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Ren X, Hu R, Zhang H. A Mendelian analysis of the causality between inflammatory cytokines and digestive tract cancers. Postgrad Med J 2024:qgae132. [PMID: 39362654 DOI: 10.1093/postmj/qgae132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 08/27/2024] [Accepted: 09/19/2024] [Indexed: 10/05/2024]
Abstract
PURPOSE In this study, we performed a two-sample Mendelian randomization (MR) analysis to assess the causality between inflammatory cytokines and the risk of digestive tract cancers (DTCs). Furthermore, we conducted a molecular docking study to predict the therapeutic mechanisms of traditional Chinese medicine (TCM) compounds in the treatment of DTCs. METHODS In our MR analysis, genetic variations associated with eight types of DTCs were utilized, which were sourced from a large publicly available genome-wide association study dataset (7929 cases and 1 742 407 controls of European ancestry) and inflammatory cytokines data from a genome-wide association study summary of 8293 European participants. Inverse-variance weighted method, MR-Egger, and weighted median were performed to analyze and strengthen the final results. We investigated the effects of 41 inflammatory molecules on 8 types of DTCs. Subsequently, the effect of DTCs on positive inflammatory factors was analyzed by means of inverse MR. Molecular docking was exploited to predict therapeutic targets with TCM compounds. RESULTS Interleukin-7, interleukin-16, macrophage colony-stimulating factor, monokine induced by interferon-gamma, and vascular endothelial growth factor may be significantly associated with various types of DTCs. Five TCM compounds (baicalin, berberine, curcumin, emodin, and salidroside) demonstrated better binding energies to both interleukin-7 and vascular endothelial growth factor than carboplatin. CONCLUSION This study provides strong evidence to support the potential causality of some inflammatory cytokines on DTCs and indicates the potential molecular mechanism of TCM compounds in the treatment of DTCs. Key message What is already known on this topic The increasing evidence indicates that inflammatory cytokines are implicated in the pathogenesis of digestive tract cancers (DTCs). Nevertheless, the causal relationship between inflammatory cytokines and DTCs remains indistinct. Additionally, certain traditional Chinese medicine compounds have been demonstrated to treat DTCs by influencing inflammatory factors, yet their underlying potential mechanisms remain ambiguous. What this study adds In this study, Mendelian randomization analysis was performed for the first time regarding the causality between human inflammatory cytokines and eight types of DTCs, which revealed that inflammatory factors may play different roles in different types of DTCs. Moreover, molecular docking of key inflammatory factors was implemented, indicating the targets for drug actions. How this study might affect research, practice, or policy This research has the potential to reveal the causality between 41 inflammatory factors and 8 DTCs, offering novel perspectives for the prevention and management strategies of DTCs. Additionally, it indicates the targets for the actions of traditional Chinese medicine on the key inflammatory factors of these cancers.
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Affiliation(s)
- Xing Ren
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Rong Hu
- Institute of Science, Technology and Humanities, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hui Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Akhlaghipour I, Moghbeli M. MicroRNA-98 as a novel diagnostic marker and therapeutic target in cancer patients. Discov Oncol 2024; 15:385. [PMID: 39210158 PMCID: PMC11362465 DOI: 10.1007/s12672-024-01270-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024] Open
Abstract
The progress of cancer treatment methods in the last decade has significantly reduced mortality rate among these patients. Nevertheless, cancer is still recognized as one of the main causes of human deaths. One of the main reasons for the high death rate in cancer patients is the late diagnosis in the advanced tumor stages. Therefore, it is necessary to investigate the molecular biology of tumor progressions in order to introduce early diagnostic markers. MicroRNAs (miRNAs) have an important role in regulating cellular processes associated with tumor progression. Due to the high stability of miRNAs in body fluids, they are widely used as non-invasive markers in the early tumor diagnosis. Since, deregulation of miR-98 has been reported in a wide range of cancers, we investigated the molecular mechanisms of miR-98 during tumor progression. It has been reported that miR-98 mainly inhibits the tumor growth by the modulation of transcription factors and signaling pathways. Therefore, miR-98 can be introduced as a tumor marker and therapeutic target among cancer patients.
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Affiliation(s)
- Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Taghipour Zahir S, Razavi SH, SafiDahaj F, Rahmani K, Sadeghinejad‐Alamabadi S. Prognosis and survival study in patients with gastric adenocarcinoma and its relationship with pRb expression alteration: A retrospective IHC-based study. Health Sci Rep 2023; 6:e1445. [PMID: 37519424 PMCID: PMC10372302 DOI: 10.1002/hsr2.1445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/25/2023] [Accepted: 07/14/2023] [Indexed: 08/01/2023] Open
Abstract
Background and Objective Among cancers, gastric cancer has the fifth highest incidence worldwide and is the third most common mortality factor, which may have been due to inadequate knowledge of its molecular pathogenesis. The retinoblastoma gene (RB1), a tumor suppressor gene, may have a role in gastric cancer. This research aims to assess Rb expression as a prognostic marker to obtain more insight regarding gastric cancer. Methods This retrospective analytical study was done on 61 patients (45 males and 16 females) with gastric adenocarcinoma admitted from 2010 to 2012 in Shahid Sadoughi and Mortaz hospitals, Yazd, Iran. Demographic data, including age, gender, clinical signs and symptoms, and pathology reports, were retrieved from patients' hospital folders. Then, the altered Retinoblastoma gene expression was evaluated by immunohistochemistry studies. Acquired data were analyzed by SPSS software v.16. p < 0.05 was statistically considered meaningful. Results In this study, the ratio of men to women was higher (2.81:1), and the mean age of patients was 62.44 years. About 90.2% of patients died during the study. There was no meaningful relationship between the presence of pRb, the intensity of staining, the percentage of staining with patients' age, gender, tumor grading, and survival rate (p > 0.05). There was only a meaningful relationship between the grade of tumors and survival rate (p = 0.039). Conclusion Altered pRB expression is not common in gastric cancer and does not impact the survival and grading of tumors. Poorly differentiated tumors had an ominous outcome with the lowest survival time.
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Affiliation(s)
| | - Seyyed Hossein Razavi
- Clinical and Surgical PathologyShahid Sadoughi University of Medical SciencesYazdIran
| | - Farzan SafiDahaj
- Clinical and Surgical PathologyShahid Sadoughi University of Medical SciencesYazdIran
| | - Koorosh Rahmani
- Clinical and Surgical PathologyShahid Sadoughi University of Medical SciencesYazdIran
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Jin Y, Cao J, Hu X, Cheng H. Long noncoding RNA TUG1 upregulates VEGFA to enhance malignant behaviors in stomach adenocarcinoma by sponging miR-29c-3p. J Clin Lab Anal 2021; 35:e24106. [PMID: 34762771 PMCID: PMC8649340 DOI: 10.1002/jcla.24106] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/12/2021] [Accepted: 10/25/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Long noncoding RNA (lncRNA) TUG1 has been reported to display a pivotal role in the tumorigenesis and malignant progression of various types of cancers, including stomach adenocarcinoma (STAD). However, the contribution of aberrant expression of TUG1 and the mechanism by which it serves as a competing endogenous RNA (ceRNA) in STAD remains largely obscure. METHODS The human STAD cell lines (MGC-803 and AGS), human normal gastric epithelial cell line (GES-1), human umbilical vein endothelial cells (HUVECs), and human embryonic kidney cells (HEK293T) were purchased and cultured to investigate the roles of TUG1 in STAD. Twenty BALB/c nude mice were purchased to establish a xenograft model to explore the roles of TUG1 in vivo. RESULTS Bioinformatics analysis revealed that TUG1 was upregulated in STAD, of which expression was negatively and positively correlated with miR-29c-3p and VEGFA, respectively. Functional analyses indicated that TUG1 functioned as an oncogene to promote malignant behaviors (proliferation, migration, and angiogenesis) of STAD cells; whereas miR-29c-3p exerted the opposite role. Mechanistically, the interaction between miR-29c-3p with TUG1 and VEGFA was demonstrated. It was observed that miR-29c-3p could reverse the TUG1-induced promotion effect on cell proliferation, migration, and angiogenesis in STAD. Furthermore, TUG1 overexpression promoted STAD cell proliferation, metastasis, and angiogenesis, whereas VEGFA silence restored these effects, both in vitro and in vivo. CONCLUSION This finding confirmed that lncRNA TUG1 acts as a ceRNA for miR-29c-3p to promote tumor progression and angiogenesis by upregulating VEGFA, indicating TUG1 as a therapeutic target in STAD management.
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Affiliation(s)
- Yanzhao Jin
- Department of General SurgeryThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Jiaqing Cao
- Department of General SurgeryThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Xiaoyun Hu
- Department of General SurgeryThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Hua Cheng
- Department of General SurgeryThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
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Wu T, Wu L. The Role and Clinical Implications of the Retinoblastoma (RB)-E2F Pathway in Gastric Cancer. Front Oncol 2021; 11:655630. [PMID: 34136392 PMCID: PMC8201093 DOI: 10.3389/fonc.2021.655630] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 05/07/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is the most common malignant tumor in the digestive tract, with very high morbidity and mortality in developing countries. The pathogenesis of gastric cancer is a complex biological process mediated by abnormal regulation of proto-oncogenes and tumor suppressor genes. Although there have been some in-depth studies on gastric cancer at the molecular level, the specific mechanism has not been fully elucidated. RB family proteins (including RB, p130, and p107) are involved in cell cycle regulation, a process that largely depends on members of the E2F gene family that encode transcriptional activators and repressors. In gastric cancer, inactivation of the RB-E2F pathway serves as a core transcriptional mechanism that drives cell cycle progression, and is regulated by cyclins, cyclin-dependent kinases, cyclin-dependent kinase inhibitors, p53, Helicobacter pylori and some other upstream molecules. The E2F proteins are encoded by eight genes (i.e. E2F1 to E2F8), each of which may play a specific role in gastric cancer. Interestingly, a single E2F such as E2F1 can activate or repress transcription, and enhance or inhibit cell proliferation, depending on the cell environment. Thus, the function of the E2F transcription factor family is very complex and needs further exploration. Importantly, the presence of H. pylori in stomach mucosa may affect the RB and p53 tumor suppressor systems, thereby promoting the occurrence of gastric cancer. This review aims to summarize recent research progress on important roles of the complex RB-E2F signaling network in the development and effective treatment of gastric cancer.
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Affiliation(s)
| | - Lizhao Wu
- Department of Pathophysiology, College of Basic Medical Sciences, China Medical University, Shenyang, China
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Zhong J, Fang L, Chen R, Xu J, Guo D, Guo C, Guo C, Chen J, Chen C, Wang X. Polysaccharides from sporoderm-removed spores of Ganoderma lucidum induce apoptosis in human gastric cancer cells via disruption of autophagic flux. Oncol Lett 2021; 21:425. [PMID: 33850566 PMCID: PMC8025153 DOI: 10.3892/ol.2021.12686] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 03/02/2021] [Indexed: 12/24/2022] Open
Abstract
The sporoderm-broken spores of Ganoderma lucidum (G. lucidum) polysaccharide (BSGLP) have been demonstrated to inhibit carcinogenesis in several types of cancer. However, to the best of our knowledge, the anticancer effects of polysaccharides extracted from the newly developed sporoderm-removed spores of G. lucidum (RSGLP) have not been assessed. The present study first compared the anticancer effects of RSGLP and BSGLP in three gastric cancer cell lines and it was found that RSGLP was more potent than BSGLP in decreasing gastric cancer cell viability. RSGLP significantly induced apoptosis in AGS cells, accompanied by downregulation of Bcl-2 and pro-caspase-3 expression levels, and upregulation of cleaved-PARP. Furthermore, RSGLP increased LC3-II and p62 expression, indicative of induction of autophagy and disruption of autophagic flux in AGS cells. These results were further verified by combined treatment of AGS cells with the late-stage autophagy inhibitor chloroquine, or early-stage autophagy inducer rapamycin. Adenoviral transfection with mRFP-GFP-LC3 further confirmed that autophagic flux was inhibited by RSGLP in AGS cells. Finally, the present study demonstrated that the RSGLP-induced autophagy and disruption of autophagic flux disruption was, at least in part, responsible for RSGLP-induced apoptosis in AGS cells. The results of the present study demonstrated for the first time that RSGLP is more effective than BSGLP in inhibiting gastric cancer cell viability, and RSGLP may serve as a promising autophagy inhibitor in the management of gastric cancer.
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Affiliation(s)
- Jiayi Zhong
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China.,Department of Pharmacy, Wenling Maternal and Child Health Care Hospital, Taizhou, Zhejiang 317500, P.R. China
| | - Liu Fang
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Rong Chen
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Jing Xu
- Zhejiang Engineering Research Center of Rare Medicinal Plants, Wuyi, Zhejiang 321200, P.R. China
| | - Dandan Guo
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Chengjie Guo
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Cuiling Guo
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Jiajun Chen
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Chaojie Chen
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Xingya Wang
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
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High expression of EZH2 as a marker for the differential diagnosis of malignant and benign myogenic tumors. Sci Rep 2018; 8:12331. [PMID: 30120321 PMCID: PMC6098067 DOI: 10.1038/s41598-018-30648-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 08/03/2018] [Indexed: 12/30/2022] Open
Abstract
Overlap in morphologic features between malignant and benign myogenic tumors, such as leiomyosarcoma (LMS) vs. leiomyoma as well as rhabdomyosarcoma (RMS) vs. rhabdomyoma, often makes differential diagnosis difficult and challenging. Here the expressions of Enhancer of Zeste Homolog 2 (EZH2), Suppressor of Zeste 12 (SUZ12), retinoblastoma protein associated protein 46 (RbAp46), Embryonic Ectoderm Development (EED) and ki-67 protein were detected by immunohistochemistry to evaluate their values in differential diagnosis. The expression of EZH2 mRNA was investigated by analyzing the Gene Expression Omnibus Datasets. The results demonstrated that EZH2 protein was detected in 81.25% (26/32) of LMS and 70.58% (36/51) of RMS, whereas none of leiomyoma (n = 16), rhabdomyoma (n = 15) and normal tissues (n = 31) showed positive immunostaining (p < 0.05). EZH2 protein was found to have a sensitivity of 91.30% and specificity of 100% in distinguishing well-differentiated LMS from cellular leiomyoma, and a sensitivity of 92.86% and specificity of 100% in distinguishing well-differentiated embryonal rhabdomyosarcoma (ERMS) from fetal rhabdomyoma. Besides, the expression of EZH2 mRNA was higher in LMS and RMS than in benign tumors (p < 0.05). The expressions of SUZ12 and RbAp46 protein were higher in RMS than in rhabdomyoma (p < 0.05). Conclusively, the high expression of EZH2 is a promising marker in distinguishing well–differentiated LMS from cellular leiomyoma, or well–differentiated ERMS from fetal rhabdomyoma, and the upregulation of EZH2 protein expression may occur at transcriptional level.
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Liu X, Wu J, Zhang D, Wang K, Duan X, Meng Z, Zhang X. Network Pharmacology-Based Approach to Investigate the Mechanisms of Hedyotis diffusa Willd. in the Treatment of Gastric Cancer. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2018; 2018:7802639. [PMID: 29853970 PMCID: PMC5954954 DOI: 10.1155/2018/7802639] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2018] [Revised: 03/27/2018] [Accepted: 04/01/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Hedyotis diffusa Willd. (HDW) is one of the renowned herbs often used in the treatment of gastric cancer (GC). However, its curative mechanism has not been fully elucidated. OBJECTIVE To systematically investigate the mechanisms of HDW in GC. METHODS A network pharmacology approach mainly comprising target prediction, network construction, and module analysis was adopted in this study. RESULTS A total of 353 targets of the 32 bioactive compounds in HDW were obtained. The network analysis showed that CA isoenzymes, p53, PIK3CA, CDK2, P27Kip1, cyclin D1, cyclin B1, cyclin A2, AKT1, BCL2, MAPK1, and VEGFA were identified as key targets of HDW in the treatment of GC. The functional enrichment analysis indicated that HDW probably produced the therapeutic effects against GC by synergistically regulating many biological pathways, such as nucleotide excision repair, apoptosis, cell cycle, PI3K/AKT/mTOR signaling pathway, VEGF signaling pathway, and Ras signaling pathway. CONCLUSIONS This study holistically illuminates the fact that the pharmacological mechanisms of HDW in GC might be strongly associated with its synergic modulation of apoptosis, cell cycle, differentiation, proliferation, migration, invasion, and angiogenesis.
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Affiliation(s)
- Xinkui Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Dan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Kaihuan Wang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Xiaojiao Duan
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Ziqi Meng
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Xiaomeng Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
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Moron RA, Jacob CE, Bresciani CJC, Simões K, Alves VAF, Irya K, Gama-Rodrigues J, Cecconello I, Longatto-Filho A, Zilberstein B. Characterization of oncogene suppressor marker expression in patients with submucosal gastric carcinoma. Mol Clin Oncol 2018; 8:477-482. [PMID: 29468062 DOI: 10.3892/mco.2017.1545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Accepted: 12/06/2017] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to determine the clinical significance of p53 and p21ras p21wafl, p27kip1 and p16ink4a expression in cases of early gastric cancer. A total of 81 patients who had undergone gastrectomy with D2 lymphadenectomy between 1971 and 2004 were retrospectively investigated. The immunohistochemical expression of p21ras, p53, p21waf1/cip1, p27kip1 and p16ink4a in the tissues was evaluated. In normal, metaplastic and tumoral mucosa, p53 was positive in 53, 87.3, and 87.1% of the cases, respectively. In the same tissues, p21ras was positivE in 85.3, 86 and 96.8%, respectively. Positivity FOR p16ink4a was DETECTED IN 46.3, 91.1 and 86% OF THE CASES, respectively, WHEREAS p27kip1 WAS positiVE IN 60, 94.7 and 95.3%, and p21wafl/cip1 WAS positivE IN 32.4, 72.7 and 71.4% OF THE CASES, respectively. All THE tumors WERE positive for p53. Tumors with lymph node invasion presented WITH OVERexpression (+4) of p53 in 47% of the cases VS. 17% OF patients who DID not HAVE lymph node involvement. THEREFORE, higher expression of p53, p21ras and p21wafl/cip1 IN the tumor exhibited a statistically significant association with lymph node involvement.
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Affiliation(s)
- Roberson A Moron
- Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, SP 14784-400, Brazil
| | - Carlos Eduardo Jacob
- Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, SP 14784-400, Brazil
| | | | - Kleber Simões
- Department of Pathology, University of São Paulo School of Medicine, São Paulo, SP 14784-400, Brazil
| | | | - Kyoshi Irya
- Department of Pathology, University of São Paulo School of Medicine, São Paulo, SP 14784-400, Brazil
| | - Joaquim Gama-Rodrigues
- Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, SP 14784-400, Brazil
| | - Ivan Cecconello
- Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, SP 14784-400, Brazil
| | - Adhemar Longatto-Filho
- Department of Pathology, University of São Paulo School of Medicine, São Paulo, SP 14784-400, Brazil.,Department of Laboratory of Medical Investigation (LIM) 14, Department of Pathology, University of São Paulo School of Medicine, São Paulo, SP 14784-400, Brazil.,Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Bruno Zilberstein
- Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, SP 14784-400, Brazil
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Gu Y, Zhang J, Guan H. Expression of EZH2 in endometrial carcinoma and its effects on proliferation and invasion of endometrial carcinoma cells. Oncol Lett 2017; 14:7191-7196. [PMID: 29344151 PMCID: PMC5754892 DOI: 10.3892/ol.2017.7171] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 09/14/2017] [Indexed: 01/07/2023] Open
Abstract
Expression of enhancer of zeste homolog 2 (EZH2) has been implicated in cancer pathology, but research on its mechanistic activity is limited. The present study sought to assess the levels expression of EZH2 in patients with endometrial carcinoma (EC) and to explore the effects of EZH2 downregulation on the biological behavior of endometrial carcinoma RL-952 cells. Samples were obtained from a total of 104 patients with EC and an immunohistochemical assay was used to detect the expression of EZH2 in cancer and adjacent tissues. The relationship between the expression of EZH2 and the clinicopathological features was analyzed. Endometrial carcinoma RL-952 cells were transfected with chemically synthesized siRNA to conduct targeting inhibition of EZH2 expression. The expression levels of EZH2 protein were detected by immunoblotting. MTT and Transwell assays were used to detect the changes of cell proliferation and invasion after EZH2 downregulation. Of the 104 cases of endometrial carcinoma samples, 71 cases showed positive expression of EZH2, with an expression rate of 68.27%. In 104 cases of adjacent tissue samples, 25 cases showed positive expression of EZH2, with an expression rate of 24.03%. The expression of EZH2 in endometrial carcinoma tissue was significantly higher than that in adjacent tissue (P<0.05). The expression of EZH2 in endometrial carcinoma tissue was not correlated with the menopausal status and age of patients (P>0.05), but was correlated with the histological grade, depth of tumor invasion, lymph node metastasis and TNM stage (P<0.05). The expression of E2H2 was significantly downregulated by si-E2H2 and the proliferation and invasion abilities of cells were significantly reduced after EZH2 downregulation (P<0.05). EZH2 is closely related to the development of endometrial carcinoma and can enhance the proliferative activity of endometrial carcinoma RL-952 cells and promote cell invasion.
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Affiliation(s)
- Yuting Gu
- Department of Gynaecology and Obstetrics, Daqing Longnan Hospital, Daqing, Heilongjiang 163000, P.R. China
| | - Jing Zhang
- Department of Gynaecology and Obstetrics, Daqing Longnan Hospital, Daqing, Heilongjiang 163000, P.R. China
| | - Huai Guan
- Department of Gynaecology and Obstetrics, Daqing Longnan Hospital, Daqing, Heilongjiang 163000, P.R. China,Correspondence to: Dr Huai Guan, Department of Gynaecology and Obstetrics, Daqing Longnan Hospital, 35 Aiguo Road, Daqing, Heilongjiang 163000, P.R. China, E-mail: ;
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Omeprazole promotes carcinogenesis of fore-stomach in mice with co-stimulation of nitrosamine. Oncotarget 2017; 8:70332-70344. [PMID: 29050283 PMCID: PMC5642558 DOI: 10.18632/oncotarget.19696] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 06/19/2017] [Indexed: 12/12/2022] Open
Abstract
Objectives To investigate if oral omeprazole application induces cancers of fore and glandular stomach in mice. Methods A total of 66 eligible male mice were randomly divided into 6 groups, which were treated with control reagent, low (6 mg/kg) and high dose omeprazole (30 mg/kg), N-methyl-N’-nitro-N-nitrosoguanidine (MNNG, 100 mg/L water), and MNNG plus low and high dose omeprazole, respectively. After 24 weeks, concentrations of acid phosphatase (ACP) and N-acetyl-β-D-glucosaminidase(NAG) in serum and spleen was examined, and p21 and mTOR levels in stomach were detected. Results The mouse spleen weight index was smaller in the omeprazole group than the control group, and in the MNNG plus omeprazole groups than the MNNG group. In the fore-stomach, more carcinomas were observed in the MNNG plus omeprazole groups than in the MNNG group. In the glandular stomach, there existed more atypical hyperplasia cases in the MNNG plus omeprazole groups than the MNNG-treated group, and one carcinoma was induced in the MNNG plus high dose omeprazole group. Omeprazole alone caused minor gastric pathological changes. Omeprazole treatment lowered both serum and spleen ACP and NAG levels in both the non-MNNG-treated and MNNG-treated subgroups. In fore-stomach, there existed decreased p21 and mTOR levels in the omeprazole-treated groups than in the control group, and in the MNNG plus omeprazole groups than the MNNG-treated group. Conclusion Omeprazole promotes carcinogenesis of the mouse fore-stomach but not the glandular stomach following treatment with MNNG. Lysosomal hydrolase activity was inhibited and some cancer-associated proteins was dysregulated, which requires further explorations.
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12
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Zhang F, Peng H. LncRNA-ANCR regulates the cell growth of osteosarcoma by interacting with EZH2 and affecting the expression of p21 and p27. J Orthop Surg Res 2017; 12:103. [PMID: 28679390 PMCID: PMC5499053 DOI: 10.1186/s13018-017-0599-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2017] [Accepted: 06/17/2017] [Indexed: 01/15/2023] Open
Abstract
Background Osteosarcoma (OS) is one of the most common malignant tumors developed in the bone. EZH2 has been found to play pivotal roles in the development of various cancers. LncRNA-ANCR (anti-differentiation ncRNA) has been reported to interact with EZH2 and regulated osteoblast differentiation. Our study aimed to investigate the effect of lncRNA-ANCR on the tumorigenesis of osteosarcoma and explore the underlying molecular mechanism. Methods RT-PCR was performed to detect the messenger RNA (mRNA) levels of lncRNA-ANCR, EZH2, p21, and p27 in OS tissues and cell lines. The cell proliferation, transwell invasion, and migration assays were conducted to evaluate the influence of lncRNA-ANCR depletion on the growth of OS cells. RNA pull-down assay was carried out to detect the interaction between lncRNA-ANCR and EZH2. Correlation between the expression of lncRNA-ANCR and the expression of EZH2 were analyzed by cross-tabulation. Results LncRNA-ANCR is highly expressed in both OS tissues and cell lines. Reduced expression of lncRNA-ANCR inhibited the cell proliferation, invasion, and migration of OS cells. The cell apoptosis rate was also increased with the overexpression of lncRNA-ANCR. Mechanistically, downregulation of lncRNA-ANCR reduced the mRNA level of EZH2 and increased the expression of p21 and p27 at both mRNA and protein levels. LncRNA-ANCR interacted with EZH2 and their expression abundance was positively correlated in OS patients. Conclusion LncRNA-ANCR inhibited the cell proliferation, migration, and invasion of OS cells possibly through interacting with EZH2 and regulating the expression of p21 and p27.
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Affiliation(s)
- Fei Zhang
- Department of Orthopaedics Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Hao Peng
- Department of Orthopaedics Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
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13
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Expression of pRb, Ki67 and HER 2/neu in gastric carcinomas: Relation to different histopathological grades and stages. Ann Diagn Pathol 2017; 30:1-7. [PMID: 28965621 DOI: 10.1016/j.anndiagpath.2017.05.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Revised: 04/11/2017] [Accepted: 05/10/2017] [Indexed: 12/18/2022]
Abstract
Gastric carcinoma is one of the aggressive malignancies with poor prognosis. The expression of pRb, Ki67, Her-2 in relation to tumor grade and stage in gastric carcinoma still needs more exploration. This study was performed aiming to study the immunohistochemical expression of altered retinoblastoma encoding protein (pRb), Ki67 and Her-2 in gastric carcinoma and to investigate their clinical and pathological significance. We studied tumor tissue specimens from 48 patients with gastric carcinoma. Paraffin sections were submitted for immunohistochemistry using pRb, Ki67 and Her-2. Statistical analysis was performed for clinical and pathological data of all studied cases. Altered pRb was expressed in 79% of the studied tumors, inversely correlated with tumor invasion and stage with no significant relation with tumor grade, age, and gender and tumor size. Ki67 LI was significantly associated with tumor grade and stage but not related to sex, age, tumor size, site, depth of invasion and lymph node metastasis. Her2 was expressed in 75% of studies tumors with significant association with tumor grade, the depth of invasion, lymph node metastasis and higher tumor stage. However, there was no significant association between Her-2 expression and gender, tumor site and size. In conclusion, altered pRb is frequently expressed in gastric carcinoma, inversely correlates with tumor invasion and tumor stage suggesting an early event in gastric carcinogenesis. Ki67 expression in gastric carcinoma is directly correlated with the tumor grade and depth of invasion. Her2 expression is significantly correlated with tumor grade, depth of invasion and stage.
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Lorenzon L, Cippitelli C, Avantifiori R, Uccini S, French D, Torrisi MR, Ranieri D, Mercantini P, Canu V, Blandino G, Cavallini M. Down-regulated miRs specifically correlate with non-cardial gastric cancers and Lauren's classification system. J Surg Oncol 2017; 116:184-194. [PMID: 28475823 DOI: 10.1002/jso.24648] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 03/22/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND OBJECTIVES Gastric cancers are usually characterized using Lauren's classification into intestinal and diffuse types. We previously documented the down-modulation of miR31, miR148a, miR204, and miR375 in gastric cancers. We aimed this manuscript to investigate these miRs with the end-points of diagnosis, Lauren's classification and prognosis. METHODS A total of 117 resected non-cardial adenocarcinomas were evaluated for miRs' expressions. The performance of miRs' expressions for cancer diagnosis was tested using ROC curves. Logistic regression was conducted with the end-point of Lauren's classification. Kaplan-Meier and Cox analyses were performed for OS, DFS, and DSS. miRs' targets were reviewed using PRISMA method and BCL-2 was further investigated in cell lines. RESULTS ROC curves documented that miRs' down-modulation was significant in differentiating cancer versus normal tissues. Diffuse type cancers were associated with female sex, young age, and miR375 higher expression. We confirmed BCL-2 as a miR204 target. However, survival analyses confirmed the pathologic criteria (advanced stages, LNR, and low LNH) as the significant variables correlated to worse prognosis. CONCLUSIONS The down-modulation of miR31, miR148a, miR204, and miR375 is significantly associated with non-cardial gastric cancers and miR375 is specifically linked to Lauren's classification. Nevertheless, standard pathological features display as the independent variables associated with worse prognosis.
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Affiliation(s)
- Laura Lorenzon
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Claudia Cippitelli
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Riccardo Avantifiori
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Stefania Uccini
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Deborah French
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Maria Rosaria Torrisi
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Danilo Ranieri
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Paolo Mercantini
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Valeria Canu
- Italian National Cancer Institute Regina Elena, Translational Oncogenomic Unit, Rome, Italy
| | - Giovanni Blandino
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Marco Cavallini
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
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15
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Yantiss RK. Immunohistochemical and Molecular Features of Gastric Hyperplastic Polyps. ACTA ACUST UNITED AC 2017. [DOI: 10.15406/acp.2017.02.00012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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16
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Pan YM, Wang CG, Zhu M, Xing R, Cui JT, Li WM, Yu DD, Wang SB, Zhu W, Ye YJ, Wu Y, Wang S, Lu YY. STAT3 signaling drives EZH2 transcriptional activation and mediates poor prognosis in gastric cancer. Mol Cancer 2016; 15:79. [PMID: 27938379 PMCID: PMC5148878 DOI: 10.1186/s12943-016-0561-z] [Citation(s) in RCA: 117] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 11/23/2016] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND STAT3 signaling plays the pivotal role in tumorigenesis through EZH2 epigenetic modification, which enhanced STAT3 activity by increased tyrosine phosphorylation of STAT3. Here, another possible feedback mechanism and clinical significance of EZH2 and STAT3 were investigated in gastric cancer (GC). METHODS STAT3, p-STAT3 (Tyr 705) and EZH2 expression were examined in 63 GC specimens with matched normal tissues by IHC staining. EZH2 and STAT3 were also identified in five GC cell lines using RT-PCR and western blot analyses. p-STAT3 protein was detected by western blotting. In order to investigate whether EZH2 expression was directly regulated by STAT3, EZH2 expression was further detected using siRNA for STAT3 or IL-6 stimulation, with dual luciferase reporter analyses, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays. The clinical significance of STAT3, p-STAT3 and EZH2 expression was evaluated by multi-factor COX regression and Kaplan-Meier analyses. RESULTS Hyper-activation of STAT3, p-STAT3 and EZH2 expression were observed in GC cells and tissues. STAT3 signaling was correlated with EZH2 expression in GC (R = 0.373, P = 0.003), which was consistent with our data showing that STAT3 as the transcriptional factor enhanced EZH2 transcriptional activity by binding the relative promoter region (-214 ~ -206). STAT3 was an independent signature for poor survival (P = 0.002). Patients with STAT3+/EZH2+ or p-STAT3+/EZH2+ had a worse outcome than others (P < 0.001); Besides, high levels of STAT3 and EZH2 was associated with advanced TNM staging (P = 0.017). Moreover, treatment with a combination of siSTAT3 and EZH2-specific inhibitor, 3-deazaneplanocin A (DZNEP), increased the apoptotic ratio of cells. It is benefit for targeting STAT3-EZH2 interplay in GC treatment. CONCLUSIONS Our results indicate that STAT3 status mediated EZH2 upregulation, associated with advanced TNM stage and poor prognosis, suggesting that combination with knockdown of STAT3 and EZH2 inhibitor might be a novel therapy in GC treatment. Collectively, STAT3, p-STAT3 and EZH2 expression were provided for the precision medicine in GC patients.
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Affiliation(s)
- Yuan-Ming Pan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute , 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Cheng-Gang Wang
- Department of Gastroenterology Surgery, Surgical Oncology Laboratory, People's Hospital, Peking University, Beijing, 100044, China.,Department of Cardiology, Anzhen Hospital, Capital Medical University, Beijing, 100029, China
| | - Min Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute , 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Rui Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute , 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Jian-Tao Cui
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute , 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Wen-Mei Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute , 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - De-Dong Yu
- Department of Oncology/Institute for Cancer Research, Baotou Central Hospital, Inner Mongolia, 014040, China
| | - Shu-Bin Wang
- Department of Oncology/Institute for Cancer Research, Baotou Central Hospital, Inner Mongolia, 014040, China
| | - Wei Zhu
- Department of Oncology/Institute for Cancer Research, Baotou Central Hospital, Inner Mongolia, 014040, China
| | - Ying-Jiang Ye
- Department of Gastroenterology Surgery, Surgical Oncology Laboratory, People's Hospital, Peking University, Beijing, 100044, China
| | - Yun Wu
- Department of Oncology/Institute for Cancer Research, Baotou Central Hospital, Inner Mongolia, 014040, China. .,Department of Oncology/Institute for Cancer Research, Baotou Central Hospital, Baotou, 014040, People's Republic of China.
| | - Shan Wang
- Department of Gastroenterology Surgery, Surgical Oncology Laboratory, People's Hospital, Peking University, Beijing, 100044, China. .,Department of Gastroenterological Surgery, Surgical Oncology Laboratory, People's Hospital, Beijing University, No. 11, South Xizhimen Street, Beijing, 100044, People's Republic of China.
| | - You-Yong Lu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute , 52 Fucheng Road, Haidian District, Beijing, 100142, China.
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17
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Lui JC, Garrison P, Nguyen Q, Ad M, Keembiyehetty C, Chen W, Jee YH, Landman E, Nilsson O, Barnes KM, Baron J. EZH1 and EZH2 promote skeletal growth by repressing inhibitors of chondrocyte proliferation and hypertrophy. Nat Commun 2016; 7:13685. [PMID: 27897169 PMCID: PMC5477487 DOI: 10.1038/ncomms13685] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 10/25/2016] [Indexed: 12/16/2022] Open
Abstract
Histone methyltransferases EZH1 and EZH2 catalyse the trimethylation of histone H3 at lysine 27 (H3K27), which serves as an epigenetic signal for chromatin condensation and transcriptional repression. Genome-wide associated studies have implicated EZH2 in the control of height and mutations in EZH2 cause Weaver syndrome, which includes skeletal overgrowth. Here we show that the combined loss of Ezh1 and Ezh2 in chondrocytes severely impairs skeletal growth in mice. Both of the principal processes underlying growth plate chondrogenesis, chondrocyte proliferation and hypertrophy, are compromised. The decrease in chondrocyte proliferation is due in part to derepression of cyclin-dependent kinase inhibitors Ink4a/b, while ineffective chondrocyte hypertrophy is due to the suppression of IGF signalling by the increased expression of IGF-binding proteins. Collectively, our findings reveal a critical role for H3K27 methylation in the regulation of chondrocyte proliferation and hypertrophy in the growth plate, which are the central determinants of skeletal growth.
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Affiliation(s)
- Julian C Lui
- Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Room 1-3330, 10 Center Drive, MSC-1103, Bethesda, Maryland 20892, USA
| | - Presley Garrison
- Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Room 1-3330, 10 Center Drive, MSC-1103, Bethesda, Maryland 20892, USA
| | - Quang Nguyen
- Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Room 1-3330, 10 Center Drive, MSC-1103, Bethesda, Maryland 20892, USA
| | - Michal Ad
- Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Room 1-3330, 10 Center Drive, MSC-1103, Bethesda, Maryland 20892, USA
| | - Chithra Keembiyehetty
- Genomic Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg8, Room 1A11, 8 Center Drive, Bethesda, Maryland 20892, USA
| | - Weiping Chen
- Genomic Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg8, Room 1A11, 8 Center Drive, Bethesda, Maryland 20892, USA
| | - Youn Hee Jee
- Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Room 1-3330, 10 Center Drive, MSC-1103, Bethesda, Maryland 20892, USA
| | - Ellie Landman
- Division of Pediatric Endocrinology. Q2:08, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, 171 76 Stockholm, Sweden
| | - Ola Nilsson
- Division of Pediatric Endocrinology. Q2:08, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, 171 76 Stockholm, Sweden.,Department of Medical Sciences, Rm C1213, Örebro University and University Hospital, 701 85 Örebro, Sweden
| | - Kevin M Barnes
- Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Room 1-3330, 10 Center Drive, MSC-1103, Bethesda, Maryland 20892, USA
| | - Jeffrey Baron
- Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Room 1-3330, 10 Center Drive, MSC-1103, Bethesda, Maryland 20892, USA
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18
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Poh AR, O'Donoghue RJJ, Ernst M, Putoczki TL. Mouse models for gastric cancer: Matching models to biological questions. J Gastroenterol Hepatol 2016; 31:1257-72. [PMID: 26809278 PMCID: PMC5324706 DOI: 10.1111/jgh.13297] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 01/12/2016] [Accepted: 01/14/2016] [Indexed: 02/06/2023]
Abstract
Gastric cancer is the third leading cause of cancer-related mortality worldwide. This is in part due to the asymptomatic nature of the disease, which often results in late-stage diagnosis, at which point there are limited treatment options. Even when treated successfully, gastric cancer patients have a high risk of tumor recurrence and acquired drug resistance. It is vital to gain a better understanding of the molecular mechanisms underlying gastric cancer pathogenesis to facilitate the design of new-targeted therapies that may improve patient survival. A number of chemically and genetically engineered mouse models of gastric cancer have provided significant insight into the contribution of genetic and environmental factors to disease onset and progression. This review outlines the strengths and limitations of current mouse models of gastric cancer and their relevance to the pre-clinical development of new therapeutics.
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Affiliation(s)
- Ashleigh R Poh
- Department of Medical BiologyUniversity of MelbourneMelbourneVictoriaAustralia
- The Walter and Eliza Hall Institute of Medical ResearchMelbourneVictoriaAustralia
| | - Robert J J O'Donoghue
- School of Cancer MedicineLa Trobe University, Olivia Newton‐John Cancer Research InstituteMelbourneVictoriaAustralia
| | - Matthias Ernst
- School of Cancer MedicineLa Trobe University, Olivia Newton‐John Cancer Research InstituteMelbourneVictoriaAustralia
| | - Tracy L Putoczki
- Department of Medical BiologyUniversity of MelbourneMelbourneVictoriaAustralia
- The Walter and Eliza Hall Institute of Medical ResearchMelbourneVictoriaAustralia
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Kazanets A, Shorstova T, Hilmi K, Marques M, Witcher M. Epigenetic silencing of tumor suppressor genes: Paradigms, puzzles, and potential. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1865:275-88. [PMID: 27085853 DOI: 10.1016/j.bbcan.2016.04.001] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 04/08/2016] [Indexed: 12/20/2022]
Abstract
Cancer constitutes a set of diseases with heterogeneous molecular pathologies. However, there are a number of universal aberrations common to all cancers, one of these being the epigenetic silencing of tumor suppressor genes (TSGs). The silencing of TSGs is thought to be an early, driving event in the oncogenic process. With this in consideration, great efforts have been made to develop small molecules aimed at the restoration of TSGs in order to limit tumor cell proliferation and survival. However, the molecular forces that drive the broad epigenetic reprogramming and transcriptional repression of these genes remain ill-defined. Undoubtedly, understanding the molecular underpinnings of transcriptionally silenced TSGs will aid us in our ability to reactivate these key anti-cancer targets. Here, we describe what we consider to be the five most logical molecular mechanisms that may account for this widely observed phenomenon: 1) ablation of transcription factor binding, 2) overexpression of DNA methyltransferases, 3) disruption of CTCF binding, 4) elevation of EZH2 activity, 5) aberrant expression of long non-coding RNAs. The strengths and weaknesses of each proposed mechanism is highlighted, followed by an overview of clinical efforts to target these processes.
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Affiliation(s)
- Anna Kazanets
- The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada.
| | - Tatiana Shorstova
- The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada.
| | - Khalid Hilmi
- The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada.
| | - Maud Marques
- The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada.
| | - Michael Witcher
- The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada.
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20
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Cai L, Wang Z, Liu D. Interference with endogenous EZH2 reverses the chemotherapy drug resistance in cervical cancer cells partly by up-regulating Dicer expression. Tumour Biol 2015; 37:6359-69. [DOI: 10.1007/s13277-015-4416-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 11/09/2015] [Indexed: 10/22/2022] Open
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21
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Zheng L, Zhang Y, Liu Y, Zhou M, Lu Y, Yuan L, Zhang C, Hong M, Wang S, Li X. MiR-106b induces cell radioresistance via the PTEN/PI3K/AKT pathways and p21 in colorectal cancer. J Transl Med 2015; 13:252. [PMID: 26238857 PMCID: PMC4522974 DOI: 10.1186/s12967-015-0592-z] [Citation(s) in RCA: 135] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Accepted: 06/30/2015] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Radioresistance is a challenge in the treatment of patients with colorectal cancer (CRC). Individuals display different therapeutic responses to preoperative radiotherapy, and the need of targeted therapies is urgent. MicroRNAs (miRNAs) are involved in essential biological activities, including chemoresistance and radioresistance. Several research studies have indicated that miRNA played an important role in sensitizing cells to ionizing radiation (IR). MiR-106b, a member of the miR-106b-25 cluster, is frequently dysregulated in many human cancers, including CRC. However, the function of miR-106b in radioresistance is currently poorly understood. METHODS A series of in vitro and in vivo studies were performed to investigate the roles of miR-106b on cell radioresistance in CRC. RESULTS We found overexpression of miR-106b could induce resistance to IR in vitro and in vivo in SW620 cells. Correspondingly, knocking down miR-106b in SW480 yielded the opposite effect. In addition, overexpression of miR-106b could enhance the tumour-initiating cell capacity without or with IR condition, such as the colony sphere formation capacity and the upregulation of stemness-related genes (CD133, Sox2). We further identified PTEN and p21 as novel direct targets of miR-106b by using target prediction algorithms and a luciferase assay. Overexpression of miR-106b reduced the expression of PTEN and p21 and increased the expression of p-AKT, which is a downstream of PTEN. Restoring the expression of PTEN or p21 in stably miR-106b-overexpressed cells could rescue the effect of miR-106b on cell radioresistance. Together, the acquisition of tumour-initiating cell capacity endowed CRC cells with the potential of resistance to irradiation. CONCLUSIONS These observations illustrated that miR-106b could induce cell radioresistance by directly targeting PTEN and p21, this process was accompanied by tumour-initiating cell capacity enhancement, which is universally confirmed to be associated with radioresistance. Our data suggested that miR-106b at least partly induces cell radioresistance in CRC.
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Affiliation(s)
- Lin Zheng
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong Province, China. .,Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
| | - Yuqin Zhang
- Department of Oncology, The First Affiliated Hospital of Jinan University, Guangzhou, 510515, Guangdong Province, China.
| | - Yan Liu
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong Province, China. .,Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
| | - Min Zhou
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong Province, China. .,Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
| | - Yanxia Lu
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong Province, China. .,Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
| | - Li Yuan
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong Province, China. .,Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
| | - Chao Zhang
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong Province, China. .,Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, 510515, Guangdong Province, China.
| | - Min Hong
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong Province, China. .,Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
| | - Shuang Wang
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong Province, China. .,Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
| | - Xuenong Li
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong Province, China. .,Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
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22
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Cito L, Indovina P, Forte IM, Pentimalli F, Di Marzo D, Somma P, Barone D, Penon A, Penon D, Ceccherini E, Micheli P, Saragoni L, Di Domenico M, Feola A, Roviello F, Mattioli E, Giordano GG, Giordano A. pRb2/p130 localizes to the cytoplasm in diffuse gastric cancer. J Cell Physiol 2015; 230:802-5. [PMID: 25205458 DOI: 10.1002/jcp.24805] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 09/05/2014] [Indexed: 12/18/2022]
Abstract
pRb2/p130 is a key tumor suppressor, whose oncosuppressive activity has mainly been attributed to its ability to negatively regulate cell cycle by interacting with the E2F4 and E2F5 transcription factors. Indeed, pRb2/p130 has been found altered in various cancer types in which it functions as a valuable prognostic marker. Here, we analyzed pRb2/p130 expression in gastric cancer tissue samples of diffuse histotype, in comparison with their normal counterparts. We found a cytoplasmic localization of pRb2/p130 in cancer tissue samples, whereas, in normal counterparts, we observed the expected nuclear localization. pRb2/p130 cytoplasmic delocalization can lead to cell cycle deregulation, but considering the emerging involvement of pRb2/p130 in other key cellular processes, it could contribute to gastric tumorigenesis also through other mechanisms. Our data support the necessity of further investigations to verify the possibility of using pRb2/p130 as a biomarker or potential therapeutic target for diffuse gastric cancer.
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Affiliation(s)
- Letizia Cito
- Oncology Research Center of Mercogliano (CROM), Istituto Nazionale per lo studio e la cura dei tumori "Fondazione Giovanni Pascale"-IRCCS, Naples, Italy
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Xia R, Jin FY, Lu K, Wan L, Xie M, Xu TP, De W, Wang ZX. SUZ12 promotes gastric cancer cell proliferation and metastasis by regulating KLF2 and E-cadherin. Tumour Biol 2015; 36:5341-51. [PMID: 25672609 DOI: 10.1007/s13277-015-3195-7] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 01/30/2015] [Indexed: 12/31/2022] Open
Abstract
SUZ12 is a core component of the polycomb repressive complex 2 (PRC2), which could silence gene transcription by generating trimethylation on lysine 27 residue of histone H3 (H3K27Me3). Meanwhile, SUZ12 has been found to be overexpressed in multiple cancers; however, the clinical significance and molecular mechanisms of SUZ12 controlling gastric cancer cell proliferation and metastasis are unclear. In this study, we found that SUZ12 expression was significantly increased in 64 gastric tumor tissues compared with normal tissues. Additionally, SUZ12 expression was associated with pathological stage, metastasis distance, and shorter overall survival of gastric cancer patients. Knockdown of SUZ12 expression impaired cell proliferation and invasion in vitro, leading to the inhibition of metastasis in vivo. Upregulation of SUZ12 was found to play a key role in gastric cancer cell proliferation and metastasis through the regulation of EMT and KLF2 expression.
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Affiliation(s)
- Rui Xia
- Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, People's Republic of China
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Neoplasms arising in large gastric hyperplastic polyps: endoscopic and pathologic features. Gastrointest Endosc 2014; 80:1005-13.e2. [PMID: 24929480 DOI: 10.1016/j.gie.2014.04.020] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 04/08/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND Little is known about gastric neoplasms arising from hyperplastic polyps (HPs). OBJECTIVE To investigate the risk factors associated with neoplasms within HPs and to evaluate the role of alterations of the p16-cyclin D1-pRb pathway in the malignant transformation of HPs. DESIGN Retrospective, case-control study. SETTING Tertiary-care center. PATIENTS Between May 1995 and January 2011, a total of 809 HPs >1 cm were investigated. Associated neoplasms were present in 30 HPs (case group); 30 HPs without neoplasms were selected as a control group. INTERVENTIONS Gastric polypectomy. MAIN OUTCOME MEASUREMENTS The risk factors associated with neoplasms within HPs and immunohistochemical expression of p16, cyclin D1, p53, and Ki-67 between case and control groups. RESULTS Of the 809 HPs, 15 had associated dysplasia, and 15 had carcinoma. Multivariate analysis showed that neoplasm was associated with patient age (odds ratio [OR] 1.159; 95% confidence interval [CI], 1.243-2.044; P < .001), polyp size (OR 1.103; 95% CI, 1.055-1.152; P < .001), and polyp lobulation (OR 4.549; 95% CI, 1.759-11.0766; P < .001) but not with location, multiplicity, intestinal metaplasia, growth pattern, or Helicobacter pylori infection. Loss of p16 expression and high Ki-67 expression were observed in dysplastic areas of HPs compared with the control group (p16 = 14.3% vs 60%; P = .001, Ki-67 = 60.7% vs 36.7%; P < .001). However, no significant differences were found in nondysplastic areas in both groups. LIMITATIONS Single-center, retrospective study. CONCLUSION HPs >1 cm may indicate the presence of neoplasms. Loss of p16 and high Ki-67 expression may be markers of HP-associated dysplasia.
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The opposite prognostic significance of nuclear and cytoplasmic p21 expression in resectable gastric cancer patients. J Gastroenterol 2014; 49:1441-52. [PMID: 24127074 DOI: 10.1007/s00535-013-0900-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Accepted: 10/06/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND Protein p21(Cip1/Waf1) is a cyclin-dependent kinase inhibitor, which plays important roles in cell cycle arrest, senescence, and apoptosis. Interestingly, the nuclear and cytoplasmic p21 executes various functions in the cell. In this study, we investigated the prognostic impact of subcellular p21 expression in gastric cancer (GC). METHODS Expressions of subcellular p21 was assessed by immunohistochemistry using a tissue microarray in a training cohort and it went into a second testing cohort and finally to a validating cohort. Prognostic and predictive role of subcellular p21 expression status was evaluated. We also studied the roles of subcellular p21 in GC cell migration and invasion. RESULTS Nuclear and cytoplasmic p21 protein levels were significantly reduced and increased in GC lesions compared with adjacent non-cancerous tissues, respectively. Low nuclear p21 or high cytoplasmic p21 expression significantly correlated with shorter overall survival (OS), as well as with clinicopathologic characteristics in patients. Multivariate regression analysis showed that low nuclear and high cytoplasmic p21 expression, separately and together, were independent negative markers of OS. Finally, we found that nuclear p21 inhibits but cytoplasmic p21 promotes cell migration and invasion abilities. CONCLUSIONS These findings suggest that nuclear and cytoplasmic p21 protein expression in tumor are novel candidate prognostic markers in resectable human gastric carcinoma, and they exert distinct roles in cell migration and invasion.
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EZH2 silencing with RNA interference induces G2/M arrest in human lung cancer cells in vitro. BIOMED RESEARCH INTERNATIONAL 2014; 2014:348728. [PMID: 24745014 PMCID: PMC3976908 DOI: 10.1155/2014/348728] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Accepted: 02/11/2014] [Indexed: 12/11/2022]
Abstract
Nonsmall-cell lung cancer has a high mortality rate and poor prognosis. In the present study, we silenced EZH2 and explored the consequent cell cycle changes. The expression of cell-cycle-related proteins, including p53, p21, Cdc2, and cyclin B1, was detected with western blotting, and the cell cycle distribution was determined with flow cytometry. Inhibition of EZH2 expression changed the cell cycle distribution, in particular inducing G2/M arrest. Expression of Cdc2 and cyclin B1 was significantly decreased in A549 and HTB-56 cells after EZH2-siRNA treatment. In addition, p53 expression was increased by 21% and 18%, and p21 expression was increased by 31% and 23%, in A549 and HTB-56 cells, respectively, in the presence of EZH2-siRNA. This study clearly demonstrates that modulation of EZH2 expression with siRNA affects the cell cycle and the expression levels of p53 and p21, thereby changing cyclin B1 and Cdc2 expression and inducing G2/M arrest. These results may explain the observed antitumor activity of EZH2 silencing. Such explorations of the molecular mechanism of EZH2 will help us develop novel approaches to the diagnosis, treatment, and prevention of nonsmall-cell lung cancer.
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Liu X, Yu H, Cai H, Wang Y. Expression of CD24, p21, p53, and c-myc in alpha-fetoprotein-producing gastric cancer: Correlation with clinicopathologic characteristics and survival. J Surg Oncol 2014; 109:859-64. [PMID: 24619835 DOI: 10.1002/jso.23599] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2013] [Accepted: 02/10/2014] [Indexed: 01/30/2023]
Abstract
BACKGROUND AND OBJECTIVE The aim of this study was to evaluate the expression of CD24, p21, p53, and c-myc in lesions of patients with Alpha-Fetoprotein (AFP)-producing gastric cancer and their correlation with clinicopathological features and prognosis. METHODS One hundred and four patients with AFP-producing gastric cancer were included into this study. The levels of CD24, p21, p53, and c-myc were examined by immunohistochemistry.The prognostic value of these biological markers and the correlation between biological markers and clinicopathological factors were investigated. RESULTS The percentages of positive expression of CD24, p21, p53, and c-myc were 31.7%, 77.9%, 75.0%, and 66.3%, respectively. CD24 expression correlated with histological grade (P = 0.045) and Lauren type (P = 0.006); p21expression with Borrmann type (P = 0.035); c-myc expression with Borrmann type (P = 0.029). p21 expression was related with poor survival in univariate analysis (P = 0.016). Multivariate analysis showed that p21 expression, vascular invasion, and pathological stage were defined as independent prognostic factors. CONCLUSION The expression of p21 was an independent prognostic factor for patients with AFP-producing gastric cancer.
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Affiliation(s)
- Xiaowen Liu
- Department of Gastric Cancer and Soft Tissue Sarcoma, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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Qi L, Du J, Zhang Z, Diao L, Chen X, Yao X. Low differentiated microvascular density and low expression of platelet-derived growth factor-BB (PDGF-BB) predict distant metastasis and poor prognosis in clear cell renal cell carcinoma. BJU Int 2013; 112:E415-23. [PMID: 23879920 DOI: 10.1111/bju.12191] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE To examine the prognostic significance of the expression of platelet-derived growth factor-BB (PDGF-BB) and differentiated microvascular density (MVD) in patients with clear cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS We used the vascular marker cluster of differentiation 34 (CD34) to identify tumour blood vessels. The expression of PDGF-BB and CD34 was detected by immunohistochemistry (IHC) in tissue microarrays (TMAs) from 100 ccRCCs. Prognostic effects of individual parameters were calculated using Cox regression models and Harrell's concordance index (c-index). RESULTS Higher grade and more advanced stage ccRCCs had significantly less PDGF-BB expression and differentiated MVD (P < 0.05). Higher PDGF-BB expression was an independent prognostic factor for longer survival, and moreover, the final model built by the addition of PDGF-BB expression improved the predictive accuracy for disease-free survival (c-index 0.707) compared with the clinicopathological-based model (c-index 0.695). PDGF-BB expression was positively associated with differentiated MVD assessed by Spearman correlation and factor analysis (r = 0.634, P < 0.001). CONCLUSION PDGF-BB is as a novel and promising prognostic marker and antiangiogenic therapeutic target for the treatment of ccRCC.
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Affiliation(s)
- Lifeng Qi
- Department of Genitourinary Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
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Calcagno DQ, Gigek CO, Chen ES, Burbano RR, Smith MDAC. DNA and histone methylation in gastric carcinogenesis. World J Gastroenterol 2013; 19:1182-92. [PMID: 23482412 PMCID: PMC3587474 DOI: 10.3748/wjg.v19.i8.1182] [Citation(s) in RCA: 89] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Revised: 06/13/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023] Open
Abstract
Epigenetic alterations contribute significantly to the development and progression of gastric cancer, one of the leading causes of cancer death worldwide. Epigenetics refers to the number of modifications of the chromatin structure that affect gene expression without altering the primary sequence of DNA, and these changes lead to transcriptional activation or silencing of the gene. Over the years, the study of epigenetic processes has increased, and novel therapeutic approaches that target DNA methylation and histone modifications have emerged. A greater understanding of epigenetics and the therapeutic potential of manipulating these processes is necessary for gastric cancer treatment. Here, we review recent research on the effects of aberrant DNA and histone methylation on the onset and progression of gastric tumors and the development of compounds that target enzymes that regulate the epigenome.
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Bria E, De Manzoni G, Beghelli S, Tomezzoli A, Barbi S, Di Gregorio C, Scardoni M, Amato E, Frizziero M, Sperduti I, Corbo V, Brunelli M, Bersani S, Tortora G, Scarpa A. A clinical-biological risk stratification model for resected gastric cancer: prognostic impact of Her2, Fhit, and APC expression status. Ann Oncol 2012; 24:693-701. [PMID: 23131390 DOI: 10.1093/annonc/mds506] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND To obtain a prognostic stratification model for resected gastric cancer patients. PATIENTS AND METHODS Clinicopathological and molecular data (expression of Cdx2, Apc, β-catenin, E-cadherin, Fhit, p53, and human epidermal growth factor receptor-2 (Her2); HER2 and TOPO2A gene copy number; PIK3CA mutations; microsatellite instability) were correlated to cancer-specific/overall survival (CSS/OS) using a Cox model. Individual patient probability (IPP) was estimated by logistic equation. A continuous score to identify risk-classes was derived according to the model ratios. RESULTS Two-hundred eight patients were studied (median follow-up 20 months). At multivariate analysis, sex, stage, margins, location, nodes, Apc, and Fhit were independent predictors for CSS; the same factors (and age and Her2, except Fhit) predicted OS. Multivariate model predicted IPP with high prognostic accuracy (0.90 for CSS; 0.91 for OS). A two-class model significantly separated low- and high-risk patients for CSS (23.4% and 85.6%, P < 0.0001) and OS (21.4% and 82.0%, P < 0.0001). A three-class model differentiated low-, intermediate-, and high-risk patients for CSS (6.3%, 35.3%, and 88.0%, P < 0.0001) and OS (6.1%, 34.6%, and 86.5%, P < 0.0001). CONCLUSIONS A risk classification system comprising the immunohistochemical expression of three proteins (Apc, Fhit, and Her2) and five clinicopathological parameters (stage, resected nodes, margins, location, and sex) accurately separates the resected gastric cancer patients into three classes of risk.
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Affiliation(s)
- E Bria
- ARC-NET the Miriam Cherubini Loro, Applied Research on Cancer Center
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Huang SD, Yuan Y, Zhuang CW, Li BL, Gong DJ, Wang SG, Zeng ZY, Cheng HZ. MicroRNA-98 and microRNA-214 post-transcriptionally regulate enhancer of zeste homolog 2 and inhibit migration and invasion in human esophageal squamous cell carcinoma. Mol Cancer 2012; 11:51. [PMID: 22867052 PMCID: PMC3496689 DOI: 10.1186/1476-4598-11-51] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2012] [Accepted: 07/26/2012] [Indexed: 12/22/2022] Open
Abstract
Background The enhancer of zeste homolog 2 (EZH2) was found to be overexpressed and associated with tumor metastasis in esophageal squamous cell carcinoma (ESCC). On the other hand, it was reported that miR-26a, miR-98, miR-101, miR-124, miR-138 and miR-214 could inhibit the expression of EZH2 in some tumors. However, the role of miRNAs in the regulation of EZH2 expression in human ESCC has not been documented. The aim of this study was to determine the role of these miRNAs in the regulation of tumor metastasis via EZH2 overexpression in human ESCC. Methods and results The expression of these miRNAs and EZH2 mRNA were examined by qPCR and the expression of EZH2 protein was detected by western blot. The role of these miRNAs in migration and invasion was studied in ESCC cell line (Eca109) transfected with miRNA mimics or cotransfected with miRNA mimics and pcDNA-EZH2 plasmid (without the 3’-UTR of EZH2). Through clinical investigation, we found that miR-98 and miR-214 expression was significantly lower in ESCC tissues than in matched normal tissues, and the expression level of miR-98 and miR-214 was inversely correlated to EZH2 protein expression and the clinical features such as pathological grade, tumor stage and lymph node metastasis in ESCC. In Eca109 cells, overexpression of miR-98 and miR-214 significantly inhibited the migration and invasion of ESCC cells, which was reversed by transfection of EZH2. Conclusions These findings suggest that decreased expression of miR-98 and miR-214 might promote metastasis of human ESCC by inducing accumulation of EZH2 protein.
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Affiliation(s)
- Sheng-Dong Huang
- Institute of Cardiothoracic Surgery, Changhai Hospital, 168, Changhai Rd, Shanghai, PR China
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Nagini S. Carcinoma of the stomach: A review of epidemiology, pathogenesis, molecular genetics and chemoprevention. World J Gastrointest Oncol 2012; 4:156-69. [PMID: 22844547 PMCID: PMC3406280 DOI: 10.4251/wjgo.v4.i7.156] [Citation(s) in RCA: 326] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Revised: 06/04/2012] [Accepted: 06/12/2012] [Indexed: 02/05/2023] Open
Abstract
Carcinoma of the stomach is still the second most common cause of cancer death worldwide, although the incidence and mortality have fallen dramatically over the last 50 years in many regions. The incidence of gastric cancer varies in different parts of the world and among various ethnic groups. Despite advances in diagnosis and treatment, the 5-year survival rate of stomach cancer is only 20 per cent. Stomach cancer can be classified into intestinal and diffuse types based on epidemiological and clinicopathological features. The etiology of gastric cancer is multifactorial and includes both dietary and nondietary factors. The major diet-related risk factors implicated in stomach cancer development include high content of nitrates and high salt intake. Accumulating evidence has implicated the role of Helicobacter pylori (H. pylori) infection in the pathogenesis of gastric cancer. The development of gastric cancer is a complex, multistep process involving multiple genetic and epigenetic alterations of oncogenes, tumor suppressor genes, DNA repair genes, cell cycle regulators, and signaling molecules. A plausible program for gastric cancer prevention involves intake of a balanced diet containing fruits and vegetables, improved sanitation and hygiene, screening and treatment of H. pylori infection, and follow-up of precancerous lesions. The fact that diet plays an important role in the etiology of gastric cancer offers scope for nutritional chemoprevention. Animal models have been extensively used to analyze the stepwise evolution of gastric carcinogenesis and to test dietary chemopreventive agents. Development of multitargeted preventive and therapeutic strategies for gastric cancer is a major challenge for the future.
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Affiliation(s)
- Siddavaram Nagini
- Siddavaram Nagini, Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, India
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Zhou Y, Du WD, Wu Q, Liu Y, Chen G, Ruan J, Xu S, Yang F, Zhou FS, Tang XF, Tang HY, Zuo XB, Zhang FY, Sun LD, Zhang XJ. EZH2 genetic variants affect risk of gastric cancer in the Chinese Han population. Mol Carcinog 2012; 53:589-97. [PMID: 22228224 DOI: 10.1002/mc.21871] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Revised: 12/09/2011] [Accepted: 12/12/2011] [Indexed: 12/20/2022]
Abstract
Enhancer of zeste 2 (EZH2) gene encodes a histone methyltransferase that constitutes the catalytic component of the polycomb repressive complex-2 (PRC2) to initiate epigenetic silencing of genes. It is reported that the expression level of EZH2 in gastric cancer tissue was highly correlated with tumor progression, however, whether EZH2 genetic variants were associated with the risk of gastric cancer remains yet unknown. In this study, we conducted a genotyping analysis for EZH2 in 311 cases of gastric cancer and 425 controls from the Chinese Han population. We found five single nucleotide polymorphisms (SNP; rs12670401, rs6464926, rs2072407, rs734005, and rs734004) of EZH2 gene were significantly associated with the risk of gastric cancer. Of which, the rs12670401 with the minor allele C and rs6464926 with the minor allele T revealed strong associations with increased gastric cancer risk [P = 0.009, adjusted odds ratio (aOR) = 1.327, 95% CI = 1.075-1.683 and P = 0.012, aOR = 1.310, 95% CI = 1.059-1.619]. The other three SNPs, rs2072407, rs734005, and rs734004 contributed to significantly reduced risk of gastric cancer (P = 0.033, aOR = 0.787, 95% CI = 0.633-0.981, P = 0.045, aOR = 0.799, 95% CI = 0.642-0.995 and P = 0.048, aOR = 0.803, 95% CI = 0.645-0.999), respectively. We further found that rs12670401 and rs6464926 were in a strong LD while rs2072407, rs734005, and rs734004 were in another. Haplotype analysis of the five SNPs showed that haplotype CCTCT reduced the risk of gastric cancer (P = 0.031 and aOR = 0.784), while haplotype GTCTC significantly elevated the risk of gastric cancer (P = 0.011 and aOR = 1.310). We concluded that EZH2 variants were significantly associated with gastric cancer risk. Our results for the first time provided new insight into susceptibility factors of EZH2 gene variants in carcinogenesis of gastric cancer of the Chinese Han population.
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Affiliation(s)
- Yuan Zhou
- Key Lab of Genome Research of Anhui Province, Anhui Medical University, Hefei, China; Department of Biology, Anhui Medical University, Hefei, China
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Alves MKS, Ferrasi AC, Lima VP, Ferreira MVP, de Moura Campos Pardini MI, Rabenhorst SHB. Inactivation of COX-2, HMLH1 and CDKN2A gene by promoter methylation in gastric cancer: relationship with histological subtype, tumor location and Helicobacter pylori genotype. Pathobiology 2011; 78:266-76. [PMID: 21849808 DOI: 10.1159/000329475] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2011] [Accepted: 05/10/2011] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE We aimed to evaluate the inactivation of COX-2, HMLH1 and CDKN2A by promoter methylation and its relationship with the infection by different Helicobacter pylori strains in gastric cancer. METHODS DNA extracted from 76 H. pylori-positive gastric tumor samples was available for promoter methylation identification by methylation-specific PCR and H. pylori subtyping by PCR. Immunohistochemistry was used to determine COX-2, p16(INK4A) and HMLH1 expression. RESULTS A strong negative correlation was found between the expression of these markers and the presence of promoter methylation in their genes. Among cardia tumors, negativity of p16(INK4A) was a significant finding. On the other hand, in noncardia tumors, the histological subtypes had different gene expression patterns. In the intestinal subtype, a significant finding was HMLH1 inactivation by methylation, while in the diffuse subtype, CDKN2A inactivation by methylation was the significant finding. Tumors with methylated COX-2 and HMLH1 genes were associated with H. pylori vacA s1 (p = 0.025 and 0.047, respectively), and the nonmethylated tumors were associated with the presence of the gene flaA. CONCLUSIONS These data suggest that the inactivation of these genes by methylation occurs by distinct pathways according to the histological subtype and tumor location and depends on the H. pylori genotype.
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Suzuki S, Dobashi Y, Hatakeyama Y, Tajiri R, Fujimura T, Heldin CH, Ooi A. Clinicopathological significance of platelet-derived growth factor (PDGF)-B and vascular endothelial growth factor-A expression, PDGF receptor-β phosphorylation, and microvessel density in gastric cancer. BMC Cancer 2010; 10:659. [PMID: 21118571 PMCID: PMC3009982 DOI: 10.1186/1471-2407-10-659] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2010] [Accepted: 11/30/2010] [Indexed: 12/21/2022] Open
Abstract
Background Angiogenesis is important in the growth and metastasis of various kinds of solid tumors, including gastric cancers. The angiogenic process is triggered by several key growth factors, including vascular endothelial growth factor (VEGF)-A and platelet-derived growth factor (PDGF)-B, that are secreted by tumors. Our aim was to define: i) the expression pattern of VEGF-A and PDGF-B in tumor cells and the activation of PDGF receptor (PDGFR)-β tyrosine kinase in stromal cells of human gastric adenocarcinomas; and ii) the relationship between VEGF-A and PDGF-B expression and microvessel density (MVD), to determine if there is a rationale for a new therapeutic strategy. Methods A series of 109 gastric adenocarcinoma cases that had undergone surgical resection was examined immunohistochemically using antibodies against VEGF-A, PDGF-B, and CD34, followed by further examination of PDGFR-β phosphorylation by immunoblotting analysis. Results MVD was higher in diffuse-type than intestinal-type cancers (p < 0.001). VEGF-A overexpression correlated to PDGF-B overexpression in both the intestinal-type (p < 0.005) and diffuse-type (p < 0.0001) groups, indicating that VEGF-A and PDGF-B are secreted simultaneously in the same tumor, and may thus play important roles together in angiogenesis. However, several differences between intestinal-type and diffuse-type cancers were observed. In the diffuse-type cancer group, higher MVD was related to the PDGF-B proportion (p < 0.05) and VEGF-A overexpression (p < 0.05), but not to PDGF-B overexpression or the VEGF-A proportion. On the other hand, in the intestinal-type cancer group, higher MVD was correlated to overexpression (p < 0.005), intensity (p < 0.05), and proportion (p < 0.05) of PDGF-B, but not of VEGF-A. In addition, phosphorylation of PDGFR-β was correlated with depth of cancer invasion at statistically significant level. Conclusions Our results indicate that PDGF-B, which is involved in the maintenance of microvessels, plays a more important role in angiogenesis in intestinal-type gastric carcinomas than VEGF-A, which plays a key role mainly in the initiation of new blood vessel formation. In contrast, VEGF-A has a critical role for angiogenesis more in diffuse-type cancers, but less in those of intestinal type. Thus, a therapy targeting the PDGF-B signaling pathway could be effective for intestinal-type gastric carcinoma, whereas targeting VEGF-A or both VEGF-A and PDGF-B signaling pathways could be effective for diffuse-type gastric carcinomas.
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Affiliation(s)
- Shioto Suzuki
- Department of Molecular and Cellular Pathology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
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A multicenter, phase II study of bortezomib (PS-341) in patients with unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma. Invest New Drugs 2010; 29:1475-81. [PMID: 20574790 DOI: 10.1007/s10637-010-9474-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2010] [Accepted: 06/07/2010] [Indexed: 12/14/2022]
Abstract
PURPOSE The transcription factor nuclear factor-kB (NFkB) is implicated in gastric cancer carcinogenesis and survival, and its inhibition by proteosome inhibition is associated with preclinical gastric cancer anti-tumor activity. We examined the single agent efficacy of bortezomib, a selective proteasome inhibitor, in gastric adenocarcinoma. EXPERIMENTAL DESIGN We performed a phase II trial of bortezomib in patients with advanced gastric adenocarcinoma. Bortezomib 1.3 mg/m(2) was administered on days 1, 4, 8, and 11 every 21 days. The primary endpoint was objective response rate(RR); the null hypothesis was RR <1% versus the alternative ≥15%. One response in the first stage(15 patients) was required before proceeding with an additional 18 patients. If at least 2 or more responses out of 33 were observed, further study with bortezomib was warranted. Correlative studies evaluated pre-treatment tumor expression of NFkB, IkB, p53, p21, and cyclin D1. RESULTS We enrolled 16 patients (15 evaluable for response) from four institutions. No patients demonstrated an objective response(95% CI, 0-22%); one patient achieved stable disease. Fourteen out of 16 patients experienced ≥ grade 2 toxicity. The most common toxicity was fatigue in six patients (n = 4 grade 2, n = 2 grade 3). Seven patients experienced neuropathy (n = 5 grade 1, and 1 each grade 2 and 3). Seven (60%) had high cytoplasmic staining for NFkB. CONCLUSIONS Single agent bortezomib is inactive in metastatic gastric adenocarcinoma and should not be pursued. Future study of proteasome inhibition in gastric adenocarcinoma should be considered in combination with targeted inhibition of other non-overlapping oncogenic pathways as a potential rational approach.
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Cai GH, Wang K, Miao Q, Peng YS, Chen XY. Expression of polycomb protein EZH2 in multi-stage tissues of gastric carcinogenesis. J Dig Dis 2010; 11:88-93. [PMID: 20402834 DOI: 10.1111/j.1751-2980.2010.00420.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To study the role and significance of the polycomb group (PcG) protein EZH2 (enhancer of zeste homolog 2) in the multi-step process of intestinal-type gastric carcinogenesis. METHODS Gastric specimens were obtained from 142 patients with gastric disease, including 34 with chronic non-atrophic gastritis (NCAG), 33 chronic atrophic gastritis (CAG) with intestinal metaplasia (IM), 40 CAG with dysplasia (DYS) and 35 with intestinal-type gastric carcinomas (GC), and 32 Helicobacter pylori-negative controls. The EZH2 protein was stained by the immunohistochemical method and was expressed as the intensity and percentage of the total number of epithelial cells. The chronic gastritis and the grading of dysplasia were classified according to Chinese National Consensus on chronic gastritis and the Padova international classification. RESULTS The EZH2 protein levels in the specimens of normal gastric tissue, NCAG, CAG with IM, DYS and intestinal-type GC were gradually increased (P < 0.05), but statistical significance was not found between the groups of DYS and GC. CONCLUSION PcG protein EZH2 plays an important role in the multi-step process of intestinal-type gastric carcinogenesis.
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Affiliation(s)
- Gan Hui Cai
- Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Begnami MD, Fregnani JHTG, Nonogaki S, Soares FA. Evaluation of cell cycle protein expression in gastric cancer: cyclin B1 expression and its prognostic implication. Hum Pathol 2010; 41:1120-7. [PMID: 20334896 DOI: 10.1016/j.humpath.2010.01.007] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2009] [Revised: 01/06/2010] [Accepted: 01/08/2010] [Indexed: 12/21/2022]
Abstract
The cell cycle progression is regulated by interactions of specific cyclin-dependent kinases at the G1-S and G2-M checkpoints. In addition, the cell cycle dysregulation plays a major role in carcinogenesis of human cancers. To investigate the role of cell cycle regulators in the pathogenesis and progression of human gastric cancer, the expression of cyclin D1, A, B1, p16(INK4a), p21(CPI1), p27(KIP1), p53, and pRb was investigated in 482 gastric carcinomas using immunohistochemistry in terms of histologic type, tumor invasion, size, location, and metastatic behavior. The cyclin D1, A, and B1 expression (>10%) was observed in 49%, 69%, and 49% of the cases, respectively. Negative cases for p16(INK4a), p21(CPI1), and p27(KIP1) were detected in 90%, 86%, and 50.5%. There were 30% and 68% of the gastric tumors positive for p53 and pRb, respectively. Diffuse carcinomas frequently were positive for cyclin B1 and pRb, and negative for p21. A relationship between p53 expression and intestinal type carcinomas was found. In addition, the expression of cyclin B1 was associated with regional lymph node metastasis and poor prognosis. No relationship was noticed between any other cell cycle proteins expression and age, sex, tumor size, tumor location, and lymph node involvement. These findings have shown alterations in several cell cycle regulators, and it was suggested that cyclin B1 expression is closely associated with poor behavior in gastric cancer.
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Affiliation(s)
- Maria D Begnami
- Department of Pathology, Hospital AC Camargo, 01509900 São Paulo, Brazil.
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Choi JH, Song YS, Yoon JS, Song KW, Lee YY. Enhancer of zeste homolog 2 expression is associated with tumor cell proliferation and metastasis in gastric cancer. APMIS 2010; 118:196-202. [PMID: 20132185 DOI: 10.1111/j.1600-0463.2009.02579.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The enhancer of zeste homolog 2 (EZH2), a member of the polycomb group of proteins, plays an important role in cell proliferation and cell cycle regulation. EZH2 is overexpressed in aggressive forms of prostate, breast, bladder, and endometrial cancers. However, the role of EZH2 expression in gastric cancer has not been fully determined. This study was conducted to investigate the correlation between EZH2 and cell cycle-related molecules, and the clinical value of EZH2 expression in gastric cancer. We analyzed EZH2 expression using Western blotting in AGS, MKN-28, SNU-16, SNU-484, SNU-601, and SNU-638 gastric cancer cell lines. After transfection of EZH2 siRNA into MKN-28 cells, the change in cell cycle-related molecules was assessed by Western blot analysis. Expression of EZH2, Ki-67, and p53 was determined by immunohistochemical staining of tissue microarrays from specimens of 137 cases of resected gastric cancer. We found high expressions of EZH2 in all of the tested gastric cancer cell lines. RNA interference of EZH2 induced upregulation of p53 and HDAC1 and downregulation of cyclin D1 and cyclin E. High EZH2 expression was observed in 60.6% of gastric cancers and in 6.7% of non-neoplastic gastric tissues (p < 0.01); 40.1% were positive for p53 in gastric cancers. High EZH2 expression was correlated with Ki-67 and p53 expressions and was significantly associated with distant metastases and non-signet ring cells. Our results suggest that high EZH2 expression is associated with tumor cell proliferation and metastasis in gastric cancer.
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Affiliation(s)
- Jung Hye Choi
- Department of Internal Medicine, Hanyang University College of Medicine, Gyunggi-do, Korea.
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Martínez-Climent JA, Fontan L, Fresquet V, Robles E, Ortiz M, Rubio A. Integrative oncogenomic analysis of microarray data in hematologic malignancies. Methods Mol Biol 2010; 576:231-277. [PMID: 19882266 DOI: 10.1007/978-1-59745-545-9_13] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
During the last decade, gene expression microarrays and array-based comparative genomic hybridization (array-CGH) have unraveled the complexity of human tumor genomes more precisely and comprehensively than ever before. More recently, the simultaneous assessment of global changes in messenger RNA (mRNA) expression and in DNA copy number through "integrative oncogenomic" analyses has allowed researchers the access to results uncovered through the analysis of one-dimensional data sets, thus accelerating cancer gene discovery. In this chapter, we discuss the major contributions of DNA microarrays to the study of hematological malignancies, focusing on the integrative oncogenomic approaches that correlate genomic and transcriptomic data. We also present the basic aspects of these methodologies and their present and future application in clinical oncology.
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Affiliation(s)
- Jose A Martínez-Climent
- Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
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41
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Karanikolas BDW, Figueiredo ML, Wu L. Polycomb group protein enhancer of zeste 2 is an oncogene that promotes the neoplastic transformation of a benign prostatic epithelial cell line. MOLECULAR CANCER RESEARCH : MCR 2009. [PMID: 19723877 DOI: 10.1158/1541‐7786.mcr‐09‐0121] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Polycomb group protein enhancer of zeste 2 (EZH2) is a master regulatory protein that plays a critical role in development as part of the polycomb repressive complex 2. Polycomb repressive complex 2 controls numerous cell cycle and regulatory genes through trimethylation of histone 3, which results in chromatin condensation and transcriptional silencing. EZH2 overexpression has been correlated with high incidence of more aggressive, metastatic prostate cancers. Although this correlation means EZH2 could prove valuable as a biomarker in clinical settings, the question remains whether EZH2 is actually responsible for the initiation of these more aggressive tumor types. In this study, EZH2-mediated neoplastic transformation of the normal prostate epithelial cell line benign prostate hyperplasia 1 (BPH1) was confirmed by in vivo tumor growth and in vitro colony formation. Furthermore, EZH2 transformation resulted in increased invasive behavior of BPH1 cells, indicating that EZH2 may be responsible for aggressive behavior in prostate cancers. BPH1 was also transformed with the classic oncogenes myristoylated Akt and activated Ras(V12) to allow phenotype comparisons with the EZH2-transformed cells. This study marks the first demonstration of neoplastic transformation in prostate cells mediated by EZH2 and establishes that EZH2 possesses stronger transforming activity than Akt but weaker activity than activated Ras.
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Affiliation(s)
- Breanne D W Karanikolas
- Departments of Molecular and Medical Pharmacology and Urology, University of California at Los Angeles, Los Angeles, California 90095-1738, USA
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Karanikolas BDW, Figueiredo ML, Wu L. Polycomb group protein enhancer of zeste 2 is an oncogene that promotes the neoplastic transformation of a benign prostatic epithelial cell line. Mol Cancer Res 2009; 7:1456-65. [PMID: 19723877 DOI: 10.1158/1541-7786.mcr-09-0121] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Polycomb group protein enhancer of zeste 2 (EZH2) is a master regulatory protein that plays a critical role in development as part of the polycomb repressive complex 2. Polycomb repressive complex 2 controls numerous cell cycle and regulatory genes through trimethylation of histone 3, which results in chromatin condensation and transcriptional silencing. EZH2 overexpression has been correlated with high incidence of more aggressive, metastatic prostate cancers. Although this correlation means EZH2 could prove valuable as a biomarker in clinical settings, the question remains whether EZH2 is actually responsible for the initiation of these more aggressive tumor types. In this study, EZH2-mediated neoplastic transformation of the normal prostate epithelial cell line benign prostate hyperplasia 1 (BPH1) was confirmed by in vivo tumor growth and in vitro colony formation. Furthermore, EZH2 transformation resulted in increased invasive behavior of BPH1 cells, indicating that EZH2 may be responsible for aggressive behavior in prostate cancers. BPH1 was also transformed with the classic oncogenes myristoylated Akt and activated Ras(V12) to allow phenotype comparisons with the EZH2-transformed cells. This study marks the first demonstration of neoplastic transformation in prostate cells mediated by EZH2 and establishes that EZH2 possesses stronger transforming activity than Akt but weaker activity than activated Ras.
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Affiliation(s)
- Breanne D W Karanikolas
- Departments of Molecular and Medical Pharmacology and Urology, University of California at Los Angeles, Los Angeles, California 90095-1738, USA
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Abstract
Honokiol is a small-molecule polyphenol isolated from the genus Magnolia. It is accompanied by other related polyphenols, including magnolol, with which it shares certain biologic properties. Recently, honokiol has been found to have antiangiogenic, antiinflammatory, and antitumor properties in preclinical models, without appreciable toxicity. These findings have increased interest in bringing honokiol to the clinic as a novel chemotherapeutic agent. In addition, mechanistic studies have tried to find the mechanism(s) of action of honokiol, for two major reasons. First, knowledge of the mechanisms of action may assist development of novel synthetic analogues. Second, mechanistic actions of honokiol may lead to rational combinations with conventional chemotherapy or radiation for enhanced response to systemic cancers. In this review, we describe the findings that honokiol has two major mechanisms of action. First, it blocks signaling in tumors with defective p53 function and activated ras by directly blocking the activation of phospholipase D by activated ras. Second, honokiol induces cyclophilin D, thus potentiating the mitochondrial permeability transition pore, and causing death in cells with wild-type p53. Knowledge of the dual activities of honokiol can assist with the development of honokiol derivatives and the design of clinical trials that will maximize the potential benefit of honokiol in the patient setting.
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Affiliation(s)
- Levi E Fried
- Department of Dermatology, Emory University School of Medicine, Winship Cancer Institute, Atlanta VA Medical Center, Atlanta, Georgia 30322, USA
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Ouellet V, Ling TH, Normandin K, Madore J, Lussier C, Barrès V, Bachvarov D, Rancourt C, Tonin PN, Provencher DM, Mes-Masson AM. Immunohistochemical profiling of benign, low malignant potential and low grade serous epithelial ovarian tumors. BMC Cancer 2008; 8:346. [PMID: 19032793 PMCID: PMC2610034 DOI: 10.1186/1471-2407-8-346] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2008] [Accepted: 11/26/2008] [Indexed: 12/20/2022] Open
Abstract
Background Serous epithelial ovarian tumors can be subdivided into benign (BOV), low malignant potential (LMP) or borderline and invasive (TOV) tumors. Although the molecular characteristics of serous BOV, LMP and low grade (LG) TOV tumors has been initiated, definitive immunohistochemical markers to distinguish between these tumor types have not been defined. Methods In the present study, we used a tissue array composed of 27 BOVs, 78 LMPs and 23 LG TOVs to evaluate the protein expression of a subset of selected candidates identified in our previous studies (Ape1, Set, Ran, Ccne1 and Trail) or known to be implicated in epithelial ovarian cancer disease (p21, Ccnb1, Ckd1). Results Statistically significant difference in protein expression was observed for Ccnb1 when BOV tumors were compared to LMP tumors (p = 0.003). When BOV were compared to LG TOV tumors, Trail was significantly expressed at a higher level in malignant tumors (p = 0.01). Expression of p21 was significantly lower in LG tumors when compared with either BOVs (p = 0.03) or LMPs (p = 0.001). We also observed that expression of p21 was higher in LMP tumors with no (p = 0.02) or non-invasive (p = 0.01) implants compared to the LMP associated with invasive implants. Conclusion This study represents an extensive analyse of the benign and highly differentiated ovarian disease from an immunohistochemical perspective.
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Affiliation(s)
- Véronique Ouellet
- Centre de recherche du centre hospitalier de l'Université de Montréal/Institut du cancer de Montréal, Montreal, Canada.
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Li W, Ge Z, Liu C, Liu Z, Björkholm M, Jia J, Xu D. CIP2A is overexpressed in gastric cancer and its depletion leads to impaired clonogenicity, senescence, or differentiation of tumor cells. Clin Cancer Res 2008; 14:3722-8. [PMID: 18559589 DOI: 10.1158/1078-0432.ccr-07-4137] [Citation(s) in RCA: 120] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogenic factor stabilizing c-MYC protein and driving cellular transformation. We determine whether CIP2A expression can serve as marker for gastric cancer and investigate the mechanism underlying CIP2A-mediated transformation and cell proliferation. EXPERIMENTAL DESIGN Normal and malignant gastric tissues derived from 37 patients with gastric cancer were analyzed for CIP2A expression using reverse transcription-PCR and immunohistochemical staining. Gastric and other cell lines with different p53 and pRB backgrounds were used to inhibit CIP2A expression using small interfering RNA and then examined for clonogenic potentials, senescence, or differentiation. RESULTS CIP2A mRNA was present in 34 of 37 (90%) of tumor specimens but absent in 27 of 37 (73%) of matched normal gastric mucosa. In 10 adjacent normal tissues with detectable CIP2A mRNA, 6 of them exhibited much weaker levels of CIP2A compared with their corresponding tumors. Thus, a total of 32 (87%) gastric cancer samples overexpressed CIP2A. CIP2A protein expression was readily detectable in the tumor tissues but absent in normal gastric mucosa. Depleting CIP2A expression substantially inhibited growth and clonogenic capabilities of tumor cell lines independently of p53 and pRB pathways. Gastric cancer-derived AGS cells underwent senescence following the inhibition of CIP2A expression. Moreover, CIP2A depletion triggered partial differentiation of leukemic HL60 cells. CONCLUSION CIP2A in tumor cells is required for sustained proliferation by preventing cell growth arrest, senescence, or differentiation and its expression is significantly (P < 0.001) discriminatory between normal and cancerous gastric tissue.
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Affiliation(s)
- Wenjuan Li
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education
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46
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Kishimoto I, Mitomi H, Ohkura Y, Kanazawa H, Fukui N, Watanabe M. Abnormal expression of p16(INK4a), cyclin D1, cyclin-dependent kinase 4 and retinoblastoma protein in gastric carcinomas. J Surg Oncol 2008; 98:60-6. [PMID: 18484097 DOI: 10.1002/jso.21087] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND OBJECTIVES The p16(INK4a) (p16), cyclin D1, cyclin-dependent kinase (CDK) 4 and retinoblastoma (Rb) genes are components of the Rb pathway that controls the G1-S checkpoint of the cell cycle. The aim of this study was to assess the relationship between their abnormalities and clinicopathological features in gastric carcinomas. METHODS Immunohistochemical analysis of the encoded proteins was performed on a series of 158 cases. RESULTS Loss of p16/Rb protein (pRb) expression and overexpression of cyclin D1/CDK4 were observed in 49%/40% and 37%/37% of gastric carcinomas, respectively. At least 1 of these abnormalities was found in 86% of the cases and a positive correlation was noted between p16 and pRb (P = 0.009). Cyclin D1 (P = 0.042) and CDK4 (P = 0.008) overexpession was inversely associated with lymph node metastasis and depth of invasion, respectively. Loss of pRb expression was more frequently in diffuse type lesions than in the intestinal type (P = 0.022). The patients with p16+/pRb-/cyclin D1-/CDK4- or p16-/pRb+/cyclin D1-/CDK4- tumors demonstrated particularly poor survival. With multivariate survival analysis, only depth of invasion and TNM stage could be proven as independent predictors. CONCLUSIONS The Rb pathway is disrupted in the vast majority of gastric carcinomas. This study also identified specific immunohistochemical marker profiles for prognosis.
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Affiliation(s)
- Ichiro Kishimoto
- Department of Surgery, National Hospital Organization Sagamihara Hospital, Kanagawa, Japan
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Rossi A, Caracciolo V, Russo G, Reiss K, Giordano A. Medulloblastoma: from molecular pathology to therapy. Clin Cancer Res 2008; 14:971-6. [PMID: 18281528 DOI: 10.1158/1078-0432.ccr-07-2072] [Citation(s) in RCA: 110] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Medulloblastoma is the most common malignant tumor of central nervous system in children. Patients affected by medulloblastoma may be categorized as high-risk and standard-risk patients, based on the clinical criteria and histologic features of the disease. Currently, multimodality treatment, including surgery, radiotherapy, and chemotherapy is considered as the most effective strategy against these malignant cerebellar tumors of the childhood. Despite the potential poor outcomes of these lesions, the 5-year survival stands, at present, at 70% to 80% for standard-risk patients, whereas high-risk patients have a 5-year survival of 55% to 76%. Attempts to further reduce the morbidity and mortality associated with medulloblastoma have been restricted by the toxicity of conventional treatments and the infiltrative nature of the disease. Over the past decade, new discoveries in molecular biology have revealed new insights in signaling pathways regulating medulloblastoma tumor formation. Recent advances in the molecular biology of medulloblastoma indicate that the classification of these embryonal tumors, solely based on histology and clinical criteria, may not be adequate enough. Better understanding of the growth control mechanisms involved in the development and progression of medulloblastoma will allow a better classification, leading to the improvement of the existing therapies, as well as to the development of new therapeutic approaches.
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Affiliation(s)
- Alessandra Rossi
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Department of Neuroscience, School of Medicine, Temple University, Philadelphia, Pennsylvania 19122, USA
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Petrocca F, Visone R, Onelli MR, Shah MH, Nicoloso MS, de Martino I, Iliopoulos D, Pilozzi E, Liu CG, Negrini M, Cavazzini L, Volinia S, Alder H, Ruco LP, Baldassarre G, Croce CM, Vecchione A. E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell 2008; 13:272-86. [PMID: 18328430 DOI: 10.1016/j.ccr.2008.02.013] [Citation(s) in RCA: 684] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2007] [Revised: 11/13/2007] [Accepted: 02/20/2008] [Indexed: 12/14/2022]
Abstract
Deregulation of E2F1 activity and resistance to TGFbeta are hallmarks of gastric cancer. MicroRNAs (miRNAs) are small noncoding RNAs frequently misregulated in human malignancies. Here we provide evidence that the miR-106b-25 cluster, upregulated in a subset of human gastric tumors, is activated by E2F1 in parallel with its host gene, Mcm7. In turn, miR-106b and miR-93 regulate E2F1 expression, establishing a miRNA-directed negative feedback loop. Furthermore, upregulation of these miRNAs impairs the TGFbeta tumor suppressor pathway, interfering with the expression of CDKN1A (p21(Waf1/Cip1)) and BCL2L11 (Bim). Together, these results suggest that the miR-106b-25 cluster is involved in E2F1 posttranscriptional regulation and may play a key role in the development of TGFbeta resistance in gastric cancer.
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Affiliation(s)
- Fabio Petrocca
- Department of Molecular Virology, Immunology and Medical Genetics, Human Cancer Genetics Program, Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA
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Tonini T, D'Andrilli G, Fucito A, Gaspa L, Bagella L. Importance of Ezh2 polycomb protein in tumorigenesis process interfering with the pathway of growth suppressive key elements. J Cell Physiol 2007; 214:295-300. [PMID: 17786943 DOI: 10.1002/jcp.21241] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
An understanding of the mechanisms that uncover the dynamic changes in the distribution of the chromatin modifying enzymes and regulatory proteins on their target loci could provide further insight into the phenomenon of malignant transformation. Based on the current available data, it seems more and more clear that an abnormal expression of Ezh2, a member of the Polycomb group (PcG) protein, may be involved in the tumorigenesis process, in addition, different studies identify Ezh2 as a potential marker that distinguish aggressive prostate and breast cancer from indolent one. Recent investigation show that ectopic expression of Ezh2 provides proliferative advantage to primary cells through interaction with the pathways of key elements that control cell growth arrest and differentiation, like members of the retinoblastoma (Rb) family. Here, we outline how these pathways converge and we review the recent advances on the molecular mechanisms that promote cell cycle progression through deregulation of Ezh2 protein level, providing novel links between cancer progression and chromatin remodeling machineries.
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Affiliation(s)
- Tiziana Tonini
- Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, USA
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Mudryj M, Reay E, Beckett L, Dandekar S, deVere White R, Gandour-Edwards R. Novel p53/p130 Axis in Bladder Tumors. Urology 2007; 70:608-12. [PMID: 17905135 DOI: 10.1016/j.urology.2007.05.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2006] [Revised: 03/14/2007] [Accepted: 05/13/2007] [Indexed: 10/22/2022]
Abstract
OBJECTIVES To identify the relationships between key components of the proliferative and apoptotic pathways in bladder tumors. METHODS A tissue array of 88 bladder tumors was assembled. Immunohistochemical analyses were used to investigate the relationship between nine different parameters: stage, proliferation (Ki67), apoptosis (in situ DNA nick end labeling), the anti-apoptotic protein Bcl-2, tumor suppressors p53 and retinoblastoma protein (Rb), the Rb-related protein p130, cyclin E, and the cyclin-dependent kinase inhibitor p27. The protein expression in each tumor was reported as the percentage of positively staining cells. RESULTS The analysis focused on Stage 1 to 3 tumors. Analysis found that p53 expression increased progressively with stage, and Rb and p27 decreased with increasing stage. Overall, the cyclin E levels correlated with the proliferative index. Cyclin E levels were low in Stage 1 tumors and elevated in Stage 2 tumors, but were decreased in Stage 3 tumors. Multivariate analysis uncovered a correlation between cyclin E and proliferation (Ki67) and a weak correlation between p53 and Bcl-2 and between p27 and Rb. A strong correlation was found between the expression of p53 and p130, which was apparent in Stages 1 and 3, but not in Stage 2. Furthermore, high levels of p130 protein were detected primarily in the cytoplasm. CONCLUSIONS These results suggest a novel p53/p130 axis in bladder tumors.
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Affiliation(s)
- Maria Mudryj
- Veterans Affairs Northern California Health Care System, Mather, California, USA.
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