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Ou ZY, Wang K, Shen WW, Deng G, Xu YY, Wang LF, Zai ZY, Ling YA, Zhang T, Peng XQ, Chen FH. Oncogenic FLT3 internal tandem duplication activates E2F1 to regulate purine metabolism in acute myeloid leukaemia. Biochem Pharmacol 2023; 210:115458. [PMID: 36803956 DOI: 10.1016/j.bcp.2023.115458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 01/28/2023] [Accepted: 02/13/2023] [Indexed: 02/19/2023]
Abstract
Oncogene FLT3 internal tandem duplication (FLT3-ITD) mutation accounts for 30 % of acute myeloid leukaemia (AML) cases and induces transformation. Previously, we found that E2F transcription factor 1 (E2F1) was involved in AML cell differentiation. Here, we reported that E2F1 expression was aberrantly upregulated in AML patients, especially in AML patients carrying FLT3-ITD. E2F1 knockdown inhibited cell proliferation and increased cell sensitivity to chemotherapy in cultured FLT3-ITD-positive AML cells. E2F1-depleted FLT3-ITD+ AML cells lost their malignancy as shown by the reduced leukaemia burden and prolonged survival in NOD-PrkdcscidIl2rgem1/Smoc mice receiving xenografts. Additionally, FLT3-ITD-driven transformation of human CD34+ hematopoietic stem and progenitor cells was counteracted by E2F1 knockdown. Mechanistically, FLT3-ITD enhanced the expression and nuclear accumulation of E2F1 in AML cells. Further study using chromatin immunoprecipitation-sequencing and metabolomics analyses revealed that ectopic FLT3-ITD promoted the recruitment of E2F1 on genes encoding key enzymatic regulators of purine metabolism and thus supported AML cell proliferation. Together, this study demonstrates that E2F1-activated purine metabolism is a critical downstream process of FLT3-ITD in AML and a potential target for FLT3-ITD+ AML patients.
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Affiliation(s)
- Zi-Yao Ou
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Ke Wang
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Wen-Wen Shen
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Ge Deng
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Ya-Yun Xu
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Long-Fei Wang
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Zhuo-Yan Zai
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Yi-An Ling
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Tao Zhang
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Xiao-Qing Peng
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
| | - Fei-Hu Chen
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China.
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Ni YL, Chien PJ, Hsieh HC, Shen HT, Lee HT, Chen SM, Chang WW. Disulfiram/Copper Suppresses Cancer Stem Cell Activity in Differentiated Thyroid Cancer Cells by Inhibiting BMI1 Expression. Int J Mol Sci 2022; 23:13276. [PMID: 36362068 PMCID: PMC9654490 DOI: 10.3390/ijms232113276] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/27/2022] [Accepted: 10/30/2022] [Indexed: 11/06/2022] Open
Abstract
Differentiated thyroid carcinomas (DTCs), which have papillary and follicular types, are common endocrine malignancies worldwide. Cancer stem cells (CSCs) are a particular type of cancer cells within bulk tumors involved in cancer initiation, drug resistance, and metastasis. Cells with high intracellular aldehyde hydrogenase (ALDH) activity are a population of CSCs in DTCs. Disulfiram (DSF), an ALDH inhibitor used for the treatment of alcoholism, reportedly targets CSCs in various cancers when combined with copper. This study reported for the first time that DSF/copper can inhibit the proliferation of papillary and follicular DTC lines. DSF/copper suppressed thyrosphere formation, indicating the inhibition of CSC activity. Molecular mechanisms of DSF/copper involved downregulating the expression of B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and cell cycle-related proteins, including cyclin B2, cyclin-dependent kinase (CDK) 2, and CDK4, in a dose-dependent manner. BMI1 overexpression diminished the inhibitory effect of DSF/copper in the thyrosphere formation of DTC cells. BMI1 knockdown by RNA interference in DTC cells also suppressed the self-renewal capability. DSF/copper could inhibit the nuclear localization and transcriptional activity of c-Myc and the binding of E2F1 to the BMI1 promoter. Overexpression of c-Myc or E2F1 further abolished the inhibitory effect of DSF/copper on BMI1 expression, suggesting that the suppression of c-Myc and E2F1 by DSF/copper was involved in the downregulation of BMI1 expression. In conclusion, DSF/copper targets CSCs in DTCs by inhibiting c-Myc- or E2F1-mediated BMI1 expression. Therefore, DSF is a potential therapeutic agent for future therapy in DTCs.
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Affiliation(s)
- Yung-Lun Ni
- Department of Pulmonary Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung City 427213, Taiwan
| | - Peng-Ju Chien
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung City 402306, Taiwan
| | - Hung-Chia Hsieh
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung City 402306, Taiwan
| | - Huan-Ting Shen
- Department of Pulmonary Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung City 427213, Taiwan
| | - Hsueh-Te Lee
- Institute of Anatomy & Cell Biology, National Yang Ming Chiao Tung University, Taipei City 112304, Taiwan
| | - Shih-Ming Chen
- Bachelor Program in Health Care and Social Work for Indigenous Students, Providence University, Taichung City 433303, Taiwan
| | - Wen-Wei Chang
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung City 402306, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung City 402306, Taiwan
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Yuan J, Song Y, Pan W, Li Y, Xu Y, Xie M, Shen Y, Zhang N, Liu J, Hua H, Wang B, An C, Yang M. LncRNA SLC26A4-AS1 suppresses the MRN complex-mediated DNA repair signaling and thyroid cancer metastasis by destabilizing DDX5. Oncogene 2020; 39:6664-6676. [PMID: 32939012 DOI: 10.1038/s41388-020-01460-3] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 09/04/2020] [Indexed: 02/06/2023]
Abstract
Lymph node metastasis is the major adverse feature for recurrence and death of thyroid cancer patients. To identify lncRNAs involved in thyroid cancer metastasis, we systemically screened differentially expressed lncRNAs in lymph node metastasis, thyroid cancer, and normal tissues via RNAseq. We found that lncRNA SLC26A4-AS1 was continuously, significantly down-regulated in normal tissues, thyroid cancer, and lymph node metastasis specimens. Low SLC26A4-AS1 levels in tissues were significantly associated with poor prognosis of thyroid cancer patients. LncRNA SLC26A4-AS1 markedly inhibited migration, invasion, and metastasis capability of cancer cells in vitro and in vivo. Intriguingly, SLC26A4-AS1 could simultaneously interact with DDX5 and the E3 ligase TRIM25, which promoting DDX5 degradation through the ubiquitin-proteasome pathway. In particular, SLC26A4-AS1 inhibited expression of multiple DNA double-strand breaks (DSBs) repair genes, especially genes coding proteins in the MRE11/RAS50/NBS1 (MRN) complex. Enhanced interaction between DDX5 and transcriptional factor E2F1 due to silencing of SLC26A4-AS1 promoted binding of the DDX5-E2F1 complex at promoters of the MRN genes and, thus, stimulate the MRN/ATM dependent DSB signaling and thyroid cancer metastasis. Our study uncovered new insights into the biology driving thyroid cancer metastasis and highlights potentials of lncRNAs as future therapeutic targets again cancer metastasis.
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Affiliation(s)
- Jupeng Yuan
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yemei Song
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Wenting Pan
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yankang Li
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yeyang Xu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Mengyu Xie
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yue Shen
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Nasha Zhang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Jiandong Liu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Hui Hua
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Bowen Wang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Changming An
- Department of Head and Neck Surgery, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
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Al-Hashimi A, Venugopalan V, Sereesongsaeng N, Tedelind S, Pinzaru AM, Hein Z, Springer S, Weber E, Führer D, Scott CJ, Burden RE, Brix K. Significance of nuclear cathepsin V in normal thyroid epithelial and carcinoma cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118846. [PMID: 32910988 DOI: 10.1016/j.bbamcr.2020.118846] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 08/29/2020] [Indexed: 12/11/2022]
Abstract
Altered expression and/or localization of cysteine cathepsins is believed to involve in thyroid diseases including cancer. Here, we examined the localization of cathepsins B and V in human thyroid tissue sections of different pathological conditions by immunolabeling and morphometry. Cathepsin B was mostly found within endo-lysosomes as expected. In contrast, cathepsin V was detected within nuclei, predominantly in cells of cold nodules, follicular and papillary thyroid carcinoma tissue, while it was less often detected in this unusual localization in hot nodules and goiter tissue. To understand the significance of nuclear cathepsin V in thyroid cells, this study aimed to establish a cellular model of stable nuclear cathepsin V expression. As representative of a specific form lacking the signal peptide and part of the propeptide, N-terminally truncated cathepsin V fused to eGFP recapitulated the nuclear localization of endogenous cathepsin V throughout the cell cycle in Nthy-ori 3-1 cells. Interestingly, the N-terminally truncated cathepsin V-eGFP was more abundant in the nuclei during S phase. These findings suggested a possible contribution of nuclear cathepsin V forms to cell cycle progression. Indeed, we found that N-terminally truncated cathepsin V-eGFP expressing cells were more proliferative than those expressing full-length cathepsin V-eGFP or wild type controls. We conclude that a specific molecular form of cathepsin V localizes to the nucleus of thyroid epithelial and carcinoma cells, where it might involve in deregulated pathways leading to hyperproliferation. These findings highlight the necessity to better understand cathepsin trafficking in health and disease. In particular, cell type specificity of mislocalization of cysteine cathepsins, which otherwise act in a functionally redundant manner, seems to be important to understand their non-canonical roles in cell cycle progression.
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Affiliation(s)
- Alaa Al-Hashimi
- Department of Life Sciences and Chemistry, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany
| | - Vaishnavi Venugopalan
- Department of Life Sciences and Chemistry, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany
| | | | - Sofia Tedelind
- Department of Life Sciences and Chemistry, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany
| | - Alexandra M Pinzaru
- Department of Life Sciences and Chemistry, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany
| | - Zeynep Hein
- Department of Life Sciences and Chemistry, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany
| | - Sebastian Springer
- Department of Life Sciences and Chemistry, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany
| | - Ekkehard Weber
- Institute of Physiological Chemistry, Martin Luther University Halle-Wittenberg, Hollystrasse 1, D-06114 Halle-Saale, Germany
| | - Dagmar Führer
- Universität Duisburg-Essen, Universitätsklinikum Essen (AöR), Klinik für Endokrinologie, Diabetologie und Stoffwechsel, Hufeland Strasse 55, D-45177 Essen, Germany
| | - Christopher J Scott
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Roberta E Burden
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Klaudia Brix
- Department of Life Sciences and Chemistry, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany.
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Pan Z, Li L, Qian Y, Ge X, Hu X, Zhang Y, Ge M, Huang P. The differences of regulatory networks between papillary and anaplastic thyroid carcinoma: an integrative transcriptomics study. Cancer Biol Ther 2020; 21:853-862. [PMID: 32887540 DOI: 10.1080/15384047.2020.1803009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Unlike papillary thyroid cancer (PTC), anaplastic thyroid carcinoma (ATC) is extremely aggressive and rapidly lethal without effective therapies. However, the differences of master regulators and regulatory networks between PTC and ATC remain unclear. Methods: Three representative datasets comprising 32 ATC, 69 PTC, and 78 normal thyroid tissue samples were combined to form a large dataset. Differentially expressed genes (DEGs) were identified and enriched by limma package and gene set enrichment analysis, respectively. Subsequently, protein-protein interaction network and transcription factors (TFs) regulatory network were constructed to identify gene modules and master regulators. Further, master regulators were validated by RT-PCR and western blot. Finally, Kaplan-Meier plotter was applied to evaluate their prognostic values. Results: A total of 560 DEGs were identified as ATC-specific malignant signature. The regulatory network analysis showed that nine master regulators were significantly correlated with three gene modules and potentially regulated the expression of DEGs in three gene modules, respectively. Furthermore, CREB3L1, FOSL2, E2F1 and CAT were significantly associated with overall survival of thyroid cancer patients. FOXM1, FOSL2, MYBL2, AVEN and E2F1 were unfavorable factors of recurrence-free survival (RFS), while CAT was a favorable factor of RFS. RT-PCR and western blot confirmed that six TFs were obviously up-regulated in ATC tissues/cell line as compared with PTC and normal thyroid tissues/cell lines, respectively. In addition, 19 ATC-specific kinases were identified to illustrate the potential post-translational modification. Conclusions: Our findings provide a comprehensive insight into malignant mechanism of ATC, which may indicate their value in the future investigation of ATC.
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Affiliation(s)
- Zongfu Pan
- Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College , Hangzhou, China
| | - Lu Li
- Department of Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University , Hangzhou, China
| | - Yangyang Qian
- Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College , Hangzhou, China.,Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Zhejiang Cancer Hospital , Hangzhou, China
| | - Xinyang Ge
- Student Council Blood Drive Committee, Heartland Christian School , Columbiana, OH, USA
| | - Xiaoping Hu
- Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College , Hangzhou, China
| | - Yiwen Zhang
- Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College , Hangzhou, China
| | - Minghua Ge
- Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College , Hangzhou, China.,Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Zhejiang Cancer Hospital , Hangzhou, China
| | - Ping Huang
- Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College , Hangzhou, China
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Mizutani K, Miyamoto S, Nagahata T, Konishi N, Emi M, Onda M. Upregulation and Overexpression of DVL1, the Human Counterpart of the Drosophila Dishevelled Gene, in Prostate Cancer. TUMORI JOURNAL 2019; 91:546-51. [PMID: 16457155 DOI: 10.1177/030089160509100616] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Aims and Background The Wnt/beta-catenin signaling pathway is one of the main carcinogenic mechanisms in human malignancies including prostate cancer. Recently, the DVL1 gene was identified as a middle molecule of the Wnt/beta-catenin signaling pathway. In addition, alterations of the DVL1 gene have been reported in breast and cervical cancer. The abnormality of beta-catenin in prostate cancer has been well studied, so the examination of the DVL1 gene in prostate cancer is appealing. Methods We investigated DVL1 messenger RNA alterations by semiquantitative PCR (SQ-PCR) in 20 primary prostate cancers and assessed the protein expression by immunohistochemical analysis in the same samples. In addition, DVL1 and beta-catenin protein expression was evaluated with a new validated set of 20 prostate cancers. Results SQ-PCR revealed significant overexpression of DVL1 in prostate cancer (65%). Upregulation of the DVL1 gene product in prostate cancer was confirmed by immunostaining. With SQ-PCR and immunostaining, none of the cases showed underexpression or downregulation of DVL1. In addition, the data showed correlations between DVL1 mRNA and protein expression. Interestingly, the expression level of DVL1 increased with worsening histological grade. In addition, a correlation between DVL1 expression and beta-catenin expression was confirmed. Conclusions DVL1 was overexpressed in prostate cancer and its overexpression might be related to prostate cancer progression through the Wnt/beta-catenin pathway.
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Affiliation(s)
- Kazunori Mizutani
- Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, Kawasaki, Japan
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A Synergistic Anti-Cancer Effect of Troglitazone and Lovastatin in a Human Anaplastic Thyroid Cancer Cell Line and in a Mouse Xenograft Model. Int J Mol Sci 2018; 19:ijms19071834. [PMID: 29932104 PMCID: PMC6073567 DOI: 10.3390/ijms19071834] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 06/20/2018] [Accepted: 06/20/2018] [Indexed: 01/10/2023] Open
Abstract
Anaplastic thyroid cancer (ATC) is a malignant subtype of thyroid cancers and its mechanism of development remains inconclusive. Importantly, there is no effective strategy for treatment since ATC is not responsive to conventional therapies, including radioactive iodine therapy and thyroid-stimulating hormone suppression. Here, we report that a combinational approach consisting of drugs designed for targeting lipid metabolism, lovastatin (an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, HMGCR) and troglitazone (an agonist of peroxisome proliferator-activated receptor gamma, PPARγ), exhibits anti-proliferation in cell culture systems and leads to tumor regression in a mouse xenograft model. The composition contains a sub-lethal concentration of both drugs and exhibits low toxicity to certain types of normal cells. Our results support a hypothesis that the inhibitory effect of the combination is partly through a cell cycle arrest at G0/G1 phase, as evidenced by the induction of cyclin-dependent kinase inhibitors, p21cip and p27kip, and the reduction of hyperphosphorylated retinoblastoma protein (pp-Rb)-E2F1 signaling. Therefore, targeting two pathways involved in lipid metabolism may provide a new direction for treating ATC.
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Zhao Y, Wang H, Wu C, Yan M, Wu H, Wang J, Yang X, Shao Q. Construction and investigation of lncRNA-associated ceRNA regulatory network in papillary thyroid cancer. Oncol Rep 2018; 39:1197-1206. [PMID: 29328463 PMCID: PMC5802034 DOI: 10.3892/or.2018.6207] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2017] [Accepted: 12/20/2017] [Indexed: 12/12/2022] Open
Abstract
Increasing evidence has experimentally proved the competitive endogenous RNA (ceRNA) hypothesis that long non-coding RNA (lncRNA) can affect the expression of RNA targets by competitively combining microRNA (miRNA) via miRNA response elements. However, an extensive ceRNA network of thyroid carcinoma in a large cohort has not been evaluated. We analyzed the RNAseq and miRNAseq data of 348 cases of primary papillary thyroid cancer (PTC) patients with clinical information downloaded from The Cancer Genome Atlas (TCGA) project to search for potential biomarkers or therapeutic targets. A computational approach was applied to build an lncRNA-miRNA-mRNA regulatory network of PTC. In total, 780 lncRNAs were detected as collectively dysregulated lncRNAs in all 3 PTC variants compared with normal tissues (fold change >2 and false discovery rate <0.05). The interactions among 45 lncRNAs, 13 miRNAs and 86 mRNAs constituted a ceRNA network of PTC. Nine out of the 45 aberrantly expressed lncRNAs were related to the clinical features of PTC patients. However, the expression levels of 3 lncRNAs (LINC00284, RBMS3-AS1 and ZFX-AS1) were identified to be tightly correlated with the patients overall survival (log-rank, P<0.05). The present study identified a list of specific lncRNAs associated with PTC progression and prognosis. This complex ceRNA interaction network in PTC may provide guidance for better understanding the molecular mechanisms underlying PTC.
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Affiliation(s)
- Yangjing Zhao
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Hui Wang
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Chengjiang Wu
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Meina Yan
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Haojie Wu
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Jingzhe Wang
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Xinxin Yang
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Qixiang Shao
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
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Uzer H, Akyıldız H, Sözüer E, Akcan A, Öz B. Prognostic value of E2F1 in rectal cancer. Turk J Surg 2017; 33:180-184. [PMID: 28944330 DOI: 10.5152/turkjsurg.2017.3576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 05/25/2016] [Indexed: 11/22/2022]
Abstract
OBJECTIVE To evaluate whether E2F transcription factor 1 is a potential prognostic marker in patients with rectal cancer. MATERIAL AND METHODS Eighty-two patients who were treated with curative resection because of rectal cancer in the Erciyes University School of Medicine, Department of General Surgery were included in the study and analyzed retrospectively. Data were obtained from patient files, pathology reports, and hospital information system. Nuclear and cytoplasmic staining of E2F transcription factor 1 was performed for immunohistochemical analysis on paraffin-embedded and blocked tumor tissue samples of patients. The findings of the study were assessed with using IBM Statistical Package for Social Sciences Statistics 20. RESULT In the 5-year follow-up period, 34 (41.5%) patients were alive. Local recurrence was identified in 7 patients. According to E2F transcription factor 1 nuclear staining, the average survival rate in patients was 60% for strong nuclear staining and 28% for weak nuclear staining. There was significant statistical difference between groups according to their degree of nuclear staining (p=0.017). When the patients were evaluated according to cytoplasmic staining with E2F transcription factor 1, the average overall survival rate of patients with positive E2F transcription factor 1 cytoplasmic staining was 48.0±4.6% versus 55.9±7.9% for patients without staining (p=0.408). CONCLUSION The survival rates are higher in rectal cancer patients with strong immunohistochemical nuclear staining of E2F transcription factor 1.
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Affiliation(s)
- Hasan Uzer
- Department of General Surgery, Erciyes University School of Medicine, Kayseri, Turkey
| | - Hızır Akyıldız
- Department of General Surgery, Erciyes University School of Medicine, Kayseri, Turkey
| | - Erdoğan Sözüer
- Department of General Surgery, Erciyes University School of Medicine, Kayseri, Turkey
| | - Alper Akcan
- Department of General Surgery, Erciyes University School of Medicine, Kayseri, Turkey
| | - Bahadır Öz
- Department of General Surgery, Erciyes University School of Medicine, Kayseri, Turkey
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10
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Tcheandjieu C, Lesueur F, Sanchez M, Baron-Dubourdieu D, Guizard AV, Mulot C, Laurent-Puig P, Schvartz C, Truong T, Guenel P. Fine-mapping of two differentiated thyroid carcinoma susceptibility loci at 9q22.33 and 14q13.3 detects novel candidate functional SNPs in Europeans from metropolitan France and Melanesians from New Caledonia. Int J Cancer 2016; 139:617-27. [PMID: 26991144 DOI: 10.1002/ijc.30088] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 02/05/2016] [Accepted: 02/15/2016] [Indexed: 12/13/2022]
Abstract
Incidence of differentiated thyroid carcinoma varies considerably between countries and ethnic groups, with particularly high incidence rates in Melanesians of New Caledonia. Differentiated thyroid cancer (DTC) has a familial relative risk higher than other cancers, highlighting the contribution of inherited factors to the disease. Recently, genome-wide association studies (GWAS) identified several DTC susceptibility loci. The most robust associations were reported at loci 9q22 (rs965513 and rs1867277) and 14q13 (rs944289 and rs116909734). In this study, we performed a fine-mapping study of the two gene regions among Europeans and Melanesians from Metropolitan France and New Caledonia. We examined 81 single nucleotide polymorphisms (SNPs) at 9q22 and 561 SNPs at 14q13 in Europeans (625 cases/776 controls) and in Melanesians (244 cases/189 controls). The association with the four SNPs previously identified in GWAS was replicated in Europeans while only rs944289 was replicated in Melanesians. Among Europeans, we found that the two SNPs previously reported at 9q22 were not independently associated to DTC and that rs965513 was the predominant signal; at 14q13, we showed that the haplotype rs944289[C]-rs116909374[C]-rs999460[T] was significantly associated with DTC risk and that the association with rs116909374 differed by smoking status (p-interaction = 0.03). Among Melanesians, a new independent signal was observed at 14q13 for rs1755774 which is strongly correlated to rs2787423; this latter is potentially a functional variant. Significant interactions with parity (p < 0.05) and body mass index were observed for rs1755774 and rs2787423. This study contributed to a better characterization of the DTC loci 9q22 and 14q13 in Europeans and in Melanesians and has identified novel variants to be prioritized for further functional studies.
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Affiliation(s)
| | - Fabienne Lesueur
- Inserm, U900, Paris, France.,Institut Curie, Paris, France.,PSL Research University, Paris, France.,Mines ParisTech, Fontainebleau, France
| | - Marie Sanchez
- CESP, INSERM, Université Paris-Sud, Université Paris-Saclay, Villejuif, France
| | | | - Anne-Valerie Guizard
- Registre Général des tumeurs du Calvados, Centre François Baclesse, Caen, France.,U1086 Inserm-UCNB, Cancers and Prevention, Caen, France
| | - Claire Mulot
- Université Paris Descartes, Inserm UMR 5775 EPIGENETEC, Paris, France
| | | | - Claire Schvartz
- Centre de Lutte Contre le Cancer Jean GODINOT, Reims, France
| | - Therese Truong
- CESP, INSERM, Université Paris-Sud, Université Paris-Saclay, Villejuif, France
| | - Pascal Guenel
- CESP, INSERM, Université Paris-Sud, Université Paris-Saclay, Villejuif, France
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11
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Cong D, He M, Chen S, Liu X, Liu X, Sun H. Expression profiles of pivotal microRNAs and targets in thyroid papillary carcinoma: an analysis of The Cancer Genome Atlas. Onco Targets Ther 2015; 8:2271-7. [PMID: 26345235 PMCID: PMC4556042 DOI: 10.2147/ott.s85753] [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] [Indexed: 11/23/2022] Open
Abstract
In the present study, we analyzed microRNA (miRNA) and gene expression profiles using 499 papillary thyroid carcinoma (PTC) samples and 58 normal thyroid tissues obtained from The Cancer Genome Atlas database. A pivotal regulatory network of 18 miRNA and 16 targets was identified. Upregulated miRNAs (miR-222, miR-221, miR-146b, miR-181a/b/d, miR-34a, and miR-424) and downregulated miRNAs (miR-9-1, miR-138, miR-363, miR-20b, miR-195, and miR-152) were identified. Among them, the upregulation of miR-424 and downregulation of miR-363, miR-195, and miR-152 were not previously identified. The genes CCNE2 (also known as cyclin E2), E2F1, RARA, CCND1 (cyclin D1), RUNX1, ITGA2, MET, CDKN1A (p21), and COL4A1 were overexpressed, and AXIN2, TRAF6, BCL2, RARB, HSP90B1, FGF7, and PDGFRA were downregulated. Among them, CCNE2, COL4A1, TRAF6, and HSP90B1 were newly identified. Based on receiver operating characteristic curves, several miRNAs (miR-222, miR-221, and miR-34a) and genes (CCND1 and MET) were ideal diagnostic indicators, with sensitivities and specificities greater than 90%. The combination of inversely expressed miRNAs and targets improved diagnostic accuracy. In a clinical feature analysis, several miRNAs (miR-34a, miR-424, miR-20b, and miR-152) and genes (CCNE2, COL4A1, TRAF6, and HSP90B1) were associated with aggressive clinical features, which have not previously been reported. Our study not only identified a pivotal miRNA regulatory network associated with PTC but also provided evidence that miRNAs and target genes can be used as biomarkers in PTC diagnosis and clinical risk evaluation.
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Affiliation(s)
- Dan Cong
- Jilin Provincial Key Laboratory of Surgical Translational Medicine, Department of Thyroid and Parathyroid Surgery, People's Republic of China-Japan Union Hospital, Jilin University, Changchun, Jilin, People's Republic of China
| | - Mengzi He
- Key Laboratory of Radiobiology (Ministry of Health), School of Public Health, Jilin University, Changchun, Jilin, People's Republic of China
| | - Silin Chen
- Key Laboratory of Radiobiology (Ministry of Health), School of Public Health, Jilin University, Changchun, Jilin, People's Republic of China
| | - Xiaoli Liu
- Jilin Provincial Key Laboratory of Surgical Translational Medicine, Department of Thyroid and Parathyroid Surgery, People's Republic of China-Japan Union Hospital, Jilin University, Changchun, Jilin, People's Republic of China
| | - Xiaodong Liu
- Key Laboratory of Radiobiology (Ministry of Health), School of Public Health, Jilin University, Changchun, Jilin, People's Republic of China
| | - Hui Sun
- Jilin Provincial Key Laboratory of Surgical Translational Medicine, Department of Thyroid and Parathyroid Surgery, People's Republic of China-Japan Union Hospital, Jilin University, Changchun, Jilin, People's Republic of China
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12
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Lam SK, Li YY, Zheng CY, Leung LL, Ho JCM. E2F1 downregulation by arsenic trioxide in lung adenocarcinoma. Int J Oncol 2014; 45:2033-43. [PMID: 25174355 DOI: 10.3892/ijo.2014.2609] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 07/01/2014] [Indexed: 11/05/2022] Open
Abstract
Lung cancer is one of the most common cancers worldwide. Arsenic trioxide (ATO) has been approved by the US Food and Drug Administration for the treatment of acute promyelocytic leukemia. Nonetheless preliminary data have suggested potential activity of ATO in solid tumors including lung cancer. This study aimed to examine the underlying mechanisms of ATO in the treatment of lung adenocarcinoma. Using a panel of 7 lung adenocarcinoma cell lines, the effects of ATO treatment on cell viability, expression of E2F1 and its downstream targets, phosphatidylserine externalization, mitochondrial membrane depolarization and alteration of apoptotic/anti-apoptotic factors were studied. Tumor growth inhibition in vivo was investigated using a nude mouse xenograft model. ATO decreased cell viability with clinically achievable concentrations (8 µM) in all cell lines investigated. This was accompanied by reduced expression of E2F1, cyclin A2, skp2, c-myc, thymidine kinase and ribonucleotide reductase M1, while p-c-Jun was upregulated. Cell viability was significantly decreased with E2F1 knockdown. Treatment with ATO resulted in phosphatidylserine externalization in H23 cells and mitochondrial membrane depolarization in all cell lines, associated with truncation of Bid, downregulation of Bcl-2, upregulation of Bax and Bak, caspase-9 and -3 activation and PARP cleavage. Using the H358 xenograft model, the tumor growth was suppressed in the ATO treatment group during 8 days of treatment, associated with downregulation of E2F1 and upregulation of truncated Bid and cleaved caspase-3. In conclusion, ATO has potent in vitro and in vivo activity in lung adenocarcinoma, partially mediated through E2F1 downregulation and apoptosis.
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Affiliation(s)
- Sze-Kwan Lam
- Division of Respiratory Medicine, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China
| | - Yuan-Yuan Li
- Division of Respiratory Medicine, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China
| | - Chun-Yan Zheng
- Division of Respiratory Medicine, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China
| | - Leanne Lee Leung
- Division of Respiratory Medicine, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China
| | - James Chung-Man Ho
- Division of Respiratory Medicine, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China
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13
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Liu MY, Guo HP, Hong CQ, Peng HW, Yang XH, Zhang H. Up-regulation of nuclear receptor coactivator amplified in breast cancer-1 in papillary thyroid carcinoma correlates with lymph node metastasis. Clin Transl Oncol 2013; 15:947-52. [PMID: 23606350 DOI: 10.1007/s12094-013-1029-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2012] [Accepted: 03/14/2013] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Nuclear receptor coactivator amplified in breast cancer-1 (AIB1), a new oncogenic coactivator, is commonly overexpressed and amplified in variety of human cancers. However, the expression of AIB1 in papillary thyroid carcinoma (PTC), the major histologic type of thyroid cancer, and its clinical significance are still unclear. MATERIALS AND METHODS AIB1 expression in PTC was examined by immunohistochemistry using tissue microarrays comprised of 90 primary PTC, 46 matched lymph node, and 20 normal thyroid tissue specimens in this study. RESULTS In the normal thyroid specimens, AIB1 expression was either absent or at low levels. In contrast, AIB1 overexpression was detected in 50 of 83 (60.2 %) primary PTC specimens. Up-regulated AIB1 was evident in 39 of 46 (73.5 %) matched lymph nodes. Overexpression of AIB1 was observed more frequently in PTCs with lymph node metastasis [N1a/N1b, 39/46 (73.5 %)] versus PTCs without lymph node metastasis [N0, 14/34 (41.2 %)]. Furthermore, high-level AIB1 expression was only observed in the lymph node-positive specimens. Moreover, we found no correlation between AIB1 expression and ER expression in PTC tissues. CONCLUSIONS Our findings suggest that overexpression of AIB1 may be a biomarker for tumorigenesis and progression of PTC and may play an important role in its acquisition of a metastatic phenotype.
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Affiliation(s)
- M-Y Liu
- Department of Head and Neck Surgery, Cancer Hospital, Shantou University Medical College, Shantou, 515000, China
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14
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Xanthoulis A, Tiniakos DG. E2F transcription factors and digestive system malignancies: How much do we know? World J Gastroenterol 2013; 19:3189-3198. [PMID: 23745020 PMCID: PMC3671070 DOI: 10.3748/wjg.v19.i21.3189] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Revised: 02/08/2013] [Accepted: 03/29/2013] [Indexed: 02/06/2023] Open
Abstract
E2F family of transcription factors regulates various cellular functions related to cell cycle and apoptosis. Its individual members have traditionally been classified into activators and repressors, based on in vitro studies. However their contribution in human cancer is more complicated and difficult to predict. We review current knowledge on the expression of E2Fs in digestive system malignancies and its clinical implications for patient prognosis and treatment. E2F1, the most extensively studied member and the only one with prognostic value, exhibits a tumor-suppressing activity in esophageal, gastric and colorectal adenocarcinoma, and in hepatocellular carcinoma (HCC), whereas in pancreatic ductal adenocarcinoma and esophageal squamous cell carcinoma may function as a tumor-promoter. In the latter malignancies, E2F1 immunohistochemical expression has been correlated with higher tumor grade and worse patient survival, whereas in esophageal, gastric and colorectal adenocarcinomas is a marker of increased patient survival. E2F2 has only been studied in colorectal cancer, where its role is not considered significant. E2F4’s role in colorectal, gastric and hepatic carcinogenesis is tumor-promoting. E2F8 is strongly upregulated in human HCC, thus possibly contributing to hepatocarcinogenesis. Adenoviral transfer of E2F as gene therapy to sensitize pancreatic cancer cells for chemotherapeutic agents has been used in experimental studies. Other therapeutic strategies are yet to be developed, but it appears that targeted approaches using E2F-agonists or antagonists should take into account the tissue-dependent function of each E2F member. Further understanding of E2Fs’ contribution in cellular functions in vivo would help clarify their role in carcinogenesis.
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15
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Molina-Privado I, Jiménez-P R, Montes-Moreno S, Chiodo Y, Rodríguez-Martínez M, Sánchez-Verde L, Iglesias T, Piris MA, Campanero MR. E2F4 plays a key role in Burkitt lymphoma tumorigenesis. Leukemia 2012; 26:2277-85. [PMID: 22475873 DOI: 10.1038/leu.2012.99] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Sporadic Burkitt lymphoma (sBL) is a rapidly growing B-cell non-Hodgkin's lymphoma whose treatment requires highly aggressive therapies that often result severely toxic. Identification of proteins whose expression or function is deregulated in sBL and play a role in its formation could facilitate development of less toxic therapies. We have previously shown that E2F1 expression is deregulated in sBL. We have now investigated the mechanisms underlying E2F1 deregulation and found that the E2F sites in its promoter fail to repress its transcriptional activity in BL cells and that the transcriptional repressor E2F4 barely interacts with these sites. We also have found that E2F4 protein levels, but not those of its mRNA, are reduced in sBL cell lines relative to immortal B-cell lines. E2F4 protein expression is also decreased in 24 of 26 sBL tumor samples from patients compared with control tissues. Our data demonstrate that enforced E2F4 expression in BL cells not only diminishes E2F1 levels, but also reduces selectively the tumorigenic properties and proliferation of BL cells, while increasing their accumulation in G(2)/M. Our results therefore point to E2F4 as a target for developing novel and less toxic treatments for sBL.
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Affiliation(s)
- I Molina-Privado
- Department of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
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16
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Pützer BM, Steder M, Alla V. Predicting and preventing melanoma invasiveness: advances in clarifying E2F1 function. Expert Rev Anticancer Ther 2011; 10:1707-20. [PMID: 21080799 DOI: 10.1586/era.10.153] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Malignant melanoma of the skin is one of the most aggressive human cancers with increasing incidence, despite efforts to improve primary prevention. In particular, the prognosis of patients at late stages of the disease has not significantly improved in the last three decades, because systemic therapies have proven disappointing. Thus, metastatic melanoma continues to be a daunting clinical problem. The increasingly high rates of lethal outcome associated with advanced melanoma rely on the acquisition of invasiveness, early metastatic dissemination of tumor cells from their primary sites, and generation of chemoresistance as a consequence of alteration of key molecules involved in the regulation of cell survival. Thus far, extensive studies have been conducted to understand the molecular mechanisms that drive tumor progression, but the specific requirements underlying the aggressive behavior are still widely unknown. Understanding the determinants of this process is key to unveiling its dynamics, especially those that promote invasiveness, and may open new routes for the development of therapeutic strategies that control metastatic spread, and eventually the prevention of life-threatening metastases. Here, we review recent advances on molecular aspects, particularly of E2F1 transcription factor function, in the context of patient data, and discuss the implications for targeting melanoma cells when they begin to invade and metastasize.
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Affiliation(s)
- Brigitte M Pützer
- Department of Vectorology and Experimental Gene Therapy, Biomedical Research Center, University of Rostock Medical School, Schillingallee 69, 18057 Rostock, Germany.
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17
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Alla V, Engelmann D, Niemetz A, Pahnke J, Schmidt A, Kunz M, Emmrich S, Steder M, Koczan D, Pützer BM. E2F1 in melanoma progression and metastasis. J Natl Cancer Inst 2009; 102:127-33. [PMID: 20026813 DOI: 10.1093/jnci/djp458] [Citation(s) in RCA: 104] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Metastases are responsible for cancer deaths, but the molecular alterations leading to tumor progression are unclear. Overexpression of the E2F1 transcription factor is common in high-grade tumors that are associated with poor patient survival. To investigate the association of enhanced E2F1 activity with aggressive phenotype, we performed a gene-specific silencing approach in a metastatic melanoma model. Knockdown of endogenous E2F1 via E2F1 small hairpin RNA (shRNA) expression increased E-cadherin expression of metastatic SK-Mel-147 melanoma cells and reduced their invasive potential but not their proliferative activity. Although growth rates of SK-Mel-147 and SK-Mel-103 xenograft tumors expressing E2F1 shRNA or control shRNA were similar, mice implanted with cells expressing E2F1 shRNA had a smaller area of metastases per lung than control mice (n = 3 mice per group; 5% vs 46%, difference = 41%, 95% confidence interval = 15% to 67%; P = .01; one-way analysis of variance). We identified epidermal growth factor receptor as a direct target of E2F1 and demonstrated that inhibition of receptor signaling abrogates E2F1-induced invasiveness, emphasizing the importance of the E2F1-epidermal growth factor receptor interaction as a driving force in melanoma progression that may serve as a paradigm for E2F1-induced metastasis in other human cancers.
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Affiliation(s)
- Vijay Alla
- Department of Vectorology and Experimental Gene Therapy, Biomedical Research Center, University of Rostock, Rostock, Germany
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18
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Abstract
Anaplastic thyroid cancer (ATC) is a rare malignancy. While external beam radiation therapy has improved locoregional control, the median survival of approximately 4 months has not changed in more than half a century due to uncontrolled systemic metastases. The objective of this study was to review the literature in order to identify potential new strategies for treating this highly lethal cancer. PubMed searches were the principal source of articles reviewed. The molecular pathogenesis of ATC includes mutations in BRAF, RAS, catenin (cadherin-associated protein), beta 1, PIK3CA, TP53, AXIN1, PTEN, and APC genes, and chromosomal abnormalities are common. Several microarray studies have identified genes and pathways preferentially affected, and dysregulated microRNA profiles differ from differentiated thyroid cancers. Numerous proteins involving transcription factors, signaling pathways, mitosis, proliferation, cell cycle, apoptosis, adhesion, migration, epigenetics, and protein degradation are affected. A variety of agents have been successful in controlling ATC cell growth both in vitro and in nude mice xenografts. While many of these new compounds are in cancer clinical trials, there are few studies being conducted in ATC. With the recent increased knowledge of the many critical genes and proteins affected in ATC, and the extensive array of targeted therapies being developed for cancer patients, there are new opportunities to design clinical trials based upon tumor molecular profiling and preclinical studies of potentially synergistic combinatorial novel therapies.
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Affiliation(s)
- Robert C Smallridge
- Department of Internal Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA.
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19
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Libertini S, Iacuzzo I, Perruolo G, Scala S, Ieranò C, Franco R, Hallden G, Portella G. Bevacizumab increases viral distribution in human anaplastic thyroid carcinoma xenografts and enhances the effects of E1A-defective adenovirus dl922-947. Clin Cancer Res 2008; 14:6505-14. [PMID: 18927290 DOI: 10.1158/1078-0432.ccr-08-0200] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Anaplastic thyroid carcinoma is a prime target for innovative therapy because it represents one of the most lethal human neoplasms and is refractory to conventional treatments such as chemotherapy and radiotherapy. We have evaluated a novel therapeutic approach based on the oncolytic replication-selective adenovirus dl922-947. EXPERIMENTAL DESIGN The antitumor efficacies of the E1ADeltaCR2 (dl922-947) and DeltaE1B55K (dl1520) mutants were compared in human thyroid anaplastic carcinoma cells in culture and in xenografts in vivo. To enhance the effects of dl922-947, anaplastic thyroid carcinoma tumor xenografts were treated with dl922-947 in combination with bevacizumab. RESULTS We showed that the efficacy of dl922-947 exceeded that of dl1520 in all tested anaplastic thyroid carcinoma cells in vitro and in vivo. Furthermore, bevacizumab in combination with dl922-947 significantly reduced tumor growth compared with single treatments alone. Bevacizumab treatment significantly improved viral distribution in neoplastic tissues. CONCLUSIONS Our data showed that dl922-947 had a higher oncolytic activity compared with dl1520 in anaplastic thyroid carcinoma cell lines and might represent a better option for virotherapy of anaplastic thyroid carcinoma. Moreover, bevacizumab increased the oncolytic effects of dl922-947 by enhancing viral distribution in tumors. The results described herein encourage the use of the dl922-947 virus in combination with bevacizumab.
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Affiliation(s)
- Silvana Libertini
- Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita di Napoli, Naples, Italy
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20
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Poplawski P, Nauman A. Thyroid hormone - triiodothyronine - has contrary effect on proliferation of human proximal tubules cell line (HK2) and renal cancer cell lines (Caki-2, Caki-1) - role of E2F4, E2F5 and p107, p130. Thyroid Res 2008; 1:5. [PMID: 19014670 PMCID: PMC2583984 DOI: 10.1186/1756-6614-1-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2008] [Accepted: 10/13/2008] [Indexed: 11/26/2022] Open
Abstract
Background Triiodothyronine regulates proliferation acting as stimulator or inhibitor. E2F4 and E2F5 in complexes with pocket proteins p107 or p130 stop cells in G1, repressing transcription of genes important for cell cycle progression. p107 and p130 inhibits activity of cyclin/cdk2 complexes. Expression of all those proteins could be regulated by triiodothyronine. In clear cell renal cell carcinoma many disturbances in T3 signaling pathway was described, in that type of cancer also expression of some key G1 to S phase progression regulators was shown. Methods We investigated role of T3 and its receptors in regulation of proliferation of HK2, Caki-2, Caki-1 cell lines (cell counting, cytometric analysis of DNA content) and expression of thyroid hormone receptors, E2F4, E2F5, p107 and p130 (western blot and semi-quantitative real time PCR). Statistical analysis was performed using one-way ANOVA. Results and Conclusion We show that T3 inhibits proliferation of HK2, and stimulates it in Caki lines. Those differences are result of disturbed expression of TR causing improper regulation of E2F4, E2F5, p107 and p130 in cancer cells.
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Affiliation(s)
- Piotr Poplawski
- Department of Biochemistry and Molecular Biology, The Medical Centre of Postgraduate Education, Warsaw, Poland.
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21
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Latini FRM, Hemerly JP, Oler G, Riggins GJ, Cerutti JM. Re-expression of ABI3-binding protein suppresses thyroid tumor growth by promoting senescence and inhibiting invasion. Endocr Relat Cancer 2008; 15:787-99. [PMID: 18559958 PMCID: PMC2742300 DOI: 10.1677/erc-08-0079] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Loss of ABI gene family member 3-binding protein (ABI3BP) expression may be functionally involved in the pathogenesis of cancer. Previous reports have indicated a loss of expression in lung cancer and a presumed role in inducing cellular senescence. We show here that ABI3BP expression is significantly decreased in most malignant thyroid tumors of all types. To better understand ABI3BP's role, we created a model by re-expressing ABI3BP in two thyroid cancer cell lines. Re-expression of ABI3BP in thyroid cells resulted in a decrease in transforming activity, cell growth, cell viability, migration, invasion, and tumor growth in nude mice. ABI3BP re-expression appears to trigger cellular senescence through the p21 pathway. Additionally, ABI3BP induced formation of heterochromatin 1-binding protein gamma-positive senescence-associated (SA) heterochromatin foci and accumulation of SA beta-galactosidase. The combination of a decrease in cell growth, invasion, and other effects upon ABI3BP re-expression in vitro helps to explain the large reduction in tumor growth that we observed in nude mice. Together, our data provide evidence that the loss of ABI3BP expression could play a functional role in thyroid tumorigenesis. Activation of ABI3BP or its pathway may represent a possible basis for targeted therapy of certain cancers.
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Affiliation(s)
- Flavia R. M. Latini
- Genetic Bases of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics; Federal University of São Paulo, SP, Brazil
| | - Jefferson P. Hemerly
- Genetic Bases of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics; Federal University of São Paulo, SP, Brazil
| | - Gisele Oler
- Genetic Bases of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics; Federal University of São Paulo, SP, Brazil
| | - Gregory J. Riggins
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Janete M. Cerutti
- Genetic Bases of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics; Federal University of São Paulo, SP, Brazil
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22
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Chromosomal rearrangements and the pathogenesis of differentiated thyroid cancer. Oncol Rev 2007. [DOI: 10.1007/s12156-007-0010-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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23
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Ashok BT, Tadi K, Garikapaty VPS, Chen Y, Huang Q, Banerjee D, Konopa J, Tiwari RK. Preclinical toxicological examination of a putative prostate cancer-specific 4-methyl-1-nitroacridine derivative in rodents. Anticancer Drugs 2007; 18:87-94. [PMID: 17159506 DOI: 10.1097/01.cad.0000236316.04199.20] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Nitroacridines are potent DNA-binding and cytotoxic agents in cancer cells, but could not be developed clinically due to high systemic toxicities. We are developing a 1-nitroacridine derivative, 9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine (C-1748), as an effective chemotherapeutic agent for prostate cancer. C-1748 demonstrates high antitumor efficacy against human prostate cancer xenografts with markedly low mutagenicity and toxicity in dogs compared with its parent 9-(2'-hydroxyethylamino)-1-nitroacridine (C-857). A surprising feature of C-1748 is the 40-fold difference in 50% inhibitory concentration between DU145 prostate cancer and HL-60 leukemia cells. In this study, we report the preclinical toxicity study of a single acute dose of C-1748 in Copenhagen rats and BALB/c mice, intraperitoneally and intravenously for 24 h and 7 days. The effect of C-1748 on hematology, cardiac and liver enzymes, and renal electrolytes was assessed by blood and serum analysis. The LD50 (lethal dose, 50%) for C-1748 was 9 and 13.42 mg/kg compared with 2.2 and 3 mg/kg for C-857 intraperitoneally and intravenously, respectively, in mice. In Copenhagen rats, LD50 was 15 and 14.4 mg/kg intraperitoneally and intravenously, respectively, compared to 4 and 1.3 mg/kg for C-857. No changes in blood cell counts were observed, which were in the normal range for rodents. No changes were observed in clinical chemistries of enzymes such as aspartate aminotransferase, alkaline phosphatase and creatine phosphokinase, which were within the normal range of values. No genome alterations were seen in prostate cancer cell lines by comparative genomic hybridization together with a lack of systemic toxicity, making it a unique cancer cell-type-specific drug that needs further clinical evaluation for toxicity and synergy in combination chemotherapy regimens.
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Affiliation(s)
- Badithe T Ashok
- Department of Microbiology & Immunology, New York Medical College, Valhalla, New York 10595, USA
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24
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Ferru A, Fromont G, Gibelin H, Guilhot J, Savagner F, Tourani JM, Kraimps JL, Larsen CJ, Karayan-Tapon L. The status of CDKN2A alpha (p16INK4A) and beta (p14ARF) transcripts in thyroid tumour progression. Br J Cancer 2006; 95:1670-7. [PMID: 17117177 PMCID: PMC2360765 DOI: 10.1038/sj.bjc.6603479] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
CDKN2A locus on chromosome 9p21 encodes two tumour suppressor proteins pl6INK4A, which is a regulator of the retinoblastoma (RB) protein, and p14ARF, which is involved in the ARF–Mdm2–p53 pathway. The aim of this study was to determine if CDKN2A gene products are implicated in differentiated thyroid carcinogenesis and progression. We used real-time quantitative RT–PCR and immunohistochemistry to assess both transcripts and proteins levels in 60 tumours specimens. Overexpression of p14ARF and pl6INK4A was observed in follicular adenomas, follicular carcinomas and papillary carcinomas, while downregulation was found in oncocytic adenomas compared to nontumoral paired thyroid tissues. These deregulations were statistically significant for pl6INK4a (P=0.006) in follicular adenomas and close to statistical significance for p14ARF in follicular adenomas (P=0.06) and in papillary carcinomas (P=0.05). In all histological types, except papillary carcinomas, we observed a statistically significant relationship between p14ARF and E2F1 (r=0.64 to 1, P<0.05). Our data are consistent with involvement of CDKN2A transcript upregulation in thyroid follicular tumorigenesis as an early event. However, these deregulations do not appear to be correlated to the clinical outcome and they could not be used as potential prognostic markers.
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MESH Headings
- Adenocarcinoma, Follicular/genetics
- Adenocarcinoma, Follicular/metabolism
- Adenocarcinoma, Follicular/pathology
- Adult
- Aged
- Aged, 80 and over
- Carcinoma, Papillary/genetics
- Carcinoma, Papillary/metabolism
- Carcinoma, Papillary/pathology
- Cell Differentiation
- Cyclin-Dependent Kinase Inhibitor p16/genetics
- Cyclin-Dependent Kinase Inhibitor p16/metabolism
- Disease Progression
- Humans
- Immunoenzyme Techniques
- Middle Aged
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Thyroid Gland/metabolism
- Thyroid Gland/pathology
- Thyroid Neoplasms/genetics
- Thyroid Neoplasms/metabolism
- Thyroid Neoplasms/pathology
- Transcription, Genetic/physiology
- Tumor Suppressor Protein p14ARF/genetics
- Tumor Suppressor Protein p14ARF/metabolism
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Affiliation(s)
- A Ferru
- Laboratoire d'Oncologie Moléculaire EA3805, PBS, Cité Hospitalière de la Milétrie, Avenue du Recteur Pineau 86021, Poitiers, France
- Service d'Oncologie Médicale, Poitiers, Cedex, France
| | - G Fromont
- Service d'Anatomie Pathologique, Poitiers Cedex, France
| | - H Gibelin
- Service de Chirurgie Viscérale et Endocrinienne, Poitiers Cedex, France
| | - J Guilhot
- Centre de Recherche Clinique, CHU-86021 Poitiers Cedex, France
| | - F Savagner
- Laboratoire INSERM U694, CHU, 49033 Angers Cedex, France
| | - J M Tourani
- Service d'Oncologie Médicale, Poitiers, Cedex, France
| | - J L Kraimps
- Service de Chirurgie Viscérale et Endocrinienne, Poitiers Cedex, France
| | - C J Larsen
- Laboratoire d'Oncologie Moléculaire EA3805, PBS, Cité Hospitalière de la Milétrie, Avenue du Recteur Pineau 86021, Poitiers, France
| | - L Karayan-Tapon
- Laboratoire d'Oncologie Moléculaire EA3805, PBS, Cité Hospitalière de la Milétrie, Avenue du Recteur Pineau 86021, Poitiers, France
- E-mail:
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25
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Okamoto J, Onda M, Hirata T, Miyamoto S, Akaishi J, Mikami I, Hirai K, Haraguchi S, Koizumi K, Shimizu K. Dissimilarity in gene expression profiles of lung adenocarcinoma in Japanese men and women. ACTA ACUST UNITED AC 2006; 3:223-35. [PMID: 17081955 DOI: 10.1016/s1550-8579(06)80210-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/21/2006] [Indexed: 01/14/2023]
Abstract
BACKGROUND Although clinical differences in lung cancer between men and women have been noted, few studies have examined the sex dissimilarity using gene expression analysis. OBJECTIVE The purpose of this study was to determine the different molecular carcinogenic mechanisms involved in lung cancers in Japanese men and women. METHODS Patients who received surgery for stage I lung adenocarcinoma were included. RNA was extracted from cancerous and normal tissue, and gene expression was then examined with oligonucleotide microarray analysis. A quantitative polymerase chain reaction assay was performed. RESULTS In a microarray analysis of tissue from 13 men and 6 women, 12 genes were under-expressed and 24 genes were overexpressed in lung adenocarcinoma in women compared with men. Genes related to cell cycle were present in underexpressed genes, and genes related to apoptosis, ubiquitination, and metabolism were observed in overexpressed genes. Of interest among the selected genes were WAP four-disulfide core domain 2 (WFDC2) and major histocompatibility complex, class II, DM alpha (HLA-DMA); these genes were classified into 2 groups by hierarchical clustering analysis. Expression of WFDC2 in nonsmokers was significantly higher than that in smokers (P=0.023). However, there was no significant difference in HLA-DMA expression between smokers and nonsmokers. CONCLUSION Thirty-six genes that characterize lung adenocarcinoma by sex were selected. This information may contribute to the development of novel diagnostic techniques and treatment modalities that consider sex differences in lung adenocarcinoma.
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Affiliation(s)
- Junichi Okamoto
- Department of Surgery II, Nippon Medical School, Tokyo, Japan
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26
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Abramova MV, Pospelova TV, Nikulenkov FP, Hollander CM, Fornace AJ, Pospelov VA. G1/S arrest induced by histone deacetylase inhibitor sodium butyrate in E1A + Ras-transformed cells is mediated through down-regulation of E2F activity and stabilization of beta-catenin. J Biol Chem 2006; 281:21040-21051. [PMID: 16717102 DOI: 10.1074/jbc.m511059200] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Tumor cells are often characterized by a high and growth factor-independent proliferation rate. We have previously shown that REF cells transformed with oncogenes E1A and c-Ha-Ras do not undergo G(1)/S arrest of the cell cycle after treatment with genotoxic factors. In this work, we used sodium butyrate, a histone deacetylase inhibitor, to show that E1A + Ras transformants were able to stop proliferation and undergo G(1)/S arrest. Apart from inducing G(1)/S arrest, sodium butyrate was shown to change expression of a number of cell cycle regulatory genes. It down-regulated cyclins D1, E, and A as well as c-myc and cdc25A and up-regulated the cyclin-kinase inhibitor p21(waf1). Accordingly, activities of cyclin E-Cdk2 and cyclin A-Cdk2 complexes in sodium butyrate-treated cells were decreased substantially. Strikingly, E2F1 expression was also down-modulated at the levels of gene transcription, the protein content, and the E2F transactivating capability. To further study the role of p21(waf1) in the sodium butyrate-induced G(1)/S arrest and the E2F1 down-modulation, we established E1A + Ras transformants from mouse embryo fibroblast cells with deletion of the cdkn1a (p21(waf1)) gene. Despite the absence of p21(waf1), sodium butyrate-treated mERas transformants reveal a slightly delayed G(1)/S arrest as well as down-modulation of E2F1 activity, implying that the observed effects are mediated through an alternative p21(waf1)-independent signaling pathway. Subsequent analysis showed that sodium butyrate induced accumulation of beta-catenin, a downstream component of the Wnt signaling. The results obtained indicate that the antiproliferative effect of histone deacetylase inhibitors on E1A + Ras-transformed cells can be mediated, alongside other mechanisms, through down-regulation of E2F activity and stabilization of beta-catenin.
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Affiliation(s)
- Maria V Abramova
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia
| | - Tatiana V Pospelova
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia
| | - Fedor P Nikulenkov
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia
| | | | - Albert J Fornace
- Gene Response Unit, NCI, National Institutes of Health, Bethesda, Maryland 20892
| | - Valery A Pospelov
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia.
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27
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Abstract
Thyroid cancer is one of the few malignancies that are increasing in incidence. Recent advances have improved our understanding of its pathogenesis; these include the identification of genetic alterations that activate a common effector pathway involving the RET-Ras-BRAF signalling cascade, and other unique chromosomal rearrangements. Some of these have been associated with radiation exposure as a pathogenetic mechanism. Defects in transcriptional and post-transcriptional regulation of adhesion molecules and cell-cycle control elements seem to affect tumour progression. This information can provide powerful ancillary diagnostic tools and can also be used to identify new therapeutic targets.
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Affiliation(s)
- Tetsuo Kondo
- Department of Pathology, University Health Network and Toronto Medical Laboratories, Department of Laboratory Medicine and Pathology, University of Toronto, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4
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28
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Zhang Z, Wang H, Li M, Rayburn ER, Agrawal S, Zhang R. Stabilization of E2F1 protein by MDM2 through the E2F1 ubiquitination pathway. Oncogene 2005; 24:7238-47. [PMID: 16170383 DOI: 10.1038/sj.onc.1208814] [Citation(s) in RCA: 108] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Although previous studies suggested that the tumorigenicity of mouse double minute 2 (MDM2) was due to its negative regulation of p53, the p53-independent interactions may be equally as important. During recent studies utilizing MDM2 inhibitors, we noted that E2F transcription factor 1 (E2F1) was down regulated upon inhibition of MDM2, regardless of the p53 status of the cancer. The present study investigated the mechanisms responsible for the MDM2-mediated increase in E2F1 expression. MDM2 prolongs the half-life of the E2F1 protein by inhibiting its ubiquitination. MDM2 displaces SCF(SKP2), the E2F1 E3 ligase. Direct binding between MDM2 and E2F1 is necessary for the negative effects of MDM2 on E2F1 ubiquitination, and deletion of the MDM2 nuclear localization signal does not result in loss of the ability to increase the E2F1 protein level. The downregulation of E2F1 upon MDM2 inhibition was not due to either pRB or p14(Arf). In addition, E2F1 was responsible for at least part of the inhibition of cell proliferation induced by MDM2 knockdown. In conclusion, the present study provides evidence that stabilization of the E2F1 protein is likely another p53-independent component of MDM2-mediated tumorigenesis. More knowledge about the MDM2-E2F1 interaction may be helpful in developing novel anticancer therapies.
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Affiliation(s)
- Zhuo Zhang
- Department of Pharmacology and Toxicology and Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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29
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Zhang Z, Li M, Rayburn ER, Hill DL, Zhang R, Wang H. Oncogenes as novel targets for cancer therapy (part III): transcription factors. ACTA ACUST UNITED AC 2005; 5:327-38. [PMID: 16196502 DOI: 10.2165/00129785-200505050-00005] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
This is the third paper in a four-part serial review on potential therapeutic targeting of oncogenes. The previous parts described the involvement of oncogenes in different aspects of cancer growth and development, and considered the new technologies responsible for the advancement of oncogene identification, target validation, and drug design. Because of such advances, new specific and more efficient therapeutic agents can be developed for cancer. This part of the review continues the exploration of various oncogenes that we have grouped within seven categories: growth factors, tyrosine kinases, intermediate signaling molecules, transcription factors, cell cycle regulators, DNA damage repair genes, and genes involved in apoptosis. Part one discussed growth factors and tyrosine kinases and part two discussed intermediate signaling molecules. This portion of the review covers transcription factors and the various strategies being used to inhibit their expression or decrease their activities.
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Affiliation(s)
- Zhuo Zhang
- Department of Pharmacology and Toxicology and Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, USA
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30
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Abstract
The E2F family of transcription factors is a central modulator of important cellular events, including cell cycle progression, apoptosis and DNA damage response. The role of E2F family members in various human malignancies is yet unclear and may provide vital clues to the diagnosis, prognosis and therapy of cancer patients. In this review we provide a brief but concise overview of E2F function and its putative role in the most common human tumour types.
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Affiliation(s)
- P K Tsantoulis
- Department of Histology and Embryology, Molecular Carcinogenesis Group, School of Medicine, University of Athens, Antaiou 53 Str, Lamprini, Ano Patissia, GR-11146, Athens, Greece
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31
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Onda M, Akaishi J, Asaka S, Okamoto J, Miyamoto S, Mizutani K, Yoshida A, Ito K, Emi M. Decreased expression of haemoglobin beta (HBB) gene in anaplastic thyroid cancer and recovery of its expression inhibits cell growth. Br J Cancer 2005; 92:2216-24. [PMID: 15956966 PMCID: PMC2361827 DOI: 10.1038/sj.bjc.6602634] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Anaplastic thyroid cancer (ATC) is one of the most fulminant and foetal diseases in human malignancies. However, the genetic alterations and carcinogenic mechanisms of ATC are still unclear. Recently, we investigated the gene expression profile of 11 anaplastic thyroid cancer cell lines (ACL) and significant decreased expression of haemoglobin beta (HBB) gene in ACL. Haemoglobin beta is located at 11p15.5, where loss of heterozygosity (LOH) was reported in various kinds of cancers, including ATC, and it has been suggested that novel tumour suppressor genes might exist in this region. In order to clarify the meaning of decreased expression of HBB in ATC, the expression status of HBB was investigated with ACL, ATC, papillary thyroid cancer (PTC) and normal human tissues. Haemoglobin beta showed significant decreased expression in ACLs and ATCs; however, in PTC, HBB expressed equal to the normal thyroid gland. In addition, HBB expressed in normal human tissues ubiquitously. To validate the tumour-suppressor function of HBB, cell growth assay was performed. Forced expression of HBB in KTA2 cell, which is a kind of ACL, significantly suppressed KTA2 growth. The mechanism of downregulation of HBB in ATC is still unclear; however, our results suggested the possibility of HBB as a novel tumour-suppressor gene.
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Affiliation(s)
- M Onda
- Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, Kawasaki, Japan.
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32
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Bélanger H, Beaulieu P, Moreau C, Labuda D, Hudson TJ, Sinnett D. Functional promoter SNPs in cell cycle checkpoint genes. Hum Mol Genet 2005; 14:2641-8. [PMID: 16081466 DOI: 10.1093/hmg/ddi298] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
A substantial number of genes mutated in human cancers encode components of the cell cycle processes. As the G1/S transition in the cell cycle is a finely regulated biological process, we hypothesized that sequence variations in the promoter region of the related genes might indeed lead to abnormal expression, thus predisposing the individuals carrying these genetic variants to cancer. In this report, we screened the promoter regions of 16 cell cycle checkpoint genes for DNA variants and assessed the functional impact of these promoter region single nucleotide polymorphisms (pSNPs) by combining in silico analysis and in vitro functional assays. We identified 127 pSNPs including 90 with predicted impact on putative binding sites of known transcription factors. Eleven pSNPs were selected for electrophoresis mobility shift assays because of their association with predicted gains of binding sites, and nine pSNPs showed differential allelic shifts in at least one cell line tested. Following the subcloning of the promoter regions into a gene reporter system, we found that at least four promoter haplotypes associated with CCND1, E2F1, HDAC1 and RB1 significantly influenced transcriptional activity in an allele-specific manner. Although the biological significance of these observations still remains to be demonstrated, the expected variability of expression levels in key cell cycle components might influence individual's risk of cancer.
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Affiliation(s)
- Hélène Bélanger
- Division of Hematology, Oncology, Research Center, Sainte-Justine Hospital, 3175 chemin de la Côte-Sainte-Catherine, Montreal, Canada QC H3T 1C5
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33
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Abstract
Thyroid carcinomas are suitable targets for gene therapy because they can be highly lethal on one hand, while being susceptible to specific tumour targeting on the other hand. Several gene therapy modalities have been evaluated so far in experimental models of thyroid cancer, including tumour suppressor gene replacement, oncogene inhibition, suicide gene therapy, immunotherapy, antiangiogenesis, and viral oncolysis. All of these strategies have shown promising results, but clinical studies are lacking. Based on the clinical experience achieved in a pilot study in patients with advanced thyroid cancer and on clinical results in other types of solid cancer, it is suggested that combined gene therapy approaches, as well as multimodality therapeutic regimens, including gene therapy and conventional treatments, should be pursued to achieve clinically significant results.
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Affiliation(s)
- Luisa Barzon
- Department of Histology, Microbiology and Medical Biotechnologies, University of Padova, Via Gabelli 63, I-35121 Padova, Italy.
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Mizutani K, Onda M, Asaka S, Akaishi J, Miyamoto S, Yoshida A, Nagahama M, Ito K, Emi M. Overexpressed in anaplastic thyroid carcinoma-1 (OEATC-1) as a novel gene responsible for anaplastic thyroid carcinoma. Cancer 2005; 103:1785-90. [PMID: 15789362 DOI: 10.1002/cncr.20988] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Anaplastic thyroid carcinoma (ATC) is one of the most fulminant human malignancies. However, the molecular carcinogenic mechanisms of ATC are understood poorly. Recently, the authors performed a cyclic DNA (cDNA) microarray analysis with 11 anaplastic thyroid carcinoma cell lines (ACLs) and discovered several novel responsible genes for ACLs and ATC. From the extended list, they focused on hypothetical and anonymous genes and investigated a novel gene, named the overexpressed in anaplastic thyroid carcinoma-1 (OEATC-1) gene. METHODS To investigate the role of the OEATC-1 gene in ATC carcinogenesis, first, the expression levels of OEATC-1 in ACLs, in various types of carcinoma cell lines, and in normal human tissues were examined with reverse transcriptase-polymerase chain reaction analysis. To explore the effect of OEATC-1 in ATC development, a cell-growth assay was performed with KTA2 cells under OEATC-1 gene silencing using small-interfering RNA (siRNA). RESULTS OEATC-1 was overexpressed significantly in ACLs and in other types of carcinoma cell lines with various expression levels. Conversely, in normal human tissues, OEATC-1 was expressed weakly in placenta, kidney, spleen, thymus, small intestine, and thyroid gland. To evaluate the effects of OEATC-1 on tumor cell growth, gene silencing was caused by transfecting the plasmid-generating siRNA effect to KTA2 cells. Consequently, the silencing of OEATC-1 significantly suppressed the cell growth compared with controls. CONCLUSIONS The current results indicated that OEATC-1 may have some oncogenic or cell growth-promoting function in ACL. OEATC-1 is considered a novel responsible gene in ATC.
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Affiliation(s)
- Kazunori Mizutani
- Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, Kanagawa, Japan
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