Throughput Genome Center, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Jian-Hua Luo
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- High Throughput Genome Center, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Yu YP, Liu S, Geller D, Luo JH. Serum Fusion Transcripts to Assess the Risk of Hepatocellular Carcinoma and the Impact of Cancer Treatment through Machine Learning. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:1262-1271. [PMID: 38537933 PMCID: PMC11220925 DOI: 10.1016/j.ajpath.2024.02.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 02/05/2024] [Accepted: 02/21/2024] [Indexed: 04/10/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the most fatal malignancies. Early diagnosis of HCC is crucial in reducing the risk for mortality. This study analyzed a panel of nine fusion transcripts in serum samples from 61 patients with HCC and 75 patients with non-HCC conditions, using TaqMan real-time quantitative RT-PCR. Seven of the nine fusions frequently detected in patients with HCC included: MAN2A1-FER (100%), SLC45A2-AMACR (62.3%), ZMPSTE24-ZMYM4 (62.3%), PTEN-NOLC1 (57.4%), CCNH-C5orf30 (55.7%), STAMBPL1-FAS (26.2%), and PCMTD1-SNTG1 (16.4%). Machine-learning models were constructed based on serum fusion-gene levels to predict HCC in the training cohort, using the leave-one-out cross-validation approach. One machine-learning model, called the four fusion genes logistic regression model (MAN2A1-FER≤40, CCNH-C5orf30≤38, SLC45A2-AMACR≤41, and PTEN-NOLC1≤40), produced accuracies of 91.5% and 83.3% in the training and testing cohorts, respectively. When serum α-fetal protein level was incorporated into the machine-learning model, a two fusion gene (MAN2A1-FER≤40, CCNH-C5orf30≤38) + α-fetal protein logistic regression model was found to generate an accuracy of 94.8% in the training cohort. The same model resulted in 95% accuracy in both the testing and combined cohorts. Cancer treatment was associated with reduced levels of most of the serum fusion transcripts. Serum fusion-gene machine-learning models may serve as important tools in screening for HCC and in monitoring the impact of HCC treatment.
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Affiliation(s)
- Yan-Ping Yu
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; High Throughput Genome Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Silvia Liu
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; High Throughput Genome Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - David Geller
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Jian-Hua Luo
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; High Throughput Genome Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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Kader M, Sun W, Ren BG, Yu YP, Tao J, Foley LM, Liu S, Monga SP, Luo JH. Therapeutic targeting at genome mutations of liver cancer by the insertion of HSV1 thymidine kinase through Cas9-mediated editing. Hepatol Commun 2024; 8:e0412. [PMID: 38497929 PMCID: PMC10948134 DOI: 10.1097/hc9.0000000000000412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 02/09/2024] [Indexed: 03/19/2024] Open
Abstract
BACKGROUND Liver cancer is one of the most lethal malignancies for humans. The treatment options for advanced-stage liver cancer remain limited. A new treatment is urgently needed to reduce the mortality of the disease. METHODS In this report, we developed a technology for mutation site insertion of a suicide gene (herpes simplex virus type 1- thymidine kinase) based on type II CRISPR RNA-guided endonuclease Cas9-mediated genome editing to treat liver cancers. RESULTS We applied the strategy to 3 different mutations: S45P mutation of catenin beta 1, chromosome breakpoint of solute carrier family 45 member 2-alpha-methylacyl-CoA racemase gene fusion, and V235G mutation of SAFB-like transcription modulator. The results showed that the herpes simplex virus type 1-thymidine kinase insertion rate at the S45P mutation site of catenin beta 1 reached 77.8%, while the insertion rates at the breakpoint of solute carrier family 45 member 2 - alpha-methylacyl-CoA racemase gene fusion were 95.1%-98.7%, and the insertion at V235G of SAFB-like transcription modulator was 51.4%. When these targeting reagents were applied to treat mouse spontaneous liver cancer induced by catenin beta 1S45P or solute carrier family 45 member 2-alpha-methylacyl-CoA racemase, the mice experienced reduced tumor burden and increased survival rate. Similar results were also obtained for the xenografted liver cancer model: Significant reduction of tumor volume, reduction of metastasis rate, and improved survival were found in mice treated with the targeting reagent, in comparison with the control-treated groups. CONCLUSIONS Our studies suggested that mutation targeting may hold promise as a versatile and effective approach to treating liver cancers.
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Affiliation(s)
- Muhamuda Kader
- Department of Pathology, University of Pittsburg School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Wei Sun
- Department of Pathology, University of Pittsburg School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Bao-Guo Ren
- Department of Pathology, University of Pittsburg School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Yan-Ping Yu
- Department of Pathology, University of Pittsburg School of Medicine, Pittsburgh, Pennsylvania, USA
- Pittsburgh Liver Research Center at Pittsburgh Liver Institute, Animal Imaging Center, University of Pittsburg School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Junyan Tao
- Department of Pathology, University of Pittsburg School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Lesley M. Foley
- University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Silvia Liu
- Department of Pathology, University of Pittsburg School of Medicine, Pittsburgh, Pennsylvania, USA
- Pittsburgh Liver Research Center at Pittsburgh Liver Institute, Animal Imaging Center, University of Pittsburg School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Satdarshan P. Monga
- Department of Pathology, University of Pittsburg School of Medicine, Pittsburgh, Pennsylvania, USA
- Pittsburgh Liver Research Center at Pittsburgh Liver Institute, Animal Imaging Center, University of Pittsburg School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Jian-Hua Luo
- Department of Pathology, University of Pittsburg School of Medicine, Pittsburgh, Pennsylvania, USA
- Pittsburgh Liver Research Center at Pittsburgh Liver Institute, Animal Imaging Center, University of Pittsburg School of Medicine, Pittsburgh, Pennsylvania, USA
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Tian Y, Zhou Y, Chen F, Qian S, Hu X, Zhang B, Liu Q. Research progress in MCM family: Focus on the tumor treatment resistance. Biomed Pharmacother 2024; 173:116408. [PMID: 38479176 DOI: 10.1016/j.biopha.2024.116408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 02/22/2024] [Accepted: 03/06/2024] [Indexed: 03/27/2024] Open
Abstract
Malignant tumors constitute a significant category of diseases posing a severe threat to human survival and health, thereby representing one of the most challenging and pressing issues in the field of biomedical research. Due to their malignant nature, which is characterized by a high potential for metastasis, rapid dissemination, and frequent recurrence, the prevailing approach in clinical oncology involves a comprehensive treatment strategy that combines surgery with radiotherapy, chemotherapy, targeted drug therapies, and other interventions. Treatment resistance remains a major obstacle in the comprehensive management of tumors, serving as a primary cause for the failure of integrated tumor therapies and a critical factor contributing to patient relapse and mortality. The Minichromosome Maintenance (MCM) protein family comprises functional proteins closely associated with the development of resistance in tumor therapy.The influence of MCMs manifests through various pathways, encompassing modulation of DNA replication, cell cycle regulation, and DNA damage repair mechanisms. Consequently, this leads to an enhanced tolerance of tumor cells to chemotherapy, targeted drugs, and radiation. Consequently, this review explores the specific roles of the MCM family in various cancer treatment strategies. Its objective is to enhance our comprehension of resistance mechanisms in tumor therapy, thereby presenting novel targets for clinical research aimed at overcoming resistance in cancer treatment. This bears substantial clinical relevance.
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Affiliation(s)
- Yuxuan Tian
- Department of Hepatobiliary and Intestinal Surgery of Hunan Cancer Hospital & the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, PR China; Department of Histology and Embryology, Basic School of Medicine Sciences, Central South University, Changsha, Hunan 410013, PR China
| | - Yanhong Zhou
- Cancer Research Institute, Basic School of Medicine Sciences, Central South University, Changsha, Hunan 410078, PR China
| | - Fuxin Chen
- Department of Histology and Embryology, Basic School of Medicine Sciences, Central South University, Changsha, Hunan 410013, PR China
| | - Siyi Qian
- Department of Histology and Embryology, Basic School of Medicine Sciences, Central South University, Changsha, Hunan 410013, PR China
| | - Xingming Hu
- The 1st Department of Thoracic Surgery of Hunan Cancer Hospital & the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, PR China
| | - Bin Zhang
- Department of Hepatobiliary and Intestinal Surgery of Hunan Cancer Hospital & the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, PR China; Department of Histology and Embryology, Basic School of Medicine Sciences, Central South University, Changsha, Hunan 410013, PR China.
| | - Qiang Liu
- Department of Hepatobiliary and Intestinal Surgery of Hunan Cancer Hospital & the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, PR China.
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Otmani K, Rouas R, Berehab M, Lewalle P. The regulatory mechanisms of oncomiRs in cancer. Biomed Pharmacother 2024; 171:116165. [PMID: 38237348 DOI: 10.1016/j.biopha.2024.116165] [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: 10/26/2023] [Revised: 01/10/2024] [Accepted: 01/11/2024] [Indexed: 02/08/2024] Open
Abstract
Cancer development is a complex process that primarily results from the combination of genetic alterations and the dysregulation of major signalling pathways due to interference with the epigenetic machinery. As major epigenetic regulators, miRNAs are central players in the control of many key tumour development factors. These miRNAs have been classified as oncogenic miRNAs (oncomiRs) when they target tumour suppressor genes and tumour suppressor miRNAs (TS miRNAs) when they inhibit oncogene protein expression. Most of the mechanisms that modulate oncomiR expression are linked to transcriptional or posttranscriptional regulation. However, non-transcriptional processes, such as gene amplification, have been described as alternative processes that are responsible for increasing oncomiR expression. The current review summarises the different mechanisms controlling the upregulation of oncomiR expression in cancer cells and the tumour microenvironment (TME). Detailed knowledge of the mechanism underlying the regulation of oncomiR expression in cancer may pave the way for understanding the critical role of oncomiRs in cancer development and progression.
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Affiliation(s)
- Khalid Otmani
- Hematology Laboratory, Hematology Department, Hôpital Universitaire de Bruxelles (H.U.B.) Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
| | - Redouane Rouas
- Hematology Laboratory, Hematology Department, Hôpital Universitaire de Bruxelles (H.U.B.) Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Mimoune Berehab
- Hematology Laboratory, Hematology Department, Hôpital Universitaire de Bruxelles (H.U.B.) Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Philippe Lewalle
- Hematology Laboratory, Hematology Department, Hôpital Universitaire de Bruxelles (H.U.B.) Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
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10
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Papadimitriou E, Chatzellis E, Dimitriadi A, Kaltsas GA, Theocharis S, Alexandraki KI. Prognostic Biomarkers in Pituitary Tumours: A Systematic Review. TOUCHREVIEWS IN ENDOCRINOLOGY 2023; 19:42-53. [PMID: 38187082 PMCID: PMC10769480 DOI: 10.17925/ee.2023.19.2.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 04/07/2023] [Indexed: 01/09/2024]
Abstract
Pituitary tumours (PTs) are the second most common intracranial tumour. Although the majority show benign behaviour, they may exert aggressive behaviour and can be resistant to treatment. The aim of this review is to report the recently identified biomarkers that might have possible prognostic value. Studies evaluating potentially prognostic biomarkers or a therapeutic target in invasive/recurrent PTs compared with either non-invasive or non-recurrent PTs or normal pituitaries are included in this review. In the 28 included studies, more than 911 PTs were evaluated. A systematic search identified the expression of a number of biomarkers that may be positively correlated with disease recurrence or invasion in PT, grouped according to role: (1) insensitivity to anti-growth signals: minichromosome maintenance protein 7; (2) evasion of the immune system: cyclooxygenase 2, arginase 1, programmed cell death protein 1 (PD-1)/programmed death ligand 2, cluster of differentiation (CD) 80/CD86; (3) sustained angiogenesis: endothelial cell-specific molecule, fibroblast growth factor receptor, matrix metalloproteinase 9, pituitary tumour transforming gene; (4) self-sufficiency in growth signals: epidermal growth factor receptor; and (5) tissue invasion: matrix metalloproteinase 9, fascin protein. Biomarkers with a negative correlation with disease recurrence or invasion include: (1) insensitivity to anti-growth signals: transforming growth factor β1, Smad proteins; (2) sustained angiogenesis: tissue inhibitor of metalloproteinase 1; (3) tissue invasion: Wnt inhibitory factor 1; and (4) miscellaneous: co-expression of glial fibrillary acidic protein and cytokeratin, and oestrogen receptors α36 and α66. PD-1/programmed cell death ligand 1 showed no clear association with invasion or recurrence, while cyclin A, cytotoxic T lymphocyte-associated protein 4, S100 protein, ephrin receptor, galectin-3 , neural cell adhesion molecule, protein tyrosine phosphatase 4A3 and steroidogenic factor 1 had no association with invasion or recurrence of PT. With the aim to develop a more personalized approach to the treatment of PT, and because of the limited number of molecular targets currently studied in the context of recurrent PT and invasion, a better understanding of the most relevant of these biomarkers by well-d esigned interventional studies will lead to a better understanding of the molecular profile of PT. This should also meet the increased need of treatable molecular targets.
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Affiliation(s)
- Eirini Papadimitriou
- First Department of Propaedeutic Medicine, Laiko Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Eleftherios Chatzellis
- Endocrinology Diabetes and Metabolism Department, 251 Hellenic Air Force and VA General Hospital, Athens, Greece
| | | | - Gregory A Kaltsas
- First Department of Propaedeutic Medicine, Laiko Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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11
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Li C, Zhang J, Bi Y. Unveiling the prognostic significance of SOX5 in esophageal squamous cell carcinoma: a comprehensive bioinformatic and experimental analysis. Aging (Albany NY) 2023; 15:7565-7582. [PMID: 37531195 PMCID: PMC10457070 DOI: 10.18632/aging.204924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 07/10/2023] [Indexed: 08/03/2023]
Abstract
BACKGROUND This study aimed to investigate the expression and prognostic significance of SOX5 in esophageal squamous cell carcinoma (ESCC). METHODS Gene Expression Omnibus (GEO) data were analyzed to assess SOX5 expression in ESCC and normal tissues. Survival analysis was performed to evaluate its prognostic significance. Pathway enrichment analysis was conducted to identify pathways associated with low SOX5 expression. Methylation status of CpG sites in ESCC cases was examined, and SOX5 expression was evaluated. Differential expression and ChIP-seq data analyses were used to identify genes significantly correlated with SOX5 and to obtain target genes. A protein-protein interaction (PPI) network was constructed using hub genes, and their association with immune cell infiltration was determined. In vitro ESCC cell experiments validated the findings. RESULTS SOX5 was significantly downregulated in ESCC samples compared to normal samples. Its downregulation was associated with shorter survival in ESCC patients. Pathway enrichment analysis revealed enrichment in regulated necrosis, NLRP3 inflammasome, formation of the cornified envelope, and PD-1 signaling. Methylation status of two CpG sites negatively correlated with SOX5 expression. Differential expression analysis identified 122 genes significantly correlated with SOX5, and 28 target genes were obtained from ChIP-seq analysis. Target genes were enriched in DNA replication, cell cycle, spindle, and ATPase activity. Five hub genes were identified, and the PPI network showed significant associations with immune cell infiltration. In vitro experiments confirmed SOX5 downregulation, upregulation of hub genes, and their functional effects on ESCC cell apoptosis and proliferation. CONCLUSIONS These findings enhance understanding of SOX5 in ESCC and potential therapeutic strategies.
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Affiliation(s)
- Chenglin Li
- Department of Cardiothoracic Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
- Department of Cardiothoracic Surgery, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian 223300, Jiangsu, China
| | - Jialing Zhang
- Department of Gastroenterology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huaian 223300, Jiangsu, China
| | - Yanwen Bi
- Department of Cardiothoracic Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
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12
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Kandhaya-Pillai R, Miro-Mur F, Alijotas-Reig J, Tchkonia T, Schwartz S, Kirkland JL, Oshima J. Key elements of cellular senescence involve transcriptional repression of mitotic and DNA repair genes through the p53-p16/RB-E2F-DREAM complex. Aging (Albany NY) 2023; 15:4012-4034. [PMID: 37219418 PMCID: PMC10258023 DOI: 10.18632/aging.204743] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 05/03/2023] [Indexed: 05/24/2023]
Abstract
Cellular senescence is a dynamic stress response process that contributes to aging. From initiation to maintenance, senescent cells continuously undergo complex molecular changes and develop an altered transcriptome. Understanding how the molecular architecture of these cells evolve to sustain their non-proliferative state will open new therapeutic avenues to alleviate or delay the consequences of aging. Seeking to understand these molecular changes, we studied the transcriptomic profiles of endothelial replication-induced senescence and senescence induced by the inflammatory cytokine, TNF-α. We previously reported gene expressional pattern, pathways, and the mechanisms associated with upregulated genes during TNF-α induced senescence. Here, we extend our work and find downregulated gene signatures of both replicative and TNF-α senescence were highly overlapped, involving the decreased expression of several genes associated with cell cycle regulation, DNA replication, recombination, repair, chromatin structure, cellular assembly, and organization. We identified multiple targets of p53/p16-RB-E2F-DREAM that are essential for proliferation, mitotic progression, resolving DNA damage, maintaining chromatin integrity, and DNA synthesis that were repressed in senescent cells. We show that repression of multiple target genes in the p53/p16-RB-E2F-DREAM pathway collectively contributes to the stability of the senescent arrest. Our findings show that the regulatory connection between DREAM and cellular senescence may play a potential role in the aging process.
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Affiliation(s)
- Renuka Kandhaya-Pillai
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA
- Systemic Autoimmune Diseases Research Unit, Vall d’Hebron Research Institute (VHIR), Barcelona 08035, Spain
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA
| | - Francesc Miro-Mur
- Systemic Autoimmune Diseases Research Unit, Vall d’Hebron Research Institute (VHIR), Barcelona 08035, Spain
| | - Jaume Alijotas-Reig
- Systemic Autoimmune Diseases Research Unit, Vall d’Hebron Research Institute (VHIR), Barcelona 08035, Spain
| | - Tamar Tchkonia
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA
- Department of Physiology, Mayo Clinic, Rochester, MN 55905, USA
| | - Simo Schwartz
- Drug Delivery and Targeting Group, Clinical Biochemistry Department, Vall d’Hebron Hospital, Barcelona 08035, Spain
| | - James L. Kirkland
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA
- Department of Physiology, Mayo Clinic, Rochester, MN 55905, USA
- Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Junko Oshima
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA
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13
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The CMG helicase and cancer: a tumor "engine" and weakness with missing mutations. Oncogene 2023; 42:473-490. [PMID: 36522488 PMCID: PMC9948756 DOI: 10.1038/s41388-022-02572-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 12/01/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022]
Abstract
The replicative Cdc45-MCM-GINS (CMG) helicase is a large protein complex that functions in the DNA melting and unwinding steps as a component of replisomes during DNA replication in mammalian cells. Although the CMG performs this important role in cell growth, the CMG is not a simple bystander in cell cycle events. Components of the CMG, specifically the MCM precursors, are also involved in maintaining genomic stability by regulating DNA replication fork speeds, facilitating recovery from replicative stresses, and preventing consequential DNA damage. Given these important functions, MCM/CMG complexes are highly regulated by growth factors such as TGF-ß1 and by signaling factors such as Myc, Cyclin E, and the retinoblastoma protein. Mismanagement of MCM/CMG complexes when these signaling mediators are deregulated, and in the absence of the tumor suppressor protein p53, leads to increased genomic instability and is a contributor to tumorigenic transformation and tumor heterogeneity. The goal of this review is to provide insight into the mechanisms and dynamics by which the CMG is regulated during its assembly and activation in mammalian genomes, and how errors in CMG regulation due to oncogenic changes promote tumorigenesis. Finally, and most importantly, we highlight the emerging understanding of the CMG helicase as an exploitable vulnerability and novel target for therapeutic intervention in cancer.
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14
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Song H, Shen R, Mahasin H, Guo Y, Wang D. DNA replication: Mechanisms and therapeutic interventions for diseases. MedComm (Beijing) 2023; 4:e210. [PMID: 36776764 PMCID: PMC9899494 DOI: 10.1002/mco2.210] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 01/08/2023] [Accepted: 01/09/2023] [Indexed: 02/09/2023] Open
Abstract
Accurate and integral cellular DNA replication is modulated by multiple replication-associated proteins, which is fundamental to preserve genome stability. Furthermore, replication proteins cooperate with multiple DNA damage factors to deal with replication stress through mechanisms beyond their role in replication. Cancer cells with chronic replication stress exhibit aberrant DNA replication and DNA damage response, providing an exploitable therapeutic target in tumors. Numerous evidence has indicated that posttranslational modifications (PTMs) of replication proteins present distinct functions in DNA replication and respond to replication stress. In addition, abundant replication proteins are involved in tumorigenesis and development, which act as diagnostic and prognostic biomarkers in some tumors, implying these proteins act as therapeutic targets in clinical. Replication-target cancer therapy emerges as the times require. In this context, we outline the current investigation of the DNA replication mechanism, and simultaneously enumerate the aberrant expression of replication proteins as hallmark for various diseases, revealing their therapeutic potential for target therapy. Meanwhile, we also discuss current observations that the novel PTM of replication proteins in response to replication stress, which seems to be a promising strategy to eliminate diseases.
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Affiliation(s)
- Hao‐Yun Song
- School of Basic Medical SciencesLanzhou UniversityLanzhouGansuChina
| | - Rong Shen
- School of Basic Medical SciencesLanzhou UniversityLanzhouGansuChina
| | - Hamid Mahasin
- School of Basic Medical SciencesLanzhou UniversityLanzhouGansuChina
| | - Ya‐Nan Guo
- School of Basic Medical SciencesLanzhou UniversityLanzhouGansuChina
| | - De‐Gui Wang
- School of Basic Medical SciencesLanzhou UniversityLanzhouGansuChina
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15
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Samdani MN, Reza R, Morshed N, Asaduzzaman M, Islam ABMMK. Ligand-based modelling for screening natural compounds targeting Minichromosome Maintenance Complex Component-7 for potential anticancer effects. INFORMATICS IN MEDICINE UNLOCKED 2023. [DOI: 10.1016/j.imu.2022.101152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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16
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Jin S, Park JH, Yun HJ, Oh YN, Oh S, Choi YH, Kim BW, Kwon HJ. Cedrol, a Sesquiterpene Isolated from Juniperus chinensis, Inhibits Human Colorectal Tumor Growth associated through Downregulation of Minichromosome Maintenance Proteins. J Cancer Prev 2022; 27:221-228. [PMID: 36713942 PMCID: PMC9836914 DOI: 10.15430/jcp.2022.27.4.221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/18/2022] [Accepted: 12/27/2022] [Indexed: 01/11/2023] Open
Abstract
Cedrol, a sesquiterpene alcohol, isolated from Juniperus chinensis has been reported to inhibit minichromosome maintenance (MCM) proteins as cancer biomarkers in human lung cancer in vitro. In the present study, we investigated the anti-cancer activity of cedrol in vitro and in vivo using human colorectal cancer HT29 cells and a human colorectal tumor xenograft model. Cedrol inhibited MCM protein expression and cell growth in HT29 cells, which are associated with G1 arrest and the induction of apoptosis. We demonstrated that cedrol effectively reduced HT29 tumor growth without apparent weight loss in a human tumor xenograft model. Compared with vehicle- and adriamycin-treated tumor tissues, cedrol induced changes in the tumor tissue structure, resulting in a reduced cell density within the tumor parenchyma and reduced vascularization. Moreover, the expression of MCM7, an important subunit of MCM helicase, was significantly suppressed by cedrol in tumor tissue. Collectively, these results suggest that cedrol may act as a potential anti-cancer agent for colorectal cancer by inhibiting MCM protein expression and tumor growth.
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Affiliation(s)
- Soojung Jin
- Core-Facility Center for Tissue Regeneration, Dong-eui University, Busan, Korea
| | - Jung-ha Park
- Core-Facility Center for Tissue Regeneration, Dong-eui University, Busan, Korea,Biopharmaceutical Engineering Major, Division of Applied Bioengineering, College of Engineering, Dong-eui University, Busan, Korea,Department of Biopharmaceutics, Dong-eui University Graduate School, Busan, Korea
| | - Hee Jung Yun
- Biopharmaceutical Engineering Major, Division of Applied Bioengineering, College of Engineering, Dong-eui University, Busan, Korea,Department of Biopharmaceutics, Dong-eui University Graduate School, Busan, Korea
| | - You Na Oh
- Core-Facility Center for Tissue Regeneration, Dong-eui University, Busan, Korea
| | - Seunghye Oh
- Department of Biopharmaceutics, Dong-eui University Graduate School, Busan, Korea
| | - Yung Hyun Choi
- Core-Facility Center for Tissue Regeneration, Dong-eui University, Busan, Korea,Department of Biochemistry, College of Korean Medicine, Busan, Korea
| | - Byung Woo Kim
- Biopharmaceutical Engineering Major, Division of Applied Bioengineering, College of Engineering, Dong-eui University, Busan, Korea,Department of Biopharmaceutics, Dong-eui University Graduate School, Busan, Korea,Blue-Bio Industry Regional Innovation Center, Dong-eui University, Busan, Korea,Byung Woo Kim, E-mail: , https://orcid.org/0000-0001-7940-1074
| | - Hyun Ju Kwon
- Core-Facility Center for Tissue Regeneration, Dong-eui University, Busan, Korea,Biopharmaceutical Engineering Major, Division of Applied Bioengineering, College of Engineering, Dong-eui University, Busan, Korea,Department of Biopharmaceutics, Dong-eui University Graduate School, Busan, Korea,Blue-Bio Industry Regional Innovation Center, Dong-eui University, Busan, Korea,Correspondence to Hyun Ju Kwon, E-mail: , https://orcid.org/0000-0002-1375-0906
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17
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Jaitly P, Legrand M, Das A, Patel T, Chauvel M, Maufrais C, d’Enfert C, Sanyal K. A phylogenetically-restricted essential cell cycle progression factor in the human pathogen Candida albicans. Nat Commun 2022; 13:4256. [PMID: 35869076 PMCID: PMC9307598 DOI: 10.1038/s41467-022-31980-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 07/13/2022] [Indexed: 12/14/2022] Open
Abstract
Chromosomal instability caused by cell division errors is associated with antifungal drug resistance in fungal pathogens. Here, we identify potential mechanisms underlying such instability by conducting an overexpression screen monitoring chromosomal stability in the human fungal pathogen Candida albicans. Analysis of ~1000 genes uncovers six chromosomal stability (CSA) genes, five of which are related to cell division genes of other organisms. The sixth gene, CSA6, appears to be present only in species belonging to the CUG-Ser clade, which includes C. albicans and other human fungal pathogens. The protein encoded by CSA6 localizes to the spindle pole bodies, is required for exit from mitosis, and induces a checkpoint-dependent metaphase arrest upon overexpression. Thus, Csa6 is an essential cell cycle progression factor that is restricted to the CUG-Ser fungal clade, and could therefore be explored as a potential antifungal target. Chromosomal instability caused by cell division errors is associated with antifungal drug resistance in fungal pathogens. Here, Jaitly et al. identify several genes involved in chromosomal stability in Candida albicans, including a phylogenetically restricted gene encoding an essential cell-cycle progression factor.
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18
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Mo L, Su B, Xu L, Hu Z, Li H, Du H, Li J. MCM7 supports the stemness of bladder cancer stem-like cells by enhancing autophagic flux. iScience 2022; 25:105029. [PMID: 36111256 PMCID: PMC9468384 DOI: 10.1016/j.isci.2022.105029] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 07/07/2022] [Accepted: 08/23/2022] [Indexed: 11/15/2022] Open
Abstract
Autophagy plays critical roles in the pluripotent stemness of cancer stem cells (CSCs). However, how CSCs maintain the elevated autophagy to support stemness remains elusive. Here, we demonstrate that bladder cancer stem-like cells (BCSLCs) are at slow-cycling state with enhanced autophagy and mitophagy. In these slow-cycling BCSLCs, the DNA replication initiator MCM7 is required for autophagy and stemness. MCM7 knockdown inhibits autophagic flux and reduces the stemness of BCSLCs. MCM7 can facilitate autolysosome formation through binding with dynein to promote autophagic flux. The enhanced autophagy/mitophagy helps BCSLCs to maintain mitochondrial respiration, thus inhibiting AMPK activation. AMPK activation can trigger switch from autophagy to apoptosis, through increasing BCL2/BECLIN1 interaction and inducing P53 accumulation. In summary, we find that MCM7 can promote autophagic flux to support.
Enhancement of autophagy and mitophagy in bladder cancer stem-like cells (BCSLCs) The autophagy/mitophagy sustains BCSLCs stemness MCM7 facilitates autophagic flux to support BCSLCs stemness
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Affiliation(s)
- Lijun Mo
- Institute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, 1023 Sha Tai Road, Guangzhou, Guangdong 510515, China
- Department of Clinical Laboratory, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Bijia Su
- Institute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, 1023 Sha Tai Road, Guangzhou, Guangdong 510515, China
| | - Lili Xu
- Institute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, 1023 Sha Tai Road, Guangzhou, Guangdong 510515, China
| | - Zhiming Hu
- Institute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, 1023 Sha Tai Road, Guangzhou, Guangdong 510515, China
| | - Hongwei Li
- Institute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, 1023 Sha Tai Road, Guangzhou, Guangdong 510515, China
| | - Hongyan Du
- Institute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, 1023 Sha Tai Road, Guangzhou, Guangdong 510515, China
- Corresponding author
| | - Jinlong Li
- Institute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, 1023 Sha Tai Road, Guangzhou, Guangdong 510515, China
- Corresponding author
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19
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He L, Qian X, Ge P, Fan D, Ma X, Wu Q, Sun J, Yang L, Shen J, Xu L. NOL6 Regulates the Proliferation and Apoptosis of Gastric Cancer Cells via Regulating TP53I3, CDK4 and MCM7 Expression. Front Oncol 2022; 12:708081. [PMID: 35494047 PMCID: PMC9039204 DOI: 10.3389/fonc.2022.708081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 03/03/2022] [Indexed: 11/20/2022] Open
Abstract
Background Gastric cancer (GC) is a prevalent cancer with high mortality and strong invasiveness, and the entire regulatory networks of GC is still unclear. Objective The aim of this study was to explore the specific mechanism of the effect of nucleolar protein 6 (NOL6) on the proliferation and apoptosis of GC cells. Methods The human gastric adenocarcinoma cell line HGC-27 and AGS were cultured. qRT-PCR was used to verify the expression level of NOL6 in GC cells; MTT and EdU were used to test cell proliferation; TUNEL staining and Flow cytometry were used to detect cell apoptosis; The downstream genes and pathways following NOL6 knockdown were explored through the microarray assay and ingenuity pathway analysis, and the downstream genes were finally verified by qRT-PCR and Western blotting. The xenograft mice were used to investigate the effect of NOL6 on GC in vivo. Results TCGA data analysis showed that NOL6 expression level was higher in GC cells than adjacent normal cells. Over-expression of NOL6 increased proliferation and colony formation, and inhibited the apoptotic rate in AGS and HGC-27 cells, while NOL6 knockdown induced the opposite effects. Through microarray assay and IPA analysis, NOL6-related downstream genes and critical signaling pathways were found. And we verified the relationship between downstream genes and GC. Additionally, NOL6 knockdown could decrease the weight and volume of tumor in the mice. Conclusion NOL6 knockdown could inhibit cell proliferation and induce cell apoptosis of GC, suggesting that NOL6 may serve as a potential therapeutic target for treating GC.
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Affiliation(s)
- Lei He
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaohan Qian
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Pingping Ge
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dong Fan
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiang Ma
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qiong Wu
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jin Sun
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lihua Yang
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jian Shen
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lijian Xu
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
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20
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Sun S, Dammann J, Lai P, Tian C. Thorough statistical analyses of breast cancer co-methylation patterns. BMC Genom Data 2022; 23:29. [PMID: 35428183 PMCID: PMC9011975 DOI: 10.1186/s12863-022-01046-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 04/01/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Breast cancer is one of the most commonly diagnosed cancers. It is associated with DNA methylation, an epigenetic event with a methyl group added to a cytosine paired with a guanine, i.e., a CG site. The methylation levels of different genes in a genome are correlated in certain ways that affect gene functions. This correlation pattern is known as co-methylation. It is still not clear how different genes co-methylate in the whole genome of breast cancer samples. Previous studies are conducted using relatively small datasets (Illumina 27K data). In this study, we analyze much larger datasets (Illumina 450K data).
Results
Our key findings are summarized below. First, normal samples have more highly correlated, or co-methylated, CG pairs than tumor samples. Both tumor and normal samples have more than 93% positive co-methylation, but normal samples have significantly more negatively correlated CG sites than tumor samples (6.6% vs. 2.8%). Second, both tumor and normal samples have about 94% of co-methylated CG pairs on different chromosomes, but normal samples have 470 million more CG pairs. Highly co-methylated pairs on the same chromosome tend to be close to each other. Third, a small proportion of CG sites’ co-methylation patterns change dramatically from normal to tumor. The percentage of differentially methylated (DM) sites among them is larger than the overall DM rate. Fourth, certain CG sites are highly correlated with many CG sites. The top 100 of such super-connector CG sites in tumor and normal samples have no overlaps. Fifth, both highly changing sites and super-connector sites’ locations are significantly different from the genome-wide CG sites’ locations. Sixth, chromosome X co-methylation patterns are very different from other chromosomes. Finally, the network analyses of genes associated with several sets of co-methylated CG sites identified above show that tumor and normal samples have different patterns.
Conclusions
Our findings will provide researchers with a new understanding of co-methylation patterns in breast cancer. Our ability to thoroughly analyze co-methylation of large datasets will allow researchers to study relationships and associations between different genes in breast cancer.
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21
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Liu S, Nalesnik MA, Singhi A, Wood‐Trageser MA, Randhawa P, Ren B, Humar A, Liu P, Yu Y, Tseng GC, Michalopoulos G, Luo J. Transcriptome and Exome Analyses of Hepatocellular Carcinoma Reveal Patterns to Predict Cancer Recurrence in Liver Transplant Patients. Hepatol Commun 2022; 6:710-727. [PMID: 34725972 PMCID: PMC8948579 DOI: 10.1002/hep4.1846] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 10/06/2021] [Accepted: 10/10/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal human cancers. Liver transplantation has been an effective approach to treat liver cancer. However, significant numbers of patients with HCC experience cancer recurrence, and the selection of suitable candidates for liver transplant remains a challenge. We developed a model to predict the likelihood of HCC recurrence after liver transplantation based on transcriptome and whole-exome sequencing analyses. We used a training cohort and a subsequent testing cohort based on liver transplantation performed before or after the first half of 2012. We found that the combination of transcriptome and mutation pathway analyses using a random forest machine learning correctly predicted HCC recurrence in 86.8% of the training set. The same algorithm yielded a correct prediction of HCC recurrence of 76.9% in the testing set. When the cohorts were combined, the prediction rate reached 84.4% in the leave-one-out cross-validation analysis. When the transcriptome analysis was combined with Milan criteria using the k-top scoring pairs (k-TSP) method, the testing cohort prediction rate improved to 80.8%, whereas the training cohort and the combined cohort prediction rates were 79% and 84.4%, respectively. Application of the transcriptome/mutation pathways RF model on eight tumor nodules from 3 patients with HCC yielded 8/8 consistency, suggesting a robust prediction despite the heterogeneity of HCC. Conclusion: The genome prediction model may hold promise as an alternative in selecting patients with HCC for liver transplant.
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Affiliation(s)
- Silvia Liu
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Michael A. Nalesnik
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Aatur Singhi
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | | | - Parmjeet Randhawa
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Bao‐Guo Ren
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Abhinav Humar
- Department of SurgeryUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Peng Liu
- Department of BiostatisticsUniversity of Pittsburgh School of Public HealthPittsburghPAUSA
| | - Yan‐Ping Yu
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - George C. Tseng
- Department of BiostatisticsUniversity of Pittsburgh School of Public HealthPittsburghPAUSA
| | - George Michalopoulos
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Jian‐Hua Luo
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
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22
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Wang J, Xia D, Lin Y, Xu W, Wu Y, Chen J, Chu J, Shen P, Weng S, Wang X, Shen L, Fan S, Shen S. Oxidative stress-induced circKIF18A downregulation impairs MCM7-mediated anti-senescence in intervertebral disc degeneration. Exp Mol Med 2022; 54:285-297. [PMID: 35332256 PMCID: PMC8979962 DOI: 10.1038/s12276-022-00732-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 09/10/2021] [Accepted: 09/29/2021] [Indexed: 11/30/2022] Open
Abstract
Low back pain, triggered by intervertebral disc degeneration (IVDD), is one of the most common causes of disability and financial expenditure worldwide. However, except for surgical interventions, effective medical treatment to prevent the progression of IVDD is lacking. This study aimed to investigate the effects of circKIF18A, a novel circRNA, on IVDD progression and to explore its underlying mechanism in IVDD. In this study, we found that oxidative stress was positively correlated with nucleus pulposus cell (NPC) senescence in IVDD and that circKIF18A was downregulated in IVDD and attenuated senescent phenotypes such as cell cycle arrest and extracellular matrix degradation in NPCs. Mechanistically, circKIF18A competitively suppressed ubiquitin-mediated proteasomal degradation of MCM7, and the protective effects of circKIF18A on NPCs were partially mediated by MCM7 under oxidative stress. Intradiscal injection of adenoviral circKIF18A ameliorated IVDD in a rat model. This study revealed that circKIF18A regulates NPC degeneration by stabilizing MCM7 and identified a novel signaling pathway, the circKIF18A-MCM7 axis, for anti-senescence molecular therapy in IVDD. A non-coding circular RNA molecule that prevents spinal cells from undergoing premature ageing offers a new therapeutic target for treating intervertebral disc degeneration (IVDD), a major cause of lower back pain. Shuying Shen of Zhejiang University School of Medicine, China, and colleagues took samples from the soft, gelatinous central portion of the intervertebral disk, the so-called nucleus pulposus, and looked for circular RNAs with high expression levels in healthy individuals and low levels in people with IVDD. They identified a specific RNA in this way, and showed how this regulatory molecule promotes the activity of a protein involved in enhancing the proliferative capacity of nucleus pulposus tissues. In rats, injections of a gene therapy vector encoding this RNA helped ameliorate signs of IVDD, highlighting the potential for similar therapeutic strategies in people with IVDD.
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Affiliation(s)
- Jianle Wang
- Department of Orthopedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310020, Hangzhou, Zhejiang, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, 310020, Hangzhou, Zhejiang, China
| | - Dongdong Xia
- Department of Orthopedics, Ningbo First Hospital, 315010, Ningbo, Zhejiang, China
| | - Yan Lin
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 325088, Wenzhou, Zhejiang Province, China.,Key Laboratory of Orthopaedics of Zhejiang Province, 325088, Wenzhou, Zhejiang Province, China
| | - Wenbin Xu
- Department of Orthopedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310020, Hangzhou, Zhejiang, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, 310020, Hangzhou, Zhejiang, China
| | - Yaosen Wu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 325088, Wenzhou, Zhejiang Province, China.,Key Laboratory of Orthopaedics of Zhejiang Province, 325088, Wenzhou, Zhejiang Province, China
| | - Jiaoxiang Chen
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 325088, Wenzhou, Zhejiang Province, China.,Key Laboratory of Orthopaedics of Zhejiang Province, 325088, Wenzhou, Zhejiang Province, China
| | - Junjie Chu
- Department of Head and Neck Surgery, Institute of Micro-Invasive Surgery of Zhejiang University, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310020, Hangzhou, Zhejiang, China
| | - Panyang Shen
- Department of Orthopedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310020, Hangzhou, Zhejiang, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, 310020, Hangzhou, Zhejiang, China
| | - Sheji Weng
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 325088, Wenzhou, Zhejiang Province, China.,Key Laboratory of Orthopaedics of Zhejiang Province, 325088, Wenzhou, Zhejiang Province, China
| | - Xiangyang Wang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 325088, Wenzhou, Zhejiang Province, China. .,Key Laboratory of Orthopaedics of Zhejiang Province, 325088, Wenzhou, Zhejiang Province, China.
| | - Lifeng Shen
- Department of Orthopedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310020, Hangzhou, Zhejiang, China. .,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, 310020, Hangzhou, Zhejiang, China.
| | - Shunwu Fan
- Department of Orthopedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310020, Hangzhou, Zhejiang, China. .,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, 310020, Hangzhou, Zhejiang, China.
| | - Shuying Shen
- Department of Orthopedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310020, Hangzhou, Zhejiang, China. .,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, 310020, Hangzhou, Zhejiang, China.
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23
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Samad A, Huq MA, Rahman MS. Bioinformatics approaches identified dasatinib and bortezomib inhibit the activity of MCM7 protein as a potential treatment against human cancer. Sci Rep 2022; 12:1539. [PMID: 35087187 PMCID: PMC8795118 DOI: 10.1038/s41598-022-05621-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 01/14/2022] [Indexed: 12/17/2022] Open
Abstract
Minichromosome Maintenance Complex Component 7 (MCM7) is a key component of the DNA replication licensing factor and hexamer MCM (MCM2-7) complex that regulates the DNA replication process. The MCM7 protein is associated with tumor cell proliferation that plays an important role in different human cancer progression. As the protein is highly expressed during the cancer development process, therefore, inhibition of the protein can be utilized as a treatment option for different human cancer. However, the study aimed to identify potential small molecular drug candidates against the MCM7 protein that can utilize treatment options for human cancer. Initially, the compounds identified from protein-drugs network analysis have been retrieved from NetworkAnalyst v3.0 server and screened through molecular docking, MM-GBSA, DFT, pharmacokinetics, toxicity, and molecular dynamics (MD) simulation approach. Two compounds namely Dasatinib (CID_3062316) and Bortezomib (CID_387447) have been identified throughout the screening process, which have the highest negative binding affinity (Kcal/mol) and binding free energy (Kcal/mol). The pharmacokinetics and toxicity analysis identified drug-like properties and no toxicity properties of the compounds, where 500 ns MD simulation confirmed structural stability of the two compounds to the targeted proteins. Therefore, we can conclude that the compounds dasatinib and bortezomib can inhibit the activity of the MCM7 and can be developed as a treatment option against human cancer.
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Affiliation(s)
- Abdus Samad
- Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore, 7408, Bangladesh
- Bioinformatics and Microbial Biotechnology Laboratory, Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore, 7408, Bangladesh
| | - Md Amdadul Huq
- Department of Food and Nutrition, College of Biotechnology and Natural Resource, Chung-Ang University, Anseong, Gyeonggi-do, 17546, Republic of Korea.
| | - Md Shahedur Rahman
- Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore, 7408, Bangladesh.
- Bioinformatics and Microbial Biotechnology Laboratory, Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore, 7408, Bangladesh.
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24
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Zhao T, Chiang ZD, Morriss JW, LaFave LM, Murray EM, Del Priore I, Meli K, Lareau CA, Nadaf NM, Li J, Earl AS, Macosko EZ, Jacks T, Buenrostro JD, Chen F. Spatial genomics enables multi-modal study of clonal heterogeneity in tissues. Nature 2022; 601:85-91. [PMID: 34912115 PMCID: PMC9301586 DOI: 10.1038/s41586-021-04217-4] [Citation(s) in RCA: 154] [Impact Index Per Article: 51.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 11/08/2021] [Indexed: 12/29/2022]
Abstract
The state and behaviour of a cell can be influenced by both genetic and environmental factors. In particular, tumour progression is determined by underlying genetic aberrations1-4 as well as the makeup of the tumour microenvironment5,6. Quantifying the contributions of these factors requires new technologies that can accurately measure the spatial location of genomic sequence together with phenotypic readouts. Here we developed slide-DNA-seq, a method for capturing spatially resolved DNA sequences from intact tissue sections. We demonstrate that this method accurately preserves local tumour architecture and enables the de novo discovery of distinct tumour clones and their copy number alterations. We then apply slide-DNA-seq to a mouse model of metastasis and a primary human cancer, revealing that clonal populations are confined to distinct spatial regions. Moreover, through integration with spatial transcriptomics, we uncover distinct sets of genes that are associated with clone-specific genetic aberrations, the local tumour microenvironment, or both. Together, this multi-modal spatial genomics approach provides a versatile platform for quantifying how cell-intrinsic and cell-extrinsic factors contribute to gene expression, protein abundance and other cellular phenotypes.
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Affiliation(s)
- Tongtong Zhao
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Zachary D. Chiang
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA,Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Julia W. Morriss
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Lindsay M. LaFave
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA,Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA,David H. Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Evan M. Murray
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Isabella Del Priore
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA,David H. Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Kevin Meli
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA,David H. Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Caleb A. Lareau
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Naeem M. Nadaf
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Jilong Li
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Andrew S. Earl
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA,Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Evan Z. Macosko
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Tyler Jacks
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA,David H. Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Jason D. Buenrostro
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA,Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Correspondence and requests for materials should be addressed to or
| | - Fei Chen
- Broad Institute of MIT and Harvard, Cambridge, MA, USA. .,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. .,Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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25
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Zuo Z, Yu Y, Ren B, Liu S, Nelson J, Wang Z, Tao J, Pradhan‐Sundd T, Bhargava R, Michalopoulos G, Chen Q, Zhang J, Ma D, Pennathur A, Luketich J, Satdarshan Monga P, Nalesnik M, Luo J. Oncogenic Activity of Solute Carrier Family 45 Member 2 and Alpha-Methylacyl-Coenzyme A Racemase Gene Fusion Is Mediated by Mitogen-Activated Protein Kinase. Hepatol Commun 2022; 6:209-222. [PMID: 34505419 PMCID: PMC8710797 DOI: 10.1002/hep4.1724] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 02/23/2021] [Accepted: 02/28/2021] [Indexed: 11/09/2022] Open
Abstract
Chromosome rearrangement is one of the hallmarks of human malignancies. Gene fusion is one of the consequences of chromosome rearrangements. In this report, we show that gene fusion between solute carrier family 45 member 2 (SLC45A2) and alpha-methylacyl-coenzyme A racemase (AMACR) occurs in eight different types of human malignancies, with frequencies ranging from 45% to 97%. The chimeric protein is translocated to the lysosomal membrane and activates the extracellular signal-regulated kinase signaling cascade. The fusion protein promotes cell growth, accelerates migration, resists serum starvation-induced cell death, and is essential for cancer growth in mouse xenograft cancer models. Introduction of SLC45A2-AMACR into the mouse liver using a sleeping beauty transposon system and somatic knockout of phosphatase and TENsin homolog (Pten) generated spontaneous liver cancers within a short period. Conclusion: The gene fusion between SLC45A2 and AMACR may be a driving event for human liver cancer development.
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Affiliation(s)
- Ze‐Hua Zuo
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Yan‐Ping Yu
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
- Pittsburgh Liver Research Center of University of Pittsburgh Medical CenterPittsburghPAUSA
| | - Bao‐Guo Ren
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Silvia Liu
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
- Pittsburgh Liver Research Center of University of Pittsburgh Medical CenterPittsburghPAUSA
| | - Joel Nelson
- Department of UrologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Zhou Wang
- Department of UrologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Junyan Tao
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | | | - Rohit Bhargava
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - George Michalopoulos
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
- Pittsburgh Liver Research Center of University of Pittsburgh Medical CenterPittsburghPAUSA
| | - Qi Chen
- Department of PharmacologyToxicology, and TherapeuticsUniversity of KansasKansas CityKSUSA
| | - Jun Zhang
- Department of MedicineUniversity of IowaIowa CityIAUSA
- Present address:
Department of MedicineUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Deqin Ma
- Department of PathologyUniversity of IowaIowa CityIAUSA
| | - Arjun Pennathur
- Thoracic SurgeryUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - James Luketich
- Thoracic SurgeryUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Paul Satdarshan Monga
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
- Pittsburgh Liver Research Center of University of Pittsburgh Medical CenterPittsburghPAUSA
| | - Michael Nalesnik
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Jian‐Hua Luo
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
- Pittsburgh Liver Research Center of University of Pittsburgh Medical CenterPittsburghPAUSA
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26
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Ney A, Garcia-Sampedro A, Goodchild G, Acedo P, Fusai G, Pereira SP. Biliary Strictures and Cholangiocarcinoma - Untangling a Diagnostic Conundrum. Front Oncol 2021; 11:699401. [PMID: 34660269 PMCID: PMC8515053 DOI: 10.3389/fonc.2021.699401] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 09/15/2021] [Indexed: 12/12/2022] Open
Abstract
Cholangiocarcinoma is an uncommon and highly aggressive biliary tract malignancy with few manifestations until late disease stages. Diagnosis is currently achieved through a combination of clinical, biochemical, radiological and histological techniques. A number of reported cancer biomarkers have the potential to be incorporated into diagnostic pathways, but all lack sufficient sensitivity and specificity limiting their possible use in screening and early diagnosis. The limitations of standard serum markers such as CA19-9, CA125 and CEA have driven researchers to identify multiple novel biomarkers, yet their clinical translation has been slow with a general requirement for further validation in larger patient cohorts. We review recent advances in the diagnostic pathway for suspected CCA as well as emerging diagnostic biomarkers for early detection, with a particular focus on non-invasive approaches.
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Affiliation(s)
- Alexander Ney
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Andres Garcia-Sampedro
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - George Goodchild
- St. Bartholomew's hospital, Barts Health NHS Trust, London, United Kingdom
| | - Pilar Acedo
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Giuseppe Fusai
- Division of Surgery and Interventional Science - University College London, London, United Kingdom
| | - Stephen P Pereira
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
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27
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Boldrini L, Faviana P, Galli L, Paolieri F, Erba PA, Bardi M. Multi-Dimensional Scaling Analysis of Key Regulatory Genes in Prostate Cancer Using the TCGA Database. Genes (Basel) 2021; 12:1350. [PMID: 34573332 PMCID: PMC8468120 DOI: 10.3390/genes12091350] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/20/2021] [Accepted: 08/26/2021] [Indexed: 12/24/2022] Open
Abstract
Prostate cancer (PC) is a polygenic disease with multiple gene interactions. Therefore, a detailed analysis of its epidemiology and evaluation of risk factors can help to identify more accurate predictors of aggressive disease. We used the transcriptome data from a cohort of 243 patients from the Cancer Genome Atlas (TCGA) database. Key regulatory genes involved in proliferation activity, in the regulation of stress, and in the regulation of inflammation processes of the tumor microenvironment were selected to test a priori multi-dimensional scaling (MDS) models and create a combined score to better predict the patients' survival and disease-free intervals. Survival was positively correlated with cortisol expression and negatively with Mini-Chromosome Maintenance 7 (MCM7) and Breast-Related Cancer Antigen2 (BRCA2) expression. The disease-free interval was negatively related to the expression of enhancer of zeste homolog 2 (EZH2), MCM7, BRCA2, and programmed cell death 1 ligand 1 (PD-L1). MDS suggested two separate pathways of activation in PC. Within these two dimensions three separate clusters emerged: (1) cortisol and brain-derived neurotrophic factor BDNF, (2) PD-L1 and cytotoxic-T-lymphocyte-associated protein 4 (CTL4); (3) and finally EZH2, MCM7, BRCA2, and c-Myc. We entered the three clusters of association shown in the MDS in several Kaplan-Meier analyses. It was found that only Cluster 3 was significantly related to the interval-disease free, indicating that patients with an overall higher activity of regulatory genes of proliferation and DNA repair had a lower probability to have a longer disease-free time. In conclusion, our data study provided initial evidence that selecting patients with a high grade of proliferation and DNA repair activity could lead to an early identification of an aggressive PC with a potentials for metastatic development.
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Affiliation(s)
- Laura Boldrini
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, 56126 Pisa, Italy;
| | - Pinuccia Faviana
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, 56126 Pisa, Italy;
| | - Luca Galli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (L.G.); (F.P.); (P.A.E.)
| | - Federico Paolieri
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (L.G.); (F.P.); (P.A.E.)
| | - Paola Anna Erba
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (L.G.); (F.P.); (P.A.E.)
| | - Massimo Bardi
- Department of Psychology & Behavioral Neuroscience, Randolph-Macon College, Ashland, VA 23005, USA;
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28
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Wan Mohd Tajuddin WNB, Abas F, Othman I, Naidu R. Molecular Mechanisms of Antiproliferative and Apoptosis Activity by 1,5-Bis(4-Hydroxy-3-Methoxyphenyl)1,4-Pentadiene-3-one (MS13) on Human Non-Small Cell Lung Cancer Cells. Int J Mol Sci 2021; 22:ijms22147424. [PMID: 34299042 PMCID: PMC8307969 DOI: 10.3390/ijms22147424] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 06/30/2021] [Accepted: 07/04/2021] [Indexed: 01/12/2023] Open
Abstract
Diarylpentanoid (DAP), an analog that was structurally modified from a naturally occurring curcumin, has shown to enhance anticancer efficacy compared to its parent compound in various cancers. This study aims to determine the cytotoxicity, antiproliferative, and apoptotic activity of diarylpentanoid MS13 on two subtypes of non-small cell lung cancer (NSCLC) cells: squamous cell carcinoma (NCI-H520) and adenocarcinoma (NCI-H23). Gene expression analysis was performed using Nanostring PanCancer Pathways Panel to determine significant signaling pathways and targeted genes in these treated cells. Cytotoxicity screening revealed that MS13 exhibited greater inhibitory effect in NCI-H520 and NCI-H23 cells compared to curcumin. MS13 induced anti-proliferative activity in both cells in a dose- and time-dependent manner. Morphological analysis revealed that a significant number of MS13-treated cells exhibited apoptosis. A significant increase in caspase-3 activity and decrease in Bcl-2 protein concentration was noted in both MS13-treated cells in a time- and dose-dependent manner. A total of 77 and 47 differential expressed genes (DEGs) were regulated in MS13 treated-NCI-H520 and NCI-H23 cells, respectively. Among the DEGs, 22 were mutually expressed in both NCI-H520 and NCI-H23 cells in response to MS13 treatment. The top DEGs modulated by MS13 in NCI-H520—DUSP4, CDKN1A, GADD45G, NGFR, and EPHA2—and NCI-H23 cells—HGF, MET, COL5A2, MCM7, and GNG4—were highly associated with PI3K, cell cycle-apoptosis, and MAPK signaling pathways. In conclusion, MS13 may induce antiproliferation and apoptosis activity in squamous cell carcinoma and adenocarcinoma of NSCLC cells by modulating DEGs associated with PI3K-AKT, cell cycle-apoptosis, and MAPK pathways. Therefore, our present findings could provide an insight into the anticancer activity of MS13 and merits further investigation as a potential anticancer agent for NSCLC cancer therapy.
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Affiliation(s)
- Wan Nur Baitty Wan Mohd Tajuddin
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia; (W.N.B.W.M.T.); (I.O.)
| | - Faridah Abas
- Laboratory of Natural Products, Faculty of Science, Universiti Putra Malaysia, UPM, Serdang 43400, Malaysia;
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, UPM, Serdang 43400, Malaysia
| | - Iekhsan Othman
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia; (W.N.B.W.M.T.); (I.O.)
- Global Asia in the 21s Century Platform, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia
| | - Rakesh Naidu
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia; (W.N.B.W.M.T.); (I.O.)
- Global Asia in the 21s Century Platform, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia
- Correspondence: ; Tel.: +60-3-5514-63-45
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Liu S, Wu I, Yu YP, Balamotis M, Ren B, Ben Yehezkel T, Luo JH. Targeted transcriptome analysis using synthetic long read sequencing uncovers isoform reprograming in the progression of colon cancer. Commun Biol 2021; 4:506. [PMID: 33907296 PMCID: PMC8079361 DOI: 10.1038/s42003-021-02024-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 03/09/2021] [Indexed: 02/02/2023] Open
Abstract
The characterization of human gene expression is limited by short read lengths, high error rates and large input requirements. Here, we used a synthetic long read (SLR) sequencing approach, LoopSeq, to generate accurate sequencing reads that span full length transcripts using standard short read data. LoopSeq identified isoforms from control samples with 99.4% accuracy and a 0.01% per-base error rate, exceeding the accuracy reported for other long-read technologies. Applied to targeted transcriptome sequencing from colon cancers and their metastatic counterparts, LoopSeq revealed large scale isoform redistributions from benign colon mucosa to primary colon cancer and metastatic cancer and identified several previously unknown fusion isoforms. Strikingly, single nucleotide variants (SNVs) occurred dominantly in specific isoforms and some SNVs underwent isoform switching in cancer progression. The ability to use short reads to generate accurate long-read data as the raw unit of information holds promise as a widely accessible approach in transcriptome sequencing.
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Affiliation(s)
- Silvia Liu
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA
- High Throughput Genome Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA
| | - Indira Wu
- Loop Genomics, Inc., San Jose, CA, 95138, USA
| | - Yan-Ping Yu
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA
- High Throughput Genome Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA
| | | | - Baoguo Ren
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA
- High Throughput Genome Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA
| | | | - Jian-Hua Luo
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
- High Throughput Genome Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
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30
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Ren Z, Li J, Zhao S, Qiao Q, Li R. Knockdown of MCM8 functions as a strategy to inhibit the development and progression of osteosarcoma through regulating CTGF. Cell Death Dis 2021; 12:376. [PMID: 33828075 PMCID: PMC8027380 DOI: 10.1038/s41419-021-03621-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 03/09/2021] [Accepted: 03/11/2021] [Indexed: 12/19/2022]
Abstract
Osteosarcoma is the most common primary malignant tumor of bone derived from osteoblasts, which is a noteworthy threat to the health of children and adolescents. In this study, we found that MCM8 has significantly higher expression level in osteosarcoma tissues in comparison with normal tissues, which was also correlated with more advanced tumor grade and pathological stage. In agreement with the role of MCM proteins as indicators of cell proliferation, knockdown/overexpression of MCM8 inhibited/promoted osteosarcoma cell proliferation in vitro and tumor growth in vivo. Also, MCM8 knockdown/overexpression was also significantly associated with the promotion/inhibition of cell apoptosis and suppression/promotion of cell migration. More importantly, mechanistic study identified CTGF as a potential downstream target of MCM8, silencing of which could enhance the regulatory effects of MCM8 knockdown and alleviate the effects of MCM8 overexpression on osteosarcoma development. In summary, MCM8/CTGF axis was revealed as critical participant in the development and progression of osteosarcoma and MCM8 may be a promising therapeutic target for osteosarcoma treatment.
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Affiliation(s)
- Zhinan Ren
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Jun Li
- Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, 678 Furong, Hefei, 230601, China
| | - Shanwen Zhao
- Department of Foot and Ankle Surgery, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510610, China.,Orthopaedic Hospital of Guangdong Province, Guangzhou, 510630, China.,Academy of Orthopaedics, Guangdong Province, Guangzhou, 510630, China.,Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases, Guangzhou, 510515, China
| | - Qi Qiao
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Runguang Li
- Department of Foot and Ankle Surgery, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510610, China. .,Orthopaedic Hospital of Guangdong Province, Guangzhou, 510630, China. .,Academy of Orthopaedics, Guangdong Province, Guangzhou, 510630, China. .,Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases, Guangzhou, 510515, China. .,Department of Orthopedics, Linzhi People's Hospital, Linzhi, 860000, China.
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31
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Zhang L, Chen J, Yang H, Pan C, Li H, Luo Y, Cheng T. Multiple microarray analyses identify key genes associated with the development of Non-Small Cell Lung Cancer from Chronic Obstructive Pulmonary Disease. J Cancer 2021; 12:996-1010. [PMID: 33442399 PMCID: PMC7797649 DOI: 10.7150/jca.51264] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 11/30/2020] [Indexed: 12/13/2022] Open
Abstract
Introduction: Chronic obstructive pulmonary disease (COPD) is an independent risk factor of non-small cell lung cancer (NSCLC). This study aimed to analyze the key genes and potential molecular mechanisms that are involved in the development from COPD to NSCLC. Methods: Expression profiles of COPD and NSCLC in GSE106899, GSE12472, and GSE12428 were downloaded from the Gene Expression Omnibus (GEO) database, followed by identification of the differentially expressed genes (DEGs) between COPD and NSCLC. Based on the identified DEGs, functional pathway enrichment and lung carcinogenesis-related networks analyses were performed and further visualized with Cytoscape software. Then, principal component analysis (PCA), cluster analysis, and support vector machines (SVM) verified the ability of the top modular genes to distinguish COPD from NSCLC. Additionally, the corrections between these key genes and clinical staging of NSCLC were studied using the UALCAN and HPA websites. Finally, a prognostic risk model was constructed based on multivariate Cox regression analysis. Kaplan-Meier survival curves of the top modular genes on the training and verification sets were generated. Results: A total of 2350, 1914, and 1850 DEGs were obtained from GSE106899, GSE12472, and GSE12428 datasets, respectively. Following analysis of protein-protein interaction networks, the identified modular gene signatures containing H2AFX, MCM2, MCM3, MCM7, POLD1, and RPA1 were identified as markers for discrimination between COPD and NSCLC. The modular gene signatures were mainly enriched in the processes of DNA replication, cell cycle, mismatch repair, and others. Besides, the expression levels of these genes were significantly higher in NSCLC than in COPD, which was further verified by the immunohistochemistry. In addition, the high expression levels of H2AFX, MCM2, MCM7, and POLD1 correlate with poor prognosis of lung adenocarcinoma (LUAD). The Cox regression prognostic risk model showed the similar results and the predictive ability of this model is independent of other clinical variables. Conclusions: This study revealed several key modules that closely relate to NSCLC with underlying disease COPD, which provide a deeper understanding of the potential mechanisms underlying the malignant development from COPD to NSCLC. This study provides valuable prognostic factors in high-risk lung cancer patients with COPD.
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Affiliation(s)
- Lemeng Zhang
- Thoracic Medicine Department 1, Hunan Cancer Hospital, Changsha, Hunan Province, P.R. China, 410013
| | - Jianhua Chen
- Thoracic Medicine Department 1, Hunan Cancer Hospital, Changsha, Hunan Province, P.R. China, 410013
| | - Hua Yang
- Thoracic Medicine Department 1, Hunan Cancer Hospital, Changsha, Hunan Province, P.R. China, 410013
| | - Changqie Pan
- Thoracic Medicine Department 1, Hunan Cancer Hospital, Changsha, Hunan Province, P.R. China, 410013
| | - Haitao Li
- Thoracic Medicine Department 1, Hunan Cancer Hospital, Changsha, Hunan Province, P.R. China, 410013
| | - Yongzhong Luo
- Thoracic Medicine Department 1, Hunan Cancer Hospital, Changsha, Hunan Province, P.R. China, 410013
| | - Tianli Cheng
- Thoracic Medicine Department 1, Hunan Cancer Hospital, Changsha, Hunan Province, P.R. China, 410013
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Loss of RBMS1 as a regulatory target of miR-106b influences cell growth, gap closing and colony forming in prostate carcinoma. Sci Rep 2020; 10:18022. [PMID: 33093529 PMCID: PMC7582885 DOI: 10.1038/s41598-020-75083-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 10/12/2020] [Indexed: 01/22/2023] Open
Abstract
Prostate carcinoma (PCa) is the second most commonly diagnosed cancer in males worldwide. Among hereditary genetic mutations and nutrient factors, a link between the deregulation of microRNA (miRNA) expression and the development of prostate carcinoma is assumed. MiRNAs are small non-coding RNAs which post-transcriptionally regulate gene expression and which are involved in tumour development and progression as oncogenes or tumour suppressors. Although many genes could be confirmed as targets for deregulated miRNAs, the impact of differentially expressed miRNA and their regulatory target genes on prostate tumour development and progression are not fully understood yet. We could validate RBMS1, a barely described RNA-binding protein, as a new target gene for oncogenic miR-106b, which was identified as an induced miRNA in PCa. Further analysis revealed a loss of RBMS1 expression in prostate tumours compared to corresponding normal tissue. Overexpression of RBMS1 in DU145 and LNCaP prostate cancer cells resulted in diminished cell proliferation, colony forming ability as well as in retarded gap closing. Our results demonstrate for the first time a miR-106b dependent downregulation of RBMS1 in prostate carcinoma. Additionally, we show new tumour suppressive properties of RBMS1 whose observed loss may further elucidate the development of PCa.
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MCM family in gastrointestinal cancer and other malignancies: From functional characterization to clinical implication. Biochim Biophys Acta Rev Cancer 2020; 1874:188415. [PMID: 32822825 DOI: 10.1016/j.bbcan.2020.188415] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 08/15/2020] [Accepted: 08/15/2020] [Indexed: 02/07/2023]
Abstract
Despite the recent advances in cancer research and treatment, gastrointestinal (GI) cancers remain the most common deadly disease worldwide. The aberrant DNA replication serves as a major source of genomic instability and enhances cell proliferation that contributes to tumor initiation and progression. Minichromosome maintenance family (MCMs) is a well-recognized group of proteins responsible for DNA synthesis. Recent studies suggested that dysregulated MCMs lead to tumor initiation, progression, and chemoresistance via modulating cell cycle and DNA replication stress. Their underlying mechanisms in various cancer types have been gradually identified. Furthermore, multiple studies have investigated the association between MCMs expression and clinicopathological features of cancer patients, implying that MCMs might serve as prominent prognostic biomarkers for GI cancers. This review summarizes the current knowledge on the oncogenic role of MCM proteins and highlights their clinical implications in various malignancies, especially in GI cancers. Targeting MCMs might shed light on the potential for identifying novel therapeutic strategies.
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34
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Tessier-Cloutier B, Cochrane DR, Karnezis AN, Colborne S, Magrill J, Talhouk A, Zhang J, Leung S, Hughes CS, Piskorz A, Cheng AS, Greening K, du Bois A, Pfisterer J, Soslow RA, Kommoss S, Brenton JD, Morin GB, Gilks CB, Huntsman DG, Kommoss F. Proteomic analysis of transitional cell carcinoma-like variant of tubo-ovarian high-grade serous carcinoma. Hum Pathol 2020; 101:40-52. [PMID: 32360491 PMCID: PMC8204941 DOI: 10.1016/j.humpath.2020.02.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 02/18/2020] [Accepted: 02/23/2020] [Indexed: 02/06/2023]
Abstract
The current World Health Organization classification does not distinguish transitional cell carcinoma of the ovary (TCC) from conventional tubo-ovarian high-grade serous carcinoma (HGSC), despite evidence suggesting improved prognosis for patients with TCC; instead, it is considered a morphologic variant of HGSC. The immunohistochemical (IHC) markers applied to date do not distinguish between TCC and HGSC. Therefore, we sought to compare the proteomic profiles of TCC and conventional HGSC to identify proteins enriched in TCC. Prognostic biomarkers in HGSC have proven to be elusive, and our aim was to identify biomarkers of TCC as a way of reliably and reproducibly identifying patients with a favorable prognosis and better response to chemotherapy compared with those with conventional HGSC. Quantitative global proteome analysis was performed on archival material of 12 cases of TCC and 16 cases of HGSC using SP3 (single-pot, solid phase-enhanced, sample preparation)-Clinical Tissue Proteomics, a recently described protocol for full-proteome analysis from formalin-fixed paraffin-embedded tissues. We identified 430 proteins that were significantly enriched in TCC over HGSC. Unsupervised co-clustering perfectly distinguished TCC from HGSC based on protein expression. Pathway analysis showed that proteins associated with cell death, necrosis, and apoptosis were highly expressed in TCCs, whereas proteins associated with DNA homologous recombination, cell mitosis, proliferation and survival, and cell cycle progression pathways had reduced expression. From the proteomic analysis, three potential biomarkers for TCC were identified, claudin-4 (CLDN4), ubiquitin carboxyl-terminal esterase L1 (UCHL1), and minichromosome maintenance protein 7 (MCM7), and tested by IHC analysis on tissue microarrays. In agreement with the proteomic analysis, IHC expression of those proteins was stronger in TCC than in HGSC (p < 0.0001). Using global proteomic analysis, we are able to distinguish TCC from conventional HGSC. Follow-up studies will be necessary to confirm that these molecular and morphologic differences are clinically significant.
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Affiliation(s)
- Basile Tessier-Cloutier
- Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada; Department of Molecular Oncology, BC Cancer, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada
| | - Dawn R Cochrane
- Department of Molecular Oncology, BC Cancer, Vancouver, BC, Canada
| | - Anthony N Karnezis
- Department of Molecular Oncology, BC Cancer, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, UC Davis Medical Center, Sacramento, CA, United States
| | - Shane Colborne
- Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | - Jamie Magrill
- Department of Molecular Oncology, BC Cancer, Vancouver, BC, Canada
| | - Aline Talhouk
- Department of Molecular Oncology, BC Cancer, Vancouver, BC, Canada
| | - Jonathan Zhang
- Department of Molecular Oncology, BC Cancer, Vancouver, BC, Canada
| | - Samuel Leung
- Department of Molecular Oncology, BC Cancer, Vancouver, BC, Canada
| | | | - Anna Piskorz
- Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK
| | - Angela S Cheng
- Genetic Pathology Evaluation Centre, The University of British Columbia, Vancouver, Canada
| | - Kendall Greening
- Department of Molecular Oncology, BC Cancer, Vancouver, BC, Canada
| | | | | | - Robert A Soslow
- Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Stefan Kommoss
- Department of Obstetrics and Gynecology, Tübingen University Hospital, Tübingen, Germany
| | - James D Brenton
- Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK
| | - Gregg B Morin
- Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - C Blake Gilks
- Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada
| | - David G Huntsman
- Department of Molecular Oncology, BC Cancer, Vancouver, BC, Canada
| | - Friedrich Kommoss
- Institute of Pathology, Medizin Campus Bodensee, Friedrichshafen, Germany.
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Yang Y, Ma S, Ye Z, Zhou X. MCM7 silencing promotes cutaneous melanoma cell autophagy and apoptosis by inactivating the AKT1/mTOR signaling pathway. J Cell Biochem 2020; 121:1283-1294. [PMID: 31535400 DOI: 10.1002/jcb.29361] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 08/20/2019] [Indexed: 01/17/2023]
Abstract
Cutaneous melanoma (CM) has become a major public health concern. Studies illustrate that minichromosome maintenance protein 7 (MCM7) participate in various diseases including skin disease. Our study aimed to study the effects of MCM7 silencing on CM cell autophagy and apoptosis by modulating the AKT threonine kinase 1 (AKT1)/mechanistic target of rapamycin kinase (mTOR) signaling pathway. Initially, microarray analysis was used to screen the CM-related gene expression data as well as differentially expressed genes. Subsequently, MCM7 expression vector and lentivirus RNA used for MCM7 silencing (LV-shRNA-MCM7) were constructed, and these vectors, dimethyl sulfoxide (DMSO) and AKT activator SC79 were then introduced into CM cell line SK-MEL-2 to validate the role of MCM7 in cell autophagy, viability, apoptosis, cell cycle, migration, and invasion. To further investigate the regulatory mechanisms of MCM7 in CM progress, the expression of MCM7, AKT1, mTOR, cyclin D1, as well as autophagy and apoptosis relative factors, such as LC3B, SOD2, DJ-1, p62, Bcl-2, Bax, and caspase-3 in melanoma cells was determined. MCM7 might mediate the AKT1/mTOR signaling pathway to influence the progress of melanoma. MCM7 silencing contributed to the increased expression of Bax, capase-3, and autophagy-related genes (LC3B, SOD2, and DJ-1), but decreased the expression of Bcl-2, which suggested that MCM7 silencing promoted autophagy and cell apoptosis. At the same time, MCM7 silencing also attenuated cell viability, invasion, and migration, and reduced the cyclin D1 expression and protein levels of p-AKT1 and p-mTOR. Taken together, MCM7 silencing inhibited CM via inactivation of the AKT1/mTOR signaling pathway.
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Affiliation(s)
- Yemei Yang
- Department of Dermatology and Venerology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Shengfang Ma
- Department of Dermatology, Baoshihua Hospital of Gansu Province, Lanzhou, China
| | - Zi Ye
- College of Information and Sciences, The Pennsylvania State University, Pennsylvania
| | - Xianyi Zhou
- Department of Dermatology and Venerology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
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36
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Modelling the Effects of MCM7 Variants, Somatic Mutations, and Clinical Features on Acute Myeloid Leukemia Susceptibility and Prognosis. J Clin Med 2020; 9:jcm9010158. [PMID: 31936215 PMCID: PMC7020054 DOI: 10.3390/jcm9010158] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 12/21/2019] [Accepted: 01/06/2020] [Indexed: 12/13/2022] Open
Abstract
The main objective of the study was to evaluate the associations between MCM7 rs2070215, rs1527423, and rs1534309 single nucleotide polymorphisms (SNPs) and acute myeloid leukemia (AML) risk and prognosis. The secondary objectives were to assess if any relationships existed between the mentioned SNPs and FLT3, DNMT3A, NPM1 mutations with clinical outcomes and overall survival (OS) in AML patients. We investigated 281 AML cases and 405 healthy subjects. The results showed a significant association between a variant allele of rs2070215 (p = 0.007), CAT haplotype (p = 0.012), and AML susceptibility. No significant association was found between MCM7 variant genotypes and overall survival of AML patients (p > 0.05), while several associations between somatic mutations, clinical and biological features, and poor OS were noticed. Lactate dehydrogenase (LDH) level ≥ 600 IU/L had a significant effect on the hazard of death (p = 0.004, HR = 1.49, 95% CI: 1.13–1.95). Our study showed that the variant allele of rs2070215, in the allelic model, and CAT haplotype were associated with AML susceptibility. The investigated FLT3, DNMT3A, and NPM1 mutations were associated with the clinical and biological features and poor OS. LDH level ≥ 600 IU/L was associated with an increased hazard of death and this association remained significant when quantifying for effect modification by FLT3 mutation status.
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37
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Wang HY, Zhang B, Zhou JN, Wang DX, Xu YC, Zeng Q, Jia YL, Xi JF, Nan X, He LJ, Yue W, Pei XT. Arsenic trioxide inhibits liver cancer stem cells and metastasis by targeting SRF/MCM7 complex. Cell Death Dis 2019; 10:453. [PMID: 31186405 PMCID: PMC6560089 DOI: 10.1038/s41419-019-1676-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 05/07/2019] [Accepted: 05/16/2019] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) has a high mortality rate due to the lack of effective treatments and drugs. Arsenic trioxide (ATO), which has been proved to successfully treat acute promyelocytic leukemia (APL), was recently reported to show therapeutic potential in solid tumors including HCC. However, its anticancer mechanisms in HCC still need further investigation. In this study, we demonstrated that ATO inhibits tumorigenesis and distant metastasis in mouse models, corresponding with a prolonged mice survival time. Also, ATO was found to significantly decrease the cancer stem cell (CSC)-associated traits. Minichromosome maintenance protein (MCM) 7 was further identified to be a potential target suppressed dramatically by ATO, of which protein expression is increased in patients and significantly correlated with tumor size, cellular differentiation, portal venous emboli, and poor patient survival. Moreover, MCM7 knockdown recapitulates the effects of ATO on CSCs and metastasis, while ectopic expression of MCM7 abolishes them. Mechanistically, our results suggested that ATO suppresses MCM7 transcription by targeting serum response factor (SRF)/MCM7 complex, which functions as an important transcriptional regulator modulating MCM7 expression. Taken together, our findings highlight the importance of ATO in the treatment of solid tumors. The identification of SRF/MCM7 complex as a target of ATO provides new insights into ATO’s mechanism, which may benefit the appropriate use of this agent in the treatment of HCC.
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Affiliation(s)
- Hai-Yang Wang
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, 100850, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, 510005, China
| | - Biao Zhang
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, 100850, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, 510005, China
| | - Jun-Nian Zhou
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, 100850, China. .,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, 510005, China. .,Experimental Hematology and Biochemistry Lab, Beijing Institute of Radiation Medicine, Beijing, 100850, China.
| | - Dong-Xing Wang
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, 100850, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, 510005, China
| | - Ying-Chen Xu
- Department of Hepatobiliary Surgery, Beijing Tongren Hospital, Beijing, 100730, China
| | - Quan Zeng
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, 100850, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, 510005, China
| | - Ya-Li Jia
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, 100850, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, 510005, China.,Experimental Hematology and Biochemistry Lab, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Jia-Fei Xi
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, 100850, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, 510005, China
| | - Xue Nan
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, 100850, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, 510005, China
| | - Li-Juan He
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, 100850, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, 510005, China
| | - Wen Yue
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, 100850, China. .,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, 510005, China.
| | - Xue-Tao Pei
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, 100850, China. .,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, 510005, China.
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Petropoulos M, Champeris Tsaniras S, Taraviras S, Lygerou Z. Replication Licensing Aberrations, Replication Stress, and Genomic Instability. Trends Biochem Sci 2019; 44:752-764. [PMID: 31054805 DOI: 10.1016/j.tibs.2019.03.011] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 03/24/2019] [Accepted: 03/27/2019] [Indexed: 01/07/2023]
Abstract
Strict regulation of DNA replication is of fundamental significance for the maintenance of genome stability. Licensing of origins of DNA replication is a critical event for timely genome duplication. Errors in replication licensing control lead to genomic instability across evolution. Here, we present accumulating evidence that aberrant replication licensing is linked to oncogene-induced replication stress and poses a major threat to genome stability, promoting tumorigenesis. Oncogene activation can lead to defects in where along the genome and when during the cell cycle licensing takes place, resulting in replication stress. We also discuss the potential of replication licensing as a specific target for novel anticancer therapies.
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Affiliation(s)
- Michalis Petropoulos
- Department of Biology, School of Medicine, University of Patras, Patras 26504, Greece
| | | | - Stavros Taraviras
- Department of Physiology, School of Medicine, University of Patras, Patras 26504, Greece.
| | - Zoi Lygerou
- Department of Biology, School of Medicine, University of Patras, Patras 26504, Greece.
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39
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Post-Translational Modifications of the Mini-Chromosome Maintenance Proteins in DNA Replication. Genes (Basel) 2019; 10:genes10050331. [PMID: 31052337 PMCID: PMC6563057 DOI: 10.3390/genes10050331] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 04/26/2019] [Accepted: 04/26/2019] [Indexed: 12/15/2022] Open
Abstract
The eukaryotic mini-chromosome maintenance (MCM) complex, composed of MCM proteins 2-7, is the core component of the replisome that acts as the DNA replicative helicase to unwind duplex DNA and initiate DNA replication. MCM10 tightly binds the cell division control protein 45 homolog (CDC45)/MCM2-7/ DNA replication complex Go-Ichi-Ni-San (GINS) (CMG) complex that stimulates CMG helicase activity. The MCM8-MCM9 complex may have a non-essential role in activating the pre-replicative complex in the gap 1 (G1) phase by recruiting cell division cycle 6 (CDC6) to the origin recognition complex (ORC). Each MCM subunit has a distinct function achieved by differential post-translational modifications (PTMs) in both DNA replication process and response to replication stress. Such PTMs include phosphorylation, ubiquitination, small ubiquitin-like modifier (SUMO)ylation, O-N-acetyl-D-glucosamine (GlcNAc)ylation, and acetylation. These PTMs have an important role in controlling replication progress and genome stability. Because MCM proteins are associated with various human diseases, they are regarded as potential targets for therapeutic development. In this review, we summarize the different PTMs of the MCM proteins, their involvement in DNA replication and disease development, and the potential therapeutic implications.
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40
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Campolina-Silva GH, Hess RA, Oliveira CA. Seasonal variation of cell proliferation and apoptosis in the efferent ductules and epididymis of the Neotropical bat Artibeus lituratus (Chiroptera, Phyllostomidae). Gen Comp Endocrinol 2019; 273:3-10. [PMID: 29427632 DOI: 10.1016/j.ygcen.2018.02.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 01/25/2018] [Accepted: 02/06/2018] [Indexed: 02/06/2023]
Abstract
The balance between cell proliferation and apoptosis is important for maintenance of male fertility, being influenced by a variety of stimuli including androgens and estrogens. However, studies concerning regulation of these processes along the male reproductive tract under physiological conditions are scarce. Therefore, in this study, we investigated the profile of cell proliferation and apoptosis in the efferent ductules and epididymis of the Neotropical bat Artibeus lituratus, a seasonal breeder that presents natural variation in components of the androgen and estrogen responsive systems along the circannual cycle. Low rates of cell proliferation and apoptosis were found in the efferent ductules and epididymis of A. lituratus during the reproductive period, as few epithelial cells were positive for MCM7 (proliferation marker) and cleaved caspase-3 or TUNEL (apoptosis markers). In contrast, during the regressive period, the rate of both proliferating and apoptotic cells was significantly higher in the epithelium lining the efferent ductules as well as throughout the epididymis. The increased proliferative activity at this phase was positively correlated with the expression of estrogen receptor alpha (ERα), whereas the variation in apoptosis appears to be unrelated to the local expression of androgen and estrogen receptors. Together, these data suggest that cell proliferation and apoptosis are differentially modulated in the efferent ductules and epididymis of A. lituratus during the annual reproductive cycle, and support the hypothesis that ERα may be important in preparing the male reproductive tract for sexual recrudescence.
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Affiliation(s)
- Gabriel H Campolina-Silva
- Department of Morphology, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, CEP 31270-901 Belo Horizonte, MG, Brazil
| | - Rex A Hess
- Department of Comparative Biosciences, University of Illinois, 2001, S. Lincoln, Urbana, IL 61802-6199, USA
| | - Cleida A Oliveira
- Department of Morphology, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, CEP 31270-901 Belo Horizonte, MG, Brazil.
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Mughal MJ, Mahadevappa R, Kwok HF. DNA replication licensing proteins: Saints and sinners in cancer. Semin Cancer Biol 2018; 58:11-21. [PMID: 30502375 DOI: 10.1016/j.semcancer.2018.11.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 11/08/2018] [Accepted: 11/26/2018] [Indexed: 12/12/2022]
Abstract
DNA replication is all-or-none process in the cell, meaning, once the DNA replication begins it proceeds to completion. Hence, to achieve maximum control of DNA replication, eukaryotic cells employ a multi-subunit initiator protein complex known as "pre-replication complex or DNA replication licensing complex (DNA replication LC). This complex involves multiple proteins which are origin-recognition complex family proteins, cell division cycle-6, chromatin licensing and DNA replication factor 1, and minichromosome maintenance family proteins. Higher-expression of DNA replication LC proteins appears to be an early event during development of cancer since it has been a common hallmark observed in a wide variety of cancers such as oesophageal, laryngeal, pulmonary, mammary, colorectal, renal, urothelial etc. However, the exact mechanisms leading to the abnormally high expression of DNA replication LC have not been clearly deciphered. Increased expression of DNA replication LC leads to licensing and/or firing of multiple origins thereby inducing replication stress and genomic instability. Therapeutic approaches where the reduction in the activity of DNA replication LC was achieved either by siRNA or shRNA techniques, have shown increased sensitivity of cancer cell lines towards the anti-cancer drugs such as cisplatin, 5-Fluorouracil, hydroxyurea etc. Thus, the expression level of DNA replication LC within the cell determines a cell's fate thereby creating a paradox where DNA replication LC acts as both "Saint" and "Sinner". With a potential to increase sensitivity to chemotherapy drugs, DNA replication LC proteins have prospective clinical importance in fighting cancer. Hence, in this review, we will shed light on importance of DNA replication LC with an aim to use DNA replication LC in diagnosis and prognosis of cancer in patients as well as possible therapeutic targets for cancer therapy.
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Affiliation(s)
- Muhammad Jameel Mughal
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau
| | - Ravikiran Mahadevappa
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau
| | - Hang Fai Kwok
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau.
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Ban X, Yan J, Yu S, Lu Z, Chang X, Jia C, Gao C, Shao H, Wu Y, Mao X, Zhang Y, Li Y, Chen J. High minichromosome maintenance protein 7 proliferation indices: a powerful predictor of progression in pancreatic neuroendocrine neoplasms without distant metastasis at the time of surgery. Hum Pathol 2018; 85:101-111. [PMID: 30447299 DOI: 10.1016/j.humpath.2018.10.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 10/26/2018] [Accepted: 10/31/2018] [Indexed: 12/28/2022]
Abstract
Pancreatic neuroendocrine neoplasms (PanNENs) have an unpredictable clinical course that varies from indolent to highly malignant. No immunohistochemical markers are available for reliable prediction of the biological behavior of early stage PanNENs. Minichromosome maintenance protein 7 (MCM7) is a putative powerful marker of cell proliferation. Whether the expression of MCM7 is related to the risk of PanNENs progression remains unclear. We assessed the clinical behavior of 156 PanNENs with respect to stage, grade, Ki-67 index, MCM7 index, and other pathologic features. A high MCM7 index was significantly associated with larger tumor size (P < .001), nonfunctioning tumor (P < .001), increased grade (P < .0001), and later TNM stage (P < .001). In multivariate analysis, G2/G3 (hazard ratio [HR], 2.21; 95% confidence interval [CI], 1.35-3.62; P < .001), stage III/IV (HR, 2.11; 95% CI, 1.31-3.41; P < .001), and MCM7 labeling index >5% (HR, 3.81; 95% CI, 1.30-11.17; P = .02) were independent negative prognostic factors related to the risk of tumor progression in stage I-IV disease. MCM7 labeling index >5% was associated with an increased risk of progression in stages I-V, I-III, and I-II. Our study confirms that MCM7 is a valuable marker for assessing the progression of PanNENs, especially in patients with early stage disease and without distant metastasis.
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Affiliation(s)
- Xinchao Ban
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences-Peking Union Medical College, Beijing 100730, China
| | - Jie Yan
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences-Peking Union Medical College, Beijing 100730, China
| | - Shuangni Yu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences-Peking Union Medical College, Beijing 100730, China
| | - Zhaohui Lu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences-Peking Union Medical College, Beijing 100730, China
| | - Xiaoyan Chang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences-Peking Union Medical College, Beijing 100730, China
| | - Congwei Jia
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences-Peking Union Medical College, Beijing 100730, China
| | - Cen Gao
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences-Peking Union Medical College, Beijing 100730, China
| | - Huilin Shao
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences-Peking Union Medical College, Beijing 100730, China
| | - Yan Wu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences-Peking Union Medical College, Beijing 100730, China
| | - Xinxin Mao
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences-Peking Union Medical College, Beijing 100730, China
| | - Yue Zhang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences-Peking Union Medical College, Beijing 100730, China
| | - Yuan Li
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences-Peking Union Medical College, Beijing 100730, China
| | - Jie Chen
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences-Peking Union Medical College, Beijing 100730, China.
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Liao X, Han C, Wang X, Huang K, Yu T, Yang C, Huang R, Liu Z, Han Q, Peng T. Prognostic value of minichromosome maintenance mRNA expression in early-stage pancreatic ductal adenocarcinoma patients after pancreaticoduodenectomy. Cancer Manag Res 2018; 10:3255-3271. [PMID: 30233242 PMCID: PMC6130532 DOI: 10.2147/cmar.s171293] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background The aim of the current study was to investigate the potential prognostic value of minichromosome maintenance (MCM) genes in patients with early-stage pancreatic ductal adenocarcinoma (PDAC) after pancreaticoduodenectomy by using the RNA-sequencing dataset from The Cancer Genome Atlas (TCGA). Methods An RNA-sequencing dataset of 112 early-stage PDAC patients who received a pancreaticoduodenectomy was obtained from TCGA. Survival analysis was used to identify potential prognostic values of MCM genes in PDAC overall survival (OS). Results Through mining public databases, we observed that MCM genes (MCM2, MCM3, MCM4, MCM5, MCM6, and MCM7) were upregulated in pancreatic cancer tumor tissue and have a strong positive coexpression with each other. Multivariate survival analysis indicated that a high expression of MCM4 significantly increased the risk of death in patients with PDAC, and time-dependent receiver operating characteristic analysis showed an area under the curve of 0.655, 0.587, and 0.509 for a 1-, 2-, and 3-year PDAC OS prediction, respectively. Comprehensive survival analysis of MCM4 using stratified and joint effects survival analysis suggests that MCM4 may be an independent prognostic indicator for PDAC OS. Gene set enrichment analysis indicated that MCM4 may participate in multiple biologic processes and pathways, including DNA replication, cell cycle, tumor protein p53, and Notch signaling pathways, thereby affecting prognosis of PDAC patients. Conclusions Our study indicates that MCM2–7 were upregulated in pancreatic cancer tumor tissues, and mRNA expression of MCM4 may serve as an independent prognostic indicator for PDAC OS prediction after pancreaticoduodenectomy.
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Affiliation(s)
- Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China,
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China,
| | - Xiangkun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China,
| | - Ketuan Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China,
| | - Tingdong Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China,
| | - Chengkun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China,
| | - Rui Huang
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Zhengqian Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China,
| | - Quanfa Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China,
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China,
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Stewart PA, Khamis ZI, Zhau HE, Duan P, Li Q, Chung LWK, Sang QXA. Upregulation of minichromosome maintenance complex component 3 during epithelial-to-mesenchymal transition in human prostate cancer. Oncotarget 2018; 8:39209-39217. [PMID: 28424404 PMCID: PMC5503607 DOI: 10.18632/oncotarget.16835] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 03/08/2017] [Indexed: 01/13/2023] Open
Abstract
Metastasis is often associated with epithelial-to-mesenchymal transition (EMT). To understand the molecular mechanisms of this process, we conducted proteomic analysis of androgen-repressed cancer of the prostate (ARCaP), an experimental model of metastatic human prostate cancer. The protein signatures of epithelial (ARCaPE) and mesenchymal (ARCaPM) cells were consistent with their phenotypes. Importantly, the expression of mini-chromosome maintenance 3 (MCM3) protein, a crucial subunit of DNA helicase, was significantly higher in ARCaPM cells than that of ARCaPE cells. This increased MCM3 protein expression level was verified using Western blot analysis of the ARCaP cell lineages. Furthermore, immunohistochemical analysis of MCM3 protein levels in human prostate tissue specimens showed elevated expression in bone metastasis and advanced human prostate cancer tissue samples. Subcutaneous injection experiments using ARCaPE and ARCaPM cells in a mouse model also revealed increased MCM3 protein levels in mesenchymal-derived tumors. This study identifies MCM3 as an upregulated molecule in mesenchymal phenotype of human prostate cancer cells and advanced human prostate cancer specimens, suggesting MCM3 may be a new potential drug target for prostate cancer treatment.
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Affiliation(s)
- Paul A Stewart
- Department of Chemistry & Biochemistry, Florida State University, Tallahassee, FL, United States of America
| | - Zahraa I Khamis
- Department of Chemistry & Biochemistry, Florida State University, Tallahassee, FL, United States of America.,Laboratory of Cancer Biology and Molecular Immunology, Department of Biochemistry, Faculty of Sciences, Lebanese University, Beirut, Lebanon
| | - Haiyen E Zhau
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
| | - Peng Duan
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
| | - Quanlin Li
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
| | - Leland W K Chung
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
| | - Qing-Xiang Amy Sang
- Department of Chemistry & Biochemistry, Florida State University, Tallahassee, FL, United States of America.,Institute of Molecular Biophysics, Florida State University, Tallahassee, FL, United States of America
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45
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YAP and TAZ in Lung Cancer: Oncogenic Role and Clinical Targeting. Cancers (Basel) 2018; 10:cancers10050137. [PMID: 29734788 PMCID: PMC5977110 DOI: 10.3390/cancers10050137] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 05/01/2018] [Accepted: 05/02/2018] [Indexed: 12/17/2022] Open
Abstract
Lung cancer is the leading cause of cancer death in the world and there is no current treatment able to efficiently treat the disease as the tumor is often diagnosed at an advanced stage. Moreover, cancer cells are often resistant or acquire resistance to the treatment. Further knowledge of the mechanisms driving lung tumorigenesis, aggressiveness, metastasization, and resistance to treatments could provide new tools for detecting the disease at an earlier stage and for a better response to therapy. In this scenario, Yes Associated Protein (YAP) and Trascriptional Coactivator with PDZ-binding motif (TAZ), the final effectors of the Hippo signaling transduction pathway, are emerging as promising therapeutic targets. Here, we will discuss the most recent advances made in YAP and TAZ biology in lung cancer and, more importantly, on the newly discovered mechanisms of YAP and TAZ inhibition in lung cancer as well as their clinical implications.
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46
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Fei L, Ma Y, Zhang M, Liu X, Luo Y, Wang C, Zhang H, Zhang W, Han Y. RACK1 promotes lung cancer cell growth via an MCM7/RACK1/ Akt signaling complex. Oncotarget 2018; 8:40501-40513. [PMID: 28465488 PMCID: PMC5522230 DOI: 10.18632/oncotarget.17120] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 04/03/2017] [Indexed: 12/17/2022] Open
Abstract
MCM7, a member of the miniature chromosome maintenance (MCM) protein family, is crucial for the initiation of DNA replication and proliferation in eukaryotic cells. In this report, we demonstrate that RACK1 regulates cell growth and cell cycle progression in human non-small-cell lung cancer by mediating MCM7 phosphorylation through an MCM7/RACK1/Akt signaling complex. RACK1 functions as a central scaffold that brings Akt into physical proximity with MCM7. Overexpression of RACK1 increases interactions between Akt and MCM7 and promotes Akt-dependent MCM7 phosphorylation, which in turn increases MCM7 binding to chromatin and MCM complex formation. Together, these changes promote DNA replication and cell proliferation. Our findings reveal a novel signaling pathway that regulates growth in non-small cell lung cancer.
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Affiliation(s)
- Liangru Fei
- Department of Pathology, School of Basic Medical Sciences, China Medical University, Shenyang 110000, China
| | - Yinan Ma
- Department of Pathology, School of Basic Medical Sciences, China Medical University, Shenyang 110000, China
| | - Meiyu Zhang
- Department of Pathology, School of Basic Medical Sciences, China Medical University, Shenyang 110000, China
| | - Xiaofang Liu
- Department of Pathology, The First Affiliated Hospital of China Medical University, Shenyang 110000, China
| | - Yuan Luo
- Department of Pathology, School of Basic Medical Sciences, China Medical University, Shenyang 110000, China
| | - Congcong Wang
- Department of Pathology, The First Affiliated Hospital of China Medical University, Shenyang 110000, China
| | - Haiyan Zhang
- Department of Pathology, The First People's Hospital of Jining, Shandong 272000, China
| | - Wenzhu Zhang
- Department of Pathology, School of Basic Medical Sciences, China Medical University, Shenyang 110000, China
| | - Yuchen Han
- Department of Pathology, School of Basic Medical Sciences, China Medical University, Shenyang 110000, China.,Department of Pathology, The First Affiliated Hospital of China Medical University, Shenyang 110000, China
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Galatenko VV, Galatenko AV, Samatov TR, Turchinovich AA, Shkurnikov MY, Makarova JA, Tonevitsky AG. Comprehensive network of miRNA-induced intergenic interactions and a biological role of its core in cancer. Sci Rep 2018; 8:2418. [PMID: 29402894 PMCID: PMC5799291 DOI: 10.1038/s41598-018-20215-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 01/16/2018] [Indexed: 12/22/2022] Open
Abstract
MicroRNAs (miRNAs) are a family of short noncoding RNAs that posttranscriptionally regulate gene expression and play an important role in multiple cellular processes. A significant percentage of miRNAs are intragenic, which is often functionally related to their host genes playing either antagonistic or synergistic roles. In this study, we constructed and analyzed the entire network of intergenic interactions induced by intragenic miRNAs. We further focused on the core of this network, which was defined as a union of nontrivial strongly connected components, i.e., sets of nodes (genes) mutually connected via directed paths. Both the entire network and its core possessed statistically significant non-random properties. Specifically, genes forming the core had high expression levels and low expression variance. Furthermore, the network core did not split into separate components corresponding to individual signalling or metabolic pathways, but integrated genes involved in key cellular processes, including DNA replication, transcription, protein homeostasis and cell metabolism. We suggest that the network core, consisting of genes mutually regulated by their intragenic miRNAs, could coordinate adjacent pathways or homeostatic control circuits, serving as a horizontal inter-circuit link. Notably, expression patterns of these genes had an efficient prognostic potential for breast and colorectal cancer patients.
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Affiliation(s)
- Vladimir V Galatenko
- Lomonosov Moscow State University, Leninskie Gory 1, 119991, Moscow, Russia. .,SRC Bioclinicum, Ugreshskaya str. 2/85, 115088, Moscow, Russia. .,Tauber Bioinformatics Research Center, University of Haifa, 199 Aba Khoushy Ave., Mount Carmel, 3498838, Haifa, Israel.
| | - Alexey V Galatenko
- Lomonosov Moscow State University, Leninskie Gory 1, 119991, Moscow, Russia
| | - Timur R Samatov
- SRC Bioclinicum, Ugreshskaya str. 2/85, 115088, Moscow, Russia.,Evotec International GmbH, Marie-Curie Str. 7, 37079, Göttingen, Germany
| | | | - Maxim Yu Shkurnikov
- P. Hertsen Moscow Oncology Research Institute, National Center of Medical Radiological Research, Second Botkinsky lane 3, 125284, Moscow, Russia
| | - Julia A Makarova
- P. Hertsen Moscow Oncology Research Institute, National Center of Medical Radiological Research, Second Botkinsky lane 3, 125284, Moscow, Russia.,Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova str. 32, 119991, Moscow, Russia
| | - Alexander G Tonevitsky
- SRC Bioclinicum, Ugreshskaya str. 2/85, 115088, Moscow, Russia. .,P. Hertsen Moscow Oncology Research Institute, National Center of Medical Radiological Research, Second Botkinsky lane 3, 125284, Moscow, Russia.
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Regulation of HMGB3 by antitumor miR-205-5p inhibits cancer cell aggressiveness and is involved in prostate cancer pathogenesis. J Hum Genet 2017; 63:195-205. [PMID: 29196733 DOI: 10.1038/s10038-017-0371-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 09/17/2017] [Accepted: 09/19/2017] [Indexed: 12/16/2022]
Abstract
Our recent determination of a microRNA (miRNA) expression signature in prostate cancer (PCa) revealed that miR-205-5p was significantly reduced in PCa tissues and that it acted as an antitumor miRNA. The aim of this study was to identify oncogenic genes and pathways in PCa cells that were regulated by antitumor miR-205-5p. Genome-wide gene expression analyses and in silico miRNA database searches showed that 37 genes were putative targets of miR-205-5p regulation. Among those genes, elevated expression levels of seven in particular (HMGB3, SPARC, MKI67, CENPF, CDK1, RHOU, and POLR2D) were associated with a shorter disease-free survival in a large number of patients in the The Cancer Genome Atlas (TCGA) database. We focused on high-mobility group box 3 (HMGB3) because it was the most downregulated by ectopic expression of miR-205-5p in PC3 cells and its expression was involved in PCa pathogenesis. Luciferase reporter assays showed that HMGB3 was directly regulated by miR-205-5p in PCa cells. Knockdown studies using si-HMGB3 showed that expression of HMGB3 enhanced PCa cell aggressiveness. Overexpression of HMGB3/HMGB3 was confirmed in naive PCa and castration-resistant PCa (CRPC) clinical specimens. Novel approaches to analysis of antitumor miRNA-regulated RNA networks in PCa cells may provide new insights into the pathogenic mechanisms of the disease.
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Chen ZH, Yu YP, Tao J, Liu S, Tseng G, Nalesnik M, Hamilton R, Bhargava R, Nelson JB, Pennathur A, Monga SP, Luketich JD, Michalopoulos GK, Luo JH. MAN2A1-FER Fusion Gene Is Expressed by Human Liver and Other Tumor Types and Has Oncogenic Activity in Mice. Gastroenterology 2017; 153:1120-1132.e15. [PMID: 28245430 PMCID: PMC5572118 DOI: 10.1053/j.gastro.2016.12.036] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 12/16/2016] [Accepted: 12/23/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Human tumors and liver cancer cell lines express the product of a fusion between the first 13 exons in the mannosidase α class 2A member 1 gene (MAN2A1) and the last 6 exons in the FER tyrosine kinase gene (FER), called MAN2A1-FER. We investigated whether MAN2A1-FER is expressed by human liver tumors and its role in liver carcinogenesis. METHODS We performed reverse transcription polymerase chain reaction analyses of 102 non-small cell lung tumors, 61 ovarian tumors, 70 liver tumors, 156 glioblastoma multiform samples, 27 esophageal adenocarcinomas, and 269 prostate cancer samples, as well as 10 nontumor liver tissues and 20 nontumor prostate tissues, collected at the University of Pittsburgh. We also measured expression by 15 human cancer cell lines. We expressed a tagged form of MAN2A1-FER in NIH3T3 and HEP3B (liver cancer) cells; Golgi were isolated for analysis. MAN2A1-FER was also overexpressed in PC3 or DU145 (prostate cancer), NIH3T3 (fibroblast), H23 (lung cancer), and A-172 (glioblastoma multiforme) cell lines and knocked out in HUH7 (liver cancer) cells. Cells were analyzed for proliferation and in invasion assays, and/or injected into flanks of severe combined immunodeficient mice; xenograft tumor growth and metastasis were assessed. Mice with hepatic deletion of PTEN were given tail-vein injections of MAN2A1-FER. RESULTS We detected MAN2A1-FER messenger RNA and fusion protein (114 kD) in the hepatocellular carcinoma cell line HUH7, as well as in liver tumors, esophageal adenocarcinoma, glioblastoma multiforme, prostate tumors, non-small cell lung tumors, and ovarian tumors, but not nontumor prostate or liver tissues. MAN2A1-FER protein retained the signal peptide for Golgi localization from MAN2A1 and translocated from the cytoplasm to Golgi in cancer cell lines. MAN2A1-FER had tyrosine kinase activity almost 4-fold higher than that of wild-type FER, and phosphorylated the epidermal growth factor receptor at tyrosine 88 in its N-terminus. Expression of MAN2A1-FER in 4 cell lines led to epidermal growth factor receptor activation of BRAF, MEK, and AKT; HUH7 cells with MAN2A1-FER knockout had significant decreases in phosphorylation of these proteins. Cell lines that expressed MAN2A1-FER had increased proliferation, colony formation, and invasiveness and formed larger (>2-fold) xenograft tumors in mice, with more metastases, than cells not expressing the fusion protein. HUH7 cells with MAN2A1-FER knockout formed smaller xenograft tumors, with fewer metastases, than control HUH7 cells. HUH7, A-172, and PC3 cells that expressed MAN2A1-FER were about 2-fold more sensitive to the FER kinase inhibitor crizotinib and the epidermal growth factor receptor kinase inhibitor canertinib; these drugs slowed growth of xenograft tumors from MAN2A1-FER cells and prevented their metastasis in mice. Hydrodynamic tail-vein injection of MAN2A1-FER resulted in rapid development of liver cancer in mice with hepatic disruption of Pten. CONCLUSIONS Many human tumor types and cancer cell lines express the MAN2A1-FER fusion, which increases proliferation and invasiveness of cancer cell lines and has liver oncogenic activity in mice.
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MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- Cell Line, Tumor
- Cell Movement
- Cell Proliferation
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Crizotinib
- Dose-Response Relationship, Drug
- Enzyme Activation
- ErbB Receptors/genetics
- ErbB Receptors/metabolism
- Gene Expression Regulation, Enzymologic
- Gene Expression Regulation, Neoplastic
- Gene Fusion
- Golgi Apparatus/enzymology
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/enzymology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Mice
- Mice, Knockout
- Mice, SCID
- Morpholines/pharmacology
- NIH 3T3 Cells
- Neoplasm Invasiveness
- Neoplasm Transplantation
- Oncogene Proteins, Fusion/antagonists & inhibitors
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/metabolism
- Oncogenes
- PTEN Phosphohydrolase/deficiency
- PTEN Phosphohydrolase/genetics
- Phosphorylation
- Protein Kinase Inhibitors/pharmacology
- Protein-Tyrosine Kinases/antagonists & inhibitors
- Protein-Tyrosine Kinases/genetics
- Protein-Tyrosine Kinases/metabolism
- Pyrazoles/pharmacology
- Pyridines/pharmacology
- RNA Interference
- Time Factors
- Transfection
- Tumor Burden
- alpha-Mannosidase/antagonists & inhibitors
- alpha-Mannosidase/genetics
- alpha-Mannosidase/metabolism
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Affiliation(s)
- Zhang-Hui Chen
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Yan P Yu
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Junyan Tao
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Silvia Liu
- Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - George Tseng
- Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Michael Nalesnik
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Ronald Hamilton
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Rohit Bhargava
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Joel B Nelson
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Arjun Pennathur
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Satdarshan P Monga
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - James D Luketich
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - George K Michalopoulos
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Jian-Hua Luo
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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50
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Ma Y, Fei L, Zhang M, Zhang W, Liu X, Wang C, Luo Y, Zhang H, Han Y. Lamin B2 binding to minichromosome maintenance complex component 7 promotes non-small cell lung carcinogenesis. Oncotarget 2017; 8:104813-104830. [PMID: 29285216 PMCID: PMC5739603 DOI: 10.18632/oncotarget.20338] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 07/17/2017] [Indexed: 12/13/2022] Open
Abstract
We investigated the role of lamin B2 in non-small cell lung cancer (NSCLC). We detected higher lamin B2 expression in 20 NSCLC tumor tissues obtained from The Cancer Genome Atlas than in adjacent normal lung tissues. LMNB2-RNAi knockdown in A549 and H1299 NSCLC cells inhibited colony formation, cell proliferation and G1-S cell cycle progression while increasing apoptosis. LMNB2 overexpression had the opposite effects. Tumor xenograft experiments showed diminished tumor growth with LMNB2 knockdown H1299 cells than with controls. Yeast two-hybrid studies revealed minichromosome maintenance complex component 7 (MCM7) to be a binding partner of lamin B2, which was confirmed by co-immunoprecipitation and co-localization studies. Lamin B2 binding enhanced DNA binding and helicase activities of MCM7. Deletion analysis with MCM7-N, MCM7-M or MCM7-C mutant proteins showed that lamin B2 binds to the C-terminus of MCM7, and competes with the binding of the tumor suppressor retinoblastoma (RB) protein. Immunohistochemical analysis of 150 NSCLC patient samples revealed that both lamin B2 and MCM7 levels positively correlated with histological grade and tumor TNM stage. Moreover, high lamin B2 and MCM7 levels correlated with shorter overall survival of NSCLC patients. In sum, these results show that lamin B2 interaction with MCM7 promotes NSCLC progression.
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Affiliation(s)
- Yinan Ma
- Departments of Pathology, School of Basic Medical Sciences, China Medical University, Liaoning, China
| | - Liangru Fei
- Departments of Pathology, School of Basic Medical Sciences, China Medical University, Liaoning, China
| | - Meiyu Zhang
- Departments of Pathology, School of Basic Medical Sciences, China Medical University, Liaoning, China
| | - Wenzhu Zhang
- Departments of Pathology, School of Basic Medical Sciences, China Medical University, Liaoning, China
| | - Xiaofang Liu
- Department of Pathology, The First Affiliated Hospital of China Medical University, Liaoning, China
| | - Congcong Wang
- Department of Pathology, The First Affiliated Hospital of China Medical University, Liaoning, China
| | - Yuan Luo
- Departments of Pathology, School of Basic Medical Sciences, China Medical University, Liaoning, China
| | - Haiyan Zhang
- Department of Pathology, The First People's Hospital of Jining, Shandong, China
| | - Yuchen Han
- Departments of Pathology, School of Basic Medical Sciences, China Medical University, Liaoning, China.,Department of Pathology, The First Affiliated Hospital of China Medical University, Liaoning, China.,Department of Pathology, Shanghai Chest Hospital, Shanghai, China
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