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Tian W, Zhao J, Zhang X, Li P, Li X, Hong Y, Li S. RUNX1 regulates MCM2/CDC20 to promote COAD progression modified by deubiquitination of USP31. Sci Rep 2024; 14:13906. [PMID: 38886545 PMCID: PMC11183096 DOI: 10.1038/s41598-024-64726-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 06/12/2024] [Indexed: 06/20/2024] Open
Abstract
Colon adenocarcinoma (COAD) is the second leading cause of cancer death, and there is still a lack of diagnostic biomarkers and therapeutic targets. In this study, bioinformatics analysis of the TCGA database was used to obtain RUNX1, a gene with prognostic value in COAD. RUNX1 plays an important role in many malignancies, and its molecular regulatory mechanisms in COAD remain to be fully understood. To explore the physiological role of RUNX1, we performed functional analyses, such as CCK-8, colony formation and migration assays. In addition, we investigated the underlying mechanisms using transcriptome sequencing and chromatin immunoprecipitation assays. RUNX1 is highly expressed in COAD patients and significantly correlates with survival. Silencing of RUNX1 significantly slowed down the proliferation and migratory capacity of COAD cells. Furthermore, we demonstrate that CDC20 and MCM2 may be target genes of RUNX1, and that RUNX1 may be physically linked to the deubiquitinating enzyme USP31, which mediates the upregulation of RUNX1 protein to promote transcriptional function. Our results may provide new insights into the mechanism of action of RUNX1 in COAD and reveal potential therapeutic targets for this disease.
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Affiliation(s)
- Wei Tian
- The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Dalian Medical University, Dalian, China
| | - Jingyuan Zhao
- Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xinyu Zhang
- The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Dalian Medical University, Dalian, China
| | - Pengfei Li
- The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Dalian Medical University, Dalian, China
| | - Xuening Li
- Dalian Medical University, Dalian, China
| | - Yuan Hong
- Clinical Laboratory Center, Dalian Municipal Central Hospital, Dalian, China.
| | - Shuai Li
- Department of Pharmacy, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
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Zhou H, Wang J, Wen T. The molecular neural mechanism underlying the acceleration of brain aging due to Dcf1 deficiency. Mol Cell Neurosci 2023; 126:103884. [PMID: 37506857 DOI: 10.1016/j.mcn.2023.103884] [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: 05/01/2023] [Revised: 07/11/2023] [Accepted: 07/24/2023] [Indexed: 07/30/2023] Open
Abstract
Owing to the continuous increase in human life expectancy, the management of aging-related diseases has become an urgent issue. The brain dominates the central nervous system; therefore, brain aging is a key area of aging-related research. We previously uncovered that dendritic cell factor 1 (Dcf1) maintains the stemness of neural stem cells and its expression in Drosophila can prolong lifespan, suggesting an association between Dcf1 and aging; however, the specific underlying neural mechanism remains unclear. In the present study, we show for the first time that hippocampal neurogenesis is decreased in aged Dcf1-/- mice, which leads to a decrease in the number of brain neurons and an increased number of senescent cells. Moreover, astrocytes proliferate abnormally and express elevated mRNA levels of aging-related factors, in addition to displaying increased activation of Akt and Foxo3a. Finally, behavioral tests confirm that aged Dcf1-/- mice exhibit a significant decline in cognitive abilities related to learning and memory. In conclusion, we reveal a novel mechanism underlying brain aging triggered by Dcf1 deficiency at the molecular, cellular, tissue, and behavioral levels, providing a new perspective for the exploration of brain aging.
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Affiliation(s)
- Haicong Zhou
- School of Environmental and Chemical Engineering, Shanghai University, Shanghai, China; Laboratory of Molecular Neural Biology, School of Life Sciences, Shanghai University Shanghai, China
| | - Jiao Wang
- Laboratory of Molecular Neural Biology, School of Life Sciences, Shanghai University Shanghai, China
| | - Tieqiao Wen
- Laboratory of Molecular Neural Biology, School of Life Sciences, Shanghai University Shanghai, China.
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Amin R, Talwar A. Factors Influencing the Aggressive Behavior of Odontogenic Keratocyst: A Narrative Review. JOURNAL OF HEALTH AND ALLIED SCIENCES NU 2022. [DOI: 10.1055/s-0042-1758036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
AbstractDuring odontogenesis, the dental lamina disintegrates, leaving behind the remnants. Odontogenic pathologies such as cysts and tumors can arise from these remnants. The odontogenic keratocyte (OKC) arises from dental lamina remnants. Among the cysts, the odontogenic keratocyst is the most controversial. There is convincing evidence that inflammation plays a significant role in the pathogenesis and expansion of OKCs. Several factors mediate the proliferative capacity of the epithelial lining. The presence of mast cells close to the epithelial lining, cystic pressure build-up by vascular endothelial growth factors (VEGFs), and other cytokines contribute to the cystic expansion. Fibroblast activation by inflammation in the connective tissue stroma and changes in the epithelial lining are responsible for the aggressive nature of OKC. The use of molecular methodologies gives more profound insights into the factors influencing the progression of the lesion and helps develop newer treatment modalities for OKC. This review describes the characteristics that determine the aggressive behavior of this unique cyst.
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Affiliation(s)
- Reshma Amin
- Nitte (Deemed to be University), AB Shetty Memorial Institute of Dental Science, Department of Oral Pathology, Mangalore
| | - Avaneendra Talwar
- Nitte (Deemed to be University), AB Shetty Memorial Institute of Dental Science, Mangalore
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MCM2 in human cancer: functions, mechanisms, and clinical significance. Mol Med 2022; 28:128. [PMID: 36303105 PMCID: PMC9615236 DOI: 10.1186/s10020-022-00555-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 10/10/2022] [Indexed: 11/18/2022] Open
Abstract
Background Aberrant DNA replication is the main source of genomic instability that leads to tumorigenesis and progression. MCM2, a core subunit of eukaryotic helicase, plays a vital role in DNA replication. The dysfunction of MCM2 results in the occurrence and progression of multiple cancers through impairing DNA replication and cell proliferation. Conclusions MCM2 is a vital regulator in DNA replication. The overexpression of MCM2 was detected in multiple types of cancers, and the dysfunction of MCM2 was correlated with the progression and poor prognoses of malignant tumors. According to the altered expression of MCM2 and its correlation with clinicopathological features of cancer patients, MCM2 was thought to be a sensitive biomarker for cancer diagnosis, prognosis, and chemotherapy response. The anti-tumor effect induced by MCM2 inhibition implies the potential of MCM2 to be a novel therapeutic target for cancer treatment. Since DNA replication stress, which may stimulate anti-tumor immunity, frequently occurs in MCM2 deficient cells, it also proposes the possibility that MCM2 targeting improves the effect of tumor immunotherapy.
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Zhang J, Zhang H, Wang Y, Wang Q. MCM2-7 in Clear Cell Renal Cell Carcinoma: MCM7 Promotes Tumor Cell Proliferation. Front Oncol 2021; 11:782755. [PMID: 34993142 PMCID: PMC8724441 DOI: 10.3389/fonc.2021.782755] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 12/02/2021] [Indexed: 11/23/2022] Open
Abstract
Background Clear cell renal cell carcinoma (ccRCC) accounts for 60-70% of renal cell carcinoma (RCC) cases. Finding more therapeutic targets for advanced ccRCC is an urgent mission. The minichromosome maintenance proteins 2-7 (MCM2-7) protein forms a stable heterohexamer and plays an important role in DNA replication in eukaryotic cells. In the study, we provide a comprehensive study of MCM2-7 genes expression and their potential roles in ccRCC. Methods The expression and prognosis of the MCM2-7 genes in ccRCC were analyzed using data from TCGA, GEO and ArrayExpress. MCM2-7 related genes were identified by weighted co-expression network analysis (WGCNA) and Metascape. CancerSEA and GSEA were used to analyze the function of MCM2–7 genes in ccRCC. The gene effect scores (CERES) of MCM2-7, which reflects carcinogenic or tumor suppressor, were obtained from DepMap. We used clinical and expression data of MCM2-7 from the TCGA dataset and the LASSO Cox regression analysis to develop a risk score to predict survival of patients with ccRCC. The correlations between risk score and other clinical indicators such as gender, age and stage were also analyzed. Further validation of this risk score was engaged in another cohort, E-MTAB-1980 from the ArrayExpress dataset. Results The mRNA and protein expression of MCM2-7 were increased in ccRCC compared with normal tissues. High MCM2, MCM4, MCM6 and MCM7 expression were associated with a poor prognosis of ccRCC patients. Functional enrichment analysis revealed that MCM2-7 might influence the progress of ccRCC by regulating the cell cycle. Knockdown of MCM7 can inhibit the proliferation of ccRCC cells. A two-gene risk score including MCM4 and MCM6 can predict overall survival (OS) of ccRCC patients. The risk score was successfully verified by further using Arrayexpress cohort. Conclusion We analyze MCM2-7 mRNA and protein levels in ccRCC. MCM7 is determined to promote tumor proliferation. Meanwhile, our study has determined a risk score model composed of MCM2-7 can predict the prognosis of ccRCC patients, which may help future treatment strategies.
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Affiliation(s)
- Junneng Zhang
- Laboratory Medicine Department, The Fifth Hospital of Xiamen, Xiamen, China
- *Correspondence: Junneng Zhang, ; Qingshui Wang,
| | - Huanzong Zhang
- Laboratory Medicine Department, The Fifth Hospital of Xiamen, Xiamen, China
| | - Yinghui Wang
- Laboratory Medicine Department, The Fifth Hospital of Xiamen, Xiamen, China
| | - Qingshui Wang
- Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, China
- *Correspondence: Junneng Zhang, ; Qingshui Wang,
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Alaeddini M, Etemad-Moghadam S. Cell kinetic markers in cutaneous squamous and basal cell carcinoma of the head and neck. Braz J Otorhinolaryngol 2020; 88:529-532. [PMID: 32972865 PMCID: PMC9422672 DOI: 10.1016/j.bjorl.2020.07.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 05/28/2020] [Accepted: 07/13/2020] [Indexed: 11/24/2022] Open
Abstract
Introduction Proliferation markers play a significant role in the biologic behavior of tumors. Geminin is a known inhibitor of the cell cycle and DNA replication and has not been previously reported in cutaneous basal and squamous cell carcinomas of the head and neck. Objectives We aimed to investigate proliferation markers ki67, MCM2, and geminin in head and neck cutaneous basal and squamous cell carcinomas. Methods Forty cases of each tumor were immuostained with ki67, MCM2, and geminin followed by assessment of labeling indices (LIs). MCM2/ki67- and geminin/ki67-ratios were also determined; t-test was used for statistical analysis (p < 0.05). Results There was no significant difference in ki67 (p = 0.06) and MCM2 (p = 0.46) between cutaneous basal and squamous cell carcinomas; however, geminin LI was significantly higher in squamous cell carcinomas compared to cutaneous basal cell carcinomas (p < 0.001). Only geminin/ki67 showed a significant difference between the two tumors with the ratio showing significantly higher numbers in squamous cell carcinomas (p = 0.015). Conclusions Geminin could be regarded as an effective factor in the pathogenesis of head and neck cutaneous cutaneous basal cell carcinomas and squamous cell carcinomas and may be one of the responsible elements in the difference between the biologic behavior of these tumors.
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Affiliation(s)
- Mojgan Alaeddini
- Dental Research Center, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahroo Etemad-Moghadam
- Dental Research Center, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
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One-Week High-Intensity Interval Training Increases Hippocampal Plasticity and Mitochondrial Content without Changes in Redox State. Antioxidants (Basel) 2020; 9:antiox9050445. [PMID: 32455608 PMCID: PMC7278594 DOI: 10.3390/antiox9050445] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/24/2020] [Accepted: 04/25/2020] [Indexed: 12/20/2022] Open
Abstract
Evidence suggests that physical exercise has effects on neuronal plasticity as well as overall brain health. This effect has been linked to exercise capacity in modulating the antioxidant status, when the oxidative stress is usually linked to the neuronal damage. Although high-intensity interval training (HIIT) is the training-trend worldwide, its effect on brain function is still unclear. Thus, we aimed to assess the neuroplasticity, mitochondrial, and redox status after one-week HIIT training. Male (C57Bl/6) mice were assigned to non-trained or HIIT groups. The HIIT protocol consisted of three days with short bouts at 130% of maximum speed (Vmax), intercalated with moderate-intensity continuous exercise sessions of 30 min at 60% Vmax. The mass spectrometry analyses showed that one-week of HIIT increased minichromosome maintenance complex component 2 (MCM2), brain derived neutrophic factor (BDNF), doublecortin (DCX) and voltage-dependent anion-selective channel protein 2 (VDAC), and decreased mitochondrial superoxide dismutase 2 (SOD 2) in the hippocampus. In addition, one-week of HIIT promoted no changes in H2O2 production and carbonylated protein concentration in the hippocampus as well as in superoxide anion production in the dentate gyrus. In conclusion, our one-week HIIT protocol increased neuroplasticity and mitochondrial content regardless of changes in redox status, adding new insights into the neuronal modulation induced by new training models.
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Maros ME, Schnaidt S, Balla P, Kelemen Z, Sapi Z, Szendroi M, Laszlo T, Forsyth R, Picci P, Krenacs T. In situ cell cycle analysis in giant cell tumor of bone reveals patients with elevated risk of reduced progression-free survival. Bone 2019; 127:188-198. [PMID: 31233932 DOI: 10.1016/j.bone.2019.06.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 05/23/2019] [Accepted: 06/21/2019] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Giant cell tumor of bone (GCTB) is a frequently recurring locally aggressive osteolytic lesion, where pathological osteoclastogenesis and bone destruction are driven by neoplastic stromal cells. Here, we studied if cell cycle fractions within the mononuclear cell compartment of GCTB can predict its progression-free survival (PFS). METHODS 154 cases (100 primaries and 54 recurrent) from 139 patients of 40 progression events, was studied using tissue microarrays. Ploidy and in situ cell cycle progression related proteins including Ki67 and those linked with replication licensing (mcm2), G1-phase (cyclin D1, Cdk4), and S-G2-M-phase (cyclin A; Cdk2) fractions; cell cycle control (p21waf1) and repression (geminin), were tested. The Prentice-Williams-Peterson (PWP) gap-time models with the Akaike information criterion (AIC) were used for PFS analysis. RESULTS Cluster analysis showed good correlation between functionally related marker positive cell fractions indicating no major cell cycle arrested cell populations in GCTB. Increasing hazard of progression was statistically associated with the elevated post-G1/S-phase cell fractions. Univariate analysis revealed significant negative association of poly-/aneuploidy (p < 0.0001), and elevated cyclin A (p < 0.001), geminin (p = 0.015), mcm2 (p = 0.016), cyclin D1 (p = 0.022) and Ki67 (B56: p = 0.0543; and Mib1: p = 0.0564 -strong trend) positive cell fractions with PFS. The highest-ranked multivariate interaction model (AIC = 269.5) also included ploidy (HR 5.68, 95%CI: 2.62-12.31, p < 0.0001), mcm2 (p = 0.609), cyclin D1 (HR 1.89, 95%CI: 0.88-4.09, p = 0.105) and cyclin A (p < 0.0001). The first and second best prognostic models without interaction (AIC = 271.6) and the sensitivity analysis (AIC = 265.7) further confirmed the prognostic relevance of combining these markers. CONCLUSION Ploidy and elevated replication licensing (mcm2), G1-phase (cyclin D1) and post-G1 phase (cyclin A) marker positive cell fractions, indicating enhanced cell cycle progression, can assist in identifying GCTB patients with increased risk for a reduced PFS.
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Affiliation(s)
- Mate E Maros
- 1(st) Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary; Department of Neuroradiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Sven Schnaidt
- Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
| | - Peter Balla
- 1(st) Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Zoltan Kelemen
- 1(st) Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Zoltan Sapi
- 1(st) Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Miklos Szendroi
- Department of Orthopedics, Semmelweis University, Budapest, Hungary
| | - Tamas Laszlo
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Semmelweis University, Budapest, Hungary
| | - Ramses Forsyth
- Department of Anatomic Pathology, University of Brussels, Belgium
| | - Piero Picci
- Laboratory of Experimental Oncology, Institute of Orthopedics Rizzoli, Bologna, Italy
| | - Tibor Krenacs
- 1(st) Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
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Wu W, Wang X, Shan C, Li Y, Li F. Minichromosome maintenance protein 2 correlates with the malignant status and regulates proliferation and cell cycle in lung squamous cell carcinoma. Onco Targets Ther 2018; 11:5025-5034. [PMID: 30174440 PMCID: PMC6109654 DOI: 10.2147/ott.s169002] [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] [Indexed: 12/13/2022] Open
Abstract
Background Minichromosome maintenance protein 2 (MCM2), which is a member of MCM family, has been found to be a relevant marker for progression and prognosis in a variety of human cancers. Due to lack of effective therapeutic target in lung squamous cell carcinoma (LUSC) patients, the aim of our study was to screen and identify biomarkers which are associated to clinicopathological characteristics including prognosis in LUSC patients. Methods The expression status of MCM2 in lung cancer was analyzed using the publicly available Gene Expression Omnibus databases (GSE3268 and GSE10245). The mRNA and protein expression of MCM2 in lung cancer tissues and cell lines was detected by quantitative real-time PCR and Western blot, and the association between MCM2 expression and clinicopathological factors was analyzed by immunohistochemistry. The loss-of-function study of MCM2 was conducted in LUSC cell lines. Results In our study, we found MCM2 expression was increased in LUSC tissues compared with paired adjacent normal lung tissues or lung adenocarcinoma tissues through analyzing microarray data sets (GSE3268 and GSE10245), which confirmed that MCM2 mRNA and protein were overexpressed in LUSC tissues and cell lines. Meanwhile, we analyzed the association between MCM2 protein expression and clinicopathological characteristics of LUSC patients, and found high expression of MCM2 protein was obviously associated with malign differentiated degree, advanced clinical stage, large tumor size, more lymph node metastasis and present distant metastasis. The survival analysis showed MCM2 overexpression was an independent unfavorable prognostic factor for LUSC patients. Conclusion MCM2 is involved in the development and progression of LUSC as an oncogene, and thereby may act as a potential therapeutic target for LUSC patients.
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Affiliation(s)
- Wei Wu
- Department of Respiratory Medicine, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, People's Republic of China,
| | - Xianwei Wang
- Department of Respiratory Medicine, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, People's Republic of China,
| | - Changting Shan
- Department of Respiratory Medicine, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, People's Republic of China,
| | - Yong Li
- Department of Emergency, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, People's Republic of China
| | - Fengzhu Li
- Department of Paediatric Surgery, Jining No 1 People's Hospital, Jining, Shandong 272011, People's Republic of China
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Wang WH, Xie TY, Xie GL, Ren ZL, Li JM. An Integrated Approach for Identifying Molecular Subtypes in Human Colon Cancer Using Gene Expression Data. Genes (Basel) 2018; 9:E397. [PMID: 30072645 PMCID: PMC6115727 DOI: 10.3390/genes9080397] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 07/18/2018] [Accepted: 07/27/2018] [Indexed: 02/08/2023] Open
Abstract
Identifying molecular subtypes of colorectal cancer (CRC) may allow for more rational, patient-specific treatment. Various studies have identified molecular subtypes for CRC using gene expression data, but they are inconsistent and further research is necessary. From a methodological point of view, a progressive approach is needed to identify molecular subtypes in human colon cancer using gene expression data. We propose an approach to identify the molecular subtypes of colon cancer that integrates denoising by the Bayesian robust principal component analysis (BRPCA) algorithm, hierarchical clustering by the directed bubble hierarchical tree (DBHT) algorithm, and feature gene selection by an improved differential evolution based feature selection method (DEFSW) algorithm. In this approach, the normal samples being completely and exclusively clustered into one class is considered to be the standard of reasonable clustering subtypes, and the feature selection pays attention to imbalances of samples among subtypes. With this approach, we identified the molecular subtypes of colon cancer on the mRNA gene expression dataset of 153 colon cancer samples and 19 normal control samples of the Cancer Genome Atlas (TCGA) project. The colon cancer was clustered into 7 subtypes with 44 feature genes. Our approach could identify finer subtypes of colon cancer with fewer feature genes than the other two recent studies and exhibits a generic methodology that might be applied to identify the subtypes of other cancers.
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Affiliation(s)
- Wen-Hui Wang
- State Key Laboratory of Organ Failure Research, Division of Nephrology, Southern Medical University, Guangzhou 510515, China.
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
- Network Information Center, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510655, China.
| | - Ting-Yan Xie
- State Key Laboratory of Organ Failure Research, Division of Nephrology, Southern Medical University, Guangzhou 510515, China.
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
| | - Guang-Lei Xie
- State Key Laboratory of Organ Failure Research, Division of Nephrology, Southern Medical University, Guangzhou 510515, China.
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
| | - Zhong-Lu Ren
- Center for Systems Medical Genetics, Department of Obstetrics & Gynecology Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
- Laboratory of Systems Neuroscience, Institute of Mental Health Southern Medical University, Southern Medical University, Guangzhou 510515, China.
| | - Jin-Ming Li
- State Key Laboratory of Organ Failure Research, Division of Nephrology, Southern Medical University, Guangzhou 510515, China.
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
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MCM2 expression in serrated polyps demonstrates aberrant cellular proliferation. Hum Pathol 2017; 63:177-183. [PMID: 28302537 DOI: 10.1016/j.humpath.2017.02.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 02/06/2017] [Accepted: 02/24/2017] [Indexed: 01/06/2023]
Abstract
In normal colonic epithelium, the proliferative zone is limited to the lower half of the colonic crypt. Evaluating the changes in the colonic epithelial proliferation can be useful in understanding pathophysiology of various diseases. Our aim was to investigate the proliferative compartment of serrated polyps (SPs) using MCM2, a protein involved in DNA replication, and assess for changes along the SP spectrum. Immunohistochemistry was performed on serrated polyps (16 microvesicular-type hyperplastic polyps (HP), 58 sessile serrated adenomas (SSA), 7 SSAs with dysplasia) and 6 sections of normal colon using anti-MCM2 antibody. Multiple sections of normal colon showed the following pattern for MCM2 and Ki-67 staining: positive nuclear staining of the lower half of the colonic crypts and/or slightly expanded to the lower two-thirds of the crypt. By MCM2, SPs show expansion of the proliferative compartments; 81.3% of HPs and 100% of SSAs showed some degree of full crypt MCM2 staining. SSAs with dysplasia showed consistent diffuse polyp staining. Aberrant staining in adjacent normal mucosa was also seen in SSAs with dysplasia and in a subset of non-dysplastic SSAs. By using MCM2, we show that serrated polyps exhibit changes in proliferation during progression along the pathway. HPs and SSAs show a similar highly proliferative profile. Aberrant proliferative cell staining patterns in adjacent normal colonic mucosa as seen in SSAs with dysplasia and a subset of SSAs suggest a field effect phenomenon. This indicates that changes in the colonic micro-environment may promote adenoma morphogenesis and predisposition to malignancy.
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Marinaro F, Marzi MJ, Hoffmann N, Amin H, Pelizzoli R, Niola F, Nicassio F, De Pietri Tonelli D. MicroRNA-independent functions of DGCR8 are essential for neocortical development and TBR1 expression. EMBO Rep 2017; 18:603-618. [PMID: 28232627 DOI: 10.15252/embr.201642800] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 01/16/2017] [Accepted: 01/19/2017] [Indexed: 12/31/2022] Open
Abstract
Recent evidence indicates that the miRNA biogenesis factors DROSHA, DGCR8, and DICER exert non-overlapping functions, and have also roles in miRNA-independent regulatory mechanisms. However, it is currently unknown whether miRNA-independent functions of DGCR8 play any role in the maintenance of neuronal progenitors and during corticogenesis. Here, by phenotypic comparison of cortices from conditional Dgcr8 and Dicer knockout mice, we show that Dgcr8 deletion, in contrast to Dicer depletion, leads to premature differentiation of neural progenitor cells and overproduction of TBR1-positive neurons. Remarkably, depletion of miRNAs upon DCGR8 loss is reduced compared to DICER loss, indicating that these phenotypic differences are mediated by miRNA-independent functions of DGCR8. We show that Dgcr8 mutations induce an earlier and stronger phenotype in the developing nervous system compared to Dicer mutants and that miRNA-independent functions of DGCR8 are critical for corticogenesis. Finally, our data also suggest that the Microprocessor complex, with DROSHA and DGCR8 as core components, directly regulates the Tbr1 transcript, containing evolutionarily conserved hairpins that resemble miRNA precursors, independently of miRNAs.
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Affiliation(s)
- Federica Marinaro
- Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genoa, Italy
| | - Matteo J Marzi
- Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy
| | - Nadin Hoffmann
- Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genoa, Italy
| | - Hayder Amin
- Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genoa, Italy
| | - Roberta Pelizzoli
- Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genoa, Italy
| | - Francesco Niola
- Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genoa, Italy
| | - Francesco Nicassio
- Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy
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Winther TL, Torp SH. MCM7 expression is a promising predictor of recurrence in patients surgically resected for meningiomas. J Neurooncol 2016; 131:575-583. [PMID: 27868157 DOI: 10.1007/s11060-016-2329-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Accepted: 11/08/2016] [Indexed: 12/27/2022]
Abstract
Patients with high risk of recurrence after meningioma resection might benefit from adjuvant radiation therapy and closer clinical follow-up. While the World Health Organization (WHO) classification and the MIB-1 biomarker are applied in the clinical practice to identify these patients, the reliability of these methods is questionable. To improve the prediction of tumor recurrence, this study evaluated and compared the prognostic usefulness of the biomarker MCM7 with the conventional mitotic index and the MIB-1 biomarker. One hundred sixty patients were retrospectively analyzed. The expression of MIB-1 and MCM7 was determined as proliferative indices (PI-percentage of positive immunoreactive cells among 1000 tumor cells) in tissue microarrays. MCM7 PI revealed significantly higher indices in recurrent meningiomas compared with non-recurrent meningiomas (p = 0.020), while mitotic index and MIB-1 PI did not reach statistical significance (p ≥ 0.547). The optimal cutoff values for recurrence prediction were 3% for MIB-1 PI and 8% for MCM7 PI. MCM7 PI was significantly associated with recurrence-free survival in COX multivariate survival analyses (p = 0.005), while no association was found with mitotic index or MIB-1 (p ≥ 0.153). MCM7 PI allowed for the most accurate prediction of recurrence, obtaining the highest sensitivity and the greatest area under the ROC curve. These results proved that MCM7 PI is a better method for identifying patients with risk of recurrence compared with the traditional methods used in the current clinical practice. MCM7 may thus improve diagnostics, prediction of prognosis and treatment decision making in patients suffering from meningiomas.
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Affiliation(s)
- Theo L Winther
- Departments of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology (NTNU), Erling Skjalgssons gate 1, 7030, Trondheim, Norway.
| | - Sverre H Torp
- Departments of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology (NTNU), Erling Skjalgssons gate 1, 7030, Trondheim, Norway.,Pathology and Medical genetics, St. Olavs Hospital, Erling Skjalgssons gate 1, 7030, Trondheim, Norway
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Molecular Biomarkers for Embryonic and Adult Neural Stem Cell and Neurogenesis. BIOMED RESEARCH INTERNATIONAL 2015; 2015:727542. [PMID: 26421301 PMCID: PMC4569757 DOI: 10.1155/2015/727542] [Citation(s) in RCA: 114] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Accepted: 11/19/2014] [Indexed: 02/07/2023]
Abstract
The procedure of neurogenesis has made numerous achievements in the past decades, during which various molecular biomarkers have been emerging and have been broadly utilized for the investigation of embryonic and adult neural stem cell (NSC). Nevertheless, there is not a consistent and systematic illustration to depict the functional characteristics of the specific markers expressed in distinct cell types during the different stages of neurogenesis. Here we gathered and generalized a series of NSC biomarkers emerging during the procedures of embryonic and adult neural stem cell, which may be used to identify the subpopulation cells with distinguishing characters in different timeframes of neurogenesis. The identifications of cell patterns will provide applications to the detailed investigations of diverse developmental cell stages and the extents of cell differentiation, which will facilitate the tracing of cell time-course and fate determination of specific cell types and promote the further and literal discoveries of embryonic and adult neurogenesis. Meanwhile, via the utilization of comprehensive applications under the aiding of the systematic knowledge framework, researchers may broaden their insights into the derivation and establishment of novel technologies to analyze the more detailed process of embryogenesis and adult neurogenesis.
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Patel A, Tripathi G, Gopalakrishnan K, Williams N, Arasaradnam RP. Field cancerisation in colorectal cancer: A new frontier or pastures past? World J Gastroenterol 2015; 21:3763-3772. [PMID: 25852261 PMCID: PMC4385523 DOI: 10.3748/wjg.v21.i13.3763] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 01/09/2015] [Accepted: 02/13/2015] [Indexed: 02/07/2023] Open
Abstract
Despite considerable advances in our understanding of cancer biology, early diagnosis of colorectal cancer remains elusive. Based on the adenoma-carcinoma sequence, cancer develops through the progressive accumulation of mutations in key genes that regulate cell growth. However, recent mathematical modelling suggests that some of these genetic events occur prior to the development of any discernible histological abnormality. Cells acquire pro-tumourigenic mutations that are not able to produce morphological change but predispose to cancer formation. These cells can grow to form large patches of mucosa from which a cancer arises. This process has been termed “field cancerisation”. It has received little attention in the scientific literature until recently. Several studies have now demonstrated cellular, genetic and epigenetic alterations in the macroscopically normal mucosa of colorectal cancer patients. In some reports, these changes were effectively utilised to identify patients with a neoplastic lesion suggesting potential application in the clinical setting. In this article, we present the scientific evidence to support field cancerisation in colorectal cancer and discuss important limitations that require further investigation. Characterisation of the field defect is necessary to enable early diagnosis of colorectal cancer and identify molecular targets for chemoprevention. Field cancerisation offers a promising prospect for experimental cancer research and has potential to improve patient outcomes in the clinical setting.
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16
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Huang TC, Renuse S, Pinto S, Kumar P, Yang Y, Chaerkady R, Godsey B, Mendell JT, Halushka MK, Civin CI, Marchionni L, Pandey A. Identification of miR-145 targets through an integrated omics analysis. MOLECULAR BIOSYSTEMS 2014; 11:197-207. [PMID: 25354783 DOI: 10.1039/c4mb00585f] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and protein synthesis. To characterize functions of miRNAs and to assess their potential applications, we carried out an integrated multi-omics analysis to study miR-145, a miRNA that has been shown to suppress tumor growth. We employed gene expression profiling, miRNA profiling and quantitative proteomic analysis of a pancreatic cancer cell line. In our transcriptomic analysis, overexpression of miR-145 was found to suppress the expression of genes that are implicated in development of cancer such as ITGA11 and MAGEA4 in addition to previously described targets such as FSCN1, YES1 and PODXL. Based on miRNA profiling, overexpression of miR-145 also upregulated other miRNAs including miR-124, miR-133b and miR-125a-3p, all of which are implicated in suppression of tumors and are generally co-regulated with miR-145 in other cancers. Using the SILAC system, we identified miR-145-induced downregulation of several oncoproteins/cancer biomarkers including SET, RPA1, MCM2, ABCC1, SPTBN1 and SPTLC1. Luciferase assay validation carried out on a subset of downregulated candidate targets confirmed them to be novel direct targets of miR-145. Overall, this multi-omics approach provided insights into miR-145-mediated tumor suppression and could be used as a general strategy to study the targets of individual miRNAs.
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Affiliation(s)
- Tai-Chung Huang
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Shimizu M, Kochi T, Shirakami Y, Genovese S, Epifano F, Fiorito S, Mori T, Tanaka T, Moriwaki H. A newly synthesized compound, 4'-geranyloxyferulic acid-N(omega)-nitro-L-arginine methyl ester suppresses inflammation-associated colorectal carcinogenesis in male mice. Int J Cancer 2014; 135:774-84. [PMID: 24474144 DOI: 10.1002/ijc.28718] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 12/07/2013] [Accepted: 12/30/2013] [Indexed: 12/25/2022]
Abstract
We previously reported the cancer chemopreventive activity of 4'-geranyloxyferulic acid (GOFA, Miyamoto et al., Nutr Cancer 2008; 60:675-84) and a β-cyclodextrin inclusion compound of GOFA (Tanaka et al., Int J Cancer 2010; 126:830-40) in colitis-related colorectal carcinogenesis. In our study, the chemopreventive effects of a newly synthesized GOFA-containing compound, GOFA-N(omega)-nitro-L-arginine methyl ester (L-NAME), which inhibits inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX) enzymes, were investigated using a colitis-associated mouse colorectal carcinogenesis model with azoxymethane (AOM) and dextran sodium sulfate (DSS). The dietary administration of GOFA-L-NAME after the AOM and DSS treatments significantly reduced the multiplicity of adenocarcinomas (inhibition rates: 100 ppm, 84%, p < 0.001; 500 ppm, 94%, p < 0.001) compared with the AOM + DSS group. Dietary GOFA-L-NAME significantly decreased the proliferation (p < 0.001) and increased the apoptosis (p < 0.001) of colonic adenocarcinoma cells. A subsequent short-term experiment revealed that dietary GOFA-L-NAME decreased the mRNA expression of inflammatory enzymes, such as iNOS and COX-2, and proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and macrophage inflammatory protein (MIP)-2 in the colonic mucosa of mice that received 1.5% DSS in their drinking water for 7 days. Our findings indicate that GOFA-L-NAME is able to inhibit colitis-associated colon carcinogenesis by modulating inflammation, proliferation, apoptosis and the expression of proinflammatory cytokines in mice.
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Affiliation(s)
- Masahito Shimizu
- Department of Internal Medicine/Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan
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Bychkov A, Saenko V, Nakashima M, Mitsutake N, Rogounovitch T, Nikitski A, Orim F, Yamashita S. Patterns of FOXE1 expression in papillary thyroid carcinoma by immunohistochemistry. Thyroid 2013; 23:817-28. [PMID: 23327367 PMCID: PMC3704107 DOI: 10.1089/thy.2012.0466] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
BACKGROUND FOXE1, a thyroid-specific transcription factor also known as TTF-2, was recently identified as a major genetic risk factor for papillary thyroid carcinoma (PTC). Its role in thyroid carcinogenesis, however, remains unknown. The purpose of the present study was to assess the relationship between the FOXE1 immunohistochemical features and the clinical and genetic characteristics of PTC. METHODS Immunohistochemical staining of FOXE1 was performed in 48 PTC cases. Two single nucleotide polymorphisms immediately inside (rs1867277) or in the vicinity (rs965513) of the FOXE1 gene were genotyped by direct sequencing. Histopathological, clinical, and genetic data were included in statistical analyses. RESULTS FOXE1 exhibited cytoplasmic overexpression in tumor tissue compared to the normal counterpart (p<0.001). Both cancer and normal thyroid cells demonstrated the highest FOXE1 scores in the areas closest to the tumor border (<300 μm) compared with more distant areas (p<0.001). No differences in FOXE1 staining distributions were found between microcarcinomas and PTC of larger size, between different histopathological variants of PTC, and encapsulated and nonencapsulated tumors. Multivariate regression analysis revealed that nuclear FOXE1 expression in neoplastic cells in the vicinity of the tumor border independently associated with the genotype at rs1867277 (the dominant model of inheritance, p=0.037) and tumor multifocality (p=0.032), and with marginal significance with capsular invasion (p=0.051). CONCLUSIONS FOXE1 overexpression and translocation to the cytoplasm are phenotypic hallmarks of tumor cells suggesting that FOXE1 is involved in the pathogenesis of PTC. Nuclear FOXE1 expression in tumor cells in the vicinity of the PTC border is associated with the presence of a risk allele of rs1867277 (c.-238G>A) in the 5' untranslated region of the FOXE1 gene, as well as with pathological characteristics of PTC, suggesting possible FOXE1 involvement in the facilitation of tumor development beginning at an early stage.
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Affiliation(s)
- Andrey Bychkov
- Department of Radiation Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Vladimir Saenko
- Department of Health Risk Control, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masahiro Nakashima
- Department of Tumor and Diagnostic Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Norisato Mitsutake
- Department of Radiation Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Nagasaki University Research Center for Genomic Instability and Carcinogenesis, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tatiana Rogounovitch
- Department of Radiation Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Alyaksandr Nikitski
- Department of Radiation Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Florence Orim
- Department of Radiation Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Shunichi Yamashita
- Department of Radiation Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Department of Health Risk Control, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Fukushima Medical University, Fukushima, Japan
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Lind-Landström T, Varughese RK, Sundstrøm S, Torp SH. Expression and clinical significance of the proliferation marker minichromosome maintenance protein 2 (Mcm2) in diffuse astrocytomas WHO grade II. Diagn Pathol 2013; 8:67. [PMID: 23618321 PMCID: PMC3648352 DOI: 10.1186/1746-1596-8-67] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 04/19/2013] [Indexed: 12/20/2022] Open
Abstract
Background The WHO classification system for astrocytomas is not considered optimal, mainly because of the subjective assessment of the histopathological features. Few prognostic variables have been found that stratify the risk of clinical progression in patients with grade II astrocytoma. For that reason there is a continuous search for biomarkers that can improve the histopathological diagnosis and prognostication of these tumours. Aim This study was designed to investigate the prognostic significance of the proliferative marker Mcm2 (minichromosome maintenance protein 2) in diffuse astrocytomas WHO grade II and correlate the findings with histopathology, mitoses, and Ki67/MIB-1 immunostaining. Method 61 patients with histologically verified grade II astrocytoma (WHO 2007) were investigated. Paraffin sections were immunostained with anti-Mcm2, and the Mcm2 proliferative index (PI) was determined as the percentage of immunoreactive tumour cell nuclei. Results Mcm2 PI was not associated with any histopathological features but correlated significantly with mitotic count and Ki67/MIB-1 PI (p<0.05). In the survival analyses Mcm2 showed trends to poorer survival, however, statistical significance was not achieved in the univariate analyses (p>0.05). Conclusions In our hands Mcm2 immunostaining has no advantage over Ki67/MIB-1 in the evaluation of grade II astrocytomas. Larger studies are needed to fully clarify the prognostic role of this biomarker. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1715002791944037
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Affiliation(s)
- Tove Lind-Landström
- Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
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Kuno T, Hatano Y, Tomita H, Hara A, Hirose Y, Hirata A, Mori H, Terasaki M, Masuda S, Tanaka T. Organomagnesium suppresses inflammation-associated colon carcinogenesis in male Crj: CD-1 mice. Carcinogenesis 2012; 34:361-9. [PMID: 23125223 DOI: 10.1093/carcin/bgs348] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Magnesium (Mg) deficiency increases genomic instability and Mg intake has been reported to be inversely associated with a risk of colorectal cancer (CRC). This study was designed to determine whether organo-Mg in drinking water suppresses inflammation-associated colon carcinogenesis in mice. Male Crj: CD-1 mice were initiated with a single i.p. injection of azoxymethane (AOM, 10mg/kg body weight) and followed by a 1 week exposure to dextran sulfate sodium (DSS, 1.5%, w/v) in drinking water to induce colonic neoplasms. They were then given the drinking water containing 7, 35 or 175 p.p.m. organo-Mg for 13 weeks. The chemopreventive efficacy of organo-Mg was determined 16 weeks after the AOM exposure. Administration with organo-Mg at all doses caused a significant inhibition of CRC development (P < 0.01 and P < 0.001). Especially, the highest dose of organo-Mg significantly suppressed the occurrence of all the colonic pathological lesions (mucosal ulcer, dysplasia, adenoma and adenocarcinoma). Organo-Mg also significantly reduced the number of mitoses/anaphase bridging, as well as proliferation of CRC. Additionally, at week 4, organo-Mg lowered the messenger RNA expression of certain proinflammatory cytokines, such as interleukin-1β, interleukin-6, interferon-γ and inducible nitric oxide synthase in the lesion-free colorectal mucosa at week 4 but increased the Nrf-2 messenger RNA expression. Our findings that organo-Mg inhibits inflammation-related mouse colon carcinogenesis by modulating the proliferative activities and chromosomal instability of CRC and suppressing colonic inflammation may suggest potential use of organo-Mg for clinical chemoprevention trials of CRC in the inflamed colon.
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Affiliation(s)
- Toshiya Kuno
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
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Clark MJ, Robien K, Slavin JL. Effect of prebiotics on biomarkers of colorectal cancer in humans: a systematic review. Nutr Rev 2012; 70:436-43. [PMID: 22835137 DOI: 10.1111/j.1753-4887.2012.00495.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Prebiotics may prevent colorectal cancer (CRC) development in humans by modifying the composition or activity of the colorectal microflora. Epidemiologic and animal studies have shown a reduction in CRC or CRC biomarkers after the administration of prebiotics. Studies using indirect chemical biomarkers of CRC in humans, however, gave mixed results. Recently, human studies measuring direct physical indices of CRC risk after prebiotic consumption have been published. The purpose of this review is to summarize those studies to provide recommendations for the use of prebiotics in CRC risk reduction. A PubMed search was conducted, revealing nine studies. One tested lactulose, two evaluated a blend of oligofructose and inulin, and six measured resistant starch. Lactulose reduced adenoma recurrence, while resistant starch had no effect on adenoma or CRC development. Crypt mitotic location, gene expression, and DNA methylation were somewhat improved after resistant starch consumption. No changes in cell proliferation and apoptosis, crypt morphology, or aberrant crypt foci were found. More human studies measuring physical changes to the gut are needed.
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Affiliation(s)
- Michelle J Clark
- Department of Food Science and Nutrition, University of Minnesota, Saint Paul, Minnesota 55108, USA
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Expression of minichromosome maintenance MCM6 protein in meningiomas is strongly correlated with histologic grade and clinical outcome. Am J Surg Pathol 2012; 36:283-91. [PMID: 22020044 DOI: 10.1097/pas.0b013e318235ee03] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The 2007 World Health Organization histologic grading of meningiomas is associated with recurrence and clinical outcome. However, distinction of grade I from grade II (atypical) meningiomas can be challenging. In the World Health Organization classification, there are 4 parameters on the basis of which grade II status can be determined: mitotic rate, cytoarchitectural features, brain invasion, and/or histologic subtype. Furthermore, this classification fails to detect grade I recurrent meningiomas, for which other prognostic criteria would be needed. The aim of this study was to evaluate the respective value of several markers involved in cell cycle as effective tools to predict recurrence. This retrospective study was based on a series of 59 meningiomas (grade I: 32 of 59, grade II: 27 of 59, all harboring ≥4 mitoses/1.6 mm), analyzed with the following immunohistochemical markers: MCM6, Ki-67, PHH3, cyclin D1, and p53. We found a significant correlation between histologic grade and mean labeling index for MCM6 (grade I: 21.8% vs. grade II: 65.8%; P<0.001), Ki-67 (3.2% vs. 16.9%; P<0.001), PHH3 (0.7‰ vs. 2.8‰; P<0.001), cyclin D1 (50.4% vs. 70.0%; P=0.005), and p53 (17.3% vs. 32.4%; P=0.017). Histologic grading and mitotic index were correlated with progression-free survival (P=0.010 and P=0.020, respectively). A nearly linear correlation was found between progression-free survival and staining for MCM6 (P<0.001), Ki-67 (P=0.003), and PHH3 (P=0.037) but not for cyclin D1 (P=0.400) and p53 (P=0.758). The interobserver agreement coefficients for MCM6, Ki-67, PHH3, cyclin D1, and p53 were, respectively, 0.97 (95% confidence interval, 0.95-0.98), 0.93 (0.89-0.96), 0.81 (0.70-0.88), 0.90 (0.83-0.94), and 0.84 (0.73-0.90). In conclusion, because of its strong level of expression and sharp difference in labeling index between indolent and recurrent tumors, MCM6 is the most efficient marker to identify tumors with a high risk of recurrence.
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Knockdown of ZNF403 inhibits cell proliferation and induces G2/M arrest by modulating cell-cycle mediators. Mol Cell Biochem 2012; 365:211-22. [DOI: 10.1007/s11010-012-1262-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2011] [Accepted: 02/08/2012] [Indexed: 12/14/2022]
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Immunohistological markers for proliferative events, gliogenesis, and neurogenesis within the adult hippocampus. Cell Tissue Res 2011; 345:1-19. [PMID: 21647561 DOI: 10.1007/s00441-011-1196-4] [Citation(s) in RCA: 244] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2011] [Accepted: 05/13/2011] [Indexed: 12/29/2022]
Abstract
Biologists long believed that, once development is completed, no new neurons are produced in the forebrain. However, as is now firmly established, new neurons can be produced at least in two specific forebrain areas: the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampal formation. Neurogenesis within the adult DG occurs constitutively throughout postnatal life, and the rate of neurogenesis within the DG can be altered under various physiological and pathophysiological conditions. The process of adult neurogenesis within the DG is a multi-step process (proliferation, differentiation, migration, targeting, and synaptic integration) that ends with the formation of a post-mitotic functionally integrated new neuron. Various markers are expressed during specific stages of adult neurogenesis. The availability of such markers allows the time-course and fate of newly born cells to be followed within the DG in a detailed and precise fashion. Several of the available markers (e.g., PCNA, Ki-67, PH3, MCM2) are markers for proliferative events, whereas others are more specific for early phases of neurogenesis and gliogenesis within the adult DG (e.g., nestin, GFAP, Sox2, Pax6). In addition, markers are available allowing events to be distinguished that are related to later steps of gliogenesis (e.g., vimentin, BLBP, S100beta) or neurogenesis (e.g., NeuroD, PSA-NCAM, DCX).
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Minichromosome maintenance proteins 2, 3 and 7 in medulloblastoma: overexpression and involvement in regulation of cell migration and invasion. Oncogene 2010; 29:5475-89. [DOI: 10.1038/onc.2010.287] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Gouvêa AF, Vargas PA, Coletta RD, Jorge J, Lopes MA. Clinicopathological features and immunohistochemical expression of p53, Ki-67, Mcm-2 and Mcm-5 in proliferative verrucous leukoplakia. J Oral Pathol Med 2010; 39:447-52. [PMID: 20412398 DOI: 10.1111/j.1600-0714.2010.00889.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Proliferative verrucous leukoplakia (PVL) is a distinct and aggressive type of oral leukoplakia which affects elderly women without risk behavior and presents high rates of malignant transformation. The objective of the present study was to evaluate the clinicopathological characteristics and the distribution of cell proliferation markers, aiming to elucidate the distinct biological behavior of the PVL. METHODS Clinical and microscopical features of 12 patients with PVL were reviewed. Immunohistochemical analysis for p53, Ki-67, Mcm-2 and Mcm-5 were performed and the data were correlated. RESULTS All patients were women, above 50 years of age, 91.7% were non-smoker and 100% were non-habitual drinker. Alveolar ridge (66.6%), tongue (50%) and buccal mucosa (41.6%) were the most affected sites. Four patients developed squamous cell carcinoma (SCC). The immunohistochemical findings showed higher positivity for p53, Ki-67, Mcm-2 and Mcm-5 in SCCs. However, some patients with mild or moderate dysplasia, specially the patients who developed SCC, presented high expression of Mcm-2 and Mcm-5. CONCLUSIONS High immunoexpression of Mcm-2 and Mcm-5 in mild and moderate dysplasia could be helpful to predict the malignant transformation of PVL.
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Affiliation(s)
- Adriele Ferreira Gouvêa
- Department of Oral Diagnosis, Oral Semiology and Pathology Section, Piracicaba Dental School, State University of Campinas, Piracicaba, Sao Paulo, Brazil
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