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Ku X, Wang J, Li H, Meng C, Yu F, Yu W, Li Z, Zhou Z, Zhang C, Hua Y, Yan W, Jin J. Proteomic Portrait of Human Lymphoma Reveals Protein Molecular Fingerprint of Disease Specific Subtypes and Progression. PHENOMICS (CHAM, SWITZERLAND) 2023; 3:148-166. [PMID: 37197640 PMCID: PMC10110798 DOI: 10.1007/s43657-022-00075-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 08/20/2022] [Accepted: 08/25/2022] [Indexed: 05/19/2023]
Abstract
An altered proteome in lymph nodes often suggests abnormal signaling pathways that may be associated with diverse lymphatic disorders. Current clinical biomarkers for histological classification of lymphomas have encountered many discrepancies, particularly for borderline cases. Therefore, we launched a comprehensive proteomic study aimed to establish a proteomic landscape of patients with various lymphatic disorders and identify proteomic variations associated with different disease subgroups. In this study, 109 fresh-frozen lymph node tissues from patients with various lymphatic disorders (with a focus on Non-Hodgkin's Lymphoma) were analyzed by data-independent acquisition mass spectrometry. A quantitative proteomic landscape was comprehensively characterized, leading to the identification of featured protein profiles for each subgroup. Potential correlations between clinical outcomes and expression profiles of signature proteins were also probed. Two representative signature proteins, phospholipid-binding proteins Annexin A6 (ANXA6) and Phospholipase C Gamma 2 (PLCG2), were successfully validated via immunohistochemistry. We also evaluated the capability of acquired proteomic signatures to segregate multiple lymphatic abnormalities and identified several core signature proteins, such as Sialic Acid Binding Ig Like Lectin 1 (SIGLEC1) and GTPase of immunity-associated protein 5 (GIMAP5). In summary, the established lympho-specific data resource provides a comprehensive map of protein expression in lymph nodes during multiple disease states, thus extending the existing human tissue proteome atlas. Our findings will be of great value in exploring protein expression and regulation underlying lymphatic malignancies, while also providing novel protein candidates to classify various lymphomas for more precise medical practice. Supplementary Information The online version contains supplementary material available at 10.1007/s43657-022-00075-w.
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Affiliation(s)
- Xin Ku
- Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240 China
| | - Jinghan Wang
- Department of Hematology, The First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, 310003 China
- Cancer Center, Zhejiang University, Hangzhou, 310003 China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, 310003 China
| | - Haikuo Li
- Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240 China
- Present Address: Division of Biology & Biomedical Sciences, Washington University in St. Louis School of Medicine, St. Louis, 63130 USA
| | - Chen Meng
- Bavarian Center for Biomolecular Mass Spectrometry, Technical University of Munich, 85354 Freising, Germany
| | - Fang Yu
- Department of Pathology, The First Affiliated Hospital of Zhejiang University, Hangzhou, 310003 China
| | - Wenjuan Yu
- Department of Hematology, The First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, 310003 China
| | - Zhongqi Li
- Department of Surgical Oncology, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310003 China
| | - Ziqi Zhou
- Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240 China
| | - Can Zhang
- Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240 China
| | - Ying Hua
- Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240 China
| | - Wei Yan
- Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240 China
| | - Jie Jin
- Department of Hematology, The First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, 310003 China
- Cancer Center, Zhejiang University, Hangzhou, 310003 China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, 310003 China
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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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The Alterations and Potential Roles of MCMs in Breast Cancer. JOURNAL OF ONCOLOGY 2021; 2021:7928937. [PMID: 34475953 PMCID: PMC8407980 DOI: 10.1155/2021/7928937] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/07/2021] [Accepted: 08/04/2021] [Indexed: 12/11/2022]
Abstract
The minichromosome maintenance (MCM) protein family plays a key role in eukaryotic DNA replication and has been confirmed to be associated with the occurrence and progression of many tumors. However, the expression levels, functions, and prognostic values of MCMs in breast cancer (BC) have not been clearly and systematically explained. In this article, we studied the transcriptional levels of MCMs in BC based on the Oncomine database. Kaplan-Meier plotter was used to analyze prognostic value of MCMs in human BC patients. Furthermore, we constructed a MCM coexpression gene network and performed functional annotation analysis through DAVID to reveal the functions of MCMs and coexpressed genes. The data showed that the expression of MCM2–8 and MCM10 but not MCM1 and MCM9 was upregulated in BC. Kaplan-Meier plotter analysis revealed that high transcriptional levels of MCM2, MCM4–7, and MCM10 were significantly related to low relapse-free survival (RFS) in BC patients. In contrast, high levels of MCM1 and MCM9 predicted high RFS for BC patients. This study suggests that MCM2, MCM4–7, and MCM10 possess great potential to be valuable prognostic biomarkers for BC and that MCM1 and MCM9 may serve as potential treatment targets for BC patients.
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Pezeshki S, Hashemi P, Salimi A, Ebrahimi S, Javanzad M, Monfaredan A. Evaluation of NUF2 and GMNN Expression in Prostate Cancer: Potential Biomarkers for Prostate Cancer Screening. Rep Biochem Mol Biol 2021; 10:224-232. [PMID: 34604412 PMCID: PMC8480293 DOI: 10.52547/rbmb.10.2.224] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 10/13/2020] [Indexed: 06/13/2023]
Abstract
BACKGROUND Prostate cancer (PC) is one of the most abundant cancers among men, and In Iran, has been responsible for 6% of all deaths from cancer in men. NUF2 and GMNN genes are considered as loci of susceptibility to tumorigenesis in humans. Alterations in expression of these genes have been reported in various malignancies. The aim of our study was to test whether different NUF2 and GMNN expression levels are associated with PC incidence and hence, might be considered as new molecular tools for PC screening. METHODS Biopsy samples from 40 PC patients and 41 healthy Iranian men were used to determine the relative gene expression. After RNA extraction and cDNA synthesis, samples were analyzed using TaqMan Quantitative Real time PCR. Patients' background information, included smoking habits and family histories of PC, were recorded. Stages and grades of their PC were classified by the TNM tumor, node, metastasis (TMN) staging system based on standard guidelines. RESULTS NUF2 expression did not significantly differ between the groups, while GMNN expression was significantly greater in the PC specimens than in the controls. CONCLUSION Regarding the significant role of GMNN in various tumor phenotypes, and its importance in PC progression, the alteration in GMNN expression in PC samples vs. controls indicate that the genetic profiling of this cancer might be considered to personalize therapy for each patient in the future.
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Affiliation(s)
- Shaghayegh Pezeshki
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Payam Hashemi
- School of Medicine, Tehran University of Medical Science, Tehran, Iran.
| | - Alireza Salimi
- Department of Molecular and Cellular Sciences, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Sheida Ebrahimi
- Department of Genetic, Faculty of biology, Yazd University, Yazd, Iran.
| | | | - Amir Monfaredan
- Department of Hematology, Faculty of Medicine, Tabriz Branch, Islamic Azad University, Tabriz, Iran.
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Zhou J, Wang M, Zhou Z, Wang W, Duan J, Wu G. Expression and Prognostic Value of MCM Family Genes in Osteosarcoma. Front Mol Biosci 2021; 8:668402. [PMID: 34239894 PMCID: PMC8257954 DOI: 10.3389/fmolb.2021.668402] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 06/10/2021] [Indexed: 11/16/2022] Open
Abstract
We performed a detailed cancer VS normal analysis to explore the expression and prognostic value of minichromosome maintenance (MCM) proteinsin human sarcoma. The mRNA expression levels of the MCM family genes in sarcoma were analyzed using data from ONCOMINE, GEPIA and CCLE databases. KEGG database was used to analyze the function of MCM2–7 complex in DNA replication and cell cycle. QRT-PCR and western blot were used to confirm the differential expression of key MCMs in osteosarcoma cell lines. Cell Counting Kit-8 and flow cytometry method were used to detect the cell proliferation and apoptosis of hFOB1.19 cells. The results showed that MCM1–7 and MCM10 were all upregulated in sarcoma in ONCOMINE database. MCM2, and MCM4–7 were highly expressed in sarcoma in GEPIA database. Moreover, all these ten factors were highly expressed in sarcoma cell lines. Furthermore, we analyzed the prognostic value of MCMs for sarcoma in GEPIA and found that MCM2, MCM3, MCM4, and MCM10 are prognostic biomarkers for human sarcoma. Analysis results using KEGG datasets showed that MCM4 and MCM6–7 constituted a core structure of MCM2-7 hexamers. We found that AzadC treatment and overexpression of MCM4 significantly promoted hFOB1.19 cell proliferation and inhibited apoptosis. The present study implied that MCM2–4 and 10 are potential biomarkers for the prognosis of sarcoma. The prognostic role of MCM4 may be attributable to the change in its DNA methylation patterns.
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Affiliation(s)
- Jian Zhou
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Mingyong Wang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China.,Institute of Osteoporosis Diagnosis and Treatments of Soochow University, Suzhou, China
| | - Zhen Zhou
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
| | - Wanchun Wang
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Juan Duan
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Gen Wu
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
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MCMs in Cancer: Prognostic Potential and Mechanisms. Anal Cell Pathol (Amst) 2020; 2020:3750294. [PMID: 32089988 PMCID: PMC7023756 DOI: 10.1155/2020/3750294] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 01/25/2020] [Indexed: 12/17/2022] Open
Abstract
Enabling replicative immortality and uncontrolled cell cycle are hallmarks of cancer cells. Minichromosome maintenance proteins (MCMs) exhibit helicase activity in replication initiation and play vital roles in controlling replication times within a cell cycle. Overexpressed MCMs are detected in various cancerous tissues and cancer cell lines. Previous studies have proposed MCMs as promising proliferation markers in cancers, while the prognostic values remain controversial and the underlying mechanisms remain unascertained. This review provides an overview of the significant findings regarding the cellular and tumorigenic functions of the MCM family. Besides, current evidence of the prognostic roles of MCMs is retrospectively reviewed. This work also offers insight into the mechanisms of MCMs prompting carcinogenesis and adverse prognosis, providing information for future research. Finally, MCMs in liver cancer are specifically discussed, and future perspectives are provided.
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Xiong DD, Zeng CM, Jiang L, Luo DZ, Chen G. Ki-67/MKI67 as a Predictive Biomarker for Clinical Outcome in Gastric Cancer Patients: an Updated Meta-analysis and Systematic Review involving 53 Studies and 7078 Patients. J Cancer 2019; 10:5339-5354. [PMID: 31632479 PMCID: PMC6775696 DOI: 10.7150/jca.30074] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 06/12/2019] [Indexed: 12/18/2022] Open
Abstract
Gastric cancer (GC) threatens human health worldwide and we performed this meta-analysis to evaluate the clinical value of Ki-67/MKI67 in patients with GC. The combined hazard ratio (HR), odds ratio (OR) and 95% confidence interval (95% CI) were calculated to assess the relationships of Ki-67/MKI67 expression with prognoses and clinicopathological characteristics. Genes co-expressed with MKI67 were collected for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and protein-protein interaction (PPI) network analyses. In total, 53 studies with 7078 patients were included in this study. The pooled HRs indicated that an elevated expression of Ki-67/MKI67 predicted an unfavorable overall survival (HR: 1.54, 95% CI: 1.33-1.78, P<0.0001) and disease-free survival (HR: 2.28, 95% CI: 1.43-3.64, P<0.0001) in GC patients. Additionally, in patients with advanced GC, a high Ki-67/MKI67 expression was also significantly connected with OS (HR: 1.37, 95% CI: 1.18-1.60, P<0.0001). The combined ORs showed that Ki-67/MKI67 expression was related to TNM stage (stage III/IV versus stage I/II: OR=1.93, 95% CI=1.34-2.78, P<0.0001), tumor differentiation (poor versus well/moderate: OR=1.94, 95% CI=1.32-2.85, P=0.001), lymph node metastasis (yes versus no: OR=1.67, 95% CI=1.23-2.25, P=0.001), distant metastasis (yes versus no: OR=1.67, 95% CI=1.24-2.26, P=0.001) and tumor invasion depth (T3/T4 versus Tis/T1/T2: OR=1.98, 95% CI=1.60-2.44, P<0.0001). The results of GO, KEGG pathway and PPI network analyses indicated that Ki-67/MKI67 may be involved in the development of GC via influencing P53 signaling pathway. Ki-67/MKI67 could be a potential indicator to predict the prognosis of patients with GC and identify high-risk cases. Detecting Ki-67/MKI67 expression in clinic may be helpful in optimizing individual treatment and further improving the survival expectancy of patients with GC.
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Affiliation(s)
- Dan-Dan Xiong
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, China
| | - Chu-Mei Zeng
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, China
| | - Ling Jiang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, China
| | - Dian-Zhong Luo
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, China
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Jinjia C, Xiaoyu W, Hui S, Wenhua L, Zhe Z, Xiaodong Z, Midie X. The use of DNA repair genes as prognostic indicators of gastric cancer. J Cancer 2019; 10:4866-4875. [PMID: 31598158 PMCID: PMC6775511 DOI: 10.7150/jca.31062] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 07/20/2019] [Indexed: 01/03/2023] Open
Abstract
DNA repair genes can be used as prognostic biomarkers in many types of cancer. We aimed to identify prognostic DNA repair genes in patients with gastric cancer (GC) by systematically bioinformatic approaches using web-based database. Global gene expression profiles from altogether 1,325 GC patients' samples from six independent datasets were included in the study. Clustering analysis was performed to screen potentially abnormal DNA repair genes related to the prognosis of GC, followed by unsupervised clustering analysis to identify molecular subtypes of GC. Characteristics and prognosis differences were analyzed among these molecular subtypes, and modular key genes in molecular subtypes were identified based on changes in expression correlation. Multivariate Cox proportional hazard analysis was used to find the independent prognostic gene. Kaplan-Meier method and log-rank test was used to estimate correlations of key DNA repair genes with GC patients'overall survival. There were 57 key genes significantly associated to GC patients' prognosis, and patients were stratified into three molecular clusters based on their expression profiles, in which patients in Cluster 3 showed the best survival (P < 0.05). After a three-phase training, test and validation process, the expression profile of 13 independent key DNA repair genes were identified can classify the prognostic risk of patients. Compared with patients with low-risk score, patients with high risk score in the training set had shorter overall survival (P < 0.0001). Furthermore, we verified equivalent findings by these key DNA repair genes in the test set (P < 0.0001) and the independent validation set (P = 0.0024). Our results suggest a great potential for the use of DNA repair gene profiling as a powerful marker in prognostication and inform treatment decisions for GC patients.
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Affiliation(s)
- Chang Jinjia
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Wang Xiaoyu
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Sun Hui
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Li Wenhua
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Zhang Zhe
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Zhu Xiaodong
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Xu Midie
- Department of Pathology & biobank, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
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The Analysis of Cell Cycle-related Proteins in Ovarian Clear Cell Carcinoma Versus High-grade Serous Carcinoma. Int J Gynecol Pathol 2019; 37:516-524. [PMID: 29019869 DOI: 10.1097/pgp.0000000000000461] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
In Japan, the frequency of ovarian clear cell carcinoma (CCC) is twice as high as that in the United States and Europe. Often, patient prognosis with CCC is poor because of chemoresistance. Here, we focus on the cell cycle, which is one of the mechanisms of chemoresistance. To detect the informative markers and improve the strategy of chemotherapy for CCC, we performed immunohistochemical staining of cell cycle-related proteins in ovarian malignant tumors. We detected that each of the 29 samples of CCC and high-grade serous carcinoma (HGSC) were necessary to reveal the significant differences in immunostaining and prognosis. We performed the immunostaining analysis using the antibodies of cell cycle-related proteins such as Ki-67, Cdt1, MCM7, and geminin. The positive rate of Cdt1 in the CCC group was significantly higher than that in the HGSC group (P<0.0001). However, the positive rate of geminin in the HGSC group was significantly higher than that in the CCC group (P<0.0001). The overall survival of CCC patients with high labeling index of Cdt1 was significantly worse than that of CCC patients with low labeling index of Cdt1 (P=0.004). The study results suggested that the cancer cells of CCC and HGSC exist in the G1 phase and S, G2, and M phases, respectively. The differences in cell cycle of CCC might be one of the reasons for chemotherapy resistance. Further investigations are necessary to reveal the usefulness of Cdt1 as a biomarker in CCC.
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10
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Meta-analysis of prognostic role of Ki-67 labeling index in gastric carcinoma. Int J Biol Markers 2017; 32:e447-e453. [PMID: 28561880 DOI: 10.5301/ijbm.5000277] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/27/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND This meta-analysis aimed to elucidate the prognostic role of the Ki-67 labeling index (LI) in gastric cancer (GC). METHODS The current study included 3,615 GC patients in 20 eligible studies, and evaluated the prognostic role of Ki-67 LI in GC. Subgroup analysis was conducted based on depth of invasion and cutoff value for high Ki-67 LI. RESULTS A high Ki-67 LI correlated significantly with worse survival (hazard ratio [HR] = 1.214, 95% confidence interval [CI], 1.004-1.468). However, there was no significant correlation between high Ki-67 LI and worse survival in advanced GC (HR = 1.252, 95% CI, 0.801-1.956). The subgroup with cutoff value ≤25% showed a significant correlation with worse survival, but this was not seen in the subgroup with cutoff >25% (HR = 1.433, 95% CI, 1.094-1.876 vs. HR = 1.005, 95% CI, 0.801-1.262). In addition, in the 10% <Ki-67 LI ≤ 20% range, there was a significant correlation between high Ki-67 LI and worse overall survival (HR = 1.931, 95% CI, 1.013-3.310). CONCLUSIONS A high Ki-67 LI correlated significantly with a worse prognosis in GC patients. Further cumulative studies for the optimal cutoff value for high Ki-67 LI are needed before application in clinical practice.
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11
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Zhao H, Wen J, Dong X, He R, Gao C, Zhang W, Zhang Z, Shen L. Identification of AQP3 and CD24 as biomarkers for carcinogenesis of gastric intestinal metaplasia. Oncotarget 2017; 8:63382-63391. [PMID: 28968998 PMCID: PMC5609930 DOI: 10.18632/oncotarget.18817] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 06/02/2017] [Indexed: 12/22/2022] Open
Abstract
Gastric intestinal metaplasia (GIM) is a precancerous gastric carcinoma (GC) lesion with pivotal roles in carcinogenesis. CD24, LGR5 and Ki67 are expressed in GIM; we previously demonstrated that aquaporin 3 (AQP3) is expressed in goblet cells and is positively correlated with GIM severity. However, the relationships of AQP3 with GIM classification and with other proteins, and their roles in the transition from GIM to gastric carcinoma (GC) remain unknown. Sixteen patients with intestinal-type GC were enrolled in this study. GIM was determined according to the updated Sydney system; GIM classification was determined via HID-AB staining, and AQP3, CD24, LGR5 and Ki67 expression were determined by immunohistochemistry. Type III GIM was more prevalent around the GC and displayed a positive association with GIM severity. CD24 was found in GIM, but LGR5 and Ki67 were found in tissues regardless of GIM. AQP3 expression showed significant correlation to type III GIM. CD24 expression was correlated with the marked GIM and incomplete GIM, while LGR5 expression decreased with GIM aggravation and did not have relationship with classification of GIM. However, Ki67 presented no association with GIM grade or classification. These observations identify AQP3 and CD24 as biomarkers for carcinogenesis of GIM, and may provide a precise strategy for screening at-risk candidates with GIM.
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Affiliation(s)
- Haijian Zhao
- Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu, China.,Division of Gastrointestinal Surgery, Department of General Surgery, Affiliated Huai'an Hospital, Xuzhou Medical University, Huai'an 223002, Jiangsu, China
| | - Jianfei Wen
- Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Xuqiang Dong
- Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Ruji He
- Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Cheng Gao
- Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Weiming Zhang
- Department of Pathology, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Zhihong Zhang
- Department of Pathology, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Lizong Shen
- Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu, China
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Abstract
Geminin is a protein involved in cell cycle progression. We aimed to evaluate the diagnostic value of geminin expression in cervical intraepithelial neoplasm (CIN).The expression of geminin, p16, and Ki67 was examined in 95 samples, including CIN1 (n = 45), CIN2/3 (n = 40), and normal cervical tissues (n = 10) by immunohistochemistry. The correlation between geminin or p16 expression and human papillomavirus (HPV) status was also evaluated.Geminin expression was negative in all normal tissues and expressed in 13.3% of CIN1 and 90.0% of CIN2/3. P16 expression was demonstrated in 24.4% of CIN1 and 87.5% of CIN2/3. The corresponding Ki67 expression was 35.6% and 95.0%. The specificity of geminin for differentiating between CIN1 and CIN2/3 was 86.7%, while for p16 and Ki67 the corresponding values were 75.6% and 64.4%. The sensitivity of geminin, p16, and Ki67 was 90.0%, 87.5%, and 95.0%, respectively. The positive predictive value (PPV) and accuracy of geminin were higher than p16 and Ki67. In addition, geminin expression showed a weak correlation with HPV status, but there was no association between p16 expression and HPV status.These results suggested that geminin had a high degree of sensitivity and specificity in determining CIN2/3. In addition to p16 and Ki67, geminin might be used as a new biomarker to distinguish between CIN1 and CIN2/3.
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Kushwaha PP, Rapalli KC, Kumar S. Geminin a multi task protein involved in cancer pathophysiology and developmental process: A review. Biochimie 2016; 131:115-127. [PMID: 27702582 DOI: 10.1016/j.biochi.2016.09.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 09/29/2016] [Indexed: 02/05/2023]
Abstract
DNA replicates in a timely manner with each cell division. Multiple proteins and factors are involved in the initiation of DNA replication including a dynamic interaction between Cdc10-dependent transcript (Cdt1) and Geminin (GMNN). A conformational change between GMNN-Cdt1 heterotrimer and heterohexamer complex is responsible for licensing or inhibition of the DNA replication. This molecular switch ensures a faithful DNA replication during each S phase of cell cycle. GMNN inhibits Cdt1-mediated minichromosome maintenance helicases (MCM) loading onto the chromatin-bound origin recognition complex (ORC) which results in the inhibition of pre-replication complex assembly. GMNN modulates DNA replication by direct binding to Cdt1, and thereby alters its stability and activity. GMNN is involved in various stages of development such as pre-implantation, germ layer formation, cell commitment and specification, maintenance of genome integrity at mid blastula transition, epithelial to mesenchymal transition during gastrulation, neural development, organogenesis and axis patterning. GMNN interacts with different proteins resulting in enhanced hematopoietic stem cell activity thereby activating the development-associated genes' transcription. GMNN expression is also associated with cancer pathophysiology and development. In this review we discussed the structure and function of GMNN in detail. Inhibitors of GMNN and their role in DNA replication, repair, cell cycle and apoptosis are reviewed. Further, we also discussed the role of GMNN in virus infected host cells.
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Affiliation(s)
- Prem Prakash Kushwaha
- School of Basic and Applied Sciences, Centre for Biochemistry and Microbial Sciences, Central University of Punjab, Bathinda, 151001, India
| | - Krishna Chaitanya Rapalli
- School of Basic and Applied Sciences, Centre for Animal Sciences, Central University of Punjab, Bathinda, 151001, India
| | - Shashank Kumar
- School of Basic and Applied Sciences, Centre for Biochemistry and Microbial Sciences, Central University of Punjab, Bathinda, 151001, India.
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Tökés AM, Szász AM, Geszti F, Lukács LV, Kenessey I, Turányi E, Meggyesházi N, Molnár IA, Fillinger J, Soltész I, Bálint K, Hanzély Z, Arató G, Szendröi M, Kulka J. Expression of proliferation markers Ki67, cyclin A, geminin and aurora-kinase A in primary breast carcinomas and corresponding distant metastases. J Clin Pathol 2015; 68:274-82. [DOI: 10.1136/jclinpath-2014-202607] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
AimsTo assess the expression of the following cell cycle regulatory proteins in primary metastatic breast carcinomas (MBCs) and on availability in matched distant metastases (DMs): Ki67, cyclin A, geminin and aurora-kinase A (aurkA); and to compare the expression of these markers in early MBC (EMBC) and late MBC separated into groups according to median time point on metastatic event occurred (28 months).MethodsThe expression of the above mentioned markers was analysed in a total of 47 primary MBCs and 59 DMs (out of which 37 were pairs) by immunohistochemistry. Fourteen breast carcinomas with no relapse over a 10-year follow-up period were utilised as control cases (CBC).ResultsAmong the MBCs, 22 metastasised to the bone, 4 to the lung and 21 to the central nervous system (CNS). Geminin (p<0.001) and Ki67 (p=0.001) were increased in the MBCs while aurkA and cyclin A showed no difference when compared with CBCs. There were no differences between aurkA, cyclin A and geminin expression in MBCs and DMs in general. Expression of Ki67 was, however, elevated (p=0.027) in DMs. In CNS metastases all markers showed elevated expression as compared to MBCs. In bone metastases, geminin was lower (p<0.001) compared with primary MBCs. In the metastases of the lung, the evaluated markers did not show different expression. According to the median follow-up until the metastatic event, Ki67 was found to be significantly elevated in EMBC (p=0.018).ConclusionsKi67 index and geminin distinguish a fraction of MBC with worse prognosis, showing increased levels in the latter in comparison to CBC being tumour-free over a 10-year follow-up period. Ki67 could possibly identify a group of MBCs that develop early DMs.
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15
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Bologna-Molina R, Bedoya-Borella AM, Soria-Moreira L, Soría-Suárez S. Molecular biomarkers of cell proliferation in ameloblastomas. World J Stomatol 2013; 2:79-85. [DOI: 10.5321/wjs.v2.i4.79] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2013] [Revised: 07/26/2013] [Accepted: 08/20/2013] [Indexed: 02/06/2023] Open
Abstract
Cell proliferation is a vital biological process that is important for all living organisms because of its role in growth and the maintenance of tissue homeostasis. The control of this important process differs greatly among benign and malignant neoplasms, and the evaluation of cell proliferation in neoplasms has become a common tool used by pathologists to provide useful information pertaining to diagnosis, clinical behavior, and treatment. The usefulness of information regarding cell proliferation has led to numerous studies on the value of these methods for diagnosing different types of tumors and for clinical decision making. Ameloblastomas are no exception. This review discusses the use of several classical molecular proliferation markers, including Ki-67, proliferating cell nuclear antigen, cyclin D1 and DNA topoisomerase II alpha, to characterize ameloblastomas and proposes the use of new proliferation markers used previously to characterize other neoplasms. The use of these biomarkers offers valuable opportunities to evaluate the biological behavior of this type of odontogenic tumor.
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Kimura F, Okayasu I, Kakinuma H, Satoh Y, Kuwao S, Saegusa M, Watanabe J. Differential diagnosis of reactive mesothelial cells and malignant mesothelioma cells using the cell proliferation markers minichromosome maintenance protein 7, geminin, topoisomerase II alpha and Ki-67. Acta Cytol 2013; 57:384-90. [PMID: 23860238 DOI: 10.1159/000350262] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Accepted: 02/25/2013] [Indexed: 11/19/2022]
Abstract
OBJECTIVE The aim of this study was to evaluate whether the immunocytochemical expression of cell proliferation markers, such as minichromosome maintenance protein 7 (MCM 7), geminin, topoisomerase II alpha (topo IIα) and Ki-67, which are different types of cell proliferation markers, could be useful for their differential diagnosis in reactive mesothelial cells and malignant mesothelioma cells obtained from body cavity fluids. STUDY DESIGN Samples diagnosed and later histologically confirmed as reactive mesothelial cells (39 cases) or malignant mesothelioma (32 cases) in body cavity fluids were examined. Immunocytochemical staining of MCM 7, geminin, topo IIα and Ki-67 was performed with the immunoperoxidase polymer method. RESULTS Labeling indices (LIs) of MCM 7 (cutoff value 20.0%; sensitivity 100%; specificity 100%), geminin (cutoff value 4.5%; sensitivity 88.0%; specificity 70.0%), topo IIα (cutoff value 11.0%; sensitivity 88.0%; specificity 92.0%) and Ki-67 (cutoff value 15.3%; sensitivity 78.0%; specificity 79.0%) of malignant mesothelioma cells were significantly higher than those of reactive mesothelial cells. CONCLUSION LIs of MCM 7, geminin and topo IIα can be reliable tools for the differential diagnosis of reactive mesothelial cells and malignant mesothelioma cells.
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Affiliation(s)
- Fumikazu Kimura
- Department of Pathological Analysis, Division of Medical Life Sciences, Hirosaki University Graduate School of Health Sciences, Hirosaki, Japan.
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Kapoor S. Emerging role of geminin as a prognostic marker in systemic malignancies. J Breast Cancer 2012; 15:481. [PMID: 23346181 PMCID: PMC3542860 DOI: 10.4048/jbc.2012.15.4.481] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Accepted: 11/13/2012] [Indexed: 12/02/2022] Open
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He WL, Li YH, Yang DJ, Song W, Chen XL, Liu FK, Wang Z, Li W, Chen W, Chen CY, He YL, Zhan WH. Combined evaluation of centromere protein H and Ki-67 as prognostic biomarker for patients with gastric carcinoma. Eur J Surg Oncol 2012; 39:141-9. [PMID: 22999412 DOI: 10.1016/j.ejso.2012.08.023] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2012] [Revised: 07/16/2012] [Accepted: 08/23/2012] [Indexed: 12/19/2022] Open
Abstract
AIM Centromere protein H (CENP-H) is one of the essential components of the human active kinetochore which close links with carcinogenesis. Its expression and clinical value of prognostic prediction for gastric cancer (GC) is unclear. METHODS CENP-H and Ki-67 expressions in specimens from 166 patients with GC were determined by tissue microarrays and immunostaining. Their correlations between patients' clinicopathologic features and prognosis were explored. For mechanisms, quantitative CENP-H examination on gastric cancer tissue and cell lines was performed via real-time quantitative PCR and Western Blot. Its effect on Survivin expression and cell function was evaluated via CENP-H knocking down (SiRNA) or overexpression. RESULTS Highly expression of CENP-H was found in 85 of 166 GC, showing a significant correlation with tumour size, depth of infiltration, lymph node metastasis, distant metastasis and UICC staging of gastric carcinoma (P < 0.05), as well as clinical prognosis (coefficient = 0.550, P < 0.001). Multivariate analysis revealed that combined CENP-H and Ki67 expression was a more valuable independent prognostic predictor for patients' survival (hazard ratio, 2.18; P = 0.0109). Furthermore, total mRNA and protein expression of CENP-H in GC tissue and cell lines were noticeably increased. Survivin expression and cell function including growth, proliferation and clonogenic ability could be inhibited by CENP-H siRNA or enhanced by overexpressing CENP-H. CONCLUSION High expression of CENP-H in GC indicates poor prognosis and Survivin may mediate its procancer role. Combined evaluation of CENP-H and Ki-67 aids in predicting the clinical prognosis.
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Affiliation(s)
- W L He
- Department of Gastrointestinal and Pancreatic Surgery and Centre of Gastric Cancer, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China
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Di Bonito M, Cantile M, Collina F, Scognamiglio G, Cerrone M, La Mantia E, Barbato A, Liguori G, Botti G. Overexpression of Cell Cycle Progression Inhibitor Geminin is Associated with Tumor Stem-Like Phenotype of Triple-Negative Breast Cancer. J Breast Cancer 2012; 15:162-71. [PMID: 22807933 PMCID: PMC3395739 DOI: 10.4048/jbc.2012.15.2.162] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2011] [Accepted: 04/16/2012] [Indexed: 01/05/2023] Open
Abstract
PURPOSE Triple-negative breast cancer, has a significant clinical relevance being associated with a shorter median time to relapse and death and does not respond to endocrine therapy or other available targeted agents. For this reason, identifying the molecular pathways associated with increased aggressiveness, for example the presence of stem cell populations within the tumor and alteration of genes associated with cell cycle regulation represents an important objective in the clinical research into this neoplasm. METHODS To investigate the role of cell cycle progression inhibitor Geminin in triple-negative breast cancers and its potential correlation with stem-like phenotype of this neoplasm, we used tissue microarray technology to build a specific triple-negative breast cancer tissue micro-array. Geminin and cancer stem cell marker CD133 expression was further investigated at the mRNA level for selected breast tumor samples through realtime polymerase chain reaction quantification. RESULTS Our results showed that CD133 expression was significantly associated to high Geminin expression (p=0.017), a strong association between Ki-67 and tumor grade (p=0.020) and an inverse association between Geminin expression and lymphonode metastases (p=0.058), and a trend of statistically significance between Geminin marker expression and survival of triple-negative breast cancer patients (p=0.076). CONCLUSION The strong association between the expression of CD133 and Geminin could be useful in molecular stratification of breast tumors and in particular of triple-negative breast cancers.
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