|
1
|
Wang H, Li F, Liu N, Liu X, Yang X, Guo Y, Bei J, Zeng Y, Shao J. Prognostic implications of a molecular classifier derived from whole-exome sequencing in nasopharyngeal carcinoma. Cancer Med 2019; 8:2705-2716. [PMID: 30950204 PMCID: PMC6558473 DOI: 10.1002/cam4.2146] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 03/04/2019] [Accepted: 03/07/2019] [Indexed: 12/30/2022] Open
Abstract
The aim of this study was to use whole-exome sequencing to derive a molecular classifier for nasopharyngeal carcinoma (NPC) and evaluate its clinical performance. We performed whole-exome sequencing on 82 primary NPC tumors from Sun Yat-sen University Cancer Center (Guangzhou cohort) to obtain somatic single-nucleotide variants, indels, and copy number variants. A novel molecular classifier was then developed and validated in another NPC cohort (Hong Kong cohort, n = 99). Survival analysis was estimated by the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards model was adopted for univariate and multivariate analyses. We identified three prominent NPC genetic subtypes: RAS/PI3K/AKT (based on RAS, AKT1, and PIK3CA mutations), cell-cycle (based on CDKN2A/CDKN2B deletions, and CDKN1B and CCND1 amplifications), and unclassified (based on dominant mutations in epigenetic regulators, such as KMT2C/2D, or the Notch signaling pathway, such as NOTCH1/2). These subtypes differed in survival analysis, with good, intermediate, and poor progression-free survival in the unclassified, cell-cycle, and RAS/PI3K/AKT subgroups, respectively, among the Guangzhou, Hong Kong, and combined cohorts (n = 82, P = 0.0342; n = 99, P = 0.0372; and n = 181, P = 0.0023; log-rank test). We have uncovered genetic subtypes of NPC with distinct mutations and/or copy number changes, reflecting discrete paths of NPC tumorigenesis and providing a roadmap for developing new prognostic biomarkers and targeted therapies.
Collapse
Affiliation(s)
- Hai‐Yun Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapySun Yat‐sen University Cancer CenterGuangzhouP. R. China
- Department of Molecular DiagnosticsSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Fugen Li
- Research and Development Institute of Precision Medicine3D Medicine Inc.ShanghaiP. R. China
| | - Na Liu
- BGI Genomics, BGI‐ShenzhenShenzhenP. R. China
| | - Xiao‐Yun Liu
- Department of Molecular DiagnosticsSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Xin‐Hua Yang
- Department of Molecular DiagnosticsSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Yun‐Miao Guo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapySun Yat‐sen University Cancer CenterGuangzhouP. R. China
- Department of Experiment ResearchSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Jin‐Xin Bei
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapySun Yat‐sen University Cancer CenterGuangzhouP. R. China
- Department of Experiment ResearchSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Yi‐Xin Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapySun Yat‐sen University Cancer CenterGuangzhouP. R. China
- Department of Experiment ResearchSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Jian‐Yong Shao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapySun Yat‐sen University Cancer CenterGuangzhouP. R. China
- Department of Molecular DiagnosticsSun Yat‐sen University Cancer CenterGuangzhouP. R. China
- School of Laboratory MedicineWannan Medical CollegeWuhu, Anhui ProvinceP. R. China
| |
Collapse
|
|
2
|
Jin Y, Cui D, Ren J, Wang K, Zeng T, Gao L. CACNA2D3 is downregulated in gliomas and functions as a tumor suppressor. Mol Carcinog 2016; 56:945-959. [PMID: 27583705 DOI: 10.1002/mc.22548] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 08/22/2016] [Accepted: 08/29/2016] [Indexed: 01/08/2023]
Abstract
CACNA2D3, an auxiliary member of the alpha-2/delta subunit three family of the voltage-dependent calcium channel complex, plays a critical role in tumor suppression. However, its role in glioma carcinogenesis remains largely unknown. Here, we investigated the putative tumor suppressive role of CACNA2D3 in gliomas. Downregulation of CACNA2D3 was frequently detected in glioma tissues and cells compared with their non-tumorigenic counterparts, and correlated with poor survival. To investigate the underlying mechanism of CACNA2D3 in the development and progression of glioma, we performed CACNA2D3 ectopic expression in glioma cells (U87 and U251) and knockdown of CACNA2D3 in LN229 cells and conducted in vitro and in vivo functional assays. Our findings showed that increased intracellular calcium (Ca2+ ) mediated by overexpression of CACNA2D3 induced mitochondrial-mediated apoptosis, upregulation of NLK (through the Wnt/Ca2+ pathway) and inhibition of the epithelial-to-mesenchymal transition. Ectopic expression of CACNA2D3 inhibited cell proliferation, migration, invasion, and tumor growth in vitro and in vivo, whereas CACNA2D3 depletion inhibited cell viability and invasion. Furthermore, we confirmed that CACNA2D3 increased NLK expression in vitro by immunostaining and found that downregulation of CACNA2D3 in glioma cells and high-grade glioma tissue was accompanied by increased methylation. A reporter assay showed increased luciferase activity in NLK knockdown glioma cells and transcriptional activity of β-cantenin/TCF was remarkably enhanced, which further confirmed that NLK antagonizes Wnt signaling-mediated anchorage-dependent and independent cell proliferation and invasion. This mechanism may contribute to a better understanding of glioma cancer pathogenesis and facilitate the development of new therapeutic strategies for the treatment of this disease. © 2016 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Yi Jin
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Daming Cui
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Jie Ren
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Ke Wang
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Tao Zeng
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Liang Gao
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| |
Collapse
|
|
3
|
Raab-Traub N. Nasopharyngeal Carcinoma: An Evolving Role for the Epstein-Barr Virus. Curr Top Microbiol Immunol 2015; 390:339-63. [PMID: 26424653 DOI: 10.1007/978-3-319-22822-8_14] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The Epstein-Barr herpesvirus (EBV) is an important human pathogen that is closely linked to several major malignancies including the major epithelial tumor, undifferentiated nasopharyngeal carcinoma (NPC). This important tumor occurs with elevated incidence in specific areas, particularly in southern China but also in Mediterranean Africa and some regions of the Middle East. Regardless of tumor prevalence, undifferentiated NPC is consistently associated with EBV. The consistent detection of EBV in all cases of NPC, the maintenance of the viral genome in every cell, and the continued expression of viral gene products suggest that EBV is a necessary factor for the malignant growth in vivo. However, the molecular characterization of the infection and identification of critical events have been hampered by the difficulty in developing in vitro models of NPC. Epithelial cell infection is difficult in vitro and in contrast to B-cell infection does not result in immortalization and transformation. Cell lines established from NPC usually do not retain the genome, and the successful establishment of tumor xenografts is difficult. However, critical genetic changes that contribute to the onset and progression of NPC and key molecular properties of the viral genes expressed in NPC have been identified. In some cases, viral expression becomes increasingly restricted during tumor progression and tumor cells may express only the viral nuclear antigen EBNA1 and viral noncoding RNAs. As NPC develops in the immunocompetent, the continued progression of deregulated growth likely reflects the combination of expression of viral oncogenes in some cells and viral noncoding RNAs that likely function synergistically with changes in cellular RNA and miRNA expression.
Collapse
Affiliation(s)
- Nancy Raab-Traub
- Department of Microbiology, Lineberger Comprehensive Cancer Center, CB#7295, University of North Carolina, Chapel Hill, NC, 27599-7295, USA.
| |
Collapse
|
|
4
|
Abstract
We detected loss of heterozygosity (LOH) and microsatellite instabilities (MSI), as well as extron expression of the fragile histidine triad (FHIT) gene in gastric carcinoma (GC), in order to evaluate their association with clinicopathological processes in gastric carcinogenesis. LOH and MSI of the FHIT were detected by using PCR at 4 microsatellite loci: D3S 1300, D3S 4103, D3S 1481, D3S 1234 in cancer tissues from 50 patients with primary GC, with normal mucosa acting as matched controls. FHIT transcripts were detected by nested RT-PCR in 30 cases of GC and their products were sequenced. Results show that the average frequencies of LOH and MSI of the FHIT gene in GC were 32.4% and 26.4%, respectively. There was no correlation between LOH and MSI of the FHIT gene in GC and the histological characteristics of gastric carcinoma (Bormann's or Lauren's classification). LOH of the FHIT gene in GC was related to depth invasiveness, and its frequency in GC where serosa was penetrated was significantly higher than that in GC without serosa penetration (73.5% vs 37.5%, P < 0.05). The frequency of MSI in GC without lymph node metastasis was significantly higher than that in GC with lymph node metastasis (66.7% vs 34.3%, P < 0.05). Aberrant transcripts were found in 11/30 GC tissues. Sequencing analysis of the aberrant fragments found a RT-PCR product missing exons 5-7 in one case of GC, and another product missing exons 4-7. Four of 10 (40.0%) cases of primary GC showed absent or decreased expression of the FHIT protein as compared to their matched normal tissues. The findings in this study suggest that LOH and MSI of FHIT gene may induce aberrant extron expression, which might play a role in gastric carcinogenesis.
Collapse
|
|
5
|
Wong AMG, Kong KL, Chen L, Liu M, Wong AMG, Zhu C, Tsang JWH, Guan XY. Characterization ofCACNA2D3as a putative tumor suppressor gene in the development and progression of nasopharyngeal carcinoma. Int J Cancer 2013; 133:2284-95. [DOI: 10.1002/ijc.28252] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Accepted: 04/04/2013] [Indexed: 12/31/2022]
Affiliation(s)
| | | | | | | | | | | | | | - Xin-Yuan Guan
- Department of Clinical Oncology; The University of Hong Kong; Hong Kong; China
| |
Collapse
|
|
6
|
Feng X, Ren C, Zhou W, Liu W, Zeng L, Li G, Wang L, Li M, Zhu B, Yao K, Jiang X. Promoter hypermethylation along with LOH, but not mutation, contributes to inactivation of DLC-1
in nasopharyngeal carcinoma. Mol Carcinog 2013; 53:858-70. [DOI: 10.1002/mc.22044] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2012] [Revised: 04/08/2013] [Accepted: 04/14/2013] [Indexed: 12/14/2022]
Affiliation(s)
- Xiangling Feng
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
| | - Caiping Ren
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
| | - Wen Zhou
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
| | - Weidong Liu
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
| | - Liang Zeng
- Department of Pathology; Hunan Tumor Hospital; Changsha, Hunan, P.R. China
| | - Guifei Li
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
| | - Lei Wang
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
| | - Min Li
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
| | - Bin Zhu
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
| | - Kaitai Yao
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
- Cancer Research Institute; Southern Medical University; Guangzhou, Guangdong, P.R. China
| | - Xingjun Jiang
- Department of Neurosurgery; Xiangya Hospital, Central South University; Changsha, Hunan, P.R. China
| |
Collapse
|
|
7
|
Shu XS, Li L, Ji M, Cheng Y, Ying J, Fan Y, Zhong L, Liu X, Tsao SW, Chan ATC, Tao Q. FEZF2, a novel 3p14 tumor suppressor gene, represses oncogene EZH2 and MDM2 expression and is frequently methylated in nasopharyngeal carcinoma. Carcinogenesis 2013; 34:1984-93. [PMID: 23677067 DOI: 10.1093/carcin/bgt165] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated tumor prevalent in southern China and southeast Asia, with the 3p14-p12 locus reported as a critical tumor suppressor gene (TSG) region during its pathogenesis. We identified a novel 3p14.2 TSG, FEZF2 (FEZ family zinc finger 2), for NPC. FEZF2 is readily expressed in normal tissues including upper respiratory epithelium, testis, brain and ovary tissues, as well as in immortalized nasopharyngeal epithelial cell line NP69, but it is completely silenced in NPC cell lines due to CpG methylation of its promoter, although no homozygous deletion of FEZF2 was detected. 5-Aza-2'-deoxycytidine treatment restored FEZF2 expression in NPC cell lines along with its promoter demethylation. FEZF2 was frequently downregulated in NPC tumors, with promoter methylation detected in 75.5% of tumors, but only in 7.1% of normal nasopharyngeal tissues. Restored FEZF2 expression suppressed NPC cell clonogenicity through inducing G2/M cell cycle arrest and apoptosis and also inhibited NPC cell migration and stemness. FEZF2 acted as a histone deacetylase-associated repressor downregulating multiple oncogenes including EZH2 and MDM2, through direct binding to their promoters. Concomitantly, overexpression of EZH2 was frequently detected in NPC tumors. Thus, we have identified FEZF2 as a novel 3p14.2 TSG frequently inactivated by promoter methylation in NPC, which functions as a repressor downregulating multiple oncogene expression.
Collapse
Affiliation(s)
- Xing-Sheng Shu
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Shatin, Hong Kong
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
8
|
Hu C, Wei W, Chen X, Woodman CB, Yao Y, Nicholls JM, Joab I, Sihota SK, Shao JY, Derkaoui KD, Amari A, Maloney SL, Bell AI, Murray PG, Dawson CW, Young LS, Arrand JR. A global view of the oncogenic landscape in nasopharyngeal carcinoma: an integrated analysis at the genetic and expression levels. PLoS One 2012; 7:e41055. [PMID: 22815911 PMCID: PMC3398876 DOI: 10.1371/journal.pone.0041055] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2012] [Accepted: 06/17/2012] [Indexed: 12/22/2022] Open
Abstract
Previous studies have reported that the tumour cells of nasopharyngeal carcinoma (NPC) exhibit recurrent chromosome abnormalities. These genetic changes are broadly assumed to lead to changes in gene expression which are important for the pathogenesis of this tumour. However, this assumption has yet to be formally tested at a global level. Therefore a genome wide analysis of chromosome copy number and gene expression was performed in tumour cells micro-dissected from the same NPC biopsies. Cellular tumour suppressor and tumour-promoting genes (TSG, TPG) and Epstein-Barr Virus (EBV)-encoded oncogenes were examined. The EBV-encoded genome maintenance protein EBNA1, along with the putative oncogenes LMP1, LMP2 and BARF1 were expressed in the majority of NPCs that were analysed. Significant downregulation of expression in an average of 76 cellular TSGs per tumour was found, whilst a per-tumour average of 88 significantly upregulated, TPGs occurred. The expression of around 60% of putative TPGs and TSGs was both up-and down-regulated in different types of cancer, suggesting that the simplistic classification of genes as TSGs or TPGs may not be entirely appropriate and that the concept of context-dependent onco-suppressors may be more extensive than previously recognised. No significant enrichment of TPGs within regions of frequent genomic gain was seen but TSGs were significantly enriched within regions of frequent genomic loss. It is suggested that loss of the FHIT gene may be a driver of NPC tumourigenesis. Notwithstanding the association of TSGs with regions of genomic loss, on a gene by gene basis and excepting homozygous deletions and high-level amplification, there is very little correlation between chromosomal copy number aberrations and expression levels of TSGs and TPGs in NPC.
Collapse
Affiliation(s)
- Chunfang Hu
- School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Wenbin Wei
- School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Xiaoyi Chen
- School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom
- Department of Pathology, Guangdong Medical College, Zhanjiang, Guangdong, China
| | - Ciaran B. Woodman
- School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Yunhong Yao
- School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom
- Department of Pathology, Guangdong Medical College, Zhanjiang, Guangdong, China
| | - John M. Nicholls
- Department of Pathology, University of Hong Kong, Hong Kong, China
| | - Irène Joab
- UMR542 Inserm-Université Paris Sud, Villejuif, France
| | - Sim K. Sihota
- School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Jian-Yong Shao
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Centre, Guangzhou, China
| | - K. Dalia Derkaoui
- Laboratoire de Biologie du Développement et de la Différenciation, Faculté des Sciences, Université d’Oran, Oran, Algeria
| | - Aicha Amari
- ORL Centre Hospitalier et Universitaire, Oran, Algeria
| | | | - Andrew I. Bell
- School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Paul G. Murray
- School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom
| | | | - Lawrence S. Young
- School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom
| | - John R. Arrand
- School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom
- * E-mail:
| |
Collapse
|
|
9
|
Wang Y, Huang JW, Li M, Cavenee WK, Mitchell PS, Zhou X, Tewari M, Furnari FB, Taniguchi T. MicroRNA-138 modulates DNA damage response by repressing histone H2AX expression. Mol Cancer Res 2011; 9:1100-11. [PMID: 21693595 DOI: 10.1158/1541-7786.mcr-11-0007] [Citation(s) in RCA: 121] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Precise regulation of DNA damage response is crucial for cellular survival after DNA damage, and its abrogation often results in genomic instability in cancer. Phosphorylated histone H2AX (γH2AX) forms nuclear foci at sites of DNA damage and facilitates DNA damage response and repair. MicroRNAs (miRNA) are short, nonprotein-encoding RNA molecules, which posttranscriptionally regulate gene expression by repressing translation of and/or degrading mRNA. How miRNAs modulate DNA damage response is largely unknown. In this study, we developed a cell-based screening assay using ionizing radiation (IR)-induced γH2AX foci formation in a human osteosarcoma cell line, U2OS, as the readout. By screening a library of human miRNA mimics, we identified several miRNAs that inhibited γH2AX foci formation. Among them, miR-138 directly targeted the histone H2AX 3'-untranslated region, reduced histone H2AX expression, and induced chromosomal instability after DNA damage. Overexpression of miR-138 inhibited homologous recombination and enhanced cellular sensitivity to multiple DNA-damaging agents (cisplatin, camptothecin, and IR). Reintroduction of histone H2AX in miR-138 overexpressing cells attenuated miR-138-mediated sensitization to cisplatin and camptothecin. Our study suggests that miR-138 is an important regulator of genomic stability and a potential therapeutic agent to improve the efficacy of radiotherapy and chemotherapy with DNA-damaging agents.
Collapse
Affiliation(s)
- Yemin Wang
- Howard Hughes Medical Institute, Division of Human Biology, University of Washington, Seattle, Washington, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
10
|
Daneshpour MS, Alfadhli S, Houshmand M, Zeinali S, Hedayati M, Zarkesh M, Azizi F. Allele frequency distribution for D11S1304, D11S1998, and D11S934 and metabolic syndrome in TLGS. EUR J LIPID SCI TECH 2010. [DOI: 10.1002/ejlt.201000340] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Maryam Sadat Daneshpour
- Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti university of Medical Science, Tehran, Iran
| | - Suad Alfadhli
- Faculty of Allied Health Sciences, Department of Medical Laboratory Sciences, Kuwait University, Kuwait
| | - Massoud Houshmand
- Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
| | - Sirous Zeinali
- Biotechnology Research Centre, Pasteur Institute of Iran, Teheran, Iran
| | - Mehdi Hedayati
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti university of Medical Science, Tehran, Iran
| | - Maryam Zarkesh
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti university of Medical Science, Tehran, Iran
| | - Fereidoun Azizi
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti university of Medical Science, Tehran, Iran
| |
Collapse
|
|
11
|
Lai PS, Pai CL, Peng CL, Shieh MJ, Berg K, Lou PJ. Enhanced cytotoxicity of saporin by polyamidoamine dendrimer conjugation and photochemical internalization. J Biomed Mater Res A 2008; 87:147-55. [DOI: 10.1002/jbm.a.31760] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
|
|
12
|
Abstract
Nasopharyngeal carcinoma (NPC) is a prevalent tumour in southern China and southeast Asia, particularly in the Cantonese population, where its incidence has remained high for decades. Recent studies have demonstrated that the aetiology of NPC is complex, involving multiple factors including genetic susceptibility, infection with the Epstein-Barr virus (EBV) and exposure to chemical carcinogens. During development of the disease, viral infection and multiple somatic genetic and epigenetic changes synergistically disrupt normal cell function, thus contributing to NPC pathogenesis. NPC is highly radiosensitive and chemosensitive, but treatment of patients with locoregionally advanced disease remains problematic. New biomarkers for NPC, including EBV DNA copy number or methylation of multiple tumour suppressor genes, which can be detected in serum and nasopharyngeal brushings, have been developed for the molecular diagnosis of this tumour. Meanwhile, new therapeutic strategies such as intensity-modulated radiation therapy and immuno- and epigenetic therapies might lead to more specific and effective treatments.
Collapse
Affiliation(s)
- Qian Tao
- Sir YK Pao Centre for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute, Chinese University of Hong Kong, Shatin, Hong Kong.
| | | |
Collapse
|
|
13
|
Shih-Hsin Wu L. Construction of evolutionary tree models for nasopharyngeal carcinoma using comparative genomic hybridization data. ACTA ACUST UNITED AC 2006; 168:105-8. [PMID: 16843099 DOI: 10.1016/j.cancergencyto.2006.02.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2005] [Accepted: 02/24/2006] [Indexed: 11/20/2022]
Abstract
Nasopharyngeal carcinoma (NPC) is a malignancy associated with remarkable racial and geographic factors. The development and progression of NPC may involve the accumulation of multiple genetic alterations over a long time. For understanding the putative order of genetic alteration in NPC tumorigenesis, we used evolutionary tree models (branching and distance-based tree models) to analyze comparative genomic hybridization (CGH) data of previously published NPC cases (n = 103). Consistent loss of 3p for both tree models was an important early event in NPC progression. Chromosome 12 gain was another important early event, and may represent a subclass different from 3p- derived subclasses of NPC. The tree models also suggested that at least two subclasses of 3p- derived NPC, one marked by 1q+, 9p-, and 13q- and the other marked by 14q-, 16q-, 9q-, and 1p-.
Collapse
Affiliation(s)
- Lawrence Shih-Hsin Wu
- Research Development Division, Vita Genomics Inc., 7 Fl., No. 6 Section 1 Jungshing Road, Wugu Shiang, Taipei County, 248 Taiwan.
| |
Collapse
|
|
14
|
Xiao YP, Wu DY, Xu L, Xin Y. Loss of heterozygosity and microsatellite instabilities of fragile histidine triad gene in gastric carcinoma. World J Gastroenterol 2006; 12:3766-9. [PMID: 16773697 PMCID: PMC4087473 DOI: 10.3748/wjg.v12.i23.3766] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect the loss of heterozygosity (LOH) and microsatellite instabilities (MSI) of fragile histidine triad (FHIT) gene in gastric carcinoma and to study their association with the clinical pathological characteristics of gastric carcinoma.
METHODS: LOH and MSI of FHIT gene were detected at four microsatellite loci D3Sl3H, D3S4l03, D3Sl48l and D3S1234 using PCR in matched normal and cancerous tissues from 50 patients with primary gastric cancer.
RESULTS: The average frequency of LOH and MSI of FHIT gene in gastric cancer was 32.4% and 26.4% respectively. LOH and MSI of FHIT gene in gastric cancer had no association with histological, Borrmann, and Lauren’s classification. LOH of FHIT gene in gastric cancer was related to invasive depth. The frequency of FHIT LOH in gastric cancer with serosa-penetration was obviously higher than that in gastric cancer without serosa-penetration (73.5% vs 37.5%, P < 0.05). MSI of FHIT gene in gastric cancer was associated with the lymph node metastasis. The frequency of MSI in gastric cancer without lymph node metastasis was significantly higher than that in gastric cancer with lymph node metastasis (66.7% vs 34.3%, P < 0.05).
CONCLUSION: LOH of FHIT gene is correlated with invasive depth of gastric carcinoma. MSI of FHIT gene is correlated with lymph node metastases. LOH and MSI of FHIT gene play an important role in carcinogenesis of gastric cancer.
Collapse
Affiliation(s)
- Yu-Ping Xiao
- Cancer Insititute, No.1 Hospital of China Medical University, Shenyang, Liaoning Province
| | | | | | | |
Collapse
|
|
15
|
Li X, Wang E, Zhao YD, Ren JQ, Jin P, Yao KT, Marincola FM. Chromosomal imbalances in nasopharyngeal carcinoma: a meta-analysis of comparative genomic hybridization results. J Transl Med 2006; 4:4. [PMID: 16423296 PMCID: PMC1403800 DOI: 10.1186/1479-5876-4-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2005] [Accepted: 01/19/2006] [Indexed: 12/02/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a highly prevalent disease in Southeast Asia and its prevalence is clearly affected by genetic background. Various theories have been suggested for its high incidence in this geographical region but to these days no conclusive explanation has been identified. Chromosomal imbalances identifiable through comparative genomic hybridization may shed some light on common genetic alterations that may be of relevance to the onset and progression of NPC. Review of the literature, however, reveals contradictory results among reported findings possibly related to factors associated with patient selection, stage of disease, differences in methodological details etc. To increase the power of the analysis and attempt to identify commonalities among the reported findings, we performed a meta-analysis of results described in NPC tissues based on chromosomal comparative genomic hybridization (CGH). This meta-analysis revealed consistent patters in chromosomal abnormalities that appeared to cluster in specific "hot spots" along the genome following a stage-dependent progression.
Collapse
Affiliation(s)
- Xin Li
- Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA
- Department of pathology and Cancer research Institute, College of Basic Medicine, Southern Medical University, Guangzhou 510515, Guangdong Province, PR. China
| | - Ena Wang
- Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ying-dong Zhao
- Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jia-Qiang Ren
- Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ping Jin
- Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Kai-Tai Yao
- Department of pathology and Cancer research Institute, College of Basic Medicine, Southern Medical University, Guangzhou 510515, Guangdong Province, PR. China
| | - Francesco M Marincola
- Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA
| |
Collapse
|
|
16
|
Xiao YP, Han CB, Mao XY, Li JY, Xu L, Ren CS, Xin Y. Relationship between abnormality of FHIT gene and EBV infection in gastric cancer. World J Gastroenterol 2005; 11:3212-6. [PMID: 15929169 PMCID: PMC4316050 DOI: 10.3748/wjg.v11.i21.3212] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the aberrant expression of fragile histidine triad (FHIT) gene and protein in gastric cancer, and to evaluate the role of FHIT gene and the relationship between FHIT gene and EBV infection in gastric carcinogenesis.
METHODS: FHIT transcripts were detected by nested RT-PCR in 30 cases of gastric cancer and their products were sequenced. FHIT protein was detected by Western blot. EBV infection was detected by PCR method in 50 cases of gastric cancer.
RESULTS: The wild type transcripts were detected in all 30 matched normal tissues of gastric cancer. Aberrant transcripts were found in 11/30 (36.7%) gastric cancerous tissues. Sequencing analysis of the aberrant fragments found an RT-PCR product missing exons 5-7 in one case of gastric cancer, and another product missing exons 4-7. Four of ten (40.0%) cases of primary gastric cancer showed absent or decreased expression of FHIT protein as compared with their matched normal tissues. EBV was detected in 5/50 (10%) gastric cancers, among which 4/5 (80%) had aberrant transcripts of FHIT gene.
CONCLUSION: Loss of FHIT gene or FHIT protein plays an important role in carcinogenesis, development and progression of gastric cancer. EBV infection might influence carcinogenesis of gastric cancer by inducing the abnormality of FHIT gene.
Collapse
Affiliation(s)
- Yu-Ping Xiao
- Cancer Institute, the First Hospital, China Medical University, Shenyang 110001, Liaoning Province, China
| | | | | | | | | | | | | |
Collapse
|
|
17
|
Lee YC, Wu CT, Shih JY, Jou YS, Chang YL. Frequent allelic deletion at the FHIT locus associated with p53 overexpression in squamous cell carcinoma subtype of Taiwanese non-small-cell lung cancers. Br J Cancer 2004; 90:2378-83. [PMID: 15150628 PMCID: PMC2409530 DOI: 10.1038/sj.bjc.6601778] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
The fragile histidine triad (FHIT) gene, encompassing the FRA3B fragile site at chromosome 3p14.2, is a tumour suppressor gene involved in different tumour types including non-small-cell lung cancers (NSCLCs). In the current study, we examined for allelic deletion at the FHIT locus in 58 primary and microdissected NSCLCs, for which a clinicopathologic profile was available. We found a loss of 87.7% in heterozygosity (LOH) frequency at one or more microsatellite markers (D3S1289, D3S2408, D3S1766, D3S1312, D3S1600). Allelic deletion of D3S1766 was related to tumour histology in 10 of 11 squamous cell carcinomas (90.9%) displaying LOH compared with nine of 17 adenocarcinomas (52.9%; P=0.049). Besides, in the subset of adenocarcinomas, a higher rate of LOH at D3S1289 was observed in male (six out of eight, 75%) than in female patients (four out of 17, 23.5%; P=0.028). However, FHIT LOH was not correlated overall with a variety of clinical parameters including sex, smoking status, staging, lymph node metastasis and survival. These results indicated that the high frequency of FHIT gene disruption was important in the development of both squamous cell carcinomas and adenocarcinomas. Furthermore, there was no association between LOH at FHIT and protein expression, suggesting the presence of complex mechanisms of Fhit inactivation. On the other hand, the association between FHIT LOH and p53 protein overexpression assessment reached statistical significance (P=0.026), implying that common alterations affect the two genes in tumour progression.
Collapse
Affiliation(s)
- Y-C Lee
- Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan
| | - C-T Wu
- Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan
| | - J-Y Shih
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan
| | - Y-S Jou
- Division of Molecular and Genomic Medicine, National Health Research Institutes, Taipei, Taiwan
| | - Y-L Chang
- Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan
- 6F-1, 99, Section 3, Roosevelt Road, Taipei 100, Taiwan. E-mail:
| |
Collapse
|
|
18
|
Jou YS, Lee CS, Chang YH, Hsiao CF, Chen CF, Chao CC, Wu LSH, Yeh SH, Chen DS, Chen PJ. Clustering of minimal deleted regions reveals distinct genetic pathways of human hepatocellular carcinoma. Cancer Res 2004; 64:3030-6. [PMID: 15126338 DOI: 10.1158/0008-5472.can-03-2320] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Systematic scan and statistical analysis of loss of heterozygosity (LOH) has been widely used to define chromosomal aberrations in various cancers for cloning of tumor suppressor genes and for development of prognostic markers. However, the establishment of novel strategies is needed, so that the nonrandom but heterogeneous chromosomal aberration data could provide significant insights into our understanding of molecular pathogenesis of cancers. After comprehensive allelotyping of recurrent allelic losses with 441 highly informative microsatellite markers and overlapping LOH regions on human hepatocellular carcinoma (HCC) chromosomes, 33 minimal deleted regions (MDRs) were revealed. Five and 15 of the 33 MDRs have physical intervals in less than 5 and 10 Mb, respectively, with the smallest MDR9p1 of 2.2 Mb located at 9p21.3-p21.2. Statistical and Kaplan-Meier survival analysis revealed a significant association between the loss of MDR15q1 (15q21.1-q22.2) and the HCC patient survival (adjusted P = 0.033). After cluster analysis of 33 MDRs that represented LOH profiles of each HCC tissue based on clinicopathological features and p53 mutations, two major genetic pathways, low-stage and advanced-stage HCC, were uncovered based on high concordance of MDR clusters. We propose that the definition of genome-wide MDRs on the cancer genome not only narrows down the location of existing tumor suppressor genes to facilitate positional candidate cloning and develop potential prognostic markers after statistical association of MDRs with clinicopathological features but also dissects genetic interactions and pathways of chromosomal aberrations in tumorigenesis.
Collapse
Affiliation(s)
- Yuh-Shan Jou
- Division of Molecular and Genomic Medicines, National Health Research Institute, Taipei, Taiwan
| | | | | | | | | | | | | | | | | | | |
Collapse
|