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Suman M, Löfgren M, Fransson S, Yousuf JI, Svensson J, Djos A, Martinsson T, Kogner P, Kling T, Carén H. Altered methylation of imprinted genes in neuroblastoma: implications for prognostic refinement. J Transl Med 2024; 22:808. [PMID: 39217334 PMCID: PMC11366169 DOI: 10.1186/s12967-024-05634-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 08/22/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Neuroblastoma (NB) is a complex disease, and the current understanding of NB biology is limited. Deregulation in genomic imprinting is a common event in malignancy. Since imprinted genes play crucial roles in early fetal growth and development, their role in NB pathogenesis could be suggested. METHODS We examined alterations in DNA methylation patterns of 369 NB tumours at 49 imprinted differentially methylated regions (DMRs) and assessed its association with overall survival probabilities and selected clinical and genomic features of the tumours. In addition, an integrated analysis of DNA methylation and allele-specific copy number alterations (CNAs) was performed, to understand the correlation between the two molecular events. RESULTS Several imprinted regions with aberrant methylation patterns in NB were identified. Regions that underwent loss of methylation in > 30% of NB samples were DMRs annotated to the genes NDN, SNRPN, IGF2, MAGEL2 and HTR5A and regions with gain of methylation were NNAT, RB1 and GPR1. Methylation alterations at six of the 49 imprinted DMRs were statistically significantly associated with reduced overall survival: MIR886, RB1, NNAT/BLCAP, MAGEL2, MKRN3 and INPP5F. RB1, NNAT/BLCAP and MKRN3 were further able to stratify low-risk NB tumours i.e. tumours that lacked MYCN amplification and 11q deletion into risk groups. Methylation alterations at NNAT/BLCAP, MAGEL2 and MIR886 predicted risk independently of MYCN amplification or 11q deletion and age at diagnosis. Investigation of the allele-specific CNAs demonstrated that the imprinted regions that displayed most alterations in NB tumours harbor true epigenetic changes and are not result of the underlying CNAs. CONCLUSIONS Aberrant methylation in imprinted regions is frequently occurring in NB tumours and several of these regions have independent prognostic value. Thus, these could serve as potentially important clinical epigenetic markers to identify individuals with adverse prognosis. Incorporation of methylation status of these regions together with the established risk predictors may further refine the prognostication of NB patients.
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Affiliation(s)
- Medha Suman
- Sahlgrenska Center for Cancer Research, Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 1F, 405 30, Gothenburg, Sweden
| | - Maja Löfgren
- Sahlgrenska Center for Cancer Research, Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 1F, 405 30, Gothenburg, Sweden
| | - Susanne Fransson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jewahri Idris Yousuf
- Sahlgrenska Center for Cancer Research, Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 1F, 405 30, Gothenburg, Sweden
| | - Johanna Svensson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anna Djos
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Tommy Martinsson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Per Kogner
- Childhood Cancer Research Unit, Women's, and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Teresia Kling
- Sahlgrenska Center for Cancer Research, Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 1F, 405 30, Gothenburg, Sweden
| | - Helena Carén
- Sahlgrenska Center for Cancer Research, Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 1F, 405 30, Gothenburg, Sweden.
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Liang Y, Hu L, Li J, Liu F, Jones KC, Li D, Liu J, Chen D, You J, Yu Z, Zhang G, Dong G, Ma H. Short-term personal PM 2.5 exposure and change in DNA methylation of imprinted genes: Panel study of healthy young adults in Guangzhou city, China. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2021; 275:116601. [PMID: 33549891 DOI: 10.1016/j.envpol.2021.116601] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/22/2021] [Accepted: 01/24/2021] [Indexed: 05/28/2023]
Abstract
DNA methylation (DNAm) plays a significant role in deleterious health effects inflicted by fine particulate matter (PM2.5) on the human body. Recent studies have reported that DNAm of imprinted control regions (ICRs) in imprinted genes may be a sensitive biomarker of environmental exposure. Less is known about specific biomarkers of imprinted genes after PM2.5 exposure. The relationship between PM2.5 and its chemical constituents and DNAm of ICRs in imprinted genes after short-term exposure was investigated to determine specific human biomarkers of its adverse health effects. A panel study was carried out in healthy young people in Guangzhou, China. Mixed-effects models were used to evaluate the influence of PM2.5 and its constituent exposure on DNAm while controlling for potential confounders. There was no significant correlation between DNAm and personal PM2.5 exposure mass. DNAm changes in eight ICRs (L3MBTL1, NNAT, PEG10, GNAS Ex1A, MCTS2, SNURF/SNRPN, IGF2R, and RB1) and a non-imprinted gene (CYP1B1) were significantly associated with PM2.5 constituents. Compared to non-imprinted genes, imprinted gene methylation was more susceptible to interference with PM2.5 constituent exposure. Among those genes, L3MBTL1 was the most sensitive to personal PM2.5 constituent exposure. Moreover, transition metals derived from traffic sources (Cd, Fe, Mn, and Ni) significantly influenced DNAm of the imprinted genes, suggesting the importance of more targeted measures to reduce toxic constituents. Bioinformatics analysis indicated that imprinted genes (RB1) may be correlated with pathways and diseases (non-small cell lung cancer, glioma, and bladder cancer). The present study suggests that screening the imprinted gene for DNAm can be used as a sensitive biomarker of PM2.5 exposure. The results will provide data for prevention of PM2.5 exposure and a novel perspective on potential mechanisms on an epigenetic level.
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Affiliation(s)
- Yaohui Liang
- State Key Laboratory of Organic Geochemistry and Guangdong Province Key Laboratory of Environmental Protection and Resources Utilization, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou, 510640, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Liwen Hu
- Department of Preventive Medicine, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Jun Li
- State Key Laboratory of Organic Geochemistry and Guangdong Province Key Laboratory of Environmental Protection and Resources Utilization, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou, 510640, China
| | - Fei Liu
- School of Business Administration, South China University of Technology, Guangzhou, 510641, China
| | - Kevin C Jones
- Lancaster Environmental Centre, Lancaster University, LA1 4YQ, Lancaster, United Kingdom
| | - Daochuan Li
- Department of Preventive Medicine, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Jing Liu
- Guangzhou First People's Hospital, Guangzhou, 510180, China
| | - Duohong Chen
- Guangdong Environmental Monitoring Center, State Environmental Protection Key Laboratory of Regional Air Quality Monitoring, Guangdong Environmental Protection Key Laboratory of Atmospheric Secondary Pollution, Guangzhou, 510308, China
| | - Jing You
- Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, Guangzhou, 511443, China
| | - Zhiqiang Yu
- State Key Laboratory of Organic Geochemistry and Guangdong Province Key Laboratory of Environmental Protection and Resources Utilization, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou, 510640, China
| | - Gan Zhang
- State Key Laboratory of Organic Geochemistry and Guangdong Province Key Laboratory of Environmental Protection and Resources Utilization, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou, 510640, China
| | - Guanghui Dong
- Department of Preventive Medicine, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Huimin Ma
- State Key Laboratory of Organic Geochemistry and Guangdong Province Key Laboratory of Environmental Protection and Resources Utilization, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou, 510640, China; Lancaster Environmental Centre, Lancaster University, LA1 4YQ, Lancaster, United Kingdom.
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TSG101 Promotes the Proliferation, Migration, and Invasion of Human Glioma Cells by Regulating the AKT/GSK3β/β-Catenin and RhoC/Cofilin Pathways. Mol Neurobiol 2021; 58:2118-2132. [PMID: 33411238 DOI: 10.1007/s12035-020-02231-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 11/24/2020] [Indexed: 10/22/2022]
Abstract
The tumor susceptibility gene 101 (TSG101) has been reported to play important roles in the development and progression of several human cancers, such as pancreatic cancer, prostate cancer, and hepatocellular carcinoma. However, its potential roles and underlined mechanisms in human glioma are still needed to be further clarified. This study was designed to assess the expression of TSG101 in glioma patients and its effects on glioma cell proliferation, migration, and invasion. Publicly available data revealed that TSG101 mRNA was significantly upregulated in glioma tissues, and high levels of TSG101 were associated with poor prognosis in glioma patients. Western blot and immunohistochemistry experiments further showed that the expression level of TSG101 protein was significantly upregulated in glioma patients, especially in the patients with high-grade glioma. The functional studies showed that knockdown of TSG101 suppressed the proliferation, migration, and invasion of glioma cells, while overexpression of TSG101 facilitated them. Mechanistic studies indicated that the proliferation, migration, and invasion induced by TSG101 in human glioma were related to AKT/GSK3β/β-catenin and RhoC/Cofilin signaling pathways. In conclusion, the above results suggest that the expression of TSG101 is elevated in glioma patients, which accelerates the proliferation, migration, and invasion of glioma cells by regulating the AKT/GSK3β/β-catenin and RhoC/Cofilin pathways.
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Gov E. Co-expressed functional module-related genes in ovarian cancer stem cells represent novel prognostic biomarkers in ovarian cancer. Syst Biol Reprod Med 2020; 66:255-266. [DOI: 10.1080/19396368.2020.1759730] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Esra Gov
- Department of Bioengineering, Faculty of Engineering, Adana Alparslan Türkeş Science and Technology University, Adana, Turkey
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Xiao H, Ding N, Liao H, Yao Z, Cheng X, Zhang J, Zhao M. Prediction of relapse and prognosis by expression levels of long noncoding RNA PEG10 in glioma patients. Medicine (Baltimore) 2019; 98:e17583. [PMID: 31702614 PMCID: PMC6855493 DOI: 10.1097/md.0000000000017583] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Long noncoding RNA paternally expressed 10 (lncRNA PEG10) is highly expressed in a variety of human cancers and related to the clinical prognosis of patients. However, to date there has been no previous study evaluating the prognostic significance of lncRNA PEG10 in gliomas. In the present study, we investigated the expression levels of lncRNA PEG10 to determine the prognostic value of this oncogene in human gliomas. METHODS Expression levels of lncRNA PEG10 were detected by real-time polymerase chain reaction in a hospital-based study cohort of 147 glioma patients and 23 cases of patients with craniocerebral trauma tissues. Associations of lncRNA PEG10 expression with clinicopathological variables and clinical outcome of glioma patients were investigated. RESULTS The results indicated that expression levels of lncRNA PEG10 were significantly increased in human gliomas compared to normal control brain tissues. In addition, lncRNA PEG10 expression was progressively increased from pathologic grade I to IV (P = .009) and correlated with the Karnofsky performance status (P = .018) in glioma patients. Furthermore, we also found that glioma patients with increased expression of lncRNA PEG10 had a higher risk to relapse and a statistically significant shorter overall survival (OS) than patients with reduced expression of lncRNA PEG10. In multivariate analysis, expression level of lncRNA PEG10 was found to be an independent prognostic factor for both progression-free survival and OS in glioma patients. CONCLUSIONS LncRNA PEG10 served as an oncogene and played crucial roles in the progression of glioma. Molecular therapy targeted on lncRNA PEG10 might bring significant benefits to the clinical outcome of malignant glioma.
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Affiliation(s)
| | - Ning Ding
- Outpatient Department, The Second Hospital of Shandong University, Shandong University
| | - Hang Liao
- Clinical laboratory, The Second Blood Insurance Center of Jinan
| | - Zhigang Yao
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan
| | - Xiankui Cheng
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan
| | - Jian Zhang
- School of Life Science, Shandong Universit, Qingdao, Shandong Province, China
| | - Miaoqing Zhao
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan
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Zhang Y, Hu C. WIF-1 and Ihh Expression and Clinical Significance in Patients With Lung Squamous Cell Carcinoma and Adenocarcinoma. Appl Immunohistochem Mol Morphol 2019; 26:454-461. [PMID: 27801732 DOI: 10.1097/pai.0000000000000449] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
This study investigated the expression of wingless-type inhibitory factor-1 (WIF-1) and Ihh protein in tumor tissues and their clinical significance in patients with lung squamous cell carcinoma and adenocarcinoma. The expression of WIF-1 and Ihh protein in 74 squamous cell carcinomas and 76 adenocarcinomas was measured by immunohistochemistry. The percentage of positive WIF-1 protein expression was significantly higher, while positive Ihh protein expression was significantly lower in patients with well-differentiated lung squamous cell carcinoma and adenocarcinoma, tumor node metastasis (TNM) stage I disease, and lymph node metastasis than that in patients with poorly differentiated tumor, TNM stage III disease, and lymph node metastasis (P<0.05, <0.01). Kaplan-Meier survival analysis showed that TNM stage and lymph node metastasis were significantly associated with the mean overall survival of patients with lung squamous cell carcinoma and adenocarcinoma (P<0.05 or <0.01). Patients with lung squamous cell carcinoma (P=0.037) and adenocarcinoma (P=0.001) with positive Ihh protein expression survived significantly shorter than patients with negative Ihh protein expression. In contrast, no significant difference in mean survival was observed in patients with lung squamous cell carcinoma and adenocarcinoma with positive and negative WIF-1 protein expression (P>0.05). Ihh is a marker for poor prognosis in patients with lung squamous cell carcinoma and adenocarcinoma. WIF-1 is not a predictive marker for lung cancer.
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Affiliation(s)
- Yue Zhang
- Department of Oncology, Second Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
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Fu Y, Bi Y, Wang F, Chen X, Liu H. Declination of long noncoding RNA paternally expressed gene 10 inhibits A375 cells proliferation, migration, and invasion via mediating microRNA‐33a. J Cell Biochem 2019; 120:19868-19877. [PMID: 31318088 DOI: 10.1002/jcb.29292] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 06/27/2019] [Indexed: 12/12/2022]
Affiliation(s)
- Yan Fu
- Department of Dermatology Binzhou People's Hospital Binzhou China
| | - Yiming Bi
- Department of Oncology Binzhou People's Hospital Binzhou China
| | - Fang Wang
- Department of Traditional Chinese Medicine Binzhou People's Hospital Binzhou China
| | - Xingxiu Chen
- Department of Oncology Binzhou People's Hospital Binzhou China
| | - Huiling Liu
- Department of Oncology Binzhou People's Hospital Binzhou China
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Yahiro Y, Maeda S, Shinohara N, Jokoji G, Sakuma D, Setoguchi T, Ishidou Y, Nagano S, Komiya S, Taniguchi N. PEG10 counteracts signaling pathways of TGF-β and BMP to regulate growth, motility and invasion of SW1353 chondrosarcoma cells. J Bone Miner Metab 2019; 37:441-454. [PMID: 30094509 DOI: 10.1007/s00774-018-0946-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 07/25/2018] [Indexed: 01/07/2023]
Abstract
Recently, we reported highly active transforming growth factor (TGF)-β and bone morphogenetic protein (BMP) signaling in human chondrosarcoma samples and concurrent downregulation of paternally expressed gene 10 (PEG10). PEG10 expression was suppressed by TGF-β signaling, and PEG10 interfered with the TGF-β and BMP-SMAD pathways in chondrosarcoma cells. However, the roles of PEG10 in bone tumors, including chondrosarcoma, remain unknown. Here, we report that PEG10 promotes SW1353 chondrosarcoma cell growth by preventing TGF-β1-mediated suppression. In contrast, PEG10 knockdown augments the TGF-β1-induced motility of SW1353 cells. Individually, TGF-β1 and PEG10 siRNA increase AKT phosphorylation, whereas an AKT inhibitor, MK2206, mitigates the effect of PEG10 silencing on cell migration. SW1353 cell invasion was enhanced by BMP-6, which was further increased by PEG10 silencing. The effect of siPEG10 was suppressed by inhibitors of matrix metalloproteinase (MMP). BMP-6 induced expression of MMP-1, -3, and -13, and PEG10 lentivirus or PEG10 siRNA downregulated or further upregulated these MMPs, respectively. PEG10 siRNA increased BMP-6-induced phosphorylation of p38 MAPK and AKT, whereas the p38 inhibitor SB203580 and MK2206 diminished SW1353 cell invasion by PEG10 siRNA. SB203580 and MK2206 impeded the enhancing effect of PEG10 siRNA on the BMP-6-induced expression of MMP-1, -3, and -13. Our findings suggest dual functions for PEG10: accelerating cell growth by suppressing TGF-β signaling and inhibiting cell motility and invasion by interfering with TGF-β and BMP signaling via the AKT and p38 pathways, respectively. Thus, PEG10 might be a molecular target for suppressing the aggressive phenotypes of chondrosarcoma cells.
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Affiliation(s)
- Yuhei Yahiro
- Department of Medical Joint Materials, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan
- Department of Orthopaedic Surgery, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan
| | - Shingo Maeda
- Department of Medical Joint Materials, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan.
| | - Naohiro Shinohara
- Department of Medical Joint Materials, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan
- Department of Orthopaedic Surgery, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan
| | - Go Jokoji
- Department of Medical Joint Materials, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan
- Department of Orthopaedic Surgery, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan
| | - Daisuke Sakuma
- Department of Medical Joint Materials, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan
- Department of Orthopaedic Surgery, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan
| | - Takao Setoguchi
- Department of Medical Joint Materials, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan
| | - Yasuhiro Ishidou
- Department of Medical Joint Materials, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan
| | - Satoshi Nagano
- Department of Orthopaedic Surgery, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan
| | - Setsuro Komiya
- Department of Medical Joint Materials, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan
- Department of Orthopaedic Surgery, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan
| | - Noboru Taniguchi
- Department of Medical Joint Materials, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan
- Department of Orthopaedic Surgery, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima, 890-8544, Japan
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Xu C, Zheng J. siRNA against TSG101 reduces proliferation and induces G0/G1 arrest in renal cell carcinoma - involvement of c-myc, cyclin E1, and CDK2. Cell Mol Biol Lett 2019; 24:7. [PMID: 30675171 PMCID: PMC6332891 DOI: 10.1186/s11658-018-0124-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 11/29/2018] [Indexed: 01/04/2023] Open
Abstract
Objective The tumor susceptibility gene 101 (TSG101) is closely associated with various tumor types, but its role in the pathogenesis of renal cell carcinoma (RCC) is still unknown. This study used RNA interference to silence the expression of TSG101 in RCC cell lines and explore the role of TSG101 in RCC. Methods Immunohistochemistry and western blot were performed to detect the expression of TSG101 in 15 paired renal tumor samples. A small interfering RNA (siRNA) targeting TSG101 was transfected into A498 and 786-O cell lines. The Cell Counting Kit-8 (CCK-8) assay and colony formation assay were used to observe the changes in cell proliferation after transfection. Flow cytometry was used to detect the effect on the cell cycle. Western blot was conducted to study the changes of related functional proteins. Results The expression of TSG101 was higher in RCC tissues than in adjacent normal tissues. The CCK-8 assay showed that the proliferation and colony formation of the A498 and 786-O cell lines were attenuated after suppression of TSG101. Flow cytometry showed that silencing of TSG101 induced G0/G1 arrest. The western blot results revealed that the levels of cell cycle-related proteins (c-myc, cyclin E1 and cyclin-dependent kinase 2 (CDK2)) were markedly decreased in the siRNA groups. Conclusions TSG101 promotes proliferation of RCC cells. This positive effect on tumor growth involves activation of c-myc and cyclin E1/CDK2 and their effect on cell cycle distribution.
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Affiliation(s)
- Chen Xu
- Department of Urology, Tenth People's Hospital of Tongji University, Yanchang Road 301, Shanghai, 200072 China
| | - Junhua Zheng
- Department of Urology, Tenth People's Hospital of Tongji University, Yanchang Road 301, Shanghai, 200072 China
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Liu Z, Tian Z, Cao K, Zhang B, Wen Q, Zhou X, Yang W, Wang T, Shi H, Wang R. TSG101 promotes the proliferation, migration and invasion of hepatocellular carcinoma cells by regulating the PEG10. J Cell Mol Med 2018; 23:70-82. [PMID: 30450735 PMCID: PMC6307771 DOI: 10.1111/jcmm.13878] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 07/11/2018] [Accepted: 08/03/2018] [Indexed: 01/19/2023] Open
Abstract
The tumour susceptibility gene 101 (TSG101) is reported to play important roles in the development and progression of several human cancers. However, its potential roles and underlined mechanisms in human hepatocellular carcinoma (HCC) are still needed to be further clarified. In the present study, we reported that knock down of TSG101 suppressed the proliferation, migration and invasion of HCC cells, while overexpression of TSG101 facilitated them. Molecularly, the results revealed that knock down of TSG101 significantly decreased the cell cycle related regulatory factor p53 and p21. In another point, knock down of TSG101 also obviously decreased the level of metallopeptidase inhibitor TIMP1 (Tissue inhibitors of metalloproteinases 1), which results in inhibition of MMP2, MMP7 and MMP9. In contrast, overexpression of TSG101 had opposite effects. The iTRAQ proteomics analysis identified that oncogenic protein PEG10 (Paternally expressed gene 10) might be a potential downstream target of TSG101. Further investigation showed that TSG101 interacted with PEG10 and protected it from proteasomal degradation thereby regulating the expression of p53, p21 and MMPs. Finally, we found that both TSG101 and PEG10 proteins are up-regulated and presented a direct correlation in HCC patients. In conclusion, these results suggest that TSG101 is up-regulated in human HCC patients, which may accelerate the proliferation, migration and invasion of HCC cells through regulating PEG10.
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Affiliation(s)
- Zhiyi Liu
- Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.,The Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Zilu Tian
- Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.,The Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Kuan Cao
- Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Bin Zhang
- Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Quan Wen
- Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xinyu Zhou
- The Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Weibin Yang
- Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.,The Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Tao Wang
- Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.,The Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Hengliang Shi
- Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Renhao Wang
- Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
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Xie T, Pan S, Zheng H, Luo Z, Tembo KM, Jamal M, Yu Z, Yu Y, Xia J, Yin Q, Wang M, Yuan W, Zhang Q, Xiong J. PEG10 as an oncogene: expression regulatory mechanisms and role in tumor progression. Cancer Cell Int 2018; 18:112. [PMID: 30123090 PMCID: PMC6090666 DOI: 10.1186/s12935-018-0610-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Accepted: 08/04/2018] [Indexed: 02/07/2023] Open
Abstract
Cancer is a major public health problem as one of the leading causes of death worldwide. Deciphering the molecular regulation mechanisms of tumor progression can make way for tumor diagnosis and therapy. Paternally expressed gene 10 (PEG10), located on human chromosome 7q21.3, has turned out to be an oncogene implicated in the proliferation, apoptosis and metastasis of tumors. PEG10 has been found to be positively expressed in a variety of cancers with seemingly complex expression regulation mechanisms. In this review, we focus on the most vital factors influencing PEG10 expression and recapitulate some of the currently known and potential mechanisms of PEG10 affecting tumor progression, as understanding the molecular regulatory mechanisms of tumor progression can provide potential PEG10 related diagnosis and biomarker specific targeted therapies.
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Affiliation(s)
- Tian Xie
- 1Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071 China
| | - Shan Pan
- 1Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071 China
| | - Hang Zheng
- 2Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071 China
| | - Zilv Luo
- 1Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071 China
| | | | - Muhammad Jamal
- 4State Key Laboratory of Agriculture Microbiology, Huazhong Agricultural University, Wuhan, 430070 China
| | - Zhongyang Yu
- 1Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071 China
| | - Yao Yu
- 1Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071 China
| | - Jing Xia
- 1Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071 China
| | - Qian Yin
- 1Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071 China
| | - Meng Wang
- 1Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071 China
| | - Wen Yuan
- 1Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071 China
| | - Qiuping Zhang
- 1Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071 China.,5Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University, Wuhan, 430071 China
| | - Jie Xiong
- 1Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, 430071 China
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Ge H, Yan Y, Wu D, Huang Y, Tian F. Prognostic value of PEG10 in Asian solid tumors: A meta-analysis. Clin Chim Acta 2018; 483:197-203. [PMID: 29727698 DOI: 10.1016/j.cca.2018.04.041] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Revised: 04/30/2018] [Accepted: 04/30/2018] [Indexed: 12/28/2022]
Abstract
BACKGROUND The involvement of paternally expressed gene 10 (PEG10) in the development of solid tumors has been demonstrated. However, the available data have not yet been fully analyzed. We conducted this meta-analysis to evaluate the correlations between PEG10 and the clinicopathological characteristics in patients with solid tumors. METHODS An electronic search for relevant articles was conducted in PubMed, Web of Science, Cochrane Library, EMBASE, Chinese CNKI, and Wan Fang. The relationships between PEG10 and the clinicopathological features and prognosis of patients with cancer were determined using pooled odds ratios and hazard ratios with 95% confidence interval (CI). RESULTS Ten studies comprising 1014 patients were included. The pooled analyses indicated the significant association of PEG10 overexpression with the risk of cancer, differentiation, lymph node metastasis and advanced TNM stage, but not with gender in cancer patients. Moreover, a high level of PEG10 expression correlated with poor prognosis and could be used as an independent prognostic biomarker for patients with solid tumors. CONCLUSIONS PEG10 expression is associated with advanced clinicopathological characteristics and can be used as a prognostic biomarker in patients with solid tumors.
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Affiliation(s)
- Hua Ge
- Department of Gastrointestinal Surgery, The First people's Hospital of Zunyi, Zunyi Medical University, Zunyi, Guizhou, PR China.
| | - Yan Yan
- Quality Control Department, The First people's Hospital of Zunyi, Zunyi Medical University, Zunyi, Guizhou, PR China
| | - Di Wu
- Department of Gastrointestinal Surgery, The First people's Hospital of Zunyi, Zunyi Medical University, Zunyi, Guizhou, PR China
| | - Yongsheng Huang
- Department of Gastrointestinal Surgery, The First people's Hospital of Zunyi, Zunyi Medical University, Zunyi, Guizhou, PR China
| | - Fei Tian
- Department of Gastrointestinal Surgery, The First people's Hospital of Zunyi, Zunyi Medical University, Zunyi, Guizhou, PR China
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LDHB and FABP4 are Associated With Progression and Poor Prognosis of Pancreatic Ductal Adenocarcinomas. Appl Immunohistochem Mol Morphol 2017; 25:351-357. [PMID: 26657874 DOI: 10.1097/pai.0000000000000306] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a fast-growth tumor with poor prognosis. The molecular events involving in the abnormal energy metabolism have been reported without being fully identified. This study investigated the expression of FABP4 and LDHB, 2 metabolism-associated molecules, in malignant and benign lesions of pancreas by immunohistochemical staining, and analyzed their clinical and pathologic significances. The results showed that FABP4 and LDHB protein were overexpressed in PDAC tumors compared with peritumoral tissues, benign pancreatic tissues, and normal pancreatic tissues (P<0.01). The percentage of patients with FABP4 and LDHB protein overexpression was significantly higher in PDAC patients with lymph node metastasis, invasion, and tumour, node, metastasis stage III/IV disease than in patients without lymph node metastasis and invasion, and having tumour, node, metastasis stage I/II stage disease (P<0.05 or P<0.01). Benign pancreatic lesions with positive FABP4 and LDHB protein expression exhibited dysplasia or intraepithelial neoplasia I and III grade. Kaplan-Meier survival analysis showed that positive FABP4 and LDHB protein expression were associated with worse survival in PDAC patients (P<0.05 or P<0.001). Cox multivariate analysis revealed that positive FABP4 and LDHB protein expression were independent poor prognosis factors in PDAC patients. In conclusion, positive FABP4 and LDHB protein expression are associated with the progression and poor prognosis in patients with PDAC.
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14
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Profiling, clinicopathological correlation and functional validation of specific long non-coding RNAs for hepatocellular carcinoma. Mol Cancer 2017; 16:164. [PMID: 29061191 PMCID: PMC5651594 DOI: 10.1186/s12943-017-0733-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 10/13/2017] [Indexed: 02/07/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most prevalent and aggressive malignancies worldwide. Studies seeking to advance the overall understanding of lncRNA profiling in HCC remain rare. Methods The transcriptomic profiling of 12 HCC tissues and paired adjacent normal tissues was determined using high-throughput RNA sequencing. Fifty differentially expressed mRNAs (DEGs) and lncRNAs (DELs) were validated in 21 paired HCC tissues via quantitative real-time PCR. The correlation between the expression of DELs and various clinicopathological characteristics was analyzed using Student’s t-test or linear regression. Co-expression networks between DEGs and DELs were constructed through Pearson correlation co-efficient and enrichment analysis. Validation of DELs’ functions including proliferation and migration was performed via loss-of-function RNAi assays. Results In this study, we identified 439 DEGs and 214 DELs, respectively, in HCC. Furthermore, we revealed that multiple DELs, including NONHSAT003823, NONHSAT056213, NONHSAT015386 and especially NONHSAT122051, were remarkably correlated with tumor cell differentiation, portal vein tumor thrombosis, and serum or tissue alpha fetoprotein levels. In addition, the co-expression network analysis between DEGs and DELs showed that DELs were involved with metabolic, cell cycle, chemical carcinogenesis, and complement and coagulation cascade-related pathways. The silencing of the endogenous level of NONHSAT122051 or NONHSAT003826 could significantly attenuate the mobility of both SK-HEP-1 and SMMC-7721 HCC cells. Conclusion These findings not only add knowledge to the understanding of genome-wide transcriptional evaluation of HCC but also provide promising targets for the future diagnosis and treatment of HCC.
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TGF-β signalling and PEG10 are mutually exclusive and inhibitory in chondrosarcoma cells. Sci Rep 2017; 7:13494. [PMID: 29044189 PMCID: PMC5647403 DOI: 10.1038/s41598-017-13994-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 10/04/2017] [Indexed: 11/24/2022] Open
Abstract
Histological distinction between enchondroma and chondrosarcoma is difficult because of a lack of definitive biomarkers. Here, we found highly active transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signalling in human chondrosarcomas compared with enchondromas by immunohistochemistry of phosphorylated SMAD3 and SMAD1/5. In contrast, the chondrogenic master regulator SOX9 was dramatically down-regulated in grade 1 chondrosarcoma. Paternally expressed gene 10 (PEG10) was identified by microarray analysis as a gene overexpressed in chondrosarcoma SW1353 and Hs 819.T cells compared with C28/I2 normal chondrocytes, while TGF-β1 treatment, mimicking higher grade tumour conditions, suppressed PEG10 expression. Enchondroma samples exhibited stronger expression of PEG10 compared with chondrosarcomas, suggesting a negative association of PEG10 with malignant cartilage tumours. In chondrosarcoma cell lines, application of the TGF-β signalling inhibitor, SB431542, increased the protein level of PEG10. Reporter assays revealed that PEG10 repressed TGF-β and BMP signalling, which are both SMAD pathways, whereas PEG10 knockdown increased the level of phosphorylated SMAD3 and SMAD1/5/9. Our results indicate that mutually exclusive expression of PEG10 and phosphorylated SMADs in combination with differentially expressed SOX9 is an index to distinguish between enchondroma and chondrosarcoma, while PEG10 and TGF-β signalling are mutually inhibitory in chondrosarcoma cells.
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Sharan Singh S, Kumar R, Singh Kushwaha V, Bhatt MLBB, Singh A, Mishra A, Ram H, Parmar D, Gupta R. Expression of Radioresistant Gene PEG10 in OSCC Patients and Its Prognostic Significance. Asian Pac J Cancer Prev 2017; 18:1513-1518. [PMID: 28669160 PMCID: PMC6373826 DOI: 10.22034/apjcp.2017.18.6.1513] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Background: Oral squamous cell carcinoma (OSCC) is one of the most common forms of cancer occurring worldwide. PEG10 is well known as a paternally expressed gene from a newly recognized imprinted region at human chromosome 7q21. Previous study had demonstrated that the significant expression of PEG10 was found in radioresistant OSCC cell line and its expression was significantly associated with poor survival in several cancers. Therefore it has been evaluated as a potential marker in OSCC patients undergoing radiotherapy. Objective: This study was conducted to analyze the mRNA expression of PEG10 in OSCC and its expression in relation to clinicpathological features, radiotherapy treatment response and survival. Methods: This study included tissue specimens obtained via biopsy of 118 patients with OSCC who were recommended for radiotherapy treatment and 80 healthy control tissues analysis of mRNA expression of PEG10 was done by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Patients were treated with 70 Gy of radiation dose by shrinking field technique using Cobalt-60 teletherapy machine. Results: Significantly higher mRNA expression of PEG10 was found in OSCC patients when compared with matched controls. High level of PEG10 mRNA expression showed a significant correlation with lymph node metastasis (p = 0.0047) and tumor stage (p = 0.0499). Multivariate Cox regression analysis revealed that high level of mRNA expression of PEG10 was significantly associated with poor survival (p < 0.05). Our research demonstrated that the expression of PEG10 was higher in radioresistant tumor. Conclusion: We observed significantly increased expression of PEG10 in context of lymph node status, advanced stage and poor survival in our study. Thus PEG10 gene can be used as potential predictive and prognostic biomarker in OSCC patients undergoing radiotherapy.
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Sharma A, Sharma KL, Gupta A, Yadav A, Kumar A. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update. World J Gastroenterol 2017; 23:3978-3998. [PMID: 28652652 PMCID: PMC5473118 DOI: 10.3748/wjg.v23.i22.3978] [Citation(s) in RCA: 250] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Revised: 02/01/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
Gallbladder cancer is a malignancy of biliary tract which is infrequent in developed countries but common in some specific geographical regions of developing countries. Late diagnosis and deprived prognosis are major problems for treatment of gallbladder carcinoma. The dramatic associations of this orphan cancer with various genetic and environmental factors are responsible for its poorly defined pathogenesis. An understanding to the relationship between epidemiology, molecular genetics and pathogenesis of gallbladder cancer can add new insights to its undetermined pathophysiology. Present review article provides a recent update regarding epidemiology, pathogenesis, and molecular genetics of gallbladder cancer. We systematically reviewed published literature on gallbladder cancer from online search engine PubMed (http://www.ncbi.nlm.nih.gov/pubmed). Various keywords used for retrieval of articles were Gallbladder, cancer Epidemiology, molecular genetics and bullion operators like AND, OR, NOT. Cross references were manually searched from various online search engines (http://www.ncbi.nlm.nih.gov/pubmed,https://scholar.google.co.in/, http://www.medline.com/home.jsp). Most of the articles published from 1982 to 2015 in peer reviewed journals have been included in this review.
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18
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Yao H, Yang Z, Liu Z, Miao X, Yang L, Li D, Zou Q, Yuan Y. Glypican-3 and KRT19 are markers associating with metastasis and poor prognosis of pancreatic ductal adenocarcinoma. Cancer Biomark 2017; 17:397-404. [PMID: 27689616 DOI: 10.3233/cbm-160655] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with metastasis in most patients at diagnosis. The molecular mechanisms associated with its high malignancy have not been fully elucidated. This study investigated the clinicopathological significances of GPC3 and KRT19 expression in PDAC. METHODS GPC3, KRT19, and CA19-9 protein expression were measured by immunohistochemistry. RESULTS GPC3 and KRT19 protein levels were overexpressed in PDAC tumors compared to normal pancreatic tissues, benign pancreatic tissues, and peritumoral tissues (P< 0.01). The percentage of positive GPC3 and KRT19 expression were significantly higher in PDAC patients with larger tumor size, poorly differentiated tumor, lymph node metastasis, invasion, and TNM stage III/IV disease than in patients with small tumor size, well-differentiated tumor, no lymph node metastasis and invasion, as well as TNM stage I/II stage disease (P< 0.05 or P< 0.01). Benign pancreatic lesions with positive GPC3 and KRT19 protein expression exhibited dysplasia or intraepithelial neoplasia. Kaplan-Meier survival analysis showed that PDAC patients with positive GPC3 and KRT19 expression survived significantly shorter than patients with negative GPC3 and KRT19 expression (P < 0.05 or P< 0.001). Cox multivariate analysis revealed that positive GPC3 and KRT19 expression were independent poor prognosis factors in PDAC patients. CONCLUSIONS GPC3 and KRT19 overexpression are associated with carcinogenesis, progression, and poor prognosis in patients with PDAC and a valuable biomarker for diagnosis of PDAC.
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Affiliation(s)
- Hongliang Yao
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhulin Yang
- Research Laboratory of Hepatobiliary Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ziru Liu
- Research Laboratory of Hepatobiliary Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiongying Miao
- Research Laboratory of Hepatobiliary Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Leping Yang
- Research Laboratory of Hepatobiliary Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Daiqiang Li
- Department of Pathology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qiong Zou
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuan Yuan
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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Huang SF, Yang ZL, Li DQ, Liu ZY, Wang CW, Miao XY, Zou Q, Yuan Y. Jagged1 and DLL4 expressions in benign and malignant pancreatic lesions and their clinicopathological significance. Hepatobiliary Pancreat Dis Int 2016; 15:640-646. [PMID: 27919854 DOI: 10.1016/s1499-3872(16)60110-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor prognosis. Despite intensive research, markers for the early diagnosis, prognosis, and targeting therapy of PDAC are not available. This study aimed to investigate the protein expressions of Jagged1 and DLL4 in PDAC tumor, benign pancreatic and normal pancreatic tissues, and analyze the associations of the two proteins with the clinical and pathological characteristics of PDAC. METHODS A total of 106 PDAC tumor tissues and 35 peritumoral tissues were collected from January 2000 to December 2011 at our hospitals. Thirteen normal pancreatic tissues and 55 benign pancreatic specimens were collected at the same period. Immunohistochemical staining was used to measure Jagged1 and DLL4 protein expressions in these tissues. RESULTS The percentage of positive Jagged1 and DLL4 was significantly higher in PDAC than in normal pancreatic tissues, benign pancreatic tissues, and peritumoral tissues (P<0.01). The higher Jagged1 and DLL4 expressions in PDAC were significantly associated with poor differentiation, maximum tumor size >5 cm, invasion, regional lymph node metastasis, and TNM III/IV disease (P<0.05). In PDAC, Jagged1 expression positively correlated with DLL4 expression. Univariate Kaplan-Meier analysis showed that positive Jagged1 and DLL4 expressions were significantly associated with shorter survival in patients with PDAC. Multivariate Cox regression analysis showed that positive Jagged1 and DLL4 expressions were independent prognostic factors for poor prognosis of patients with PDAC. CONCLUSION Positive Jagged1 and DLL4 expression is closely correlated with severe clinicopathological characteristics and poor prognosis in patients with PDAC.
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Affiliation(s)
- Sheng-Fu Huang
- Research Laboratory of Hepatobiliary Diseases, Second Xiangya Hospital, Central South University, Changsha 410011, China.
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Zhang M, Sui C, Dai B, Shen W, Lu J, Yang J. PEG10 is imperative for TGF-β1-induced epithelial‑mesenchymal transition in hepatocellular carcinoma. Oncol Rep 2016; 37:510-518. [PMID: 28004118 DOI: 10.3892/or.2016.5282] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 11/07/2016] [Indexed: 11/06/2022] Open
Abstract
Substantial evidence indicates that transforming growth factor-beta 1 (TGF-β1) plays a vital role in epithelial-mesenchymal transition (EMT). PEG10 has been shown involved in invasion and metastasis of tumors. The present study investigated the role of PEG10 in TGF-β1-triggered EMT in hepatocellular carcinoma (HCC) progression. Immunohistochemistry and real-time PCR were used to measure the expression level of PEG10 in clinical HCC tissues with or without lymph node metastasis, and normal tissues. The results showed that PEG10 expression is higher in HCC tissues and associated with overall survival (OS) and lymph node metastasis. Moreover, PEG10 expression level was remarkably higher in hepatic cancer cells than the normal hepatic cell line L02. In the present study, we constructed an adenovirus vector containing the coding area of PEG10 (Ad-PEG10) and infected HepG2 cells and found that overexpression of PEG10 promoted the cell migration, invasion ability and EMT of HepG2 cells. TGF-β1 acted on HepG2 cells by enhancing cell migration, invasion, EMT and upregulating PEG10 expression level. However, cells pretreated with adenovirus vector of PEG10 shRNAs (Ad-shRNA1 and Ad-shRNA2) did not occur EMT prior to TGF-β1 stimulation. Moreover, TGF-β1 did not increase the migration and invasion of cells with PEG10 knockdown and overexpression of PEG10 confers chemoresistance to HepG2 cells. Accordingly, sufficient PEG10 expression level is essential for TGF-β1 induced EMT and associated with the chemoresistance in HepG2 cells.
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Affiliation(s)
- Minfeng Zhang
- Department of Special Medical Care Ⅰ and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, P.R. China
| | - Chengjun Sui
- Department of Special Medical Care Ⅰ and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, P.R. China
| | - Binghua Dai
- Department of Special Medical Care Ⅰ and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, P.R. China
| | - Weifeng Shen
- Department of Special Medical Care Ⅰ and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, P.R. China
| | - Jiongjiong Lu
- Department of Special Medical Care Ⅰ and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, P.R. China
| | - Jiamei Yang
- Department of Special Medical Care Ⅰ and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, P.R. China
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Boot A, Oosting J, de Miranda NFCC, Zhang Y, Corver WE, van de Water B, Morreau H, van Wezel T. Imprinted survival genes preclude loss of heterozygosity of chromosome 7 in cancer cells. J Pathol 2016; 240:72-83. [DOI: 10.1002/path.4756] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 05/21/2016] [Accepted: 05/24/2016] [Indexed: 12/19/2022]
Affiliation(s)
- Arnoud Boot
- Department of Pathology; Leiden University Medical Center; Leiden The Netherlands
| | - Jan Oosting
- Department of Pathology; Leiden University Medical Center; Leiden The Netherlands
| | - Noel FCC de Miranda
- Department of Pathology; Leiden University Medical Center; Leiden The Netherlands
| | - Yinghui Zhang
- Division of Toxicology, Leiden Academic Center for Drug Research; Leiden University; The Netherlands
| | - Willem E Corver
- Department of Pathology; Leiden University Medical Center; Leiden The Netherlands
| | - Bob van de Water
- Division of Toxicology, Leiden Academic Center for Drug Research; Leiden University; The Netherlands
| | - Hans Morreau
- Department of Pathology; Leiden University Medical Center; Leiden The Netherlands
| | - Tom van Wezel
- Department of Pathology; Leiden University Medical Center; Leiden The Netherlands
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Yuan Y, Yang Z, Miao X, Li D, Liu Z, Zou Q. The clinical significance of FRAT1 and ABCG2 expression in pancreatic ductal adenocarcinoma. Tumour Biol 2015; 36:9961-8. [PMID: 26178481 DOI: 10.1007/s13277-015-3752-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 07/02/2015] [Indexed: 01/28/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with intrinsic resistance to cytotoxic agents. The molecular mechanisms associated with high malignancy and resistance to chemotherapy and radiotherapy have not been fully elucidated. This study investigated the clinicopathological significances of frequently rearranged in advanced T-cell lymphomas-1 (FRAT1) and ATP-binding cassette subfamily G member 2 (ABCG2) expression in PDAC. FRAT1 and ABCG2 protein expression in 106 PDAC, 35 peritumoral tissues, 55 benign pancreatic tissues, and 13 normal pancreatic tissues was measured by immunohistochemistry. FRAT1 and ABCG2 protein was overexpressed in PDAC tumors compared to peritumoral tissues, benign pancreatic tissues, and normal pancreatic tissues (P < 0.01). The percentage of cases with positive FRAT1 and ABCG2 overexpression was significantly higher in PDAC patients with poor differentiation, lymph node metastasis, invasion, and TNM stage III/IV disease than in patients with well-differentiated tumor, no lymph node metastasis and invasion, and TNM stage I/II disease (P < 0.05 or P < 0.01). In pancreatic tissues with benign lesions, tissues with positive FRAT1 and ABCG2 protein expression exhibited dysplasia or intraepithelial neoplasia. Kaplan-Meier survival analysis showed that PDAC patients with positive FRAT1 and ABCG2 expression survived significantly shorter than patients with negative FRAT1 and ABCG2 expression (P < 0.05 or P < 0.001). Cox multivariate analysis revealed that positive FRAT1 and ABCG2 expression was an independent poor prognosis factor in PDAC patients. FRAT1 and ABCG2 overexpression is associated with carcinogenesis, progression, and poor prognosis in patients with PDAC.
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Affiliation(s)
- Yuan Yuan
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Zhulin Yang
- Research Laboratory of Hepatobiliary Diseases, Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China.
| | - Xiongying Miao
- Research Laboratory of Hepatobiliary Diseases, Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China
| | - Daiqiang Li
- Department of Pathology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China
| | - Ziru Liu
- Research Laboratory of Hepatobiliary Diseases, Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China
| | - Qiong Zou
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China
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Peng W, Fan H, Wu G, Wu J, Feng J. Upregulation of long noncoding RNA PEG10 associates with poor prognosis in diffuse large B cell lymphoma with facilitating tumorigenicity. Clin Exp Med 2015; 16:177-82. [PMID: 25864113 DOI: 10.1007/s10238-015-0350-9] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 04/02/2015] [Indexed: 12/22/2022]
Abstract
Diffuse large B cell lymphoma (DLBCL) is one of the most common malignancies worldwide. To date, there has been little progress in improving the overall survival of DLBCL patients. Emerging evidences have implicated that long noncoding RNAs (lncRNAs) have important regulatory roles in fundamental biological processes, and some of them are involved in cancer initiation, development and progression. This study was to investigate the expression of lncRNA PEG10 in a cohort of DLBCL patients to assess its clinical value and biological function in DLBCL. We first found that the expression of PEG10 was upregulated in DLBCL tumorous tissues and that cell lines compared with the normal. Moreover, we illustrated that PEG10 was significantly correlated with B symptoms, IPI score, CHOP-like treatment and rituximab. In addition, ROC(AUC) of PEG10 was up to 0.8228, implicating that PEG10 could be a diagnostic marker for distinguishing DLBCL from normal. Importantly, we verified that PEG10 was a key independent predictive factor for DLBCL prognosis from sizable samples through the longtime follow-ups. Furthermore, we revealed that knockdown of PEG10 expression by siRNA could lead to growth arrest and cell apoptosis in vitro. Our results suggested that PEG10 could represent a novel indicator of poor prognosis and might be served as a potential target for the diagnosis and gene therapy of DLBCL.
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Affiliation(s)
- Wei Peng
- Department of Medical Oncology, Jiangsu Cancer Hospital, Nanjing Medical University, No. 42 Baiziting Road, Nanjing, 210009, China
| | - Hong Fan
- Laboratory of Cancer Research, First People's Hospital of Yunnan, No. 175 Jinbi Road, Kunming, 650032, China
| | - Guoqiu Wu
- Laboratory of Cancer Research, Southeast University Affiliated Zhongda Hospital, No. 87 Dingjiaqiao Road, Nanjing, 210012, China
| | - Jianzhong Wu
- Center of Clinical Cancer Research, Jiangsu Cancer Hospital, Nanjing Medical University, No. 42 Baiziting Road, Nanjing, 210009, China
| | - Jifeng Feng
- Department of Medical Oncology, Jiangsu Cancer Hospital, Nanjing Medical University, No. 42 Baiziting Road, Nanjing, 210009, China.
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Bang H, Ha SY, Hwang SH, Park CK. Expression of PEG10 Is Associated with Poor Survival and Tumor Recurrence in Hepatocellular Carcinoma. Cancer Res Treat 2015; 47:844-52. [PMID: 25687862 PMCID: PMC4614193 DOI: 10.4143/crt.2014.124] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Accepted: 08/13/2014] [Indexed: 12/15/2022] Open
Abstract
Purpose Paternally expressed gene 10 (PEG10), first identified as an imprinted gene, is paternally expressed and maternally silenced. In hepatocellular carcinoma (HCC), PEG10 has been identified as a potential target gene located within the amplified 7q21 locus. The purpose of this study was to investigate the expression of PEG10 protein in HCC and evaluate its prognostic significance. Materials and Methods PEG10 protein expression was examined by immunohistochemistry in tumor tissues from 218 HCC patients undergoing curative resection. Furthermore, the relationships between PEG10 expression and clinicopathologic features or postoperative survival of HCC patients were evaluated. The median follow-up period was 119.8 months for survivors. Results PEG10 expression was observed in 148 of the 218 HCCs (67.9%) and was significantly correlated with younger age, female, higher Edmondson grade, microvascular invasion, intrahepatic metastasis, higher American Joint Committee on Cancer T-stage, and higher α-fetoprotein level. PEG10 expression was an independent predictor of early recurrence (p=0.013), and it showed an unfavorable influence on recurrence-free survival (p < 0.001). A subgroup analysis showed that among patients with α-fetoprotein ≤ 20 ng/mL (80 patients), the PEG10-positive group also showed an unfavorable influence on recurrence-free survival (p=0.002). Moreover, a multivariate survival analysis identified PEG10 as an independent predictor of shorter recurrence-free survival (p=0.005). PEG10 expression showed an unfavorable influence on overall survival (p=0.007) but was not an independent predictor of shorter overall survival (p=0.128). Conclusion PEG10 protein could be a potential biomarker predicting early recurrence and recurrence-free survival in HCC patients after curative resection, even in those with normal serum α-fetoprotein levels.
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Affiliation(s)
- Heejin Bang
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang Yun Ha
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Soo Hyun Hwang
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Cheol-Keun Park
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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25
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Deng X, Hu Y, Ding Q, Han R, Guo Q, Qin J, Li J, Xiao R, Tian S, Hu W, Zhang Q, Xiong J. PEG10 plays a crucial role in human lung cancer proliferation, progression, prognosis and metastasis. Oncol Rep 2014; 32:2159-67. [PMID: 25199998 DOI: 10.3892/or.2014.3469] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Accepted: 08/14/2014] [Indexed: 11/05/2022] Open
Abstract
Paternally expressed gene 10 (PEG10) has been identified as a genetic imprinted gene, which is important for apoptosis resistance in cancer cells. Mounting evidence suggests that PEG10 is expressed in the majority of hepatocellular carcinoma (HCC) cells with growth-promoting activity. In the present study, we evaluated the correlation between PEG10 expression and the clinicopathological features of lung, breast and HCC tumors, and predicted the relationship between survival and expression levels of PEG10 in lung cancer patients. Furthermore, we chose non-small cell lung cancer cell line A549 as a model to analyze the function of PEG10 in proliferation and metastasis in vitro. Our results revealed that expression of PEG10 was closely correlated with clinical TNM grade and patient prognosis in lung cancer. PEG10 enhanced cell proliferation and promoted tumor cell migration and invasion by upregulating the expression of β-catenin, MMP-2 and MMP-9, and decreased the expression of E-cadherin in the A549 cells. Our findings provide significant insight into the molecular mechanisms of lung cancer and offer novel ideas for designing new therapeutic targets for lung carcinoma.
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Affiliation(s)
- Xinzhou Deng
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Yi Hu
- Department of Clinical Laboratory, The First Affiliated Hosptial of Xiamen University, Xiamen, Fujian 361003, P.R. China
| | - Qianshan Ding
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Rongfei Han
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Qian Guo
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Jian Qin
- Central Laboratory, Wuhan University, Renmin Hospital, Wuhan, Hubei 430060, P.R. China
| | - Jie Li
- Central Laboratory, Taihe Hospital, Shiyan, Hubei 442000, P.R. China
| | - Ruijing Xiao
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Sufang Tian
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Weidong Hu
- Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Qiuping Zhang
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Jie Xiong
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, Hubei 430071, P.R. China
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26
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Gronnier C, Bruyère E, Lahdaoui F, Jonckheere N, Perrais M, Leteurtre E, Piessen G, Mariette C, Van Seuningen I. The MUC1 mucin regulates the tumorigenic properties of human esophageal adenocarcinomatous cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2014; 1843:2432-7. [PMID: 25003315 DOI: 10.1016/j.bbamcr.2014.06.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Revised: 06/19/2014] [Accepted: 06/27/2014] [Indexed: 02/07/2023]
Abstract
MUC1 is a membrane-bound mucin known to participate in tumor proliferation. It has been shown that MUC1 pattern of expression is modified during esophageal carcinogenesis, with a progressive increase from metaplasia to adenocarcinoma. The principal cause of development of esophageal adenocarcinoma is gastro-esophageal reflux and MUC1 was previously shown to be up-regulated by several bile acids present in reflux. In this report, our aim was thus to determine whether MUC1 plays a role in biological properties of human esophageal cancer cells. For that, a stable MUC1-deficient esophageal cancer cell line was established using a shRNA approach. In vitro (proliferation, migration and invasion) and in vivo (tumor growth following subcutaneous xenografts in SCID mice) biological properties of MUC1-deficient cells were analyzed. Our results show that esophageal cancer cells lacking MUC1 were less proliferative and had decreased migration and invasion properties. These alterations were accompanied by a decreased activity of NFKB p65, Akt and MAPK (p44/42, JNK and p38) pathways. MCM6 and TSG101 tumor-associated markers were also decreased. Subcutaneous xenografts showed a significant decrease in tumor size when cells did not express MUC1. Altogether, the data indicate that MUC1 plays a key role in proliferative, migrating and invasive properties of esophageal cancer cells as well as in tumor growth promotion. MUC1 mucin appears thus as a good therapeutic target to slow down esophageal tumor progression.
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Affiliation(s)
- Caroline Gronnier
- Inserm, UMR837, Jean-Pierre Aubert Research Center, Team 5 "Mucins, Epithelial Differentiation and Carcinogenesis", Lille, France; Université Lille-Nord de France, Lille, France; Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Lille, France
| | - Emilie Bruyère
- Inserm, UMR837, Jean-Pierre Aubert Research Center, Team 5 "Mucins, Epithelial Differentiation and Carcinogenesis", Lille, France; Université Lille-Nord de France, Lille, France; Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Lille, France
| | - Fatima Lahdaoui
- Inserm, UMR837, Jean-Pierre Aubert Research Center, Team 5 "Mucins, Epithelial Differentiation and Carcinogenesis", Lille, France; Université Lille-Nord de France, Lille, France; Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Lille, France
| | - Nicolas Jonckheere
- Inserm, UMR837, Jean-Pierre Aubert Research Center, Team 5 "Mucins, Epithelial Differentiation and Carcinogenesis", Lille, France; Université Lille-Nord de France, Lille, France
| | - Michaël Perrais
- Inserm, UMR837, Jean-Pierre Aubert Research Center, Team 5 "Mucins, Epithelial Differentiation and Carcinogenesis", Lille, France; Université Lille-Nord de France, Lille, France
| | - Emmanuelle Leteurtre
- Inserm, UMR837, Jean-Pierre Aubert Research Center, Team 5 "Mucins, Epithelial Differentiation and Carcinogenesis", Lille, France; Université Lille-Nord de France, Lille, France; Centre de Biologie-Pathologie, Department of Pathology, Centre Hospitalier Régional et Universitaire, Lille, France
| | - Guillaume Piessen
- Inserm, UMR837, Jean-Pierre Aubert Research Center, Team 5 "Mucins, Epithelial Differentiation and Carcinogenesis", Lille, France; Université Lille-Nord de France, Lille, France; Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Lille, France
| | - Christophe Mariette
- Inserm, UMR837, Jean-Pierre Aubert Research Center, Team 5 "Mucins, Epithelial Differentiation and Carcinogenesis", Lille, France; Université Lille-Nord de France, Lille, France; Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Lille, France
| | - Isabelle Van Seuningen
- Inserm, UMR837, Jean-Pierre Aubert Research Center, Team 5 "Mucins, Epithelial Differentiation and Carcinogenesis", Lille, France; Université Lille-Nord de France, Lille, France.
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27
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Barreto SG, Dutt A, Chaudhary A. A genetic model for gallbladder carcinogenesis and its dissemination. Ann Oncol 2014; 25:1086-97. [PMID: 24705974 PMCID: PMC4037856 DOI: 10.1093/annonc/mdu006] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gallbladder cancer, although regarded as the most common malignancy of the biliary tract, continues to be associated with a dismal overall survival even in the present day. While complete surgical removal of the tumour offers a good chance of cure, only a fraction of the patients are amenable to curative surgery owing to their delayed presentation. Moreover, the current contribution of adjuvant therapies towards prolonging survival is marginal, at best. Thus, understanding the biology of the disease will not only enable a better appreciation of the pathways of progression but also facilitate the development of an accurate genetic model for gallbladder carcinogenesis and dissemination. This review provides an updated, evidence-based model of the pathways of carcinogenesis in gallbladder cancer and its dissemination. The model proposed could serve as the scaffolding for elucidation of the molecular mechanisms involved in gallbladder carcinogenesis. A better understanding of the pathways involved in gallbladder tumorigenesis will serve to identify patients at risk for the cancer (and who thus could be offered prophylactic cholecystectomy) as well as aid oncologists in planning the most suitable treatment for a particular patient, thereby setting us on the vanguard of transforming the current treatment paradigm for gallbladder cancer.
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Affiliation(s)
- S G Barreto
- Department of Gastrointestinal Surgery, Gastrointestinal Oncology, and Bariatric Surgery, Medanta Institute of Digestive and Hepatobiliary Sciences, Medanta, The Medicity, Gurgaon
| | - A Dutt
- The Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, India
| | - A Chaudhary
- Department of Gastrointestinal Surgery, Gastrointestinal Oncology, and Bariatric Surgery, Medanta Institute of Digestive and Hepatobiliary Sciences, Medanta, The Medicity, Gurgaon
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28
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Li J, Yang Z, Zou Q, Yuan Y, Li J, Liang L, Zeng G, Chen S. PKM2 and ACVR 1C are prognostic markers for poor prognosis of gallbladder cancer. Clin Transl Oncol 2014; 16:200-7. [PMID: 23793810 DOI: 10.1007/s12094-013-1063-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Accepted: 05/30/2013] [Indexed: 12/21/2022]
Abstract
PURPOSE To identify biological markers related to the progression and prognosis of GBC. METHODS The expressions of pyruvate kinase isoenzyme type M2 (PKM2) and activin A receptor type IC (ACVR 1C) in 46 squamous cell/adenosquamous carcinomas (SC/ASC) and 80 adenocarcinomas (AC) were examined using immunohistochemistry. RESULTS Positive PKM2 and negative ACVR 1C expressions were significantly associated with lymph node metastasis, invasion and TNM stage of SC/ASCs and ACs. Univariate Kaplan-Meier analysis showed that either elevated PKM2 or loss of ACVR 1C expression significantly correlated with shorter average survival times in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive PKM2 expression and loss of ACVR 1C expression were poor prognosis biomarkers in both SC/ASC and AC patients. CONCLUSIONS Our study suggested that PKM2 overexpression is a marker of metastasis, invasion and poor prognosis of GBC. ACVR 1C is a tumor suppressor, and lowered ACVR 1C expression is an important marker for the metastasis, invasion, and prognosis of GBC.
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MESH Headings
- Activin Receptors, Type I/metabolism
- Activin Receptors, Type I/physiology
- Adenocarcinoma/diagnosis
- Adenocarcinoma/metabolism
- Adenocarcinoma/mortality
- Adenocarcinoma/pathology
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/metabolism
- Carcinoma, Adenosquamous/diagnosis
- Carcinoma, Adenosquamous/metabolism
- Carcinoma, Adenosquamous/mortality
- Carcinoma, Adenosquamous/pathology
- Carcinoma, Squamous Cell/diagnosis
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/mortality
- Carcinoma, Squamous Cell/pathology
- Carrier Proteins/metabolism
- Carrier Proteins/physiology
- Female
- Gallbladder Neoplasms/diagnosis
- Gallbladder Neoplasms/metabolism
- Gallbladder Neoplasms/mortality
- Gallbladder Neoplasms/pathology
- Humans
- Male
- Membrane Proteins/metabolism
- Membrane Proteins/physiology
- Middle Aged
- Neoplasm Metastasis
- Prognosis
- Thyroid Hormones/metabolism
- Thyroid Hormones/physiology
- Thyroid Hormone-Binding Proteins
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Affiliation(s)
- J Li
- Department of Surgery, Central South University, Changsha, 410011, Hunan, People's Republic of China
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29
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Riordan JD, Dupuy AJ. Domesticated transposable element gene products in human cancer. Mob Genet Elements 2013; 3:e26693. [PMID: 24251072 DOI: 10.4161/mge.26693] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Revised: 09/24/2013] [Accepted: 10/03/2013] [Indexed: 11/19/2022] Open
Abstract
The adaptation of transposable elements inserted within the genome to serve novel functions in a host cell, a process known as molecular domestication, is a widespread phenomenon in nature. Around fifty protein-coding genes in humans have arisen through this mechanism. Functional characterization of these domesticated genes has revealed involvement in a multitude of diverse cellular processes. Some of these functions are related to cellular activities and pathways known to be involved in cancer development. In this mini-review we discuss such roles of domesticated genes that may be aberrantly regulated in human cancer, as well as studies that have identified disrupted expression in tumors. We also describe studies that have provided definitive experimental evidence for transposable element-derived gene products in promoting tumorigenesis.
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Affiliation(s)
- Jesse D Riordan
- Department of Anatomy & Cell Biology; Roy J. & Lucille A. Carver College of Medicine; University of Iowa; Iowa City, IA USA
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30
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Kameyama T, Suzuki H, Mayeda A. Re-splicing of mature mRNA in cancer cells promotes activation of distant weak alternative splice sites. Nucleic Acids Res 2012; 40:7896-906. [PMID: 22675076 PMCID: PMC3439910 DOI: 10.1093/nar/gks520] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Transcripts of the human tumor susceptibility gene 101 (TSG101) are aberrantly spliced in many cancers. A major aberrant splicing event on the TSG101 pre-mRNA involves joining of distant alternative 5′ and 3′ splice sites within exon 2 and exon 9, respectively, resulting in the extensive elimination of the mRNA. The estimated strengths of the alternative splice sites are much lower than those of authentic splice sites. We observed that the equivalent aberrant mRNA could be generated from an intron-less TSG101 gene expressed ectopically in breast cancer cells. Remarkably, we identified a pathway-specific endogenous lariat RNA consisting solely of exonic sequences, predicted to be generated by a re-splicing between exon 2 and exon 9 on the spliced mRNA. Our results provide evidence for a two-step splicing pathway in which the initial constitutive splicing removes all 14 authentic splice sites, thereby bringing the weak alternative splice sites into close proximity. We also demonstrate that aberrant multiple-exon skipping of the fragile histidine triad (FHIT) pre-mRNA in cancer cells occurs via re-splicing of spliced FHIT mRNA. The re-splicing of mature mRNA can potentially generate mutation-independent diversity in cancer transcriptomes. Conversely, a mechanism may exist in normal cells to prevent potentially deleterious mRNA re-splicing events.
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Affiliation(s)
- Toshiki Kameyama
- Division of Gene Expression Mechanism, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan
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31
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Shu GS, Yang ZL, Liu DC. Immunohistochemical study of Dicer and Drosha expression in the benign and malignant lesions of gallbladder and their clinicopathological significances. Pathol Res Pract 2012; 208:392-7. [PMID: 22658478 DOI: 10.1016/j.prp.2012.05.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Revised: 04/27/2012] [Accepted: 05/02/2012] [Indexed: 02/07/2023]
Abstract
Dicer and Drosha are two key enzymes that are involved in the processing of miRNA production. Their expressions in gallbladder cancer have not been investigated. In this study, we studied Dicer and Drosha expression in 21 non-dysplastic gallbladder epithelia and 108 gallbladder adenocarcinomas by immunohistochemical staining. The clinicopathological significance of Dicer and Drosha expressions was analyzed. We demonstrated that the percent of positive Dicer or Drosha expression was significantly lower in gallbladder adenocarcinoma than that in non-dysplastic gallbladder epithelia (p<0.01). The percent of positive Dicer and Drosha expression was significantly lower in poorly differentiated adenocarcinoma with lymph node metastasis, invasiveness, and no resection than in well-differentiated adenocarcinoma without metastasis, invasiveness, and with radical resection (p<0.05 or p<0.01). Univariate Kaplan-Meier analysis showed that loss of Dicer and Drosha expression was associated with decreased overall survival (p<0.05 or p<0.01). Multivariate Cox regression analysis showed that loss of Dicer and Drosha expression was an independent poor-prognostic predictor in patients with gallbladder adenocarcinoma. In conclusion, loss of Dicer and Drosha expression is closely related to the metastasis, invasion, and poor-prognosis in gallbladder adenocarcinoma.
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Affiliation(s)
- Guo-shun Shu
- Department of Geriatric Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
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32
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van der Horst PH, Wang Y, Vandenput I, Kühne LC, Ewing PC, van Ijcken WFJ, van der Zee M, Amant F, Burger CW, Blok LJ. Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer. PLoS One 2012; 7:e30840. [PMID: 22295114 PMCID: PMC3266274 DOI: 10.1371/journal.pone.0030840] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2011] [Accepted: 12/22/2011] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Every year approximately 74,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs) as well as progesterone receptor (PR) positivity has been correlated with improved prognosis. This study describes two mechanisms by which progesterone inhibits metastatic spread of endometrial cancer: by stimulating T-cell infiltration and by inhibiting epithelial-to-mesenchymal cell transition (EMT). METHODOLOGY AND PRINCIPAL FINDINGS Paraffin sections from patients with (n = 9) or without (n = 9) progressive endometrial cancer (recurrent or metastatic disease) were assessed for the presence of CD4+ (helper), CD8+ (cytotoxic) and Foxp3+ (regulatory) T-lymphocytes and PR expression. Progressive disease was observed to be associated with significant loss of TILs and loss of PR expression. Frozen tumor samples, used for genome-wide expression analysis, showed significant regulation of pathways involved in immunesurveillance, EMT and metastasis. For a number of genes, such as CXCL14, DKK1, DKK4, PEG10 and WIF1, quantitive RT-PCR was performed to verify up- or downregulation in progressive disease. To corroborate the role of progesterone in regulating invasion, Ishikawa (IK) endometrial cancer cell lines stably transfected with PRA (IKPRA), PRB (IKPRB) and PRA+PRB (IKPRAB) were cultured in presence/absence of progesterone (MPA) and used for genome-wide expression analysis, Boyden- and wound healing migration assays, and IHC for known EMT markers. IKPRB and IKPRAB cell lines showed MPA induced inhibition of migration and loss of the mesenchymal marker vimentin at the invasive front of the wound healing assay. Furthermore, pathway analysis of significantly MPA regulated genes showed significant down regulation of important pathways involved in EMT, immunesuppression and metastasis: such as IL6-, TGF-β and Wnt/β-catenin signaling. CONCLUSION Intact progesterone signaling in non-progressive endometrial cancer seems to be an important factor stimulating immunosurveilance and inhibiting transition from an epithelial to a more mesenchymal, more invasive phenotype.
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Affiliation(s)
- Paul H van der Horst
- Department of Obstetrics and Gynaecology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
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