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Liu LY, Tian L, Gao LH, Cui HJ, Li XM, Li YH. E2F8 facilitates malignant phenotypes of muscle-invasive bladder cancer via increasing MCM7 expression. Biochem Cell Biol 2025; 103:1-14. [PMID: 39601318 DOI: 10.1139/bcb-2024-0083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2024] Open
Abstract
E2F transcription factor 8 (E2F8) is an important regulator of the cell cycle. In this study, we first assessed the expression of E2F8 in bladder cancer and examined its effects in the malignant phenotypes of bladder cancer cell lines. We found that E2F8 was upregulated in bladder cancer tissues, and the increased expression was positively associated with higher clinical stage. E2F8 knockdown suppressed bladder cancer cell proliferation, accompanied by the performance of G1 phase arrest and the upregulated Cyclin D1 protein expression. The migrative and invasive capability was reduced in E2F8-depleted bladder cancer cells. Cisplatin resistance is an important cause of bladder cancer relapse. E2F8 downregulation facilitated cisplatin-induced apoptosis of bladder cancer cells. MCM7 is regulated by E2F and has been shown to participate in bladder cancer. There was a positive correlation between E2F8 and MCM7 expression in bladder cancer. We confirmed that E2F8 bound to the promoter region of MCM7 and activated MCM7 transcription. MCM7 overexpression abrogated the suppressive effects of E2F8 knockdown on malignant phenotypes of bladder cancer cells. We also demonstrated that E2F8 knockdown suppressed bladder cancer progression in vivo. In conclusion, we verify that E2F8 functioned in bladder cancer, and might exert its function via MCM7.
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Affiliation(s)
- Li-Yun Liu
- Department of Pathology, The Second Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
- Department of Pathology, Tangshan Gongren Hospital, Tangshan, People's Republic of China
| | - Liang Tian
- Department of Pathology, Cangzhou Central Hospital, Cangzhou, People's Republic of China
| | - Ling-Huan Gao
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, People's Republic of China
| | - Hai-Jun Cui
- Department of Urology, Tangshan Gongren Hospital, Tangshan, People's Republic of China
| | - Xue-Mei Li
- Department of Pathology, Tangshan Gongren Hospital, Tangshan, People's Republic of China
| | - Yue-Hong Li
- Department of Pathology, The Second Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
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2
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Rudzinskas SA, Goff AC, Mazzu MA, Schiller CE, Meltzer-Brody S, Rubinow DR, Schmidt PJ, Goldman D. Intrinsically dysregulated cellular stress signaling genes and gene networks in postpartum depression. Mol Psychiatry 2023; 28:3023-3032. [PMID: 36782063 PMCID: PMC10507674 DOI: 10.1038/s41380-023-01985-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 01/18/2023] [Accepted: 01/25/2023] [Indexed: 02/15/2023]
Abstract
Postpartum depression (PPD) is a leading cause of morbidity and mortality among women. Clinically, the administration and withdrawal of supraphysiologic estradiol and progesterone (E2 + P) can cause affective symptom reoccurrence in women with a history of PPD, but not matched controls. To investigate the cellular basis underlying this differential affective response, lymphoblastoid cell lines (LCLs) were derived from women with and without past PPD and compared transcriptomically in hormone conditions mimicking pregnancy and parturition: supraphysiologic E2 + P-addback; supraphysiologic E2 + P-withdrawal; and no added E2 + P (Baseline). RNA-sequencing identified unique differentially expressed genes (DEGs) in all hormone conditions, but the majority tended to be downregulated in PPD and observed in E2 + P-addback. Two of these DEGs were evolutionarily conserved cellular stress regulators: IMPACT, an integrative response protein maintaining translational homeostasis, and WWTR1, a transcriptional coactivator in the 'Hippo' pathway mediating cell proliferation and survival. Correspondingly, significant gene network modules were linked to cell cycle progression, estrogen response, and immune dysregulation, suggesting innate differences in intracellular signaling in PPD. In certain hormone conditions, PPD LCLs displayed increased GATA3 expression (an upstream regulator of IMPACT and WWTR1) and differentially phosphorylated eiF2α (the ultimate downstream target of IMPACT). Taken together, these transcriptomic data primarily implicate innately dysregulated cellular responses as potentially influencing mood and/or escalating PPD risk. Furthermore, the intrinsic downregulation of IMPACT's translation and WWTR1's transcription networks may suggest a novel link between PPD and a compromised ability to maintain homeostasis in the context of cellular stress occurring during pregnancy and parturition.
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Affiliation(s)
- Sarah A Rudzinskas
- Behavioral Endocrinology Branch, NIMH, Bldg. 10CRC, Room 25330, 10 Center Drive MSC 1277, Bethesda, 20892-1277, MD, USA
- Laboratory of Neurogenetics, NIAAA, Bethesda, MD, USA
| | - Allison C Goff
- Behavioral Endocrinology Branch, NIMH, Bldg. 10CRC, Room 25330, 10 Center Drive MSC 1277, Bethesda, 20892-1277, MD, USA
- Laboratory of Neurogenetics, NIAAA, Bethesda, MD, USA
| | - Maria A Mazzu
- Behavioral Endocrinology Branch, NIMH, Bldg. 10CRC, Room 25330, 10 Center Drive MSC 1277, Bethesda, 20892-1277, MD, USA
- Laboratory of Neurogenetics, NIAAA, Bethesda, MD, USA
| | | | | | - David R Rubinow
- Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA
| | - Peter J Schmidt
- Behavioral Endocrinology Branch, NIMH, Bldg. 10CRC, Room 25330, 10 Center Drive MSC 1277, Bethesda, 20892-1277, MD, USA.
| | - David Goldman
- Laboratory of Neurogenetics, NIAAA, Bethesda, MD, USA
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Lee DY, Chun JN, Cho M, So I, Jeon JH. Emerging role of E2F8 in human cancer. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166745. [PMID: 37164180 DOI: 10.1016/j.bbadis.2023.166745] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 05/01/2023] [Accepted: 05/02/2023] [Indexed: 05/12/2023]
Abstract
E2F8 is a multifaceted transcription factor that plays a crucial role in mediating the hallmarks of cancer, including sustaining proliferative signaling, resisting cell death, and activating invasion and metastasis. Aberrant E2F8 expression is associated with poor clinical outcomes in most human cancers. However, E2F8 also exhibits tumor-suppressing activity; thus, the role of E2F8 in cell-fate determination is unclear. In this review, we highlight the recent progress in understanding the role of E2F8 in human cancers, which will contribute to building a conceptual framework and broadening our knowledge pertaining to E2F8. This review provides insight into future challenges and perspectives regarding the translation of biological knowledge into therapeutic strategies for the treatment of cancer.
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Affiliation(s)
- Da Young Lee
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jung Nyeo Chun
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Seoul National University, Seoul, Republic of Korea
| | - Minsoo Cho
- Independent researcher, Seoul, Republic of Korea
| | - Insuk So
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Seoul National University, Seoul, Republic of Korea
| | - Ju-Hong Jeon
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Seoul National University, Seoul, Republic of Korea.
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Du K, Sun S, Jiang T, Liu T, Zuo X, Xia X, Liu X, Wang Y, Bu Y. E2F2 promotes lung adenocarcinoma progression through B-Myb- and FOXM1-facilitated core transcription regulatory circuitry. Int J Biol Sci 2022; 18:4151-4170. [PMID: 35844795 PMCID: PMC9274503 DOI: 10.7150/ijbs.72386] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 06/14/2022] [Indexed: 11/15/2022] Open
Abstract
Lung adenocarcinoma (LUAD) causes severe cancer death worldwide. E2F2 is a canonical transcription factor implicated in transcription regulation, cell cycle and tumorigenesis. The role of E2F2 as well as its transcription regulatory network in LUAD remains obscure. In this study, we constructed a weighted gene co-expression network and identified several key modules and networks overrepresented in LUAD, including the E2F2-centered transcription regulatory network. Function analysis revealed that E2F2 overexpression accelerated cell growth, cell cycle progression and cell motility in LUAD cells whereas E2F2 knockdown inhibited these malignant phenotypes. Mechanistic investigations uncovered various E2F2-regulated downstream genes and oncogenic signaling pathways. Notably, three core transcription factors of E2F2, B-Myb and FOXM1 from the LUAD transcription regulatory network exhibited positive expression correlation, associated with each other, mutually transactivated each other, and regulated similar downstream gene cascades, hence constituting a consolidated core transcription regulatory circuitry. Moreover, E2F2 could promote and was essentially required for LUAD growth in orthotopic mouse models. Prognosis modeling revealed that a two-gene signature of E2F2 and PLK1 from the transcription regulatory circuitry remarkably stratified patients into low- and high-risk groups. Collectively, our results clarified the critical roles of E2F2 and the exquisite core transcription regulatory circuitry of E2F2/B-Myb/FOXM1 in LUAD progression.
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Affiliation(s)
- Kailong Du
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Shijie Sun
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Tinghui Jiang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Tao Liu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Xiaofeng Zuo
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Xing Xia
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Xianjun Liu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Yitao Wang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Youquan Bu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
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5
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Lin Q. MicroRNA-1-3p affects lung adenocarcinoma progression through E2F8 and regulating NF-кB pathway. Cytokine 2022; 156:155922. [PMID: 35660716 DOI: 10.1016/j.cyto.2022.155922] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 05/12/2022] [Accepted: 05/19/2022] [Indexed: 11/30/2022]
Abstract
E2F8 can modulate development and progression of various cancers including cervical cancer, breast cancer and hepatocellular carcinoma. But its mechanism in lung adenocarcinoma (LUAD) remains underexplored. In this study, we conducted a series of experiments including qRT-PCR, western blot, CCK-8, scratch healing assay, Transwell, and flow cytometry. Through these assays, we confirmed the notable overexpression of E2F8 in LUAD and its promoting effects on LUAD cell proliferation, migration and invasion. Subsequently, microRNA-1-3p that was negatively associated with E2F8 expression was identified through bioinformatics analysis. qRT-PCR was then carried out for quantification of microRNA-1-3p expression, which displayed low microRNA-1-3p expression in LUAD cells. In addition, dual-luciferase reporter gene assay was utilized for validating the targeted relationship between microRNA-1-3p and E2F8. The results denoted that microRNA-1-3p could bind to the promoter region of E2F8. Finally, the results of rescue experiment revealed that microRNA-1-3p negatively modulated E2F8 level. It regulated NF-κB pathway to repress LUAD cell proliferative, migratory, and invasive properties, lead to cell cycle arrest in G0/G1 phase, and enhance cell apoptosis level. This study unraveled that microRNA-1-3p/E2F8 constrained LUAD malignant progression through NF-κB pathway, which may provide possible targets for LUAD diagnosis and treatment.
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Affiliation(s)
- Qingsheng Lin
- Cardiothoracic Surgery, Puyang Oilfield General Hospital, China.
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6
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Chen Y, Gong W, Dai W, Jiang H, Xu X. E2F1/2/4 mRNA is associated with immune infiltration and are potential biomarkers for the prognosis of human gastric carcinoma. Transl Cancer Res 2022; 10:2801-2811. [PMID: 35116590 PMCID: PMC8797903 DOI: 10.21037/tcr-21-45] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 04/27/2021] [Indexed: 12/19/2022]
Abstract
Background E2Fs are genes that regulate DNA synthesis and the cell cycle by encoding a family of transcription factors. Increasing experimental evidence has revealed that E2Fs play key roles in tumor progression in various types of cancer. Methods We investigated the survival, expression and transcriptional data of E2F1/2/4 in gastric cancer (GC) patients using the immunohistochemistry assay, Kaplan-Meier Plotter, cBioPortal, String, and GEPIA databases. The plasma of GC patients was analyzed using the real-time reverse transcription polymerase chain reaction (RT-PCR) assay. The correlation between E2F1/2/4 expression and clinical features was analyzed using the quartile method. As well, the correlation between E2F1/2/4 and GC immune infiltration was also investigated using the TIMER database. Database of Immune Cell Expression (DICE) was also used to analyze correlations between SOX4 and immune responses. Results RT-PCR and tissue immunohistochemistry confirmed that E2F1/2/4 was highly expressed in serum and GC tissue samples of GC patients, the expression of which was not affected by patient age and gender. Also, the survival analysis revealed that low levels of E2F1/2/4 expression were significantly associated with a longer overall survival (OS) in GC patients. E2F1/2/4 was correlated with patient prognosis and immune cell infiltration, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and DCs in GC. Our findings indicated that E2F1/2/4 could be used as a prognostic biomarker and indicator of immune infiltration in GC. Conclusions This study revealed that E2F1/2/4 could be a promising indicator for tumor-associated immune infiltration and prognosis in GC patients.
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Affiliation(s)
- Yongyi Chen
- Department of Clinical Lab, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Wangang Gong
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China.,Zhejiang Cancer Research Institute, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | - Wumin Dai
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China.,Zhejiang Cancer Research Institute, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | - Huifen Jiang
- Department of Clinical Lab, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Xiaohong Xu
- Department of Clinical Lab, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
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7
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Luo L, Zhang G, Wu T, Wu G. Prognostic Value of E2F Transcription Factor Expression in Pancreatic Adenocarcinoma. Med Sci Monit 2021; 27:e933443. [PMID: 34799547 PMCID: PMC8611937 DOI: 10.12659/msm.933443] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background Pancreatic adenocarcinoma (PAAD) is one of the deadliest types of cancer. In the early stages, patients often have atypical symptoms, making diagnosis difficult. The prognosis of diagnosed patients is very poor and treating PAAD is challenging. Therefore, determining reliable risk factors related to PAAD development is critical for improving patient prognosis. E2F family transcription factors (TFs) are essential regulators of DNA synthesis and cell cycle progression in eukaryotic cells, and they have been identified as prognostic biomarkers associated with multiple cancer types. However, further research is necessary to establish the prognostic relevance of these TFs in PAAD patients. Material/Methods We assessed PAAD patient transcriptional and outcome data using the TIMER, ONCOMINE, STRING, GEPIA, cBioPortal, Kaplan-Meier Plotter, GSCALite, and starBase databases. Results PAAD tumor tissues exhibited increased expression of E2F1/3/5/7/8 relative to that in normal tissues, while the expression of E2F2/3/6/8 was associated with a more advanced tumor stage. Survival analyses indicated that PAAD patients expressing higher levels of E2F1/2/3/7/8 exhibited shorter overall survival (OS) and disease-free survival (DFS) than patients expressing lower levels of these TFs. In addition, E2F4 and E2F6 overexpression was associated with poorer DFS and OS, respectively. We also found that the expression of E2Fs was significantly correlated with immune infiltrates, including CD8+ T cells, CD4+ T cells, B cells, dendritic cells, neutrophils, and macrophages. Conclusions Our study may provide new insights into the optimal choice of immunotherapy and promising novel targets for therapeutic intervention in PAAD patients.
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Affiliation(s)
- Lin Luo
- Department of Critical Care Medicine, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China (mainland)
| | - Gerui Zhang
- Department of Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China (mainland)
| | - Taihua Wu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China (mainland)
| | - Guangzhen Wu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China (mainland)
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Comprehensive Analysis of the Expression and Prognosis for E2Fs in Human Clear Cell Renal Cell Carcinoma. JOURNAL OF HEALTHCARE ENGINEERING 2021; 2021:5790416. [PMID: 34531966 PMCID: PMC8440094 DOI: 10.1155/2021/5790416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/15/2021] [Accepted: 07/14/2021] [Indexed: 11/18/2022]
Abstract
Background E2F transcription factors is a family of transcription factors, and lots of studies have shown that they play a key role in the occurrence and development of many tumors. However, the association between expression, prognostic value, and immune infiltration in the tumor microenvironment of the eight E2Fs members in ccRCC is still unclear. Method s. We used online databases, such as ONCOMINE, UALCAN, Kaplan–Meier plotter, GEPIA, Metascape, TIMER, and cBioPortal, to analyze the effect of mRNA expression of E2Fs family members in ccRCC on the prognosis of patients and the relationship with immune infiltration. Results Except for E2F5, other seven members of the family of E2Fs mRNA expression levels in ccRCC tissues were significantly higher than control tissues. And the high expression of E2Fs mRNA in ccRCC patients was related to cancer stage and tumor grade. Survival analysis results suggested that elevated mRNA expression levels of E2F1/2/3/4/7/8 were significantly related to the shorter overall survival (OS) in ccRCC patients (P = 3.9E – 06), while high mRNA expression of E2F6 is not related to OS (P = 0.061). Mutations of E2Fs were correlated with shorter OS of ccRCC patients (P = 7.094E – 5). In addition, mRNA expression of E2F1/2/3/4/7/8 was positively correlated with infiltration of six types of immune cells, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Conclusions These results indicate that E2F1/2/3/4/7/8 may be used as a prognostic marker for the survival of ccRCC patients and laid the foundation for studying the immune infiltration role of E2Fs family members in tumors.
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Fan X, Wang Y, Jiang T, Liu T, Jin Y, Du K, Niu Y, Zhang C, Liu Z, Lei Y, Bu Y. B-Myb accelerates colorectal cancer progression through reciprocal feed-forward transactivation of E2F2. Oncogene 2021; 40:5613-5625. [PMID: 34316028 PMCID: PMC8445821 DOI: 10.1038/s41388-021-01961-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 07/04/2021] [Accepted: 07/13/2021] [Indexed: 11/29/2022]
Abstract
B-Myb is an important transcription factor that plays a critical role in gene expression regulation and tumorigenesis. However, its functional implication in colorectal cancer remains elusive. In this study, we found that B-Myb was significantly upregulated at both mRNA and protein levels in colorectal cancer samples compared to non-tumor counterparts. B-Myb overexpression accelerated cell proliferation, cell cycle progression and cell motility in colorectal cancer cells, and promoted tumor growth in orthotopic nude mouse models in vivo. In contrast, B-Myb depletion inhibited these malignant phenotypes. Mechanistic investigations revealed that E2F2 was a novel transcriptional target of B-Myb and is essential to B-Myb-induced malignant phenotypes. Notably, B-Myb and E2F2 exhibited positive expression correlation, and interacted with each other in colorectal cancer cells. In addition to their autoregulatory mechanisms, B-Myb and E2F2 can also directly transactivate each other, thus constituting consolidated reciprocal feed-forward transactivation loops. Moreover, both B-Myb and E2F2 are required for the activation of ERK and AKT signaling pathways in colorectal cancer cells. Taken together, our data clarified a critical role for B-Myb in colorectal cancer and unraveled an exquisite mutual collaboration and reciprocal cross regulation between B-Myb and E2F2 that contribute to the malignant progression of human colorectal cancer.
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Affiliation(s)
- Xiaoyan Fan
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China
- Dermopathic Research Institute, Taizhou University Hospital, Taizhou University, Taizhou, China
| | - Yitao Wang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China
| | - Tinghui Jiang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China
| | - Tao Liu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China
| | - Yuelei Jin
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China
| | - Kailong Du
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China
| | - Yulong Niu
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China
| | - Chunxue Zhang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China
| | - Zhongyu Liu
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China
| | - Yunlong Lei
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China.
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China.
| | - Youquan Bu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China.
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China.
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E2F2 stimulates CCR4 expression and activates synovial fibroblast-like cells in rheumatoid arthritis. Cent Eur J Immunol 2021; 46:27-37. [PMID: 33897281 PMCID: PMC8056345 DOI: 10.5114/ceji.2021.105243] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Accepted: 10/03/2019] [Indexed: 01/01/2023] Open
Abstract
Aim of the study E2F transcription factor 2 (E2F2) has increased expression in synovial tissues of rheumatoid arthritis (RA) and stimulates interleukin (IL)-1 α and IL-β production in cultured RA synovial fibroblast-like cells (RASF), which supports the importance of E2F2 in RA pathogenesis. This study investigated the effect and mechanism of E2F2 in RA. Material and methods Cultured RASF were transfected with anti-E2F2 siRNA, and the expression profile was analyzed with an inflammatory response and autoimmunity PCR array loaded with 84-relative genes to explore the pathogenic pathway of E2F2. Apoptosis, migration and tube-like structure formation in the RASF with transfection of anti-E2F2 siRNA or E2F2-expressing plasmids were examined using flow cytometry, transwell assays and Matrigel assays, respectively. Results Significantly decreased expression of chemokine receptor 4 (CCR4) was detected in RASF with inhibited E2F2 expression, and the CCR4 expression was increased in RASF with transfection of E2F2-expressing plasmids. Silencing E2F2 expression stimulated apoptosis, but retarded migration and tube-like structure formation in RASF. The opposite observation was obtained in RASF with E2F2 overexpression. Conclusions High E2F2 expression decreases apoptosis and increases migration and tube-like structure ability in RASF and might perform this role by up-regulating CCR4 expression, which ultimately contributes to the disease progression of RA synovial tissues.
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Selected E2F2 Polymorphisms in Oral and Oropharyngeal Squamous Cell Carcinoma. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8098130. [PMID: 33860054 PMCID: PMC8024082 DOI: 10.1155/2021/8098130] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 11/03/2020] [Accepted: 03/12/2021] [Indexed: 12/24/2022]
Abstract
Oral squamous cell carcinoma (OSCC) and oropharyngeal squamous cell carcinoma (OPSCC) are subgroups of head and neck squamous cell carcinoma. E2F Transcription Factor 2 (E2F2) could contribute to cancer development, because it plays a critical role in many cellular processes, including the cell cycle, proliferation, differentiation, DNA damage response, and cell death. In the current study, we assessed the associations of five E2F2 polymorphisms (rs6667575, rs3218121, rs3218211, rs3218148, and rs3218203) with OSCC and OPSCC and influence on the TNM staging and grading. This is the first such survey to concern the European population. The study included 94 primary tumour samples following surgical resection from patients, whereas the control group consisted of 99 healthy individuals. We tried a matching of cases and controls for age and sample size. DNA samples were genotyped by employing the 5′ nuclease assay for allelic discrimination. Our results suggested that the most significant difference between the control group and the cancer group was the A/G heterozygote for rs3218121. Samples containing this genotype were mostly found in the control group. In our samples, rs6667575, rs3218121, rs3218211, and rs3218148 polymorphisms may affect the course of OSCC and OPSCC, while rs3218203 was not associated with OSCC and OPSCC. However, further studies are warranted to confirm our findings.
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Cao J, Wang H, Liu G, Tang R, Ding Y, Xu P, Wang H, Miao J, Gu X, Han S. LBX2-AS1 promotes ovarian cancer progression by facilitating E2F2 gene expression via miR-455-5p and miR-491-5p sponging. J Cell Mol Med 2021; 25:1178-1189. [PMID: 33342041 PMCID: PMC7812289 DOI: 10.1111/jcmm.16185] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 11/07/2020] [Accepted: 11/17/2020] [Indexed: 02/06/2023] Open
Abstract
LBX2-AS1 is a long non-coding RNA that facilitates the development of gastrointestinal cancers and lung cancer, but its participation in ovarian cancer development remained uninvestigated. Clinical data retrieved from TCGA ovarian cancer database and the clinography of 60 ovarian cancer patients who received anti-cancer treatment in our facility were analysed. The overall cell growth, colony formation, migration, invasion, apoptosis and tumour formation on nude mice of ovarian cancer cells were evaluated before and after lentiviral-based LBX2-AS1 knockdown. ENCORI platform was used to explore LBX2-AS1-interacting microRNAs and target genes of the candidate microRNAs. Luciferase reporter gene assay and RNA pulldown assay were used to verify the putative miRNA-RNA interactions. Ovarian cancer tissue specimens showed significant higher LBX2-AS1 expression levels that non-cancerous counterparts. High expression level of LBX2-AS1 was significantly associated with reduced overall survival of patients. LBX2-AS1 knockdown significantly down-regulated the cell growth, colony formation, migration, invasion and tumour formation capacity of ovarian cancer cells and increased their apoptosis in vitro. LBX2-AS1 interacts with and thus inhibits the function of miR-455-5p and miR-491-5p, both of which restrained the expression of E2F2 gene in ovarian cancer cells via mRNA targeting. Transfection of miRNA inhibitors of these two miRNAs or forced expression of E2F2 counteracted the effect of LBX2-AS1 knockdown on ovarian cancer cells. LBX2-AS1 was a novel cancer-promoting lncRNA in ovarian cancer. This lncRNA increased the cell growth, survival, migration, invasion and tumour formation of ovarian cancer cells by inhibiting miR-455-5p and miR-491-5p, thus liberating the expression of E2F2 cancer-promoting gene.
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Affiliation(s)
- Jian Cao
- Department of GynecologyWomen's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital)NanjingChina
| | - Huan Wang
- Department of GynecologyWomen's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital)NanjingChina
| | - Guangquan Liu
- Department of GynecologyWomen's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital)NanjingChina
| | - Ranran Tang
- Department of GynecologyWomen's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital)NanjingChina
| | - Ye Ding
- Department of GynecologyWomen's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital)NanjingChina
| | - Pengfei Xu
- Department of GynecologyWomen's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital)NanjingChina
| | - Huayu Wang
- Department of GynecologyWomen's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital)NanjingChina
| | - Juan Miao
- Department of GynecologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Xiaoyan Gu
- Department of GynecologyWomen's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital)NanjingChina
| | - Suping Han
- Department of GynecologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
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E2F8 Induces Cell Proliferation and Invasion through the Epithelial-Mesenchymal Transition and Notch Signaling Pathways in Ovarian Cancer. Int J Mol Sci 2020; 21:ijms21165813. [PMID: 32823614 PMCID: PMC7460858 DOI: 10.3390/ijms21165813] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 08/02/2020] [Accepted: 08/06/2020] [Indexed: 12/16/2022] Open
Abstract
Background: Despite the recent research implicating E2F8 (E2F Transcription Factor 8) in cancer, the role of E2F8 in the progression of ovarian cancer has remained unclear. Hence, we explored the bio-functional effects of E2F8 knockdown on ovarian cancer cell lines in vitro and in vivo. Methods: The expression of E2F8 was compared between ovarian cancer and noncancer tissues, and its association with the progression-free survival of ovarian cancer patients was analyzed. To demonstrate the function of E2F8 in cell proliferation, migration, and invasion, we employed RNA interference to suppress E2F8 expression in ovarian cancer cell lines. Finally, the effect of E2F8 knockdown was investigated in a xenograft mouse model of ovarian cancer. Results: Ovarian cancer tissue exhibited significantly higher E2F8 expression compared to that of normal ovarian tissue. Clinical data showed that E2F8 was a significant predictor of progression-free survival. Moreover, the prognosis of the ovarian cancer patients with high E2F8 expression was poorer than that of the patients with low E2F8 expression. In vitro experiments using E2F8-knockdown ovarian cancer cell lines demonstrated that E2F8 knockdown inhibited cell proliferation, migration, and tumor invasion. Additionally, E2F8 was a potent inducer and modulator of the expression of epithelial–mesenchymal transition and Notch signaling pathway-related markers. We confirmed the function of E2F8 in vivo, signifying that E2F8 knockdown was significantly correlated with reduced tumor size and weight. Conclusions: Our findings indicate that E2F8 is highly correlated with ovarian cancer progression. Hence, E2F8 can be utilized as a prognostic marker and therapeutic target against ovarian malignancy.
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Harnessing Gene Expression Profiles for the Identification of Ex Vivo Drug Response Genes in Pediatric Acute Myeloid Leukemia. Cancers (Basel) 2020; 12:cancers12051247. [PMID: 32429253 PMCID: PMC7281398 DOI: 10.3390/cancers12051247] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 05/06/2020] [Accepted: 05/12/2020] [Indexed: 12/28/2022] Open
Abstract
Novel treatment strategies are of paramount importance to improve clinical outcomes in pediatric AML. Since chemotherapy is likely to remain the cornerstone of curative treatment of AML, insights in the molecular mechanisms that determine its cytotoxic effects could aid further treatment optimization. To assess which genes and pathways are implicated in tumor drug resistance, we correlated ex vivo drug response data to genome-wide gene expression profiles of 73 primary pediatric AML samples obtained at initial diagnosis. Ex vivo response of primary AML blasts towards cytarabine (Ara C), daunorubicin (DNR), etoposide (VP16), and cladribine (2-CdA) was associated with the expression of 101, 345, 206, and 599 genes, respectively (p < 0.001, FDR 0.004–0.416). Microarray based expression of multiple genes was technically validated using qRT-PCR for a selection of genes. Moreover, expression levels of BRE, HIF1A, and CLEC7A were confirmed to be significantly (p < 0.05) associated with ex vivo drug response in an independent set of 48 primary pediatric AML patients. We present unique data that addresses transcriptomic analyses of the mechanisms underlying ex vivo drug response of primary tumor samples. Our data suggest that distinct gene expression profiles are associated with ex vivo drug response, and may confer a priori drug resistance in leukemic cells. The described associations represent a fundament for the development of interventions to overcome drug resistance in AML, and maximize the benefits of current chemotherapy for sensitive patients.
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Morrell BC, Perego MC, Maylem ERS, Zhang L, Schütz LF, Spicer LJ. Regulation of the transcription factor E2F1 mRNA in ovarian granulosa cells of cattle. J Anim Sci 2020; 98:5674948. [PMID: 31832639 DOI: 10.1093/jas/skz376] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 12/11/2019] [Indexed: 12/13/2022] Open
Abstract
The E2F family of transcription factors plays an important role in the control of the cell cycle, cell proliferation, and differentiation, and their role in ovarian function is just emerging. Although some evidence suggests a possible role of E2F1 in ovarian follicular development, what regulates its production in ovarian cells is unknown. Objectives of this study were to determine whether: (i) E2F1 gene expression in granulosa cells (GCs) and theca cells (TCs) change with follicular development and (ii) E2F1 mRNA abundance in TC and GC is hormonally regulated. Using real-time PCR, E2F1 mRNA abundance in GC was 5.5-fold greater (P < 0.05) in small (SM; 1 to 5 mm) than large (LG; >8 mm) follicles, but in TC, E2F1 expression did not differ among follicle sizes. SM-follicle GC had 2.1-fold greater (P < 0.05) E2F1 mRNA than TC. In SM-follicle GC, FGF9 induced a 7.6-fold increase in E2F1 mRNA abundance; however, FGF9 did not affect (P > 0.10) abundance of E2F1 mRNA in LG-follicle TC or GC. Follicle-stimulating hormone (FSH) had no effect (P > 0.10) on E2F1 gene expression in SM- or LG-follicle GC. SM-follicle GC were concomitantly treated with insulin-like growth factor 1 (30 ng/mL), FSH (30 ng/mL), and either 0 or 30 ng/mL of FGF9 with or without 50 µM of an E2F inhibitor (E2Fi; HLM0064741); FGF9 alone increased (P < 0.05) GC numbers, whereas E2Fi alone decreased (P < 0.05) GC numbers, and concomitant treatment of E2Fi with FGF9 blocked (P < 0.05) this stimulatory effect of FGF9. Estradiol production was inhibited (P < 0.05) by FGF9 alone and concomitant treatment of E2Fi with FGF9 attenuated (P < 0.05) this inhibitory effect of FGF9. SM-follicle GC treated with E2Fi decreased (P < 0.05) E2F1 mRNA abundance by 70%. Collectively, our studies show that GC E2F1 mRNA is developmentally and hormonally regulated in cattle. Inhibition of E2F1 reduced FGF9-induced GC proliferation and attenuated FGF9-inhibited estradiol production, indicating that E2F1 may be involved in follicular development in cattle.
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Affiliation(s)
- Breanne C Morrell
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK
| | - M Chiara Perego
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK
| | - Excel Rio S Maylem
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK
| | - Lingna Zhang
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK
| | - Luis F Schütz
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK
| | - Leon J Spicer
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK
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Lü Y, Zhang J, Li L, Li S, Yang Z. Carcinogenesis effects of E2F transcription factor 8 (E2F8) in hepatocellular carcinoma outcomes: an integrated bioinformatic report. Biosci Rep 2020; 40:BSR20193212. [PMID: 31990034 PMCID: PMC7012657 DOI: 10.1042/bsr20193212] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 01/14/2020] [Accepted: 01/20/2020] [Indexed: 02/05/2023] Open
Abstract
This report aimed to investigate the carcinogenesis effects of E2F transcription factor 8 (E2F8) in hepatocellular carcinoma (HCC). E2F8 expression level was compared in Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA) and Oncomine. Survival analysis of E2F8 for HCC were conducted in Kaplan-Meier plotter. Correlations of E2F8 and clinico-pathological features were performed in TCGA. Enrichment of interacted and similar genes with E2F8 was evaluated in Gene Set Enrichment Analysis (GSEA) and Metascape. We found that E2F8 was significantly up-regulated in tumor tissues compared with nontumor tissues (all P < 0.01). Moreover, E2F8 was significantly overexpressed in peripheral blood mononuclear cell (PBMC) in HCC patients than that in healthy individuals (P < 0.001). Meta-analysis in Oncomine database confirmed that E2F8 was significantly higher in HCC tumors (P = 4.28E-08). Additionally, E2F8 elevation significantly correlated with overall survival (OS), recurrence-free survival (RFS), disease-specific survival (DSS) and progression-free survival (PFS) in HCC patients (all P < 0.01). E2F8 level was significantly higher in HCC patients with advanced neoplasm histologic grade, American Joint Committee on Cancer (AJCC) stage and α-fetoprotein (AFP) elevation (all P < 0.05). Cox regression model demonstrated that high E2F8 was an independent risk factor for OS and DFS in HCC patients (HR = 2.16, P = 0.003 and HR = 1.64, P = 0.002, respectively). Enrichment analysis revealed that genes interacted/similar with E2F8 were mainly enriched in cell cycle pathways/biological process. Conclusively, up-regulated in tumors, E2F8 might accelerate tumor progression and result in unfavorable outcomes in HCC patients.
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Affiliation(s)
- Ying Lü
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Jing Zhang
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Lei Li
- Department of Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Shun Li
- Department of Laboratory Animal, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Zongguo Yang
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
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Yao H, Lu F, Shao Y. The E2F family as potential biomarkers and therapeutic targets in colon cancer. PeerJ 2020; 8:e8562. [PMID: 32117628 PMCID: PMC7035869 DOI: 10.7717/peerj.8562] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 01/13/2020] [Indexed: 12/22/2022] Open
Abstract
Background The E2F family is a group of genes encoding a series of transcription factors in higher eukaryotes and participating in the regulation of cell cycle and DNA synthesis in mammals. This study was designed to investigate the role of E2F family in colon cancer. Methods In this study, the transcriptional levels of E2F1-8 in patients with colon cancer from GEPIA was examined. Meanwhile, the immunohistochemical data of the eight genes were also obtained in the The Human Protein Atlas website. Additionally, we re-identified the mRNA expression levels of these genes via real time PCR. Furthermore, the association between the levels of E2F family and stage plot as wells overall survival of patients with colon cancer were analyzed. Results We found that the mRNA and protein levels of E2F1, E2F2, E3F3, E2F5, E2F7 and E2F8 were significantly higher in colon cancer tissues than in normal colon tissues while the expression levels of E2F4 and E2F6 displayed no significant difference between colon cancer tissues and normal tissues. Additionally, E2F3, E2F4, E2F7 and E2F8 were significantly associated with the stages of colon cancer. The Kaplan-Meier Plotter showed that the high levels of E2F3 conferred a worse overall survival and disease free survival of patients with colon cancer. Also, high levels of E2F4 resulted in a worse overall survival. Conclusion Our study implied that E2F3, E2F4, E2F7 and E2F8 are potential targets of precision therapy for patients with colon cancer while E2F1, E2F2, E3F3, E2F5, E2F7 and E2F8 are potential biomarkers for the diagnosis of colon cancer.
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Affiliation(s)
- Haibo Yao
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College, Key Laboratory of Gastroenterology of Zhejiang Province), Hangzhou, China
| | - Fang Lu
- Department of Neurology, Second People's Hospital of Yuhang District, Hangzhou, China
| | - Yanfei Shao
- Department of Pharmacy, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
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Morrell BC, Zhang L, Schütz LF, Perego MC, Maylem ERS, Spicer LJ. Regulation of the transcription factor E2F8 gene expression in bovine ovarian cells. Mol Cell Endocrinol 2019; 498:110572. [PMID: 31493442 DOI: 10.1016/j.mce.2019.110572] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 09/01/2019] [Accepted: 09/03/2019] [Indexed: 12/31/2022]
Abstract
Overexpression of the transcription factor, E2F8, has been associated with ovarian cancer. Objectives of this study were to determine: 1) if E2F8 gene expression in granulosa cells (GC) and theca cells (TC) change with follicular development, and 2) if E2F8 mRNA abundance in TC and GC is hormonally regulated. Using real-time PCR, E2F8 mRNA abundance in GC and TC was greater (P < 0.05) in small than large follicles. FGF9 induced an increase (P < 0.05) in E2F8 mRNA abundance by 1.6- to 7-fold in large-follicle (8-20 mm) TC and GC as well as in small-follicle (1-5 mm) GC. Abundance of E2F8 mRNA in TC was increased (P < 0.05) with FGF2, FGF9 or VEGFA treatments alone in vitro, and concomitant treatment of VEGFA with FGF9 increased (P < 0.05) abundance of E2F8 mRNA above any of the singular treatments; BMP4, WNT3A and LH were without effect. IGF1 amplified the stimulatory effect of FGF9 on E2F8 mRNA abundance by 2.7-fold. Collectively, our studies show for the first time that follicular E2F8 is developmentally and hormonally regulated indicating that E2F8 may be involved in follicular development.
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Affiliation(s)
- Breanne C Morrell
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, 74078, USA
| | - Lingna Zhang
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, 74078, USA
| | - Luis F Schütz
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, 74078, USA
| | - M Chiara Perego
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, 74078, USA
| | - Excel Rio S Maylem
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, 74078, USA
| | - Leon J Spicer
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, 74078, USA.
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Lafta IJ. E2F6 is essential for cell viability in breast cancer cells during replication stress. ACTA ACUST UNITED AC 2019; 43:293-304. [PMID: 31768102 PMCID: PMC6823915 DOI: 10.3906/biy-1905-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
E2F6 is a member of the E2F family of transcription factors involved in regulation of a wide variety of genes through both activation and repression. E2F6 has been reported as overexpressed in breast cancers but whether or not this is important for tumor development is unclear. We first checked E2F6 expression in tumor cDNAs and the protein level in a range of breast cancer cell lines. RNA interference-mediated depletion was then used to assess the importance of E2F6 expression in cell lines with regard to cell cycle profile using fluorescence-activated cell sorting and a cell survival assay using (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The overexpression of E2F6 was confirmed in breast tumor cDNA samples and breast cancer cell lines. Depletion of E2F6 in the breast cancer cells reduced cell viability in MCF-7, T-47D, and MDA-MB-231 cells. There was little effect in the nontumor breast cell line MCF-10A. The deleterious effect on cancer cells was greater during replication stress, leading to an increase in the proportion of breast cancer cells with sub-G1 DNA content. These results suggest that E2F6 might be essential for the survival of breast cancer cells experiencing replication stress, and therefore it could be a target for combined therapy.
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Affiliation(s)
- Inam Jasim Lafta
- Department of Microbiology, College of Veterinary Medicine, University of Baghdad, Baghdad, Iraq
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20
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Nichols JA, Perego MC, Schütz LF, Hemple AM, Spicer LJ. Hormonal regulation of vascular endothelial growth factor A (VEGFA) gene expression in granulosa and theca cells of cattle1. J Anim Sci 2019; 97:3034-3045. [PMID: 31077271 DOI: 10.1093/jas/skz164] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 05/10/2019] [Indexed: 12/13/2022] Open
Abstract
Vascular endothelial growth factor A (VEGFA) stimulates angiogenesis and is associated with increased vascularity in ovarian follicles of cattle. The objectives of this study were to investigate the developmental and hormonal regulation of VEGFA expression in ovarian granulosa and theca cells (TC) of cattle. Bovine ovaries were collected from a local slaughterhouse and granulosa cells (GC) and TC were collected from small (SM; 1 to 5 mm) and large (LG; 8 to 20 mm) follicles. Cells were collected fresh or cultured in serum-free medium and treated with various factors that regulate angiogenesis and follicular development. RNA was collected for analysis of VEGFA mRNA abundance via quantitative PCR. In SM-follicle GC (SMGC), prostaglandin E2 (PGE2) and FSH decreased (P < 0.05) VEGFA mRNA abundance by 30 to 46%, whereas in LG-follicle GC (LGGC), PGE2 and FSH were without effect (P > 0.10). In SMGC, dihydrotestosterone (DHT), sonic hedgehog (SHH), and growth differentiation factor-9 (GDF9) decreased (P < 0.05) VEGFA expression by 30 to 40%. Fibroblast growth factor-9 (FGF9) and estradiol (E2) were without effect (P > 0.10) on VEGFA mRNA in both SMGC and LGGC, whereas progesterone increased (P < 0.05) VEGFA mRNA in LGGC but had no effect in LGTC. Bone morphogenetic protein-4 (BMP4), LH, and FGF9 increased (P < 0.05) abundance of VEGFA mRNA by 1.5- to 1.9-fold in LGTC. Insulin-like growth factor-1 (IGF1) was without effect (P > 0.10) on VEGFA mRNA in both TC and GC. An E2F transcription factor inhibitor, HLM0064741 (E2Fi), dramatically (i.e., 8- to 13-fold) stimulated (P < 0.01) the expression of VEGFA mRNA expression in both SMGC and LGTC. Abundance of VEGFA mRNA was greater (P < 0.05) in LGGC and SMGC than in LGTC. Also, SMTC had greater (P < 0.05) abundance of VEGFA mRNA than LGTC. In conclusion, VEGFA mRNA abundance was greater in GC than TC, and VEGFA expression decreased in TC during follicle development. Some treatments either suppressed, stimulated, or had no effect on VEGFA expression depending on the cell type. The inhibition of E2F transcription factors had the greatest stimulatory effect of all treatments evaluated, and thus, E2Fs may play an important role in regulating angiogenesis during follicle growth in cattle.
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Affiliation(s)
- Jacqueline A Nichols
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, 74078
| | - Maria Chiara Perego
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, 74078
| | - Luis F Schütz
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, 74078
| | - Amber M Hemple
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, 74078
| | - Leon J Spicer
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, 74078
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Kim JY, Bang SI, Lee SD. α-Casein Changes Gene Expression Profiles and Promotes Tumorigenesis of Prostate Cancer Cells. Nutr Cancer 2019; 72:239-251. [PMID: 31155933 DOI: 10.1080/01635581.2019.1622742] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Prostate cancer is among the most prevalent malignancies in men. High intake of dairy products is associated with an increased risk of prostate cancer. No study has examined the gene profile changes and molecular mechanism by which casein, milk protein, affects prostate cancer cells. In this study, we used gene expression profiling to identify gene changes in PC3 prostate cancer cells exposed to α-casein. α-casein altered the expression of a large number of genes-related prostate cancer, transcription factor, apoptotic, metabolic, and cell cycle pathways, in addition to the expected cell proliferation signaling pathways. To clarify the molecular events involved in the effect of α-casein on proliferation and progression of PC3 cells, we examined cell proliferation assay, quantitative real-time PCR, Western blotting, and immunohistochemical and immunofluorescence staining. α-casein promoted PC3 cell proliferation and survival under serum-free conditions by increasing the expression of E2F1 and its target gene PCNA. α-casein also protected PC3 cells from serum-starved autophagic cell death by activating the PI3K/Akt pathway through activation of mTORC1, up-regulation of p70S6K, and down-regulation of LC3 autophagosome formation. Our data provide new insights into the molecular mechanisms underlying the tumorigenic effect of α-casein in prostate cancer cells.
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Affiliation(s)
- Joo-Young Kim
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
| | - Seong Ik Bang
- Department of Urology, Pusan National University School of Medicine, Yangsan, Republic of Korea
| | - Sang Don Lee
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea.,Department of Urology, Pusan National University School of Medicine, Yangsan, Republic of Korea
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Zhou Q, Zhang F, He Z, Zuo MZ. E2F2/5/8 Serve as Potential Prognostic Biomarkers and Targets for Human Ovarian Cancer. Front Oncol 2019; 9:161. [PMID: 30967995 PMCID: PMC6439355 DOI: 10.3389/fonc.2019.00161] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 02/25/2019] [Indexed: 12/21/2022] Open
Abstract
E2Fs are a family of pivotal transcription factors. Accumulative evidence indicates that aberrant expression or activation of E2Fs is a common phenomenon in malignances, and significant associations have been noted between E2Fs and tumorigenesis or progression in a wide range of cancers. However, the expression patterns and exact roles of each E2F contributing to tumorigenesis and progression of ovarian cancer (OC) have not yet been elucidated. In this study, we investigated the distinct expression and prognostic value of E2Fs in patients with OC by analyzing a series of databases, including ONCOMINE, GEPIA, cBioPortal, Metascape, and Kaplan–Meier plotter. The mRNA expression levels of E2F1/3/5/8 were found to be significantly upregulated in patients with OC and were obviously associated with tumor stage for OC. Aberrant expression of E2F2/5/7/8 was found to be associated with the clinical outcomes of patients with OC. These results suggest that E2F2/5/8 might serve as potential prognostic biomarkers and targets for OC. However, future studies are required to validate our findings and promote the clinical utility of E2Fs in OC.
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Affiliation(s)
- Quan Zhou
- Department of Gynecology and Obstetrics, The People's Hospital of China Three Gorges University/The First People's Hospital of Yichang, Yichang, China
| | - Fan Zhang
- Department of Gynecology and Obstetrics, The People's Hospital of China Three Gorges University/The First People's Hospital of Yichang, Yichang, China
| | - Ze He
- Department of Gynecology and Obstetrics, The People's Hospital of China Three Gorges University/The First People's Hospital of Yichang, Yichang, China
| | - Man-Zhen Zuo
- Department of Gynecology and Obstetrics, The People's Hospital of China Three Gorges University/The First People's Hospital of Yichang, Yichang, China
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23
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Li M, Guan H, Liu Y, Gan X. LncRNA ZEB1-AS1 reduces liver cancer cell proliferation by targeting miR-365a-3p. Exp Ther Med 2019; 17:3539-3547. [PMID: 30988735 PMCID: PMC6447761 DOI: 10.3892/etm.2019.7358] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 11/01/2018] [Indexed: 12/19/2022] Open
Abstract
Liver carcinoma is one of the most common malignancies worldwide. Previous studies have demonstrated that long non-coding RNAs (lncRNAs) are crucial mediators that participate in a wide range of molecular processes associated with carcinogenesis. However, little is known about the specific mechanisms that underlie the majority of lncRNAs. Many studies have indicated that lncRNAs affect microRNA (miRNA or miR) activities via physical base-paired binding, therefore serving as competing endogenous RNAs (ceRNAs) that indirectly regulate the expression of miRNA targets. In the current study, it was revealed that lncRNA zinc-finger E-box binding homeobox 1 antisense 1 (ZEB1-AS1) serves as a ceRNA for miR-365a-3p, functioning to positively modulate E2F transcription factor 2 (E2F2) expression in liver cancer cells. Additionally, reverse transcription-quantitative polymerase chain reaction demonstrated that levels of ZEB1-AS1 were abnormally upregulated in liver cancer and this was positively correlated with E2F2 expression. Furthermore, high levels of ZEB1-AS1 exhibited a trend for poor survival in patients with liver cancer. Western blot analysis demonstrated that ZEB1-AS1 silencing could reduce E2F2 expression. EdU staining and flow cytometry analysis indicated that downregulation of ZEB1-AS1 could suppress cell proliferation and decrease the S phase proportion of liver cancer cells, which was effectively reversed by the inhibition of miR-365a-3p. ZEB1-AS1 was also determined to be physically associated with miR-365a-3p, while miR-365a-3p was revealed to target the E2F2 3′UTR for degradation or translational repression. The results also demonstrated that ZEB1-AS1 positively regulates E2F2 expression by competitively binding to miR-365a-3p. It was further revealed to enhance liver cancer cell proliferation. Thus, these results indicate that ZEB1-AS1 is required for liver cancer progression in a ceRNA dependent manner. ZEB1-AS1 may therefore be a potential target for liver cancer intervention.
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Affiliation(s)
- Mingfei Li
- Department of Hepatobiliary Surgery, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
| | - Hua Guan
- Health Management Centre, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
| | - Yuping Liu
- Health Management Centre, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
| | - Xianfeng Gan
- Department of Hepatobiliary Surgery, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
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24
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Farra R, Dapas B, Grassi M, Benedetti F, Grassi G. E2F1 as a molecular drug target in ovarian cancer. Expert Opin Ther Targets 2019; 23:161-164. [PMID: 30724632 DOI: 10.1080/14728222.2019.1579797] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 01/25/2019] [Indexed: 01/28/2023]
Affiliation(s)
- Rossella Farra
- a Department of Life Sciences , Cattinara University Hospital, Trieste University , Trieste , Italy
| | - Barbara Dapas
- a Department of Life Sciences , Cattinara University Hospital, Trieste University , Trieste , Italy
| | - Mario Grassi
- b Department of Engineering and Architecture , University of Trieste , Trieste , Italy
| | - Fabio Benedetti
- c Dipartimento di Scienze Chimiche e Farmaceutiche , Università degli Studi di Trieste , Trieste , Italy
| | - Gabriele Grassi
- a Department of Life Sciences , Cattinara University Hospital, Trieste University , Trieste , Italy
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25
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Prognostic values of E2F mRNA expression in human gastric cancer. Biosci Rep 2018; 38:BSR20181264. [PMID: 30487158 PMCID: PMC6435564 DOI: 10.1042/bsr20181264] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 11/08/2018] [Accepted: 11/26/2018] [Indexed: 12/19/2022] Open
Abstract
Gastric cancer (GC) is the second most frequent cause of cancer-related mortality in the world, with Eastern Asia having the highest incidence rates. E2F is a family of transcription factor proteins that has a variety of functions, which include control of cell cycle, cell differentiation, DNA damage response and cell death. E2F transcription factors are divided into two subfamilies: transcription activators (E2F transcription factors 1 (E2F1), 2 (E2F2) and 3a (E2F3a)) and repressors (E2F3b, E2F transcription factors 4 (E2F4), 5 (E2F5), 6 (E2F6), 7 (E2F7) and 8 (E2F8)). Studies have demonstrated that E2F had prognostic significance in a number of cancers. However, the entirety of the prognostic roles of E2F mRNA expression in GC has not yet been apparently determined. In the present study, the prognostic value of individual family members of E2F mRNA expression for overall survival (OS) was evaluated by using online Kaplan-Meier Plotter (KM Plotter) database. Our result demonstrated that high expressions of three family members of E2F (E2F1, E2F3, E2F4) mRNA were significantly associated with unfavourable OS in all GC patients. However, increased expressions of E2F2, E2F5, E2F6 and E2F7 were significantly associated with favourable OS, especially for higher clinical stages in GC patients. These results provided a better insight into the prognostic functions of E2F mRNA genes in GC. Although the results should be further verified in clinical trials, our findings may be a favourable prognostic predictor for the development of newer therapeutic drugs in the treatment of GC.
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26
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Chen Y, Zhao F, Cui D, Jiang R, Chen J, Huang Q, Shi J. HOXD-AS1/miR-130a sponge regulates glioma development by targeting E2F8. Int J Cancer 2018; 142:2313-2322. [PMID: 29341117 DOI: 10.1002/ijc.31262] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 12/04/2017] [Accepted: 01/03/2018] [Indexed: 12/20/2022]
Abstract
Glioma development is an extremely complex process with changes occurring in numerous genes. HOXD antisense growth-associated long noncoding RNA (HOXD-AS1), an important long noncoding RNA (lncRNA), is known to regulate metastasis-related gene expression in bladder cancer, ovarian cancer and neuroblastoma. Here, we elucidated the function and possible molecular mechanisms of lncRNA HOXD-AS1 in human glioma cells. Our results proved that HOXD-AS1 expression was upregulated in glioma tissues and in glioma cell lines. HOXD-AS1 overexpression promoted cell migration and invasion in vitro, whereas knockdown of HOXD-AS1 expression repressed these cellular processes. Mechanistic studies further revealed that HOXD-AS1 could compete with the transcription factor E2F8 to bind with miR-130a, thus affecting E2F8 expression. Additionally, reciprocal repression was observed between HOXD-AS1 and miR-130a, and miR-130a mediated the tumor-suppressive effects of HOXD-AS1 knockdown. Taken together, these results provide a comprehensive analysis of the role of HOXD-AS1 in glioma cells and offer important clues to understand the key roles of competing endogenous RNA (ceRNA) mechanisms in human glioma.
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Affiliation(s)
- Yinan Chen
- Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair and Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu Province, 226001, People's Republic of China
| | - Fengbo Zhao
- Medical School of Nantong University, 19 Qixiu Road, Basic Medical Research Center, Nantong, Jiangsu Province, 226001, People's Republic of China
| | - Daming Cui
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, People's Republic of China
| | - Rui Jiang
- Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair and Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu Province, 226001, People's Republic of China
| | - Jian Chen
- Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair and Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu Province, 226001, People's Republic of China
| | - Qingfeng Huang
- Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair and Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu Province, 226001, People's Republic of China
| | - Jinlong Shi
- Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair and Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu Province, 226001, People's Republic of China
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27
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De Meulder B, Lefaudeux D, Bansal AT, Mazein A, Chaiboonchoe A, Ahmed H, Balaur I, Saqi M, Pellet J, Ballereau S, Lemonnier N, Sun K, Pandis I, Yang X, Batuwitage M, Kretsos K, van Eyll J, Bedding A, Davison T, Dodson P, Larminie C, Postle A, Corfield J, Djukanovic R, Chung KF, Adcock IM, Guo YK, Sterk PJ, Manta A, Rowe A, Baribaud F, Auffray C. A computational framework for complex disease stratification from multiple large-scale datasets. BMC SYSTEMS BIOLOGY 2018; 12:60. [PMID: 29843806 PMCID: PMC5975674 DOI: 10.1186/s12918-018-0556-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 02/21/2018] [Indexed: 01/05/2023]
Abstract
BACKGROUND Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-'omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-'omics signatures of disease states. METHODS The framework is divided into four major steps: dataset subsetting, feature filtering, 'omics-based clustering and biomarker identification. RESULTS We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-'omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. CONCLUSIONS This framework will help health researchers plan and perform multi-'omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine.
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Affiliation(s)
- Bertrand De Meulder
- European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, EISBM, 50 Avenue Tony Garnier, 69007, Lyon, France.
| | - Diane Lefaudeux
- European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, EISBM, 50 Avenue Tony Garnier, 69007, Lyon, France
| | - Aruna T Bansal
- Acclarogen Ltd, St John's Innovation Centre, Cambridge, CB4 OWS, UK
| | - Alexander Mazein
- European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, EISBM, 50 Avenue Tony Garnier, 69007, Lyon, France
| | - Amphun Chaiboonchoe
- European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, EISBM, 50 Avenue Tony Garnier, 69007, Lyon, France
| | - Hassan Ahmed
- European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, EISBM, 50 Avenue Tony Garnier, 69007, Lyon, France
| | - Irina Balaur
- European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, EISBM, 50 Avenue Tony Garnier, 69007, Lyon, France
| | - Mansoor Saqi
- European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, EISBM, 50 Avenue Tony Garnier, 69007, Lyon, France
| | - Johann Pellet
- European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, EISBM, 50 Avenue Tony Garnier, 69007, Lyon, France
| | - Stéphane Ballereau
- European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, EISBM, 50 Avenue Tony Garnier, 69007, Lyon, France
| | - Nathanaël Lemonnier
- European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, EISBM, 50 Avenue Tony Garnier, 69007, Lyon, France
| | - Kai Sun
- Data Science Institute, Imperial College, London, SW7 2AZ, UK
| | - Ioannis Pandis
- Data Science Institute, Imperial College, London, SW7 2AZ, UK.,Janssen Research and Development Ltd, High Wycombe, HP12 4DP, UK
| | - Xian Yang
- Data Science Institute, Imperial College, London, SW7 2AZ, UK
| | | | | | | | | | - Timothy Davison
- Janssen Research and Development Ltd, High Wycombe, HP12 4DP, UK
| | - Paul Dodson
- AstraZeneca Ltd, Alderley Park, Macclesfield, SK10 4TG, UK
| | | | - Anthony Postle
- Faculty of Medicine, University of Southampton, Southampton, SO17 1BJ, UK
| | - Julie Corfield
- AstraZeneca R & D, 43150, Mölndal, Sweden.,Arateva R & D Ltd, Nottingham, NG1 1GF, UK
| | - Ratko Djukanovic
- Faculty of Medicine, University of Southampton, Southampton, SO17 1BJ, UK
| | - Kian Fan Chung
- National Hearth and Lung Institute, Imperial College London, London, SW3 6LY, UK
| | - Ian M Adcock
- National Hearth and Lung Institute, Imperial College London, London, SW3 6LY, UK
| | - Yi-Ke Guo
- Data Science Institute, Imperial College, London, SW7 2AZ, UK
| | - Peter J Sterk
- Department of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, AZ1105, The Netherlands
| | - Alexander Manta
- Research Informatics, Roche Diagnostics GmbH, 82008, Unterhaching, Germany
| | - Anthony Rowe
- Janssen Research and Development Ltd, High Wycombe, HP12 4DP, UK
| | | | - Charles Auffray
- European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, EISBM, 50 Avenue Tony Garnier, 69007, Lyon, France.
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28
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Li Y, Huang J, Yang D, Xiang S, Sun J, Li H, Ren G. Expression patterns of E2F transcription factors and their potential prognostic roles in breast cancer. Oncol Lett 2018; 15:9216-9230. [PMID: 29844824 PMCID: PMC5958806 DOI: 10.3892/ol.2018.8514] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 03/01/2018] [Indexed: 11/12/2022] Open
Abstract
E2Fs, as a family of pivotal transcription factors, have been implicated in multiple biological functions in human cancer; however, the expression and prognostic significance of E2Fs in breast cancer remains unknown. In the present study, the mRNA expression patterns of E2Fs in breast cancer were investigated with Oncomine and The Cancer Genome Atlas data. Prognostic values of E2Fs for patients with breast cancer were determined using the Kaplan-Meier plotter database. The results strongly indicated that E2F1, E2F2, E2F3, E2F5, E2F7 and E2F8 were overexpressed in patients with breast cancer, whereas E2F4 and E2F6 exhibited no expression difference between patients with cancer and healthy controls. In survival analyses, elevated E2F1, E2F3, E2F5, E2F7 and E2F8 expression levels were significantly associated with lower overall survival, relapse-free survival (RFS), distant metastasis-free survival (DMFS) or post-progression survival for patients with breast cancer. Furthermore, high expression of E2F4 indicated improved RFS but reduced DMFS. Subgroup analyses based on four clinicopathological factors further revealed that E2Fs were associated with the prognosis of patients with breast cancer in an estrogen receptor-, progesterone receptor-, human epidermal growth factor 2- and lymph node status-specific manner. These data indicated that E2Fs may serve as promising biomarkers and therapeutic targets for breast cancer.
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Affiliation(s)
- Yunhai Li
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.,Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Jing Huang
- Department of Pneumology Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Dejuan Yang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.,Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Shili Xiang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Jiazheng Sun
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Hongzhong Li
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.,Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Guosheng Ren
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.,Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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29
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Ye L, Guo L, He Z, Wang X, Lin C, Zhang X, Wu S, Bao Y, Yang Q, Song L, Lin H. Upregulation of E2F8 promotes cell proliferation and tumorigenicity in breast cancer by modulating G1/S phase transition. Oncotarget 2018; 7:23757-71. [PMID: 26992224 PMCID: PMC5029661 DOI: 10.18632/oncotarget.8121] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 02/25/2016] [Indexed: 01/04/2023] Open
Abstract
E2F transcription factors are involved in cell cycle regulation and synthesis of DNA in mammalian cells, and simultaneously play important roles in the development and progression of cancer when dysregulated. E2F8, a novel identified E2F family member, was found to be associated with the progression of several human cancers; however, the biological role and clinical significance of E2F8 in breast cancer remain to be further elucidated. Herein, we report that E2F8 is robustly elevated in breast cancer cell lines and clinical breast cancer tissue samples, respectively. The high expression level of E2F8 significantly correlates with clinical progression (P = 0.001), poor patient survival (P < 0.001) and a high Ki67 staining index (P = 0.008) in 187 human breast cancer specimens. Furthermore, we find that overexpressing E2F8 promotes, whereas silencing E2F8 suppresses, the proliferation and tumorigenicity of breast cancer cells both in vitro and in vivo. We further demonstrate that E2F8 transcriptionally upregulates CCNE1 and CCNE2 via directly interacting with their respective gene promoter, which accelerates the transition of G1 to S phase of breast cancer cells. Taken together, these findings uncover a novel biologic role and regulatory mechanism of E2F8 responsible for the progression of breast cancer, indicating E2F8 may represent a novel prognostic biomarker and therapeutic target against breast cancer.
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Affiliation(s)
- Liping Ye
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Ling Guo
- Department of Nasopharyngeal Carcinoma, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Zhenyu He
- Department of Radiation Oncology, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Xi Wang
- Department of Breast Surgery, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Chuyong Lin
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Xin Zhang
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Shu Wu
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Yong Bao
- Department of Radiation Oncology, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Qi Yang
- Department of Nasopharyngeal Carcinoma, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Libing Song
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Huanxin Lin
- Department of Radiation Oncology, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
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30
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Lv Y, Xiao J, Liu J, Xing F. E2F8 is a Potential Therapeutic Target for Hepatocellular Carcinoma. J Cancer 2017; 8:1205-1213. [PMID: 28607595 PMCID: PMC5463435 DOI: 10.7150/jca.18255] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 01/11/2017] [Indexed: 12/15/2022] Open
Abstract
E2F transcriptional factors are widely expressed in a number of tissues and organs, possessing many regulatory functions related to cellular proliferation, differentiation, DNA repair, cell-cycle and cell apoptosis. E2F8 is a recently identified member of the E2F family with a duplicated DNA-binding domain feature discriminated from E2F1-6, controlling gene expression in a dimerization partner-independent manner. It is indispensable for angiogenesis, lymphangiogenesis and embryonic development. Although E2F8 and E2F7 perform complementary and overlapping functions in many cell metabolisms, E2F8, but not E2F7, overexpresses remarkably in hepatocellular carcinoma (HCC) to facilitate the HCC occurrence and development via activating a E2F1/ Cyclin D1 signaling pathway to regulate the G1- to S-phase transition of cell cycle progression or transcriptionally suppressing CDK1 to induce hepatocyte polyploidization. It also involves closely a variety of cellular physiological functions and pathological processes, which may bring a new breakthrough for the treatment of certain diseases, especially the HCC. Here, we summarize the latest progress of E2F8 on its relevant functions and mechanisms as well as potential application.
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Affiliation(s)
- Yi Lv
- Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China.,Key Laboratory of Functional Protein Research of Guangdong, Higher Education Institutes, Jinan University, Guangzhou, China
| | - Jia Xiao
- Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China
| | - Jing Liu
- Department of Stomatology, Jinan University, Guangzhou, China
| | - Feiyue Xing
- Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China.,Key Laboratory of Functional Protein Research of Guangdong, Higher Education Institutes, Jinan University, Guangzhou, China
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31
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Sun J, Shi R, Zhao S, Li X, Lu S, Bu H, Ma X, Su C. E2F8, a direct target of miR-144, promotes papillary thyroid cancer progression via regulating cell cycle. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:40. [PMID: 28270228 PMCID: PMC5341194 DOI: 10.1186/s13046-017-0504-6] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Accepted: 02/16/2017] [Indexed: 12/27/2022]
Abstract
Background Thyroid cancer is the most common malignancy of endocrine system, and papillary thyroid cancer (PTC) is the most common subtype. E2F8, a novel identified E2F family member, was reported to associate with progression of several human cancers, however, its clinical significance and biological role in PTC remain unknown. Methods E2F8 or miR-144 expression profiles in PTC tissues were obtained from The Cancer Genome Atlas (TCGA) datasets, and the correlation of E2F8 expression with clinicopathological features was analyzed in a cohort PTC patients. The effects of E2F8 and miR-144 on proliferation were evaluated both in vitro and in vivo. Luciferase reporter assay was used to determine E2F8 was a direct target of miR-144. Results E2F8 was widely upregulated in PTC tissues, and overexpression of E2F8 was correlated with more aggressive clinicopathological features. In contrast, we found that silence of E2F8 significantly suppressed proliferation of PTC cells by inducing G1-phase arrest via downregulating Cyclin D1 (CCND1) both in vitro and in vivo. We also identified miR-144 as a tumor-suppressive microRNA that directly targeted E2F8 to inhibit proliferation of PTC cells in vitro and in vivo. Moreover, miR-144 was widely downregulated in PTC, where its expression correlated inversely with E2F8 expression. Conclusions Our results demonstrate a new miR-144/E2F8/CCND1 regulatory axis controlling PTC development, which may offer a potential prognostic and therapeutic strategy. Trial registration No applicable. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0504-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jing Sun
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Run Shi
- The Fourth Clinical College of Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China
| | - Sha Zhao
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Xiaona Li
- Health Management Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Shan Lu
- Department of Nutriology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Hemei Bu
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Xianghua Ma
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
| | - Chuan Su
- Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Pathogen Biology, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, China.
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Li Y, Sturgis EM, Zhu L, Cao X, Wei Q, Zhang H, Li G. E2F transcription factor 2 variants as predictive biomarkers for recurrence risk in patients with squamous cell carcinoma of the oropharynx. Mol Carcinog 2017; 56:1335-1343. [PMID: 27864908 DOI: 10.1002/mc.22595] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 10/05/2016] [Accepted: 11/17/2016] [Indexed: 12/25/2022]
Abstract
Because E2F transcription factor 2 (E2F2) promoter polymorphisms have been implicated in carcinogenesis and prognosis, we investigated associations between genetic variants in five E2F2 promoter polymorphisms and recurrence risk of squamous cell carcinoma of the oropharynx (SCCOP) in 1 008 patients. A log-rank test and multivariable Cox models were used to assess the associations. Compared with patients with variant genotypes of E2F2-rs2742976 and E2F2-rs3218123, patients with common homozygous genotypes had better disease-free survival (both log-rank, P < 0.001) and lower SCCOP recurrence risk (HR, 0.4, 95% CI, 0.3-0.6 and HR, 0.3, 95% CI, 0.2-0.5, respectively) after multivariable adjustment. Furthermore, among patients with HPV16-positive tumors, those with common homozygous genotypes of E2F2-rs2742976 and E2F2-rs3218123 had better disease-free survival rates (both log-rank, P < 0.001) and lower recurrence risk (HR, 0.1, 95% CI, 0.1-0.4 and HR, 0.1, 95% CI, 0.0-0.2, respectively) than patients with variant genotypes. However, no significant differences were found for the other three polymorphisms. After combining the risk genotypes of the five polymorphisms and using the high-risk group (2-5 risk genotypes) as the reference group, we found that the low-risk groups (0 or 1 risk genotype) had significantly lower recurrence risk among all patients (HR, 0.4, 95% CI, 0.3-0.6) and among HPV16-positive patients (HR, 0.2, 95% CI, 0.1-0.5). Our findings suggest that E2F2 polymorphisms may individually or jointly modify SCCOP recurrence risk, particularly for SCCOP patients with HPV16-positive tumors. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Yuncheng Li
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science Technology, Wuhan, China.,Department of Head Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Erich M Sturgis
- Department of Head Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Lijun Zhu
- Department of Head Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Oral Maxillofacial Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xiaoli Cao
- Department of Head Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Ultrasound, Yantai Yuhuangding Hospital, Yantai, China
| | - Qingyi Wei
- Duke University Medical Center, Duke Cancer Institute, Durham, North Carolina
| | - Hua Zhang
- Department of Head Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Otorhinolaryngology-Head and Neck Surgery, Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Guojun Li
- Department of Head Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Gao Z, Shi R, Yuan K, Wang Y. Expression and prognostic value of E2F activators in NSCLC and subtypes: a research based on bioinformatics analysis. Tumour Biol 2016; 37:14979-14987. [PMID: 27655285 DOI: 10.1007/s13277-016-5389-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Accepted: 09/09/2016] [Indexed: 11/24/2022] Open
Abstract
E2F activators (E2F1-3) codify a family of transcription factors (TFs) in higher eukaryotes. E2F activators are involved in the cell cycle regulation and synthesis of DNA in mammalian cells, and their overexpression has been detected in many human cancers. However, their clinical significance has not been deeply researched in non-small-cell lung cancer (NSCLC), and bioinformatics analysis has never been reported to explore their clinical role in NSCLC. In the current study, we investigated the expression and prognostic value of E2F activators in NSCLC patients through the "TCGA datasets" and the "Kaplan-Meier plotter" (KM plotter) database. Hazard ratio (HR), 95 % confidence intervals, and log-rank P were calculated. Compared with normal tissue samples, E2F activators were overexpressed in NSCLC tissues, in lung adenocarcinoma (LUAD) tissues, and in lung squamous cell carcinoma (LUSC) tissues. In NSCLC patients, E2F1 expression was significantly correlated with age, sex, and tumor stage. E2F2 expression was found to be significantly correlated with sex and tumor size. We further demonstrated that E2F1 and E2F2 overexpressions were significantly associated with poor prognosis. In LUAD patients, E2F1 expression was significantly correlated with tumor size and tumor stage. E2F2 expression was significantly correlated with lymph node status and tumor stage. E2F1 and E2F2 overexpression showed a significant association with poor prognosis, while E2F3 overexpression was significantly correlated to better prognosis. In LUSC patients, E2F1 was concluded to be significantly correlated with tumor stage. However, E2F activators were not found to be correlated to prognosis.
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Affiliation(s)
- Zhaojia Gao
- Department of Cardiothoracic Surgery, Changzhou NO. 2 People's Hospital affiliated to Nanjing Medical University, Changzhou, 213003, China
| | - Run Shi
- Department of Thoracic Surgery, Jiangsu Cancer Hospital affiliated to Nanjing Medical University, Nanjing, 210009, China
| | - Kai Yuan
- Department of Cardiothoracic Surgery, Changzhou NO. 2 People's Hospital affiliated to Nanjing Medical University, Changzhou, 213003, China
| | - Yong Wang
- Department of Cardiothoracic Surgery, Changzhou NO. 2 People's Hospital affiliated to Nanjing Medical University, Changzhou, 213003, China.
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Velma V, Dasari SR, Tchounwou PB. Low Doses of Cisplatin Induce Gene Alterations, Cell Cycle Arrest, and Apoptosis in Human Promyelocytic Leukemia Cells. Biomark Insights 2016; 11:113-21. [PMID: 27594783 PMCID: PMC4998075 DOI: 10.4137/bmi.s39445] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 04/17/2016] [Accepted: 04/26/2016] [Indexed: 12/20/2022] Open
Abstract
Cisplatin is a known antitumor drug, but its mechanisms of action are not fully elucidated. In this research, we studied the anticancer potential of cisplatin at doses of 1, 2, or 3 µM using HL-60 cells as a test model. We investigated cisplatin effects at the molecular level using RNA sequencing, cell cycle analysis, and apoptotic assay after 24, 48, 72, and 96 hours of treatment. The results show that many genes responsible for molecular and cellular functions were significantly altered. Cisplatin treatment also caused the cells to be arrested at the DNA synthesis phase, and as the time increases, the cells gradually accumulated at the sub-G1 phase. Also, as the dose increases, a significant number of cells entered into the apoptotic and necrotic stages. Altogether, the data show that low doses of cisplatin significantly impact the viability of HL-60 cells, through modulation of gene expression, cell cycle, and apoptosis.
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Affiliation(s)
- Venkatramreddy Velma
- Cellomics and Toxicogenomics Research Laboratory, NIH/NIMHD RCMI-Center for Environmental Health, College of Science, Engineering and Technology, Jackson State University, Jackson, MS, USA
| | - Shaloam R Dasari
- Cellomics and Toxicogenomics Research Laboratory, NIH/NIMHD RCMI-Center for Environmental Health, College of Science, Engineering and Technology, Jackson State University, Jackson, MS, USA
| | - Paul B Tchounwou
- Cellomics and Toxicogenomics Research Laboratory, NIH/NIMHD RCMI-Center for Environmental Health, College of Science, Engineering and Technology, Jackson State University, Jackson, MS, USA
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35
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Song H, Zhang Y, Liu N, Zhang D, Wan C, Zhao S, Kong Y, Yuan L. Let-7b inhibits the malignant behavior of glioma cells and glioma stem-like cells via downregulation of E2F2. J Physiol Biochem 2016; 72:733-744. [DOI: 10.1007/s13105-016-0512-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 08/01/2016] [Indexed: 12/20/2022]
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Gao Y, Ma X, Yao Y, Li H, Fan Y, Zhang Y, Zhao C, Wang L, Ma M, Lei Z, Zhang X. miR-155 regulates the proliferation and invasion of clear cell renal cell carcinoma cells by targeting E2F2. Oncotarget 2016; 7:20324-37. [PMID: 26967247 PMCID: PMC4991458 DOI: 10.18632/oncotarget.7951] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 02/18/2016] [Indexed: 01/09/2023] Open
Abstract
MicroRNAs (miRNAs) have emerged as critical modulators of carcinogenesis and tumor progression. In the present work, we sought to identify the biological function of miR-155 as well as its underlying mechanism in clear cell renal cell carcinoma (ccRCC). We examined the expression of miR-155 in clear cell RCC (ccRCC) and adjacent normal tissues and then explored the roles of miR-155 both in vitro and in vivo. The results of this analysis indicated that miR-155 activity was significantly upregulated in ccRCC tissues compared with the corresponding normal tissues. miR-155 was associated with ccRCC aggressiveness in both cell lines and clinical specimens, and a specific and inverse correlation between miR-155 and E2F2 expression was found in human ccRCC samples. Overexpression of miR-155 in 786-O cells decreased E2F2 expression while reduction of miR-155 by anti-miR-155 in ACHN cells elevated E2F2 expression. Re-expression of E2F2 in 786-O cells repressed the cell migration/invasion abilities elevated by miR-155, whereas knockdown of E2F2 in ACHN cells restored these cellular functions hampered by the miR-155 inhibitor. Using Western blot and luciferase reporter assays, we determined that E2F2 was a direct target of miR-155. Taken together, the in vitro and in vivo results demonstrate that miR-155 functions as a tumor-promoting miRNA by targeting E2F2 in ccRCC.
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Affiliation(s)
- Yu Gao
- Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
| | - Xin Ma
- Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
| | - Yuanxin Yao
- Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
| | - Hongzhao Li
- Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
| | - Yang Fan
- Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
| | - Yu Zhang
- Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
| | - Chaofei Zhao
- Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
| | - Lei Wang
- Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
| | - Minghui Ma
- Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
| | - Zhengwei Lei
- Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
| | - Xu Zhang
- Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China
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E2F1: a promising regulator in ovarian carcinoma. Tumour Biol 2016; 37:2823-31. [PMID: 26749284 DOI: 10.1007/s13277-015-4770-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 12/29/2015] [Indexed: 10/22/2022] Open
Abstract
E2F is a family of transcription factors that recognized to regulate the expression of genes essential for a wide range of cellular functions, including cell cycle progression, DNA repair, DNA replication, differentiation, proliferation, and apoptosis. E2F1, the most classic member of the E2F family, exhibits a complex role in tumor development regulation. In recent years, a growing body of data suggested an intimate relationship between E2F1 and ovarian carcinoma. And E2F1 was well identified to play dual functions and serve as a useful prognostic indicator in ovarian carcinoma. However, the mechanism underlying E2F1 associated with ovarian carcinoma remains elusive. It is necessary to clarify the fundamental role of E2F1 in ovarian carcinoma. In this review, we tried to sum up the knowledge of E2F1, including its structure and related mechanism. We also attempt to absorb the research achievements and collect the mechanism of E2F1 in ovarian carcinoma.
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Zhang Y, Han D, Wei W, Cao W, Zhang R, Dong Q, Zhang J, Wang Y, Liu N. MiR-218 Inhibited Growth and Metabolism of Human Glioblastoma Cells by Directly Targeting E2F2. Cell Mol Neurobiol 2015; 35:1165-73. [PMID: 26012781 PMCID: PMC11486278 DOI: 10.1007/s10571-015-0210-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2015] [Accepted: 05/13/2015] [Indexed: 01/15/2023]
Abstract
In recent years, microRNA has become a hotspot in research on diseases, especially in the initiation and progression of different types of cancer. In this study, we found that miR-218 could inhibit growth and metabolism in gliomas by directly targeting E2F2. First, we obtained data from the Chinese Glioma Genome Atlas (CGGA) database to analyze miR-218 expression in different grades of gliomas. The effects of miR-218 on cell cycle progression and cell proliferation in U87 and U251 cell lines were investigated by flow cytometry, specifically CCK8 assay and tablet cloning, respectively. Glucose consumption and lactate production of glioma cell lines were measured by correlative test kits. Furthermore, we used Western blot analysis and luciferase reporter assay to identify the direct and functional target of miR-218. Data from the CGGA database and real-time quantitative reverse transcription-PCR demonstrated that miR-218 was obviously reduced in human glioblastoma tissues, as well as in the cell lines. When miR-218 level was elevated in vitro, cell cycle progression was arrested in the G1 phase, and cell proliferation was dramatically inhibited. Both glucose consumption and lactate production of glioma cells were significantly reduced. Western blot analysis and luciferase reporter assay revealed that E2F2 was a direct target of miR-218 in glioma cells. This investigation demonstrated that elevated E2F2 expression could partly weaken the effect of miR-218 in vitro. This study also showed that miR-218 may be a repressor in glioma by directly targeting E2F2, as well as a potential therapeutic target in gliomas.
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Affiliation(s)
- Yaxuan Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Dongfeng Han
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Wenjin Wei
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Wenping Cao
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Rui Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Qingsheng Dong
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Junxia Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Yingyi Wang
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China.
| | - Ning Liu
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China.
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Meng P, Ghosh R. Transcription addiction: can we garner the Yin and Yang functions of E2F1 for cancer therapy? Cell Death Dis 2014; 5:e1360. [PMID: 25101673 PMCID: PMC4454301 DOI: 10.1038/cddis.2014.326] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Revised: 06/24/2014] [Accepted: 06/26/2014] [Indexed: 12/29/2022]
Abstract
Classically, as a transcription factor family, the E2Fs are known to regulate the expression of various genes whose products are involved in a multitude of biological functions, many of which are deregulated in diseases including cancers. E2F is deregulated and hyperactive in most human cancers with context dependent, dichotomous and contradictory roles in almost all cancers. Cancer cells have an insatiable demand for transcription to ensure that gene products are available to sustain various biological processes that support their rapid growth and survival. In this context, cutting-off hyperactivity of transcription factors that support transcription dependence could be a valuable therapeutic strategy. However, one of the greatest challenges of targeting a transcription factor is the global effects on non-cancerous cells given that they control cellular functions in general. Recently, there is growing realization regarding the possibility to target the oncogenic activation of transcription factors to modulate transcription addiction without affecting the normal activity required for cell functions. In this review, we used E2F1 as a prototype transcription factor to address transcription factor activity in cancer cell functions. We focused on melanoma considering that E2F1 executes critical functions in response to UV, an etiological factor of cutaneous melanoma and lies immediately downstream of the CDKN2A/pRb axis, which is frequently deregulated in melanoma. Further, activation of E2F1 in melanomas can also occur independent of loss of CDKN2A. Given its activated status and the ability to transcriptionally control a plethora of genes involved in regulating melanoma development and progression, we review the current literature on its differential role in controlling signaling pathways involved in melanoma as well as therapeutic resistance, and discuss the practical value of weaning melanoma cells from E2F1-mediated transcription dependence for melanoma management.
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Affiliation(s)
- P Meng
- Department of Urology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - R Ghosh
- 1] Department of Urology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA [2] Department of Pharmacology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA [3] Department of Molecular Medicine, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA [4] Cancer Therapy and Research Center, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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Srivastava P, Mangal M, Agarwal SM. Understanding the transcriptional regulation of cervix cancer using microarray gene expression data and promoter sequence analysis of a curated gene set. Gene 2013; 535:233-8. [PMID: 24291025 DOI: 10.1016/j.gene.2013.11.028] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Revised: 11/12/2013] [Accepted: 11/15/2013] [Indexed: 02/08/2023]
Abstract
Cervical cancer, the malignant neoplasm of the cervix uteri is the second most common cancer among women worldwide and the top-most cancer in India. Several factors are responsible for causing cervical cancer, which alter the expression of oncogenic genes resulting in up or down-regulation of gene expression and inactivation of tumor-suppressor genes/gene products. Gene expression is regulated by interactions between transcription factors (TFs) and specific regulatory elements in the promoter regions of target genes. Thus, it is important to decipher and analyze TFs that bind to regulatory regions of diseased genes and regulate their expression. In the present study, computational methods involving the combination of gene expression data from microarray experiments and promoter sequence analysis of a curated gene set involved in the cervical cancer causation have been utilized for identifying potential regulatory elements. Consensus predictions of two approaches led to the identification of twelve TFs that might be crucial to the regulation of cervical cancer progression. Subsequently, TF enrichment and oncomine expression analysis suggested that the transcription factor family E2F played an important role for the regulation of genes involve in cervical carcinogenesis. Our results suggest that E2F possesses diagnostic/prognostic value and can act as a potential drug target in cervical cancer.
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Affiliation(s)
- Prashant Srivastava
- Integrative Genomics and Medicine, MRC Clinical Sciences, Imperial College, London, UK
| | - Manu Mangal
- Bioinformatics Division, Institute of Cytology and Preventive Oncology, Noida-201301, India
| | - Subhash Mohan Agarwal
- Bioinformatics Division, Institute of Cytology and Preventive Oncology, Noida-201301, India.
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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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Whitfield TW, Wang J, Collins PJ, Partridge EC, Aldred SF, Trinklein ND, Myers RM, Weng Z. Functional analysis of transcription factor binding sites in human promoters. Genome Biol 2012; 13:R50. [PMID: 22951020 PMCID: PMC3491394 DOI: 10.1186/gb-2012-13-9-r50] [Citation(s) in RCA: 121] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2011] [Revised: 04/19/2012] [Accepted: 06/18/2012] [Indexed: 12/19/2022] Open
Abstract
Background The binding of transcription factors to specific locations in the genome is integral to the orchestration of transcriptional regulation in cells. To characterize transcription factor binding site function on a large scale, we predicted and mutagenized 455 binding sites in human promoters. We carried out functional tests on these sites in four different immortalized human cell lines using transient transfections with a luciferase reporter assay, primarily for the transcription factors CTCF, GABP, GATA2, E2F, STAT, and YY1. Results In each cell line, between 36% and 49% of binding sites made a functional contribution to the promoter activity; the overall rate for observing function in any of the cell lines was 70%. Transcription factor binding resulted in transcriptional repression in more than a third of functional sites. When compared with predicted binding sites whose function was not experimentally verified, the functional binding sites had higher conservation and were located closer to transcriptional start sites (TSSs). Among functional sites, repressive sites tended to be located further from TSSs than were activating sites. Our data provide significant insight into the functional characteristics of YY1 binding sites, most notably the detection of distinct activating and repressing classes of YY1 binding sites. Repressing sites were located closer to, and often overlapped with, translational start sites and presented a distinctive variation on the canonical YY1 binding motif. Conclusions The genomic properties that we found to associate with functional TF binding sites on promoters -- conservation, TSS proximity, motifs and their variations -- point the way to improved accuracy in future TFBS predictions.
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Affiliation(s)
- Troy W Whitfield
- Program in Bioinformatics and Integrative Biology and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA
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Vui-Kee K, Mohd Dali AZH, Mohamed Rose I, Ghazali R, Jamal R, Mokhtar NM. Molecular markers associated with nonepithelial ovarian cancer in formalin-fixed, paraffin-embedded specimens by genome wide expression profiling. Kaohsiung J Med Sci 2012; 28:243-50. [PMID: 22531302 DOI: 10.1016/j.kjms.2011.11.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2011] [Accepted: 07/11/2011] [Indexed: 01/05/2023] Open
Abstract
Nonepithelial ovarian cancer (NEOC) is a rare cancer that is often misdiagnosed as other malignant tumors. Research on this cancer using fresh tissues is nearly impossible because of its limited number of samples within a limited time provided. The study is to identify potential genes and their molecular pathways related to NEOC using formalin-fixed paraffin embedded samples. Total RNA was extracted from eight archived NEOCs and seven normal ovaries. The RNA samples with RNA integrity number >2.0, purity >1.7 and cycle count value <28 cycles were hybridized to the Illumina Whole-Genome DASL assay (cDNA-mediated annealing, selection, extension, and ligation). We analyzed the results using the GeneSpring GX11.0 and FlexArray software to determine the differentially expressed genes. Microarray results were validated using an immunohistochemistry method. Statistical analysis identified 804 differentially expressed genes with 443 and 361 genes as overexpressed and underexpressed in cancer, respectively. Consistent findings were documented for the overexpression of eukaryotic translation elongation factor 1 alpha 1, E2F transcription factor 2, and fibroblast growth factor receptor 3, except for the down-regulated gene, early growth response 1 (EGR1). The immunopositivity staining for EGR1 was found in the majority of cancer tissues. This finding suggested that the mRNA level of a transcript did not always match with the protein expression in tissues. The current gene profile can be the platform for further exploration of the molecular mechanism of NEOC.
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Affiliation(s)
- Koon Vui-Kee
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Furusawa Y, Wei ZL, Sakurai H, Tabuchi Y, Li P, Zhao QL, Nomura T, Saiki I, Kondo T. TGF-β-activated kinase 1 promotes cell cycle arrest and cell survival of X-ray irradiated HeLa cells dependent on p21 induction but independent of NF-κB, p38 MAPK and ERK phosphorylations. Radiat Res 2012; 177:766-74. [PMID: 22490020 DOI: 10.1667/rr2792.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Transforming growth factor-β-activated kinase 1 (TAK1) appears to play a role in inhibiting apoptotic death in response to multiple stresses. To assess the role of TAK1 in X-ray induced apoptosis and cell death, we irradiated parental and siRNA-TAK1-knockdown HeLa cells. Changes in gene expression levels with and without TAK1-knockdown were also examined after irradiation to elucidate the molecular mechanisms involved. After X-ray irradiation, cell death estimated by the colony formation assay increased in the TAK1-knockdown cells. Apoptosis induction, determined by caspase-3 cleavage, suggested that the increased radiosensitivity of the TAK1-knockdown cells could be partially explained by the induction of apoptosis. However, cell cycle analysis revealed that the percentage of irradiated cells in the G(2)/M-phase decreased, and those in the S- and SubG(1)-phases increased due to TAK1 depletion, suggesting that the loss of cell cycle checkpoint regulation may also be involved in the observed increased radiosensitivity. Interestingly, significant differences in the induction of NF-κB, p38 MAPK and ERK phosphorylation, the major downstream molecules of TAK1, were not observed in TAK1 knockdown cells compared to their parental control cells after irradiation. Instead, global gene expression analysis revealed differentially expressed genes after irradiation that bioinformatics analysis suggested are associated with cell cycle regulatory networks. In particular, CDKN1A (coding p21(WAF1)), which plays a central role in the identified network, was up-regulated in control cells but not in TAK1 knockdown cells after X-ray irradiation. Si-RNA knockdown of p21 decreased the percentage of cells in the G(2)/M phase and increased the percentage of cells in the S- and SubG(1)-phases after X-ray irradiation in a similar manner as TAK-1 knockdown. Taken together, these findings suggest that the role of TAK1 in cell death, cell cycle regulation and apoptosis after X irradiation is independent of NF-κB, p38 MAPK, and ERK phosphorylation, and dependent, in part, on p21 induction.
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Affiliation(s)
- Yukihiro Furusawa
- Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan
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Kaur M, MacPherson CR, Schmeier S, Narasimhan K, Choolani M, Bajic VB. In Silico discovery of transcription factors as potential diagnostic biomarkers of ovarian cancer. BMC SYSTEMS BIOLOGY 2011; 5:144. [PMID: 21923952 PMCID: PMC3184078 DOI: 10.1186/1752-0509-5-144] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2011] [Accepted: 09/19/2011] [Indexed: 01/21/2023]
Abstract
BACKGROUND Our study focuses on identifying potential biomarkers for diagnosis and early detection of ovarian cancer (OC) through the study of transcription regulation of genes affected by estrogen hormone. RESULTS The results are based on a set of 323 experimentally validated OC-associated genes compiled from several databases, and their subset controlled by estrogen. For these two gene sets we computationally determined transcription factors (TFs) that putatively regulate transcription initiation. We ranked these TFs based on the number of genes they are likely to control. In this way, we selected 17 top-ranked TFs as potential key regulators and thus possible biomarkers for a set of 323 OC-associated genes. For 77 estrogen controlled genes from this set we identified three unique TFs as potential biomarkers. CONCLUSIONS We introduced a new methodology to identify potential diagnostic biomarkers for OC. This report is the first bioinformatics study that explores multiple transcriptional regulators of OC-associated genes as potential diagnostic biomarkers in connection with estrogen responsiveness. We show that 64% of TF biomarkers identified in our study are validated based on real-time data from microarray expression studies. As an illustration, our method could identify CP2 that in combination with CA125 has been reported to be sensitive in diagnosing ovarian tumors.
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Affiliation(s)
- Mandeep Kaur
- Computational Bioscience Research Center, King Abdullah University of Science and Technology, Thuwal 23955-6900, Kingdom of Saudi Arabia
| | - Cameron R MacPherson
- Computational Bioscience Research Center, King Abdullah University of Science and Technology, Thuwal 23955-6900, Kingdom of Saudi Arabia
| | - Sebastian Schmeier
- Computational Bioscience Research Center, King Abdullah University of Science and Technology, Thuwal 23955-6900, Kingdom of Saudi Arabia
| | - Kothandaraman Narasimhan
- Centre for Excellence in Genomic Medicine Research, King Abdul Aziz University, PO. Box 80216, Jeddah 21589, Kingdom of Saudi Arabia
| | - Mahesh Choolani
- Diagnostic Biomarker Discovery Laboratory, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University Health System, 5 Lower Kent Ridge Road, 119074, Singapore
| | - Vladimir B Bajic
- Computational Bioscience Research Center, King Abdullah University of Science and Technology, Thuwal 23955-6900, Kingdom of Saudi Arabia
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Yamaki H, Nakajima M, Shimotohno KW, Tanaka N. Molecular basis for the actions of Hsp90 inhibitors and cancer therapy. J Antibiot (Tokyo) 2011; 64:635-44. [PMID: 21811259 DOI: 10.1038/ja.2011.60] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Heat-shock protein 90 (Hsp90) inhibitor downregulates c-Myc expression and upregulates the expression of tumor repressor proteins such as p53 and pRB, inhibiting the G1/S transition and causing G2/M arrest during cell cycle progression. The cycle progression is extensively controlled by the pRB/E2F signaling pathway. E2F is released from the pRB/E2F complex with the phosphorylation of pRB by cyclin-cyclin-dependent kinase (CDK) complexes. The released E2F promotes the transcription of target genes involved in cell cycle progression. The pRB/E2F signaling pathway is controlled by DNA methyltransferase-1 (Dnmt-1). The elevated expression of Dnmt-1 has been reported in carcinomas of the colon, lung and prostate. A defect of pRB expression in Rb -/- cancer cells is caused by the aberrant methylation of CpG in the Rb promoter. The Hsp90 inhibitor disrupts the Dnmt-1/Hsp90 association and upregulates pRB expression. In this review, the Hsp90 inhibitors that show promise for cancer therapy are summarized.
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Affiliation(s)
- Hiroshi Yamaki
- Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
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Trinh XB, Tjalma WAA, Dirix LY, Vermeulen PB, Peeters DJ, Bachvarov D, Plante M, Berns EM, Helleman J, Van Laere SJ, van Dam PA. Microarray-based oncogenic pathway profiling in advanced serous papillary ovarian carcinoma. PLoS One 2011; 6:e22469. [PMID: 21799864 PMCID: PMC3143137 DOI: 10.1371/journal.pone.0022469] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2011] [Accepted: 06/21/2011] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION The identification of specific targets for treatment of ovarian cancer patients remains a challenge. The objective of this study is the analysis of oncogenic pathways in ovarian cancer and their relation with clinical outcome. METHODOLOGY A meta-analysis of 6 gene expression datasets was done for oncogenic pathway activation scores: AKT, β-Catenin, BRCA, E2F1, EGFR, ER, HER2, INFα, INFγ, MYC, p53, p63, PI3K, PR, RAS, SRC, STAT3, TNFα, and TGFβ and VEGF-A. Advanced serous papillary tumours from uniformly treated patients were selected (N = 464) to find differences independent from stage-, histology- and treatment biases. Survival and correlations with documented prognostic signatures (wound healing response signature WHR/genomic grade index GGI/invasiveness gene signature IGS) were analysed. RESULTS The GGI, WHR, IGS score were unexpectedly increased in chemosensitive versus chemoresistant patients. PR and RAS activation score were associated with survival outcome (p = 0.002;p = 0.004). Increased activations of β-Catenin (p = 0.0009), E2F1 (p = 0.005), PI3K (p = 0.003) and p63 (p = 0.05) were associated with more favourable clinical outcome and were consistently correlated with three prognostic gene signatures. CONCLUSIONS Oncogenic pathway profiling of advanced serous ovarian tumours revealed that increased β-Catenin, E2F1, p63, PI3K, PR and RAS-pathway activation scores were significantly associated with favourable clinical outcome. WHR, GGI and IGS scores were unexpectedly increased in chemosensitive tumours. Earlier studies have shown that WHR, GGI and IGS are strongly associated with proliferation and that high-proliferative ovarian tumours are more chemosensitive. These findings may indicate opposite confounding of prognostic versus predictive factors when studying biomarkers in epithelial ovarian cancer.
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Affiliation(s)
- Xuan Bich Trinh
- Translational Cancer Research Unit, St Augustinus GZA Hospitals, Antwerp, Belgium
- Department of Gynaecological Oncology, Antwerp University Hospital, Antwerp, Belgium
| | - Wiebren A. A. Tjalma
- Department of Gynaecological Oncology, Antwerp University Hospital, Antwerp, Belgium
| | - Luc Y. Dirix
- Translational Cancer Research Unit, St Augustinus GZA Hospitals, Antwerp, Belgium
| | - Peter B. Vermeulen
- Translational Cancer Research Unit, St Augustinus GZA Hospitals, Antwerp, Belgium
| | - Dieter J. Peeters
- Translational Cancer Research Unit, St Augustinus GZA Hospitals, Antwerp, Belgium
| | - Dimcho Bachvarov
- Cancer Research Centre, Hôpital L'Hôtel-Dieu de Québec, Centre Hospitalier Universitaire de Québec (CHUQ), Québec City, Canada
| | - Marie Plante
- Cancer Research Centre, Hôpital L'Hôtel-Dieu de Québec, Centre Hospitalier Universitaire de Québec (CHUQ), Québec City, Canada
| | - Els M. Berns
- Department of Medical Oncology, Erasmus MC/Josephine Nefkens Institute, Rotterdam, The Netherlands
| | - Jozien Helleman
- Department of Medical Oncology, Erasmus MC/Josephine Nefkens Institute, Rotterdam, The Netherlands
| | - Steven J. Van Laere
- Translational Cancer Research Unit, St Augustinus GZA Hospitals, Antwerp, Belgium
| | - Peter A. van Dam
- Translational Cancer Research Unit, St Augustinus GZA Hospitals, Antwerp, Belgium
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Regulation of cell cycle and DNA repair in post-mitotic GABA neurons in psychotic disorders. Neuropharmacology 2010; 60:1232-42. [PMID: 21184762 DOI: 10.1016/j.neuropharm.2010.12.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2010] [Revised: 11/24/2010] [Accepted: 12/15/2010] [Indexed: 11/24/2022]
Abstract
Disturbances of cell cycle regulation and DNA repair in post-mitotic neurons have been implicated in degenerative and malignant diseases of the human brain. Recent work is now suggesting that abnormal regulation of these functions in GABA cells of the adult hippocampus may also play a role in two neuropsychiatric disorders. In schizophrenia and bipolar disorder, a network of genes involved in the regulation of GAD₆₇, a marker for the functional differentiation of GABA cells, show pronounced changes in expression and include kainate receptor subunits, TGFβ and Wnt signaling pathways, epigenetic factors and transcription factors. One of these genes, cyclin D2, is involved in the regulation of cell cycle and DNA repair and appears to be a pivotal element in linking GAD₆₇ expression with these functional clusters of genes. Dysfunction of post-mitotic GABAergic neurons in the adult hippocampus of patients with psychotic disorders is associated with changes in the expression of genes that are involved in the maintenance of functional and genomic integrity of GABA cells. The nature of these changes is quite different in schizophrenia and bipolar disorder, suggesting that a common cell phenotype (in this case, decreased GAD₆₇ expression) may involve two fundamentally different molecular endophenotypes and reflect unique susceptibility genes involved in the respective disorders. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
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Liang D, Meyer L, Chang DW, Lin J, Pu X, Ye Y, Gu J, Wu X, Lu K. Genetic variants in MicroRNA biosynthesis pathways and binding sites modify ovarian cancer risk, survival, and treatment response. Cancer Res 2010; 70:9765-76. [PMID: 21118967 DOI: 10.1158/0008-5472.can-10-0130] [Citation(s) in RCA: 104] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
MicroRNAs (miRNA) play important roles in tumorigenesis. Genetic variations in miRNA processing genes and miRNA binding sites may affect the biogenesis of miRNA and the regulatory effect of miRNAs to their target genes, hence promoting tumorigenesis. This study analyzed 226 single nucleotide polymorphisms (SNP) in miRNA processing genes and miRNA binding sites in 339 ovarian cancer cases and 349 healthy controls to assess association with cancer risk, overall survival, and treatment response. Thirteen polymorphisms were found to have significant association with risk. The most significant were 2 linked SNPs (r(2) = 0.99), rs2740351 and rs7813 in GEMIN4 [odds ratio (OR) = 0.71; 95% confidence interval (CI), 0.57-0.87 and OR = 0.71; 95% CI, 0.57-0.88, respectively]. Unfavorable genotype analysis showed the cumulative effect of these 13 SNPs on risk (P for trend < 0.0001). Potential higher order gene-gene interactions were identified, which categorized patients into different risk groups according to their genotypic signatures. In the clinical outcome study, 24 SNPs exhibited significant association with overall survival and 17 SNPs with treatment response. Notably, patients carrying a rare homozygous genotype of rs1425486 in PDGFC had poorer overall survival [hazard ratio (HR) = 2.69; 95% CI, 1.67-4.33] and worse treatment response (OR = 3.38; 95% CI, 1.39-8.19), compared to carriers of common homozygous and heterozygous genotypes. Unfavorable genotype analyses also showed a strong gene-dosage effect with decreased survival and increased risk of treatment nonresponse in patients with greater number of unfavorable genotypes (P for trend < 0.0001). Taken together, miRNA-related genetic polymorphisms may impact ovarian cancer predisposition and clinical outcome both individually and jointly.
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Affiliation(s)
- Dong Liang
- College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, USA
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Bryant CS, Kumar S, Chamala S, Shah J, Pal J, Haider M, Seward S, Qazi AM, Morris R, Semaan A, Shammas MA, Steffes C, Potti RB, Prasad M, Weaver DW, Batchu RB. Sulforaphane induces cell cycle arrest by protecting RB-E2F-1 complex in epithelial ovarian cancer cells. Mol Cancer 2010; 9:47. [PMID: 20196847 PMCID: PMC2838815 DOI: 10.1186/1476-4598-9-47] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2009] [Accepted: 03/02/2010] [Indexed: 12/14/2022] Open
Abstract
Background Sulforaphane (SFN), an isothiocyanate phytochemical present predominantly in cruciferous vegetables such as brussels sprout and broccoli, is considered a promising chemo-preventive agent against cancer. In-vitro exposure to SFN appears to result in the induction of apoptosis and cell-cycle arrest in a variety of tumor types. However, the molecular mechanisms leading to the inhibition of cell cycle progression by SFN are poorly understood in epithelial ovarian cancer cells (EOC). The aim of this study is to understand the signaling mechanisms through which SFN influences the cell growth and proliferation in EOC. Results SFN at concentrations of 5 - 20 μM induced a dose-dependent suppression of growth in cell lines MDAH 2774 and SkOV-3 with an IC50 of ~8 μM after a 3 day exposure. Combination treatment with chemotherapeutic agent, paclitaxel, resulted in additive growth suppression. SFN at ~8 μM decreased growth by 40% and 20% on day 1 in MDAH 2774 and SkOV-3, respectively. Cells treated with cytotoxic concentrations of SFN have reduced cell migration and increased apoptotic cell death via an increase in Bak/Bcl-2 ratio and cleavage of procaspase-9 and poly (ADP-ribose)-polymerase (PARP). Gene expression profile analysis of cell cycle regulated proteins demonstrated increased levels of tumor suppressor retinoblastoma protein (RB) and decreased levels of E2F-1 transcription factor. SFN treatment resulted in G1 cell cycle arrest through down modulation of RB phosphorylation and by protecting the RB-E2F-1 complex. Conclusions SFN induces growth arrest and apoptosis in EOC cells. Inhibition of retinoblastoma (RB) phosphorylation and reduction in levels of free E2F-1 appear to play an important role in EOC growth arrest.
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Affiliation(s)
- Christopher S Bryant
- Department of Surgery, Wayne State University, 4100 John R Street, Detroit, MI 48201, USA
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