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Lima BM, de Azevedo ALK, Giner IS, Gomig THB, Ribeiro EMDSF, Cavalli IJ. Biomarker potential of the LEF1/TCF family members in breast cancer: Bioinformatic investigation on expression and clinical significance. Genet Mol Biol 2023; 46:e20220346. [PMID: 38100720 PMCID: PMC10723634 DOI: 10.1590/1678-4685-gmb-2022-0346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 10/18/2023] [Indexed: 12/17/2023] Open
Abstract
The LEF1/TCF transcription factor family is related to the development of diverse tissue types, including the mammary tissue, and dysregulation of its expression and function has been described to favor breast tumorigenesis. However, the clinical and biological relevance of this gene family in breast cancer is still poorly understood. Here, we used bioinformatics approaches aiming to reduce this gap. We investigated its expression patterns in molecular and immune breast cancer subtypes; its correlation with immune cell infiltration, and its prognostic values in predicting outcomes. Also, through regulons construction, we determined the genes whose expression is influenced by these transcription factors, and the pathways in which they are involved. We found that LEF1 and TCF3 are over-expressed in breast tumors regarding non-tumor samples, while TCF4 and TCF7 are down-expressed, with the gene's methylation status being associated with its expression dysregulation. All four transcription factors presented significance at the diagnostic and prognostic levels. LEF1, TCF4, and TCF7 presented a significant correlation with immune cell infiltration, being associated with the immune subtypes of less favorable outcomes. Altogether, this research contributes to a more accurate understanding of the expression and clinical and biomarker significance of the LEF1/TCF transcription factors in breast cancer.
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Affiliation(s)
- Beatriz Miotto Lima
- Universidade Federal do Paraná, Departamento de Genética,
Curitiba, Paraná, Brasil
| | | | - Igor Samesima Giner
- Universidade Federal do Paraná, Departamento de Genética,
Curitiba, Paraná, Brasil
| | | | | | - Iglenir João Cavalli
- Universidade Federal do Paraná, Departamento de Genética,
Curitiba, Paraná, Brasil
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2
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Dadgar-Zankbar L, Shariati A, Bostanghadiri N, Elahi Z, Mirkalantari S, Razavi S, Kamali F, Darban-Sarokhalil D. Evaluation of enterotoxigenic Bacteroides fragilis correlation with the expression of cellular signaling pathway genes in Iranian patients with colorectal cancer. Infect Agent Cancer 2023; 18:48. [PMID: 37644520 PMCID: PMC10463534 DOI: 10.1186/s13027-023-00523-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 08/02/2023] [Indexed: 08/31/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common cancers all over the world, and dysbiosis in the gut microbiota may play a role in colorectal carcinogenesis. Bacteroides fragilis can lead to tumorigenesis by changing signaling pathways, including the WNT/β-catenin pathway. Therefore, in the present study, we investigated the correlation between the enterotoxigenic B. fragilis amount and the expression of signaling pathway genes involved in CRC. MATERIALS AND METHODS B. fragilis was determined in 30 tumors and adjacent healthy tissues by the qPCR method. Next, the relationship between enterotoxigenic B. fragilis and the expression of signaling pathway genes, including CCND1, TP53, BCL2, BAX, WNT, TCF, AXIN, APC, and CTNNB1 was investigated. Additionally, possible correlations between clinicopathological features of the tumor samples and the abundance of B. fragilis were analyzed. RESULTS The results showed that B. fragilis was detected in 100% of tumor samples and 86% of healthy tissues. Additionally, enterotoxigenic B. fragilis colonized 47% of all samples, and bft-1 toxin was the most frequently found isotype among the samples. The analysis showed that the high level of B. fragilis has a significant relationship with the high expression of AXIN, CTNNB1, and BCL2 genes. On the other hand, our results did not show any possible correlation between this bacterium and the clinicopathological features of the tumor sample. CONCLUSION B. fragilis had a higher abundance in the tumor samples than in healthy tissues, and this bacterium may lead to CRC by making changes in cellular signaling pathways and genes. Therefore, to better understand the physiological effects of B. fragilis on the inflammatory response and CRC, future research should focus on dissecting the molecular mechanisms by which this bacterium regulates cellular signaling pathways.
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Affiliation(s)
- Leila Dadgar-Zankbar
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Aref Shariati
- Molecular and Medicine Research Center, Khomein University of Medical Sciences, Khomein, Iran
- Student Research Committee, Khomein University of Medical Sciences, Khomein, Iran
| | - Narjess Bostanghadiri
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Elahi
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shiva Mirkalantari
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shabnam Razavi
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Kamali
- Iran National Tumor Bank, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Darban-Sarokhalil
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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3
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Zhu Y, Li X. Advances of Wnt Signalling Pathway in Colorectal Cancer. Cells 2023; 12:cells12030447. [PMID: 36766788 PMCID: PMC9913588 DOI: 10.3390/cells12030447] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 01/25/2023] [Accepted: 01/28/2023] [Indexed: 01/31/2023] Open
Abstract
Colorectal cancer (CRC) represents one of the most common cancers worldwide, with a high mortality rate despite the decreasing incidence and new diagnostic and therapeutic strategies. CRC arises from both epidemiologic and molecular backgrounds. In addition to hereditary factor and genetic mutations, the strongly varying incidence of CRC is closely linked to chronic inflammatory disorders of the intestine and terrible dietary habits. The Wnt signalling pathway is a complex regulatory network that is implicated in many CRC physiological processes, including cancer occurrence, development, prognosis, invasion, and metastasis. It is currently believed to include classical Wnt/β-catenin, Wnt/PCP, and Wnt/Ca2+. In this review, we summarise the recent mechanisms and potential regulators of the three branches of the Wnt signalling pathway in CRC.
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Affiliation(s)
- Yaoyao Zhu
- Marine College, Shandong University, Weihai 264200, China
| | - Xia Li
- Marine College, Shandong University, Weihai 264200, China
- Shandong Kelun Pharmaceutical Co., Ltd., Binzhou 256600, China
- Correspondence: ; Tel.: +86-0531-8838-2612
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Shirin M, Madadi S, Peyravian N, Pezeshkian Z, Rejali L, Hosseini M, Moradi A, Khanabadi B, Sherkat G, Aghdaei HA, Nazemalhosseini-Mojarad E. A linkage between effectual genes in progression of CRC through canonical and non-canonical TGF-β signaling pathways. Med Oncol 2022; 39:40. [PMID: 35092502 DOI: 10.1007/s12032-021-01634-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 12/17/2021] [Indexed: 12/31/2022]
Abstract
Different molecular signaling pathways have been involved in the incidence and progression of CRC. We aimed to examine the correlation between eight candidate genes, including TFGβ, SMAD2, SMAD4, RhoA, EGFR, MAP2K1, MTA1, and LEF1 in the progression of colorectal cancer (CRC) and their association with clinicopathological variables and CRC patients prognosis. Immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR) analysis 2-ΔΔct, were performed to assess the expression of eight genes in 64 and 122 patients with CRC, respectively and 20 normal samples were added for verification. We showed a positive correlation between SMAD2 and MAP2K1 (r = 0.337, P < 0.001), MAP2K1 and LEF1 (r = 0.187, P = 0.03), SMAD4 and RhoA (r = 0.214, P = 0.01) and as well, a negative correlation between SMAD2 and TGFβ (r = - 0.197, P = 0.02), and RhoA and LEF1 (r = - 0.180, P = 0.04) in tumor tissues. A decrease in RhoA mRNA expression was associated with the advanced TNM stage (P = 0.01), while the EGFR and SMAD2 mRNA expression upregulated in advanced stages (P = 0.03, P = 0.03), respectively. Also, an increase in EGFR and SMAD4 protein expression was significantly associated with the advanced TNM stage (P = 0.000) (P = .002), respectively. Perceiving the connections between canonical and non-canonical Transforming growth factor (TGF-β) signaling pathway along with the epidermal growth factor receptor (EGFR) and WNT cascades may trigger the development of novel approaches for CRC prediction.
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Affiliation(s)
- Marzieh Shirin
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, 19875-17411, Tehran, Iran
| | - Sajedeh Madadi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, 19875-17411, Tehran, Iran
| | - Noshad Peyravian
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, 19875-17411, Tehran, Iran
| | - Zahra Pezeshkian
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, 19875-17411, Tehran, Iran
| | - Leili Rejali
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, 19875-17411, Tehran, Iran
| | - Masoumeh Hosseini
- Department of Pathology, Shohada Hospital, Shahid Beheshti University of Medical Sciences, 19875-17411, Tehran, Iran
| | - Afshin Moradi
- Department of Pathology, Shohada Hospital, Shahid Beheshti University of Medical Sciences, 19875-17411, Tehran, Iran
| | - Binazir Khanabadi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, 19875-17411, Tehran, Iran
| | - Ghazal Sherkat
- Medicin Faculty of Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, 19875-17411, Tehran, Iran
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Yaman Street, Chamran Expressway, 19857-17411, Tehran, Iran.
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5
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Nayak P, Neogi K, Tewari M, Singh A, Sharma K, Tej GVC, Verma S, Gupta S. Transcription factor 4 expression and correlation with tumor progression in gallbladder cancer. J Cancer Res Ther 2022; 18:668-676. [DOI: 10.4103/jcrt.jcrt_1381_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Simakou T, Freeburn R, Henriquez FL. Gene expression during THP-1 differentiation is influenced by vitamin D3 and not vibrational mechanostimulation. PeerJ 2021; 9:e11773. [PMID: 34316406 PMCID: PMC8286059 DOI: 10.7717/peerj.11773] [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: 02/17/2021] [Accepted: 06/23/2021] [Indexed: 11/20/2022] Open
Abstract
Background In injury or infection, monocytes migrate into the affected tissues from circulation and differentiate into macrophages which are subsequently involved in the inflammatory responses. Macrophage differentiation and activation have been studied in response to multiple chemokines and cytokines. However, mechanical, and physical stimuli can also influence macrophage differentiation, activation, cytokine production, and phagocytic activity. Methods In this study the macrophage differentiation from THP-1 monocytes was assessed upon the stimulation with 1,25-dihydroxyvitamin D3 and 1,000 Hz vibrations, using qPCR for quantification of transcript expression. Vitamin D binds the vitamin D receptor (VDR) and subsequently modulates the expression of a variety of genes in monocytes. The effects of the 1,000 Hz vibrational stimulation, and the combined treatment of vitamin D3 and 1000 Hz vibrations were unknown. The differentiation of macrophages was assessed by looking at transcription of macrophage markers (e.g., CD14, CD36), antigen presenting molecules (e.g., HLA-DRA), transcription factors (e.g., LEF-1, TCF7L2), and mechanosensors (e.g., PIEZO1 and PKD2). Results The results showed that vitamin D3 induced THP-1 macrophage differentiation, which was characterized by upregulation of CD14 and CD36, downregulation of HLA-DRA, upregulation of the PKD2 (TRPP2), and an inverse relationship between TCF7L2 and LEF-1, which were upregulated and downregulated respectively. The 1,000 Hz vibrations were sensed from the cells which upregulated PIEZO1 and TCF3, but they did not induce expression of genes that would indicate macrophage differentiation. The mRNA transcription profile in the cells stimulated with the combined treatment was comparable to that of the cells stimulated by the vitamin only. The 1,000 Hz vibrations slightly weakened the effect of the vitamin for the regulation of CD36 and HLA-DMB in the suspension cells, but without causing changes in the regulation patterns. The only exception was the upregulation of TCF3 in the suspension cells, which was influenced by the vibrations. In the adherent cells, the vitamin D3 cancelled the upregulating effect of the 1,000 Hz vibrations and downregulated TCF3. The vitamin also cancelled the upregulation of PIEZO1 gene by the 1,000 Hz vibrations in the combined treatment. Conclusion The mechanical stimulation with 1,000 Hz vibrations resulted in upregulation of PIEZO1 in THP-1 cells, but it did not affect the differentiation process which was investigated in this study. Vitamin D3 induced THP-1 macrophage differentiation and could potentially influence M2 polarization as observed by upregulation of CD36 and downregulation of HLA-DRA. In addition, in THP-1 cells undergoing the combined stimulation, the gene expression patterns were influenced by vitamin D3, which also ablated the effect of the mechanical stimulus on PIEZO1 upregulation.
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Affiliation(s)
- Theodoros Simakou
- School of Health and Life Sciences, University of West of Scotland, Paisley, United Kingdom.,Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Robin Freeburn
- School of Health and Life Sciences, University of West of Scotland, Paisley, United Kingdom
| | - Fiona L Henriquez
- School of Health and Life Sciences, University of West of Scotland, Paisley, United Kingdom
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Ghasemian M, Rajabibazl M, Sadeghi H, Mirfakhraie R. DACT1 variants and colorectal cancer. Br J Biomed Sci 2021; 78:221-224. [PMID: 33843483 DOI: 10.1080/09674845.2021.1914919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- M Ghasemian
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - M Rajabibazl
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - H Sadeghi
- Molecular Genetics Department, Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - R Mirfakhraie
- Molecular Genetics Department, Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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8
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High expression of LEF1 correlates with poor prognosis in solid tumors, but not blood tumors: a meta-analysis. Biosci Rep 2021; 40:226206. [PMID: 32856045 PMCID: PMC7468095 DOI: 10.1042/bsr20202520] [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: 07/14/2020] [Revised: 08/23/2020] [Accepted: 08/26/2020] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Previously published studies have indicated that lymphoid enhancer-binding factor 1 (LEF1) expression could be recognized as a valuable biomarker to evaluate clinical outcome for various types of malignant cancer, but the results remained controversial. Therefore, we conducted this meta-analysis to pool the published estimates and discuss the relationship of LEF1 expression with cancer prognosis. METHODS Five electronic databases Pubmed, Web of Science, Embase, CNKI, and Wanfang were systematically searched for eligible literatures. Hazard ratios (HRs) and 95% confidence intervals (CIs) from the included studies were combined to estimate the effect of LEF1 expression on cancer patients' survival. RESULTS Eleven original studies met the criteria and were enrolled for analysis. The results indicated that compared with patients in low LEF1 expression group, patients in high LEF1 expression group tended to have shorter overall survival (HR = 1.74, 95% CI: 1.06-2.86, P=0.029), especially for patients with solid tumors (HR = 2.39, 95% CI: 1.86-3.08, P=0.000). CONCLUSIONS Individual evidence about the prognostic value of LEF1 expression in human cancers was limited. Our meta-analysis supported the suggestion that elevated LEF1 expression could function as a promising biomarker to predict the clinical outcomes for malignant cancers, especially solid tumors. More high-quality clinical studies are warranted to highlight the prognostic value of LEF1 expression in human cancers.
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9
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Skopelitou D, Miao B, Srivastava A, Kumar A, Kuswick M, Dymerska D, Paramasivam N, Schlesner M, Lubinski J, Hemminki K, Försti A, Bandapalli OR. Whole Exome Sequencing Identifies APCDD1 and HDAC5 Genes as Potentially Cancer Predisposing in Familial Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22041837. [PMID: 33673279 PMCID: PMC7917948 DOI: 10.3390/ijms22041837] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/06/2021] [Accepted: 02/07/2021] [Indexed: 01/01/2023] Open
Abstract
Germline mutations in predisposition genes account for only 20% of all familial colorectal cancers (CRC) and the remaining genetic burden may be due to rare high- to moderate-penetrance germline variants that are not explored. With the aim of identifying such potential cancer-predisposing variants, we performed whole exome sequencing on three CRC cases and three unaffected members of a Polish family and identified two novel heterozygous variants: a coding variant in APC downregulated 1 gene (APCDD1, p.R299H) and a non-coding variant in the 5′ untranslated region (UTR) of histone deacetylase 5 gene (HDAC5). Sanger sequencing confirmed the variants segregating with the disease and Taqman assays revealed 8 additional APCDD1 variants in a cohort of 1705 familial CRC patients and no further HDAC5 variants. Proliferation assays indicated an insignificant proliferative impact for the APCDD1 variant. Luciferase reporter assays using the HDAC5 variant resulted in an enhanced promoter activity. Targeting of transcription factor binding sites of SNAI-2 and TCF4 interrupted by the HDAC5 variant showed a significant impact of TCF4 on promoter activity of mutated HDAC5. Our findings contribute not only to the identification of unrecognized genetic causes of familial CRC but also underline the importance of 5’UTR variants affecting transcriptional regulation and the pathogenesis of complex disorders.
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Affiliation(s)
- Diamanto Skopelitou
- Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (D.S.); (B.M.); (A.S.); (A.K.); (K.H.); (A.F.)
- Hopp Children’s Cancer Center (KiTZ), 69120 Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
- Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany
| | - Beiping Miao
- Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (D.S.); (B.M.); (A.S.); (A.K.); (K.H.); (A.F.)
- Hopp Children’s Cancer Center (KiTZ), 69120 Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
| | - Aayushi Srivastava
- Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (D.S.); (B.M.); (A.S.); (A.K.); (K.H.); (A.F.)
- Hopp Children’s Cancer Center (KiTZ), 69120 Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
- Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany
| | - Abhishek Kumar
- Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (D.S.); (B.M.); (A.S.); (A.K.); (K.H.); (A.F.)
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India
- Manipal Academy of Higher Education (MAHE), Manipal 576104, India
| | - Magdalena Kuswick
- Department of Genetics and Pathology, Pomeranian Medical University, 71252 Szczecin, Poland; (M.K.); (D.D.); (J.L.)
| | - Dagmara Dymerska
- Department of Genetics and Pathology, Pomeranian Medical University, 71252 Szczecin, Poland; (M.K.); (D.D.); (J.L.)
| | - Nagarajan Paramasivam
- Computational Oncology, Molecular Diagnostics Program, National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany;
| | - Matthias Schlesner
- Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;
| | - Jan Lubinski
- Department of Genetics and Pathology, Pomeranian Medical University, 71252 Szczecin, Poland; (M.K.); (D.D.); (J.L.)
| | - Kari Hemminki
- Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (D.S.); (B.M.); (A.S.); (A.K.); (K.H.); (A.F.)
- Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, 30605 Pilsen, Czech Republic
| | - Asta Försti
- Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (D.S.); (B.M.); (A.S.); (A.K.); (K.H.); (A.F.)
- Hopp Children’s Cancer Center (KiTZ), 69120 Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
| | - Obul Reddy Bandapalli
- Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (D.S.); (B.M.); (A.S.); (A.K.); (K.H.); (A.F.)
- Hopp Children’s Cancer Center (KiTZ), 69120 Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
- Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany
- Correspondence: ; Tel.: +49-6221-421809
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Wang T, Hao Z, Liu C, Yuan L, Li L, Yin M, Li Q, Qi Z, Wang Z. LEF1 mediates osteoarthritis progression through circRNF121/miR-665/MYD88 axis via NF-кB signaling pathway. Cell Death Dis 2020; 11:598. [PMID: 32732957 PMCID: PMC7393488 DOI: 10.1038/s41419-020-02769-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 07/07/2020] [Accepted: 07/10/2020] [Indexed: 12/20/2022]
Abstract
Osteoarthritis (OA) is a joint disease that causes great pain to patients and imposes a tremendous burden on the world’s medical resources. Regulatory noncoding RNAs, including circular RNAs (circRNAs) and microRNAs (miRNAs), play an important role in OA progression. Here, we identified differential expression of transcription factor LEF1 that increased circRNA circRNF121 levels in normal and OA cartilage tissues. The expression of LEF1 and circRNF121 was positively associated with Mankin’s scores. Alteration of circRNF121 mediated the degradation of extracellular mechanisms (ECM), apoptosis, and proliferation of chondrocytes. MiR-665 was identified as a direct regulatory target of circRNF121 and MYD88. Functional analysis showed that circRNF121 and MYD88 modulated ECM degradation, apoptosis, and proliferation of chondrocytes, which could be reversed by miR-665. MYD88 regulated the activity of the NF-кB signaling pathway by circRNF121 via sponging miR-665. Collectively, these data indicated that LEF1 impacted OA progression by modulating the circRNF121/miR-665/MYD88 axis via NF-кB pathway. Our research proposed a new molecular mechanism for the development of OA, and provided a prospective therapeutic target for OA.
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Affiliation(s)
- Tianfu Wang
- Department of Sports Medicine, Dalian Municipal Central Hospital, Dalian, 116033, Liaoning Province, China.,Department of Spinal Surgery, The Second Hospital of Dalian Medical University, Dalian, 116033, Liaoning Province, China
| | - Zhiyu Hao
- Department of Medical Imageology, Dalian Medical University, Dalian, 116044, Liaoning Province, China
| | - Changcheng Liu
- Department of Sports Medicine, Dalian Municipal Central Hospital, Dalian, 116033, Liaoning Province, China
| | - Lebin Yuan
- Department of Sports Medicine, Dalian Municipal Central Hospital, Dalian, 116033, Liaoning Province, China
| | - Li Li
- Department of Sports Medicine, Dalian Municipal Central Hospital, Dalian, 116033, Liaoning Province, China
| | - Menghong Yin
- Department of Sports Medicine, Dalian Municipal Central Hospital, Dalian, 116033, Liaoning Province, China
| | - Qing Li
- Department of Sports Medicine, Dalian Municipal Central Hospital, Dalian, 116033, Liaoning Province, China
| | - Zhiming Qi
- Department of Sports Medicine, Dalian Municipal Central Hospital, Dalian, 116033, Liaoning Province, China
| | - Zi Wang
- Department of Sports Medicine, Dalian Municipal Central Hospital, Dalian, 116033, Liaoning Province, China.
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Michelli M, Zougros A, Chatziandreou I, Michalopoulos NV, Lazaris AC, Saetta AA. Concurrent Wnt pathway component expression in breast and colorectal cancer. Pathol Res Pract 2020; 216:153005. [PMID: 32534708 DOI: 10.1016/j.prp.2020.153005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/27/2020] [Accepted: 05/07/2020] [Indexed: 02/07/2023]
Abstract
Wnt signaling pathway regulates important cell functions such as proliferation and migration and is frequently deregulated in colorectal and breast cancer. Thus, it constitutes an attractive therapeutic target with many drugs being investigated in clinical trials. Eighty-two breast and 102 colorectal carcinomas were analyzed for: relative mRNA expression levels of Wnt pathway components namely Wnt3 ligand, Frizzled 7 receptor and LEF1 transcriptional factor, their concurrent expression patterns and their correlation with clinicopathological features. Regarding breast carcinomas, increased relative mRNA expression levels of WNT3 were found in 54 % of cases whereas decreased relative mRNA expression levels were observed in FZD7 and LEF1 in 82 % and 43 % of cases, respectively. Expression levels of WNT3 were significantly correlated with tumour grade (p = 0.021) in breast cancer. As far as colorectal carcinomas are concerned, increased relative mRNA expression levels of WNT3, FZD7 and LEF1 were found in 60 %, 37 % and 48 % of cases respectively. A statistically significant correlation emerged between LEF1expression levels and pT-category (p = 0.027), suggesting a possible association with tumour aggressiveness in colorectal carcinomas. Statistically significant linear correlations were observed between the expression of WNT3/LEF1 (R = 0.233, p = 0.035) and FZD7/LEF1 (R = 0.359, p = 0.001) in breast carcinomas as well as in colorectal carcinomas (R = 0.536, p < 0.01 and R = 0.210, p = 0.034) respectively. Our results demonstrate a possible clinical significance of Wnt pathway gene expression levels in both tumour types. The distinct expression patterns and simultaneous expression of the investigated genes underscore the complexity of this pathway in breast and colorectal carcinogenesis and highlights the necessity of patient selection with regard to the effectiveness of Wnt pathway inhibitors.
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Affiliation(s)
- Maria Michelli
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, Athens, Greece
| | - Alexandros Zougros
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, Athens, Greece
| | - Ilenia Chatziandreou
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, Athens, Greece
| | - Nikolaos V Michalopoulos
- Fourth Department of Surgery, Medical School, National and Kapodistrian University of Athens, Attikon University Hospital, Rimini 1, Haidari, Athens, Greece
| | - Andreas C Lazaris
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, Athens, Greece
| | - Angelica A Saetta
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, Athens, Greece.
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12
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Su H, Qiao Y, Xi Z, Wang J, Bao Z. The Impact of High-mobility Group Box Mutation of T-cell Factor 4 on Its Genomic Binding Pattern in Non-small Cell Lung Cancer. Transl Oncol 2019; 13:79-85. [PMID: 31805518 PMCID: PMC6909080 DOI: 10.1016/j.tranon.2019.09.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 09/25/2019] [Accepted: 09/26/2019] [Indexed: 10/25/2022] Open
Abstract
T-cell factor 4 (TCF-4) is determined to play a crucial role in Wnt/β-catenin signaling pathway activation. The mutations and alternative splice isoforms of TCF-4 can cause cancers and other diseases. The high-mobility group (HMG) box domain of TCF-4 contributes to interacting with DNA motif for transcriptional regulation. However, the impact of the mutations within HMG box of TCF-4 on the genomic binding pattern is poorly investigated. Herein, we generated non-small cell lung cancer (NSCLC) cell line A549 with stably overexpressed TCF-4 with HMG box hot spot mutation (10th exon partial deletion), and conducted TCF-4 and β-catenin chromatin immunoprecipitation sequence to explore the differential genomic binding patterns. Our results revealed that TCF-4 lost 19365 but gained 1724 peaks, and β-catenin lost 4035 but gained 5287 peaks upon mutant TCF-4 compared with the wild type (log2FC > 1 or < -1, FDR<0.01). The transcriptional levels of the genes associated with these differential peaks such as H3F3C, KRT1, KRT14, MMp1, and MMP15 were all found to strongly change responding to TCF-4 binding (P < 0.05). Furthermore, A549 cells with TCF-4 mutation displayed a more compromising tumor characterization on cell proliferation and invasion. Our data determined the important role of TCF-4 in gene transcription controlling and provided the gain function evidence of TCF-4 caused by the TCF-4 mutation in NSCLC.
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Affiliation(s)
- Hongjian Su
- The Second Department of Respiratory and Critical Care, Henan Provincial Chest Hospital, 450008, China
| | - Yahong Qiao
- The Second Department of Respiratory and Critical Care, Henan Provincial Chest Hospital, 450008, China.
| | - Zhuona Xi
- The Second Department of Respiratory and Critical Care, Henan Provincial Chest Hospital, 450008, China
| | - Jifang Wang
- The Second Department of Respiratory and Critical Care, Henan Provincial Chest Hospital, 450008, China
| | - Zhen Bao
- The Second Department of Respiratory and Critical Care, Henan Provincial Chest Hospital, 450008, China
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13
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Chen F, Chen X, Ren Y, Weng G, Keng PC, Chen Y, Lee SO. Radiation-induced glucocorticoid receptor promotes CD44+ prostate cancer stem cell growth through activation of SGK1-Wnt/β-catenin signaling. J Mol Med (Berl) 2019; 97:1169-1182. [PMID: 31187175 DOI: 10.1007/s00109-019-01807-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 05/03/2019] [Accepted: 05/27/2019] [Indexed: 12/21/2022]
Abstract
We observed cancer stem cell (CSC) population increase in radioresistant LNCaP (LNCaPR18) and C4-2 (C4-2R26) prostate cancer (PCa) cells compared with respective parental cells. Since the CD44 level increase was most significant in radioresistant PCa cells compared with parental cells among CSC markers tested, we isolated the CD44+ population from LNCaP/LNCaPR18 and C4-2/C4-2R26 cell sets via the immunomagnetic separation method and used them as CSC sources. We detected lower AR level, but higher glucocorticoid receptor (GR) level in CD44+ CSCs than CD44- non-CSCs. Higher GR level in CD44+ CSCs than CD44- cells was also detected when cells were isolated from mouse tumor tissues of LNCaPR18 cell and C4-2R26 cell-derived human xenografts and grown in culture. We then found blocking the GR signaling by adding the anti-GR agent mifepristone into the cell culture inhibited the CD44+ CSC growth while the addition of the anti-AR agent enzalutamide enhanced the CSC growth. In xenograft mouse studies in which tumors were developed from the injection of CD44+ CSCs of LNCaPR18 or C4-2R26 cell lines, retarded tumor growth in mifepristone-injected mice was observed compared with vehicle-treated mice. We next discovered the GR regulation of Wnt/β-catenin signaling pathway. We further found that the serum/glucocorticoid regulated kinase 1 (SGK1) is the GR downstream molecule that mediates Wnt/β-catenin signaling activation. Therefore, inhibition of either SGK1 or Wnt/β-catenin signaling impaired the in vitro CD44+ CSC growth. From these results, we suggest that blocking GR signaling or its downstream SGK1-Wnt/β-catenin signaling axis may suppress the radiation-induced CSC increase in PCa. KEY MESSAGES: Higher CSC population exists in radioresistant PCa cells than parental cells. Higher GR levels (and lower AR level) in CD44+ CSCs than CD44- non-CSCs. Use of anti-GR agent blocked the growth of CD44+ CSCs in in vitro/in vivo tests. GR downstream SGK1-Wnt/β-catenin signaling axis mediates the CSC increase. Targeting this signaling axis may enhance the radiotherapy efficacy in treating PCa.
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Affiliation(s)
- Feng Chen
- Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA.,Department of Urology, Ningbo Urology and Nephrology Hospital, Ningbo, 315100, Zhejiang, People's Republic of China
| | - Xiaodong Chen
- Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA.,Department of Urology, Ningbo Urology and Nephrology Hospital, Ningbo, 315100, Zhejiang, People's Republic of China
| | - Yu Ren
- Department of Urology, Ningbo Urology and Nephrology Hospital, Ningbo, 315100, Zhejiang, People's Republic of China
| | - Guobin Weng
- Department of Urology, Ningbo Urology and Nephrology Hospital, Ningbo, 315100, Zhejiang, People's Republic of China
| | - Peter C Keng
- Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA
| | - Yuhchyau Chen
- Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA. .,Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester, 601 Elmwood Ave., Box 647, Rochester, NY, 14642, USA.
| | - Soo Ok Lee
- Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA. .,Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester, 601 Elmwood Ave., Box 647, Rochester, NY, 14642, USA.
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14
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Zhan Y, Feng J, Lu J, Xu L, Wang W, Fan S. Expression of LEF1 and TCF1 (TCF7) proteins associates with clinical progression of nasopharyngeal carcinoma. J Clin Pathol 2019; 72:425-430. [DOI: 10.1136/jclinpath-2019-205698] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 02/22/2019] [Accepted: 02/26/2019] [Indexed: 12/24/2022]
Abstract
AimsOur previous study has demonstrated that β-catenin pathway was abnormally activated in nasopharyngeal carcinoma (NPC). The purposes of the present study are to investigate whether the alterations of LEF1 and TCF1 (TCF7) proteins, the important components of the canonical Wnt/β-catenin pathway, are associated with clinicopathological features and prognostic implications.MethodsWe collected 391 cases of NPC, 53 non-cancerous control nasopharyngeal mucosa and 28 pairs of NPC and their matched metastases, detected expression of LEF1 and TCF1 (TCF7) proteins in these tissues by immunohistochemistry. ResultsResults showed that there were significantly increased expression of both LEF1 and TCF1 (TCF7) proteins and coexpression of LEF1 and TCF1 (TCF7) in NPC than these in non-cancerous nasopharyngeal mucosa (all p<0.001), as well as LEF1 and coexpression of LEF1 and TCF1 (TCF7) in matched metastasis NPCs than these in the primary NPCs (p=0.003 and p=0.014, respectively). In addition, expression of LEF1 and the coexpression of LEF1 and TCF1 (TCF7) proteins were positively correlated with lymph node metastasis (p=0.001 and p=0.020, respectively), advanced clinical stage (p<0.003 and p=0.027, respectively) and poor survival status of patients with NPC (p<0.001 and p=0.004, respectively). Moreover, multivariate Cox regression analysis identified that the positive expression of LEF1 was the independent poor prognostic factor for overall survival of patients with NPC (p<0.001).ConclusionsThe expression of LEF1 associated positively with TCF1 (TCF7) and clinical progression of NPC, and positive expression of LEF1 protein may act as valuable independent biomarker to predict poor prognosis for patients with NPC.
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15
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Kusonmano K, Halle MK, Wik E, Hoivik EA, Krakstad C, Mauland KK, Tangen IL, Berg A, Werner HMJ, Trovik J, Øyan AM, Kalland KH, Jonassen I, Salvesen HB, Petersen K. Identification of highly connected and differentially expressed gene subnetworks in metastasizing endometrial cancer. PLoS One 2018; 13:e0206665. [PMID: 30383835 PMCID: PMC6211718 DOI: 10.1371/journal.pone.0206665] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 10/17/2018] [Indexed: 12/22/2022] Open
Abstract
We have identified nine highly connected and differentially expressed gene subnetworks between aggressive primary tumors and metastatic lesions in endometrial carcinomas. We implemented a novel pipeline combining gene set and network approaches, which here allows integration of protein-protein interactions and gene expression data. The resulting subnetworks are significantly associated with disease progression across tumor stages from complex atypical hyperplasia, primary tumors to metastatic lesions. The nine subnetworks include genes related to metastasizing features such as epithelial-mesenchymal transition (EMT), hypoxia and cell proliferation. TCF4 and TWIST2 were found as central genes in the subnetwork related to EMT. Two of the identified subnetworks display statistically significant association to patient survival, which were further supported by an independent validation in the data from The Cancer Genome Atlas data collection. The first subnetwork contains genes related to cell proliferation and cell cycle, while the second contains genes involved in hypoxia such as HIF1A and EGLN3. Our findings provide a promising context to elucidate the biological mechanisms of metastasis, suggest potential prognostic markers and further identify therapeutic targets. The pipeline R source code is freely available, including permutation tests to assess statistical significance of the identified subnetworks.
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Affiliation(s)
- Kanthida Kusonmano
- Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
- Bioinformatics and Systems Biology Program, School of Bioresources and Technology, King Mongkut’s University of Technology Thonburi, Bangkok, Thailand
- * E-mail:
| | - Mari K. Halle
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
- Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Elisabeth Wik
- Centre for Cancer Biomarkers, Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Pathology, The Gade Institute, Haukeland University Hospital, Bergen, Norway
| | - Erling A. Hoivik
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
- Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Camilla Krakstad
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
- Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Karen K. Mauland
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
- Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Ingvild L. Tangen
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
- Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Anna Berg
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
- Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Henrica M. J. Werner
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
- Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Jone Trovik
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
- Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Anne M. Øyan
- Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Microbiology, Haukeland University Hospital, Bergen, Norway
| | - Karl-Henning Kalland
- Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Microbiology, Haukeland University Hospital, Bergen, Norway
| | - Inge Jonassen
- Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway
- Centre for Cancer Biomarkers, Department of Informatics, University of Bergen, Bergen, Norway
| | - Helga B. Salvesen
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
- Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Kjell Petersen
- Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway
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Eskandari E, Mahjoubi F, Motalebzadeh J. An integrated study on TFs and miRNAs in colorectal cancer metastasis and evaluation of three co-regulated candidate genes as prognostic markers. Gene 2018; 679:150-159. [PMID: 30193961 DOI: 10.1016/j.gene.2018.09.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 08/06/2018] [Accepted: 09/03/2018] [Indexed: 01/20/2023]
Abstract
Molecular alterations that occur in cancer have the potential to be considered as either cancer biomarkers or targeted therapies or even both. In the presented study, we aimed to elucidate the gene regulatory network of metastatic colorectal cancer using data acquired from microarrays to reach the most common DEGs in colorectal cancer metastasis and find their possible regulatory mechanism by DETFs and DEmiRs. In this regards, seven microarray datasets were employed to assess the most important DEGs, DETFs and DEmiRs in colorectal cancer metastasis. Afterward, GRN based on DETFs and DEmiRs were constructed. Also ARACNE algorithm was used to construct an accurate GRN. GRN was analyzed structurally and then, two DETFs (LEF1 and ETV4) and a less-well known DEG (FABP6) by real time qRT-PCR in 50 patients with colorectal cancer were quantified. The constructed GRN highlighted the importance of some DETFs and DEmiRs in colorectal cancer metastasis. Interestingly the gene expression analysis by qRT-PCR on three candidate genes (LEF1, ETV4 and FABP6) indicated that the three genes were co-expressed in tumor samples, and were significantly associated with metastasis in colorectal cancer. Therefore, our experimental results proved a part of our comprehensive data analysis and system biology results. In summary, according to our empirical study we found the importance of three candidate genes as the potent prognostic factors in colorectal cancer metastasis. Also our study in a holistic insight on gene regulatory mechanism revealed the importance of some gene regulatory factors (DETFs and DEmiRs) and their potential as prognostic factors and/or targets in molecular targeted therapies in colorectal cancer.
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Affiliation(s)
- Elaheh Eskandari
- Department of Clinical Genetics, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Frouzandeh Mahjoubi
- Department of Clinical Genetics, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Jamshid Motalebzadeh
- Department of Clinical Genetics, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.
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Davidsen J, Larsen S, Coskun M, Gögenur I, Dahlgaard K, Bennett EP, Troelsen JT. The VTI1A-TCF4 colon cancer fusion protein is a dominant negative regulator of Wnt signaling and is transcriptionally regulated by intestinal homeodomain factor CDX2. PLoS One 2018; 13:e0200215. [PMID: 29975781 PMCID: PMC6033461 DOI: 10.1371/journal.pone.0200215] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 06/21/2018] [Indexed: 02/07/2023] Open
Abstract
Sequencing of primary colorectal tumors has identified a gene fusion in approximately 3% of colorectal cancer patients of the VTI1A and TCF7L2 genes, encoding a VTI1A-TCF4 fusion protein containing a truncated TCF4. As dysregulation of the Wnt signaling pathway is associated with colorectal cancer development and progression, the functional properties and transcriptional regulation of the VTI1A-TCF4 fusion protein may also play a role in these processes. Functional characteristics of the VTI1A-TCF4 fusion protein in Wnt signaling were analyzed in NCI-H508 and LS174T colon cancer cell lines. The NCI-H508 cell line, containing the VTI1A-TCF7L2 fusion gene, showed no active Wnt signaling, and overexpression of the VTI1A-TCF4 fusion protein in LS174T cells along with a Wnt signaling luciferase reporter plasmid showed inhibition of activity. The transcriptional regulation of the VTI1A-TCF4 fusion gene was investigated in LS174T cells where the activity of the VTI1A promoter was compared to that of the TCF7L2 promoter, and the transcription factor CDX2 was analyzed for gene regulatory activity of the VTI1A promoter through luciferase reporter gene assay using colon cancer cell lines as a model. Transfection of LS174T cells showed that the VTI1A promoter is highly active compared to the TCF7L2 promoter, and that CDX2 activates transcription of VTI1A. These results suggest that the VTI1A-TCF4 fusion protein is a dominant negative regulator of the Wnt signaling pathway, and that transcription of VTI1A is activated by CDX2.
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Affiliation(s)
- Johanne Davidsen
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
- Department of Surgery, Zealand University Hospital, Roskilde, Denmark
| | - Sylvester Larsen
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
- Department of Clinical Immunology, Naestved Hospital, Naestved, Denmark
| | - Mehmet Coskun
- Department of Gastroenterology, Herlev Hospital, Herlev, Denmark
| | - Ismail Gögenur
- Department of Surgery, Zealand University Hospital, Roskilde, Denmark
| | - Katja Dahlgaard
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Eric Paul Bennett
- Copenhagen Center for Glycomics, Department of Odontology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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18
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The role of Pygo2 for Wnt/ß-catenin signaling activity during intestinal tumor initiation and progression. Oncotarget 2018; 7:80612-80632. [PMID: 27811361 PMCID: PMC5348345 DOI: 10.18632/oncotarget.13016] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 10/21/2016] [Indexed: 12/16/2022] Open
Abstract
Pygo2 acts as a co-activator of Wnt signaling in a nuclear complex with ß-catenin/BCL9/BCL9-2 to increase target gene transcription. Previous studies showed that Pygo2 is upregulated in murine intestinal tumors and human colon cancer, but is apparently dispensable for normal intestinal homeostasis. Here, we have evaluated the in vivo role of Pygo2 during intestinal tumorigenesis using Pygo2 deficient mice. We analyzed chemically induced colon tumor development and conditional intestine specific mouse models harboring either Apc loss-of-function (LOF) or Ctnnb1 gain-of-function (ß-catenin GOF). Remarkably, the number and size of chemically induced tumors was significantly reduced in Pygo2 deficient mice, suggesting that Pygo2 has a tumor promoting function. Furthermore, loss of Pygo2 rescued early tumorigenesis of Ctnnb1 GOF mutants. In contrast, Pygo2 ablation was not sufficient to prevent tumor development of Apc LOF mice. The effect on tumor formation by Pygo2 knockout was linked to the repression of specific deregulated Wnt target genes, in particular of c-Myc. Moreover, the role of Pygo2 appears to be associated with the signaling output of deregulated Wnt signaling in the different tumor models. Thus, targeting Pygo2 might provide a novel strategy to suppress tumor formation in a context dependent manner.
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Han W, He L, Cao B, Zhao X, Zhang K, Li Y, Beck P, Zhou Z, Tian Y, Cheng S, Wang H. Differential expression of LEF1/TCFs family members in colonic carcinogenesis. Mol Carcinog 2017; 56:2372-2381. [PMID: 27433921 DOI: 10.1002/mc.22530] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 07/04/2016] [Accepted: 07/11/2016] [Indexed: 01/19/2023]
Abstract
Lef1/Tcfs family, which includes Lef1, Tcf1, Tcf3, and Tcf4, is required for the transcriptional activation induced by β-catenin. However, whether all the members play the same role in colon carcinogenesis is not clear. We found that Lef1 and Tcf1, but not Tcf3 and Tcf4, were upregulated at both mRNA and protein level with the formation of colon tumor in AOM-DSS mouse model. The same profiles were seen in human specimens with the evolvement from adenoma to adenocarcinoma. Additionally, Lef1 and Tcf1 were correlated with a subgroup of Wnt target genes, including Lgr5, a key gene of intestinal stem cell. Further studies supported the role of Tcf1 on sphere formation and transcriptional regulation of Lgr5 in vitro. Interestingly, 3' UTR of each Lef1/Tcfs member were targeted by diverse miRNAs, which were negatively correlated with respective member in human colon cancer specimens. Furthermore, these miRNAs were verified to repress Tcf1 and Lef1 in vitro. Taken together, Lef1 and Tcf1 showed oncogenic effect in colonic carcinogenesis. Cellular context of miRNAs might play important roles in carcinogenesis by altering the expression pattern of Lef/Tcfs members. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Wenxiao Han
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Longmei He
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bangrong Cao
- Department of etiology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Basic Research, Sichuan Cancer Hospital and Institute, Sichuan, China
| | - Xinhua Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Kaitai Zhang
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of etiology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan Li
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada
| | - Paul Beck
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada
| | - Zhixiang Zhou
- Department of Gastrointestinal Cancer Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yantao Tian
- Department of Gastrointestinal Cancer Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shujun Cheng
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of etiology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongying Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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20
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Yang Q, Feng M, Ma X, Li H, Xie W. Gene expression profile comparison between colorectal cancer and adjacent normal tissues. Oncol Lett 2017; 14:6071-6078. [PMID: 29113248 DOI: 10.3892/ol.2017.6915] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 10/13/2016] [Indexed: 01/07/2023] Open
Abstract
The present study aimed to compare gene expression profiles between colorectal cancer and adjacent normal tissues, and to perform a preliminarily analysis of the key genes and underlying molecular mechanisms implicated in colorectal cancer development. Gene expression microarray chips were used to screen genes that were differently expressed between colorectal cancer and adjacent normal tissues. Approximately 1,183 genes were differentially expressed in cancer tissues compared with adjacent normal tissues (P≤0.05; fold difference, >2.0), of which 570 genes were upregulated and 613 genes were downregulated. In total, 6 upregulated genes, including keratin 23, collagen type X α1, collagen type XI α1, cell migration-inducing hyaluronan-binding protein, transforming growth factor-β1 and V-Myc avian myelocytomatosis viral oncogene homolog, and 2 downregulated genes, including channel α subunit 7 and EPH receptor A7, were selected and validated using reverse transcription-quantitative polymerase chain reaction, which exhibited results that were consistent with the microarray analysis. These 1,183 differentially expressed genes were further classified into 71 groups based on their functions using gene ontology and pathway analyses. Kyoto Encyclopedia of Genes and Genomes analysis of these upregulated or downregulated genes suggested that 23 signaling pathways were involved. The present study preliminarily screened for and identified key genes and signaling pathways that may be closely associated with colorectal cancer development. However, subsequent gene function studies are required to verify these findings.
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Affiliation(s)
- Qian Yang
- Department of Ultrasound, Hubei Cancer Hospital, Wuhan, Hubei 430071, P.R. China
| | - Maohui Feng
- Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Xiang Ma
- Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Huachi Li
- Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Wei Xie
- Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
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21
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Emons G, Spitzner M, Reineke S, Möller J, Auslander N, Kramer F, Hu Y, Beissbarth T, Wolff HA, Rave-Fränk M, Heßmann E, Gaedcke J, Ghadimi BM, Johnsen SA, Ried T, Grade M. Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/β-catenin Signaling. Mol Cancer Res 2017; 15:1481-1490. [PMID: 28811361 DOI: 10.1158/1541-7786.mcr-17-0205] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 07/11/2017] [Accepted: 08/08/2017] [Indexed: 01/21/2023]
Abstract
Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer. The Wnt-transcription factor, TCF7L2, is overexpressed in primary rectal cancers that are resistant to chemoradiotherapy and TCF7L2 mediates resistance to chemoradiotherapy. However, it is unclear whether the resistance is mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. Here, inhibition of β-catenin by siRNAs or a small-molecule inhibitor (XAV-939) resulted in sensitization of colorectal cancer cells to chemoradiotherapy. To investigate the potential role of Wnt/β-catenin signaling in controlling therapeutic responsiveness, nontumorigenic RPE-1 cells were stimulated with Wnt-3a, a physiologic ligand of Frizzled receptors, which increased resistance to chemoradiotherapy. This effect could be recapitulated by overexpression of a degradation-resistant mutant of β-catenin (S33Y), also boosting resistance of RPE-1 cells to chemoradiotherapy, which was, conversely, abrogated by siRNA-mediated silencing of β-catenin. Consistent with these findings, higher expression levels of active β-catenin were observed as well as increased TCF/LEF reporter activity in SW1463 cells that evolved radiation resistance due to repeated radiation treatment. Global gene expression profiling identified several altered pathways, including PPAR signaling and other metabolic pathways, associated with cellular response to radiation. In summary, aberrant activation of Wnt/β-catenin signaling not only regulates the development and progression of colorectal cancer, but also mediates resistance of rectal cancers to chemoradiotherapy.Implications: Targeting Wnt/β-catenin signaling or one of the downstream pathways represents a promising strategy to increase response to chemoradiotherapy. Mol Cancer Res; 15(11); 1481-90. ©2017 AACR.
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Affiliation(s)
- Georg Emons
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany.,Genetics Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Melanie Spitzner
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany
| | - Sebastian Reineke
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany
| | - Janneke Möller
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany
| | - Noam Auslander
- Genetics Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Frank Kramer
- Department of Medical Statistics, University Medical Center Goettingen, Goettingen, Germany
| | - Yue Hu
- Genetics Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Tim Beissbarth
- Department of Medical Statistics, University Medical Center Goettingen, Goettingen, Germany
| | - Hendrik A Wolff
- Department of Radiotherapy and Radiooncology, University Medical Center Goettingen, Goettingen, Germany.,Department of Radiology, Nuclear Medicine and Radiotherapy, Radiology Munich, Munich, Germany
| | - Margret Rave-Fränk
- Department of Radiotherapy and Radiooncology, University Medical Center Goettingen, Goettingen, Germany
| | - Elisabeth Heßmann
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany
| | - Jochen Gaedcke
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany
| | - B Michael Ghadimi
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany
| | - Steven A Johnsen
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany
| | - Thomas Ried
- Genetics Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Marian Grade
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany.
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22
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Hsu HH, Chen MC, Day CH, Lin YM, Li SY, Tu CC, Padma VV, Shih HN, Kuo WW, Huang CY. Thymoquinone suppresses migration of LoVo human colon cancer cells by reducing prostaglandin E2 induced COX-2 activation. World J Gastroenterol 2017; 23:1171-1179. [PMID: 28275297 PMCID: PMC5323442 DOI: 10.3748/wjg.v23.i7.1171] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 11/09/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To identify potential anti-cancer constituents in natural extracts that inhibit cancer cell growth and migration.
METHODS Our experiments used high dose thymoquinone (TQ) as an inhibitor to arrest LoVo (a human colon adenocarcinoma cell line) cancer cell growth, which was detected by cell proliferation assay and immunoblotting assay. Low dose TQ did not significantly reduce LoVo cancer cell growth. Cyclooxygenase 2 (COX-2) is an enzyme that is involved in the conversion of arachidonic acid into prostaglandin E2 (PGE2) in humans. PGE2 can promote COX-2 protein expression and tumor cell proliferation and was used as a control.
RESULTS Our results showed that 20 μmol/L TQ significantly reduced human LoVo colon cancer cell proliferation. TQ treatment reduced the levels of p-PI3K, p-Akt, p-GSK3β, and β-catenin and thereby inhibited the downstream COX-2 expression. Results also showed that the reduction in COX-2 expression resulted in a reduction in PGE2 levels and the suppression of EP2 and EP4 activation. Further analysis showed that TG treatment inhibited the nuclear translocation of β-catenin in LoVo cancer cells. The levels of the cofactors LEF-1 and TCF-4 were also decreased in the nucleus following TQ treatment in a dose-dependent manner. Treatment with low dose TQ inhibited the COX-2 expression at the transcriptional level and the regulation of COX-2 expression efficiently reduced LoVo cell migration. The results were further verified in vivo by confirming the effects of TQ and/or PGE2 using tumor xenografts in nude mice.
CONCLUSION TQ inhibits LoVo cancer cell growth and migration, and this result highlights the therapeutic advantage of using TQ in combination therapy against colorectal cancer.
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23
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Sinha S. A pedagogical walkthrough of computational modeling and simulation of Wnt signaling pathway using static causal models in MATLAB. EURASIP JOURNAL ON BIOINFORMATICS & SYSTEMS BIOLOGY 2016; 2017:1. [PMID: 27547217 PMCID: PMC4977324 DOI: 10.1186/s13637-016-0044-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 07/22/2016] [Indexed: 12/26/2022]
Abstract
Simulation study in systems biology involving computational experiments dealing with Wnt signaling pathways abound in literature but often lack a pedagogical perspective that might ease the understanding of beginner students and researchers in transition, who intend to work on the modeling of the pathway. This paucity might happen due to restrictive business policies which enforce an unwanted embargo on the sharing of important scientific knowledge. A tutorial introduction to computational modeling of Wnt signaling pathway in a human colorectal cancer dataset using static Bayesian network models is provided. The walkthrough might aid biologists/informaticians in understanding the design of computational experiments that is interleaved with exposition of the Matlab code and causal models from Bayesian network toolbox. The manuscript elucidates the coding contents of the advance article by Sinha (Integr. Biol. 6:1034-1048, 2014) and takes the reader in a step-by-step process of how (a) the collection and the transformation of the available biological information from literature is done, (b) the integration of the heterogeneous data and prior biological knowledge in the network is achieved, (c) the simulation study is designed, (d) the hypothesis regarding a biological phenomena is transformed into computational framework, and (e) results and inferences drawn using d-connectivity/separability are reported. The manuscript finally ends with a programming assignment to help the readers get hands-on experience of a perturbation project. Description of Matlab files is made available under GNU GPL v3 license at the Google code project on https://code.google.com/p/static-bn-for-wnt-signaling-pathway and https: //sites.google.com/site/shriprakashsinha/shriprakashsinha/projects/static-bn-for-wnt-signaling-pathway. Latest updates can be found in the latter website.
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24
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Kaya S, Gumus M, Gurbuz Y, Cabuk D, Acikgoz O, Temiz S, Uygun K. The prognostic value of β-catenin and LEF-1 expression in patients with operable gastric carcinoma. Am J Transl Res 2016; 8:1228-1236. [PMID: 27158409 PMCID: PMC4846966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Accepted: 02/08/2016] [Indexed: 06/05/2023]
Abstract
AIM The aim of this study is to evaluate the prognostic value of β-catenin and LEF-1 expression in patients with operable gastric cancer that receive adjuvant treatment and the relationship between demographic and histopathological variables. MATERIAL AND METHOD In this study, 82 gastric cancer patients treated with adjuvant treatment after surgery and followed in the Medical Oncology Department of Kocaeli University were included. β-catenin and LEF-1 expression were examined by immunuhistochemical analysis in paraffin embedded tumor tissues of the patients. RESULTS Median age was 56 (26-81) and follow up was 19 months (4-61). Performance status (ECOG) were 0-1 in all patients. Male/female ratio was 53/29 (64.6/35.4%). The median disease free survival (DFS) time was 17 months (SE: 3 95% CI: 11-23) and 3 years DFS rate was 39.7%. The median overall survival (OS) time was 28 months (SE: 4 95% CI: 20-36) and 3 years OS rate was 41.2%. There was no statistical correlation between β-catenin and LEF-1 expression and age, gender, performance status, tumor localization, T and N stage, lymphovascular, perinoral invasion, grade and operation type (>0.005). According to univariate analysis, we did not find significant effect of age, gender, T stage, lymphovascular, perinoral invasion, grade and operation type on overall survival (p>0.005). Good performance status (ECOG 0), tumor infiltration without diffuse type like linitis plastica, and lower N stage had positive effect on survival respectively (p=0.04, 0.033 and 0.005). CONCLUSION In this study group, we found that only N stage was an independent prognostic factor (<0.005). Demographic features of the patients, histopathological characteristics other than N stage, β-catenin and LEF-1 prognostic effects have not been shown.
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Affiliation(s)
- Serap Kaya
- Department of Medical Oncology, Medical Faculty, Kocaeli UniversityKocaeli, Turkey
| | - Mahmut Gumus
- Department of Medical Oncology, Medical Faculty, Bezmialem UniversityIstanbul, Turkey
| | - Yesim Gurbuz
- Department of Pathology, Medical Faculty, Kocaeli UniversityKocaeli, Turkey
| | - Devrim Cabuk
- Department of Medical Oncology, Medical Faculty, Kocaeli UniversityKocaeli, Turkey
| | - Ozgur Acikgoz
- Department of Medical Oncology, Medical Faculty, Kocaeli UniversityKocaeli, Turkey
| | - Suleyman Temiz
- Department of Medical Oncology, Medical Faculty, Kocaeli UniversityKocaeli, Turkey
| | - Kazim Uygun
- Department of Medical Oncology, Medical Faculty, Kocaeli UniversityKocaeli, Turkey
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25
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Kaller M, Hermeking H. Interplay Between Transcription Factors and MicroRNAs Regulating Epithelial-Mesenchymal Transitions in Colorectal Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 937:71-92. [DOI: 10.1007/978-3-319-42059-2_4] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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26
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LEF-1 is frequently expressed in colorectal carcinoma and not in other gastrointestinal tract adenocarcinomas: an immunohistochemical survey of 602 gastrointestinal tract neoplasms. Appl Immunohistochem Mol Morphol 2015; 22:728-34. [PMID: 25394300 DOI: 10.1097/pai.0000000000000109] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
LEF-1 is a DNA-binding protein that interacts with β-catenin and activates Wnt-responsive target genes. We analyzed the immunohistochemical expression of LEF-1 in 602 gastrointestinal and pancreatobiliary neoplasms in an attempt to (1) investigate the utility of LEF-1 immunohistochemistry as an ancillary marker in gastrointestinal/pancreatobiliary neoplasia, and (2) to perform a clinicopathologic and survival analysis of colorectal carcinoma stratified by LEF-1 expression. LEF-1 nuclear positivity was frequently identified in colorectal carcinoma (89/241, 37%) and only infrequently identified in other neoplasms: 11% esophagus/esophagogastric adenocarcinomas, 7% gastric adenocarcinomas, 1% pancreatic ductal adenocarcinomas, 4% pancreatic intraductal papillary mucinous neoplasms, and in no cases of appendiceal mucinous neoplasms or pancreatic mucinous cystic neoplasms. LEF-1 expression was identified in 35% of colorectal carcinomas that lacked CK20 and CDX2 expression. In colorectal carcinomas, LEF-1-positive tumors more frequently harbored KRAS mutations compared with LEF-1-negative tumors (39% vs. 16%, P=0.005). Patients with moderate/strong LEF-1-positive colorectal carcinoma had a trend of worse overall survival compared with patients with colorectal carcinomas with weak/negative LEF-1 expression (5 y overall survival, 31% vs. 47%, P=0.15). In conclusion, LEF-1 is most commonly expressed in colorectal carcinoma and infrequently observed in the upper gastrointestinal tract and pancreatic adenocarcinoma. LEF-1 Immunohistochemistry may be especially useful as an ancillary diagnostic marker in colorectal carcinomas, which lack the expression of both CK20 and CDX2. LEF-1 expression is associated with the presence of KRAS mutations and may have prognostic value as a trend of worse overall survival is seen in patients with LEF-1-positive colorectal carcinoma.
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27
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Sinha S. Integration of prior biological knowledge and epigenetic information enhances the prediction accuracy of the Bayesian Wnt pathway. Integr Biol (Camb) 2015; 6:1034-48. [PMID: 25167061 DOI: 10.1039/c4ib00124a] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Computational modeling of the Wnt signaling pathway has gained prominence for its use as a diagnostic tool to develop therapeutic cancer target drugs and predict test samples as tumorous/normal. Diagnostic tools entail modeling of the biological phenomena behind the pathway while prediction requires inclusion of factors for discriminative classification. This manuscript develops simple static Bayesian network predictive models of varying complexity by encompassing prior partially available biological knowledge about intra/extracellular factors and incorporating information regarding epigenetic modification into a few genes that are known to have an inhibitory effect on the pathway. Incorporation of epigenetic information enhances the prediction accuracy of test samples in human colorectal cancer. In comparison to the Naive Bayes model where β-catenin transcription complex activation predictions are assumed to correspond to sample predictions, the new biologically inspired models shed light on differences in behavior of the transcription complex and the state of samples. Receiver operator curves and their respective area under the curve measurements obtained from predictions of the state of the test sample and the corresponding predictions of the state of activation of the β-catenin transcription complex of the pathway for the test sample indicate a significant difference between the transcription complex being on (off) and its association with the sample being tumorous (normal). The two-sample Kolmogorov-Smirnov test confirms the statistical deviation between the distributions of these predictions. Hitherto unknown relationship between factors like DKK2, DKK3-1 and SFRP-2/3/5 w.r.t. the β-catenin transcription complex has been inferred using these causal models.
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Affiliation(s)
- Shriprakash Sinha
- Netherlands Bioinformatics Centre, 6500 HB, Nijmegen, The Netherlands.
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28
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Jankova L, Dent OF, Molloy MP, Chan C, Chapuis PH, Howell VM, Clarke SJ. Reporting in studies of protein biomarkers of prognosis in colorectal cancer in relation to the REMARK guidelines. Proteomics Clin Appl 2015; 9:1078-86. [PMID: 25755195 DOI: 10.1002/prca.201400177] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Revised: 01/14/2015] [Accepted: 03/03/2015] [Indexed: 12/28/2022]
Abstract
PURPOSE The REMARK guidelines give authors comprehensive and specific advice on the complete and transparent reporting of studies of prognostic tumor markers. The aim of this study was to use the REMARK guidelines to evaluate the quality of reporting in a sample of studies assessing tissue-based protein markers for survival after resection of colorectal cancer. EXPERIMENTAL DESIGN Eighty pertinent articles were scored according to their conformity to 26 items derived from the REMARK criteria. RESULTS Overall, on a scale of adequacy of reporting that potentially ranged from 26 to 78, the median for these studies was 60 (interquartile range 54-64) and several criteria were adequately covered in a large proportion of studies. However, others were either not dealt with or inadequately covered, including description of the study design (35%), definition of survival endpoints (48%), adjuvant therapy (54%), follow-up procedures and time (59%), neoadjuvant therapy (63%), inclusion/exclusion criteria (73%), multivariable modeling methods and results (74%), and discussion of study limitations (85%). CONCLUSIONS AND CLINICAL RELEVANCE Inadequacies in presentation militate against comparability among protein marker studies and undermine the generalizability of their findings. The quality of reporting could be improved if journal editors were to require authors to ensure that their work satisfied the REMARK criteria.
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Affiliation(s)
- Lucy Jankova
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW, Australia
| | - Owen F Dent
- Department of Colorectal Surgery, Concord Hospital, The University of Sydney, Sydney, NSW, Australia.,Discipline of Surgery, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Mark P Molloy
- Australian Proteome Analysis Facility, Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia
| | - Charles Chan
- Department of Anatomical Pathology, Concord Hospital, The University of Sydney, Sydney, NSW, Australia.,Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Pierre H Chapuis
- Department of Colorectal Surgery, Concord Hospital, The University of Sydney, Sydney, NSW, Australia.,Discipline of Surgery, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Viive M Howell
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW, Australia
| | - Stephen J Clarke
- Department of Medical Oncology, Royal North Shore Hospital, The University of Sydney, Sydney, NSW, Australia.,Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
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29
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Su MC, Chen CT, Huang FI, Chen YL, Jeng YM, Lin CY. Expression of LEF1 is an independent prognostic factor for patients with oral squamous cell carcinoma. J Formos Med Assoc 2014; 113:934-9. [DOI: 10.1016/j.jfma.2013.07.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Revised: 07/23/2013] [Accepted: 07/25/2013] [Indexed: 11/27/2022] Open
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30
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Kriegl L. [In situ analyses of molecular mechanisms of colorectal carcinogenesis]. DER PATHOLOGE 2014; 34 Suppl 2:269-73. [PMID: 24196627 DOI: 10.1007/s00292-013-1821-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The main signaling pathways of colorectal carcinogenesis encompass the classical adenoma-carcinoma sequence and the serrated route. In the classical adenoma-carcinoma sequence there are initially frequent mutations of the APC gene which lead to an activation of the WNT signaling pathway. When the WNT signaling pathway is activated β-catenin mediates the transcription of diverse factors which cause migration, invasion and proliferation of cells. Although APC mutations occur in all tumor cells, a heterogeneous distribution pattern of β-catenin is found in tumors and β-catenin also represents an important prognostic marker. A similar picture is found for γ-catenin which is expressed independently from β-catenin. Clearly more homogeneous is the expression of TCF4 and LEF1 which are the main binding partners of β-catenin and γ-catenin and are likewise important prognostic markers. The TRAIL signaling pathway is therapeutically interesting and within this pathway loss of the main receptors TRAIL-R1 and TRAIL-R2 is frequently found. Furthermore, the membranous localization of both factors correlates with a better overall survival. These results might be therapeutically relevant with respect to therapy with recombinant TRAIL molecules binding to TRAIL-R1 and TRAIL-R2. In the serrated route oncogen-induced senescence caused by mutations of the KRAS and BRAF oncogenes initially plays an important role. This senescence blockade is overcome by hypermethylation of the p16(INK4a) promoter and leads to the development of invasive tumors. The SIRT1 and c-Myc genes also contribute to progression of lesions in the serrated route and are activated through the RAS/RAF/MAPK-kinase signaling pathway as well as the WNT/β-catenin signaling pathway.
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Affiliation(s)
- L Kriegl
- Pathologisches Institut, Ludwig-Maximilians-Universität München, Thalkirchner Str. 36, 80337, München, Deutschland,
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31
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Overexpression of lymphoid enhancer-binding factor 1 (LEF1) in solid-pseudopapillary neoplasms of the pancreas. Mod Pathol 2014; 27:1355-63. [PMID: 24658583 PMCID: PMC4318228 DOI: 10.1038/modpathol.2014.40] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Revised: 01/13/2014] [Accepted: 01/15/2014] [Indexed: 12/13/2022]
Abstract
Solid-pseudopapillary neoplasms are rare, but are distinctive pancreatic tumors of low-malignant potential. While the histogenesis of these tumors is unclear, they are often associated with gain-of-function mutations in the catenin (cadherin-associated protein), beta 1 (88 kDa), or CTNNB1 gene, resulting in nuclear accumulation of CTNNB1. CTNNB1 is a central component of the Wnt signaling pathway and mediates gene expression through the lymphoid enhancer-binding factor 1 (LEF1) /T-cell factor transcription complex. Although LEF1 has a pivotal role in the transactivation of Wnt/CTNNB1 responsive genes, the status of LEF1 in solid-pseudopapillary neoplasms and other pancreatic tumors has not been examined. We analyzed both LEF1 and CTNNB1 in a large cohort of pancreatic tumors (n=155). In all cases of solid-pseudopapillary neoplasms including surgical resections (n=27) and cytologic samples (n=8) had strong and diffuse nuclear labeling for both LEF1 and CTNNB1. The surrounding uninvolved pancreatic parenchyma was devoid of any LEF1 staining. All resection and cytologic specimens from well-differentiated pancreatic neuroendocrine tumors (n=44; n=29, respectively), high-grade pancreatic neuroendocrine carcinomas (n=2; n=1), pancreatic ductal adenocarcinomas (n=25; n=12), and acinar cell carcinomas (n=9; n=2) studied were negative for both nuclear LEF1 and CTNNB1. However, nuclear LEF1 and CTNNB1 were detected in all four resected pancreatoblastomas (no cytologic specimens were available for immunolabeling), but primarily centered around and within squamoid corpuscles. In summary, abnormal CTNNB1 accumulation was accompanied by nuclear LEF1 overexpression in both solid-pseudopapillary neoplasms and pancreatoblastomas. But, in contrast to pancreatoblastomas, a diffuse, nuclear labeling was observed in solid-pseudopapillary neoplasms and further implicates the CTNNB1/LEF1 transcriptional complex in the development of solid-pseudopapillary neoplasms. In addition, as part of an immunohistochemical panel, LEF1 can be a useful ancillary stain in the diagnosis of solid-pseudopapillary neoplasms.
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32
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TCF4 silencing sensitizes the colon cancer cell line to oxaliplatin as a common chemotherapeutic drug. Anticancer Drugs 2014; 25:908-16. [DOI: 10.1097/cad.0000000000000118] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Zhang Z, Kim K, Li X, Moreno M, Sharp T, Goodheart MJ, Safe S, Dupuy AJ, Amendt BA. MicroRNA-26b represses colon cancer cell proliferation by inhibiting lymphoid enhancer factor 1 expression. Mol Cancer Ther 2014; 13:1942-1951. [PMID: 24785257 PMCID: PMC4090280 DOI: 10.1158/1535-7163.mct-13-1000] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
microRNAs (miR) can act as oncogenes and tumor suppressors and several miRs are associated with cancer development and progression through the modulation of multiple cellular processes. miR26b is downregulated in several cancers and tumors and miR26b directly targets the lymphoid enhancer factor 1 (Lef1)3'UTR and inhibits endogenous Lef1 expression. We report that miR26b expression is associated with human colon cancer through the regulation of LEF1 expression in colon cancer cells. Analyses of multiple colon cancer cell lines revealed an inverse correlation between miR26b and LEF1 expression. Normal human colon cells express low levels of LEF1 and high levels of miR26b; however, human colon cancer cells have decreased miR26b expression and increased LEF1 expression. We demonstrate that miR26b expression is a potent inhibitor of colon cancer cell proliferation and significantly decreases LEF1 expression. The LEF1-regulated genes cyclin D1 and c-Myc were indirectly repressed by miR26b and this was consistent with decreased proliferation. miR26b overexpression in SW480 colon cancer cells also inhibited tumor growth in nude mice and this was due to decreased tumor growth and not apoptosis. Analyses of human colon cancer databases also demonstrated a link between miR26b and LEF1 expression. c-Myc expression is associated with multiple cancers and we propose that miR26b may act as a potential therapeutic agent in reducing cancer cell proliferation through repressing LEF1 activation of c-Myc and cyclin D1 expression.
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Affiliation(s)
- Zichao Zhang
- Authors' Affiliations: Craniofacial Anomalies Research Center, and
| | - KyoungHyun Kim
- Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio; and
| | - Xiao Li
- Authors' Affiliations: Craniofacial Anomalies Research Center, and
| | - Myriam Moreno
- Authors' Affiliations: Craniofacial Anomalies Research Center, and
| | - Thad Sharp
- Authors' Affiliations: Craniofacial Anomalies Research Center, and
| | | | | | - Adam J Dupuy
- Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa
| | - Brad A Amendt
- Authors' Affiliations: Craniofacial Anomalies Research Center, and
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34
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Kafka A, Tomas D, Beroš V, Pećina HI, Zeljko M, Pećina-Šlaus N. Brain metastases from lung cancer show increased expression of DVL1, DVL3 and beta-catenin and down-regulation of E-cadherin. Int J Mol Sci 2014; 15:10635-51. [PMID: 24933634 PMCID: PMC4100173 DOI: 10.3390/ijms150610635] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Revised: 05/14/2014] [Accepted: 05/27/2014] [Indexed: 12/21/2022] Open
Abstract
The susceptibility of brain to secondary formation from lung cancer primaries is a well-known phenomenon. In contrast, the molecular basis for invasion and metastasis to the brain is largely unknown. In the present study, 31 brain metastases that originated from primary lung carcinomas were analyzed regarding over expression of Dishevelled-1 (DVL1), Dishevelled-3 (DVL3), E-cadherin (CDH1) and beta-catenin (CTNNB1). Protein expressions and localizations were analyzed by immunohistochemistry. Genetic alterations of E-cadherin were tested by polymerase chain reaction (PCR)/loss of heterozygosity (LOH). Heteroduplex was used to investigate mutations in beta-catenin. DVL1 and DVL3 showed over expression in brain metastasis in 87.1% and 90.3% of samples respectively. Nuclear staining was observed in 54.8% of cases for DVL1 and 53.3% for DVL3. The main effector of the Wnt signaling, beta-catenin, was up-regulated in 56%, and transferred to the nucleus in 36% of metastases. When DVL1 and DVL3 were up-regulated the number of cases with nuclear beta-catenin significantly increased (p=0.0001). Down-regulation of E-cadherin was observed in 80% of samples. Genetic analysis showed 36% of samples with LOH of the CDH1. In comparison to other lung cancer pathologies, the diagnoses adenocarcinoma and small cell lung cancer (SCLC) were significantly associated to CDH1 LOH (p=0.001). Microsatellite instability was detected in one metastasis from adenocarcinoma. Exon 3 of beta-catenin was not targeted. Altered expression of Dishevelled-1, Dishevelled-3, E-cadherin and beta-catenin were present in brain metastases which indicates that Wnt signaling is important and may contribute to better understanding of genetic profile conditioning lung cancer metastasis to the brain.
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Affiliation(s)
- Anja Kafka
- Laboratory of Neuro-Oncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 12, 10000 Zagreb, Croatia.
| | - Davor Tomas
- Ljudevit Jurak Department of Pathology, University Hospital "Sisters of Charity", 10000 Zagreb, Croatia.
| | - Vili Beroš
- Department of Neurosurgery, University Hospital "Sisters of Charity", 10000 Zagreb, Croatia.
| | - Hrvoje Ivan Pećina
- Department of Radiology, University Hospital "Sisters of Charity", 10000 Zagreb, Croatia.
| | - Martina Zeljko
- Laboratory of Neuro-Oncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 12, 10000 Zagreb, Croatia.
| | - Nives Pećina-Šlaus
- Laboratory of Neuro-Oncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 12, 10000 Zagreb, Croatia.
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de la Roche M, Ibrahim AEK, Mieszczanek J, Bienz M. LEF1 and B9L shield β-catenin from inactivation by Axin, desensitizing colorectal cancer cells to tankyrase inhibitors. Cancer Res 2014; 74:1495-505. [PMID: 24419084 PMCID: PMC3947273 DOI: 10.1158/0008-5472.can-13-2682] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Hyperactive β-catenin drives colorectal cancer, yet inhibiting its activity remains a formidable challenge. Interest is mounting in tankyrase inhibitors (TNKSi), which destabilize β-catenin through stabilizing Axin. Here, we confirm that TNKSi inhibit Wnt-induced transcription, similarly to carnosate, which reduces the transcriptional activity of β-catenin by blocking its binding to BCL9, and attenuates intestinal tumors in Apc(Min) mice. By contrast, β-catenin's activity is unresponsive to TNKSi in colorectal cancer cells and in cells after prolonged Wnt stimulation. This TNKSi insensitivity is conferred by β-catenin's association with LEF1 and BCL9-2/B9L, which accumulate during Wnt stimulation, thereby providing a feed-forward loop that converts transient into chronic β-catenin signaling. This limits the therapeutic value of TNKSi in colorectal carcinomas, most of which express high LEF1 levels. Our study provides proof-of-concept that the successful inhibition of oncogenic β-catenin in colorectal cancer requires the targeting of its interaction with LEF1 and/or BCL9/B9L, as exemplified by carnosate.
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Affiliation(s)
- Marc de la Roche
- corresponding authors Phone +44 1223 267 093, +44 1223 746 851 Fax +44 1223 268 305 ,
| | - Ashraf E. K. Ibrahim
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK
| | - Juliusz Mieszczanek
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK
| | - Mariann Bienz
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK
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Wang WJ, Yao Y, Jiang LL, Hu TH, Ma JQ, Liao ZJ, Yao JT, Li DF, Wang SH, Nan KJ. Knockdown of lymphoid enhancer factor 1 inhibits colon cancer progression in vitro and in vivo. PLoS One 2013; 8:e76596. [PMID: 24098538 PMCID: PMC3788715 DOI: 10.1371/journal.pone.0076596] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 09/03/2013] [Indexed: 01/24/2023] Open
Abstract
Expression of lymphoid enhancer factor 1 (LEF1) is frequently altered in different human cancers. This study aimed to assess LEF1 expression in colon cancer tissues and to explore changed phenotypes, gene expressions, and the possible mechanism after knocked down LEF1 expression in colon cancer cell lines. A total of 106 colon cancer and matched paratumorous normal tissues were used to assess LEF1 expression using immunohistochemistry and qRT-PCR. LEF1 lentivirus was used to knockdown LEF1 expression for the assessment of cell viability, cell cycle distribution, apoptosis, and gene expressions. The nude mouse xenograft assay was performed to detect the effects of LEF1 knockdown in vivo. The data showed that the levels of LEF1 mRNA and protein were significantly increased in human colon cancer tissues compared to the matched paratumorous normal tissues and were associated with infiltration depth, lymph node and distant metastases, advanced TNM (tumor-node-metastasis) stages, and shorter overall survival. Furthermore, LEF1 knockdown reduced tumor cell viability, invasion capacity, MMP2 and MMP-9 expression, but induced apoptosis. Nude mouse xenograft assay showed that LEF1 knockdown suppressed tumor formation and growth in vivo. In addition, the expression of Notch pathway-related proteins RBP-jκ and Hes1 was reduced in LEF1 knockdown cells. Taken together, LEF1 protein was overexpressed in colon cancer tissues and knockdown of LEF1 expression inhibited colon cancer growth in vitro and in vivo. These data suggest that targeting of LEF1 expression should be further evaluated for colon cancer prevention and therapy.
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Affiliation(s)
- Wen-Juan Wang
- Department of Oncology, First Affiliated Hospital of Medical College of Xi’an Jiaotong University, Xi’an, China
| | - Yu Yao
- Department of Oncology, First Affiliated Hospital of Medical College of Xi’an Jiaotong University, Xi’an, China
| | - Li-Li Jiang
- Department of Oncology, First Affiliated Hospital of Medical College of Xi’an Jiaotong University, Xi’an, China
| | - Ting-Hua Hu
- Department of Oncology, First Affiliated Hospital of Medical College of Xi’an Jiaotong University, Xi’an, China
| | - Jie-Qun Ma
- Department of Oncology, First Affiliated Hospital of Medical College of Xi’an Jiaotong University, Xi’an, China
| | - Zi-Jun Liao
- Affiliated Shaanxi Provincial Cancer Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an, China
| | - Jun-Tao Yao
- Affiliated Shaanxi Provincial Cancer Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an, China
| | | | - Shu-Hong Wang
- Department of Oncology, First Affiliated Hospital of Medical College of Xi’an Jiaotong University, Xi’an, China
- * E-mail: (K-JN); (S-HW)
| | - Ke-Jun Nan
- Department of Oncology, First Affiliated Hospital of Medical College of Xi’an Jiaotong University, Xi’an, China
- * E-mail: (K-JN); (S-HW)
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Increased LEF1 expression and decreased Notch2 expression are strong predictors of poor outcomes in colorectal cancer patients. DISEASE MARKERS 2013; 35:395-405. [PMID: 24223455 PMCID: PMC3810108 DOI: 10.1155/2013/983981] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Revised: 07/14/2013] [Accepted: 08/05/2013] [Indexed: 01/27/2023]
Abstract
Background/Objective. We aimed to examine the expression of lymphoid enhancer factor 1 (LEF1) and Notch2 in colorectal cancer (CRC) and their association with clinicopathologic variables and CRC patients' prognosis. Methods. Immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot analysis were performed to assess the expression of LEF1 and Notch2 in 184 patients with CRC. Results. We observed a strong negative correlation between LEF1 expression and Notch2 expression (P < 0.001). Both LEF1 mRNA and protein expression increased while the Notch2 mRNA and protein expression decreased in tumor specimens compared with the matched paratumorous normal tissue (P < 0.001). An increase in LEF1 protein expression was significantly associated with lymph node metastases, distant metastasis, advanced TNM (tumor-node-metastasis) stage, and shorter overall survival. A decrease in Notch2 protein expression was associated with poorly differentiated tumors, lymph node metastases, distant metastasis, advanced TNM stage, and shorter overall survival of patients. In the multivariate Cox regression analysis, the LEF1 protein expression (P < 0.001), Notch2 protein expression (P < 0.001), TNM stage (P < 0.001), and the combination of increased LEF1 protein coexpression and decreased Notch2 protein coexpression (P < 0.001) were found to be independent prognostic indicators in CRC. Conclusion. Our results suggest that increased LEF1 coexpression and decreased Notch2 coexpression represent a risk factor for poor overall survival of CRC patients.
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Zhang Z, Pal S, Bi Y, Tchou J, Davuluri RV. Isoform level expression profiles provide better cancer signatures than gene level expression profiles. Genome Med 2013; 5:33. [PMID: 23594586 PMCID: PMC3706752 DOI: 10.1186/gm437] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Revised: 03/26/2013] [Accepted: 04/17/2013] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND The majority of mammalian genes generate multiple transcript variants and protein isoforms through alternative transcription and/or alternative splicing, and the dynamic changes at the transcript/isoform level between non-oncogenic and cancer cells remain largely unexplored. We hypothesized that isoform level expression profiles would be better than gene level expression profiles at discriminating between non-oncogenic and cancer cellsgene level. METHODS We analyzed 160 Affymetrix exon-array datasets, comprising cell lines of non-oncogenic or oncogenic tissue origins. We obtained the transcript-level and gene level expression estimates, and used unsupervised and supervised clustering algorithms to study the profile similarity between the samples at both gene and isoform levels. RESULTS Hierarchical clustering, based on isoform level expressions, effectively grouped the non-oncogenic and oncogenic cell lines with a virtually perfect homogeneity-grouping rate (97.5%), regardless of the tissue origin of the cell lines. However, gene levelthis rate was much lower, being 75% at best based on the gene level expressions. Statistical analyses of the difference between cancer and non-oncogenic samples identified the existence of numerous genes with differentially expressed isoforms, which otherwise were not significant at the gene level. We also found that canonical pathways of protein ubiquitination, purine metabolism, and breast-cancer regulation by stathmin1 were significantly enriched among genes thatshow differential expression at isoform level but not at gene level. CONCLUSIONS In summary, cancer cell lines, regardless of their tissue of origin, can be effectively discriminated from non-cancer cell lines at isoform level, but not at gene level. This study suggests the existence of an isoform signature, rather than a gene signature, which could be used to distinguish cancer cells from normal cells.
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Affiliation(s)
- ZhongFa Zhang
- Center for Systems and Computational Biology, Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Sharmistha Pal
- Center for Systems and Computational Biology, Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Yingtao Bi
- Center for Systems and Computational Biology, Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Julia Tchou
- Department of Surgery, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
| | - Ramana V Davuluri
- Center for Systems and Computational Biology, Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA
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Bleckmann A, Siam L, Klemm F, Rietkötter E, Wegner C, Kramer F, Beissbarth T, Binder C, Stadelmann C, Pukrop T. Nuclear LEF1/TCF4 correlate with poor prognosis but not with nuclear β-catenin in cerebral metastasis of lung adenocarcinomas. Clin Exp Metastasis 2012; 30:471-82. [PMID: 23224985 PMCID: PMC3616220 DOI: 10.1007/s10585-012-9552-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Accepted: 11/12/2012] [Indexed: 01/15/2023]
Abstract
An essential function of the transcription factors LEF1/TCF4 in cerebral metastases of lung adenocarcinomas has been described in mouse models, suggesting a WNT/β-catenin effect as potential mechanism. Their role in humans is still unclear, thus we analyzed LEF1, TCF4, β-catenin, and early stage prognostic markers in 25 adenocarcinoma brain metastases using immunohistochemistry (IHC). IHC revealed nuclear TCF4 in all adenocarcinoma samples, whereas only 36 % depicted nuclear LEF1 and nuclear β-catenin signals. Samples with nuclear LEF1 as well as high TCF4 (++++) expression were associated with a shorter survival (p = 0.01, HR = 6.68), while nuclear β-catenin had no significant impact on prognosis and did not significantly correlate with nuclear LEF1. High proliferation index Ki67 was associated with shorter survival in late-stage disease (p = 0.03, HR 3.27). Additionally, we generated a LEF1/TCF4 as well as an AXIN2 signature, the latter as representative of WNT/β-catenin activity, following a bioinformatics approach with a gene expression dataset of cerebral metastases in lung adenocarcinoma. To analyze the prognostic relevance in primary lung adenocarcinomas, we applied both signatures to a microarray dataset of 58 primary lung adenocarcinomas. Only the LEF1/TCF4 signature was able to separate clusters with impact on survival (p = 0.01, HR = 0.32). These clusters displayed diverging enrichment patterns of the cell cycle pathway. In conclusion, our data show that LEF1/TCF4, but not β-catenin, have prognostic relevance in primary and cerebrally metastasized human lung adenocarcinomas. In contrast to the previous in vivo findings, these results indicate that LEF1/TCF4 act independently of β-catenin in this setting.
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Affiliation(s)
- A. Bleckmann
- Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany
- Department of Medical Statistics, University Medical Center Göttingen, 37099 Göttingen, Germany
| | - L. Siam
- Department of Neurosurgery, University Medical Center Göttingen, 37099 Göttingen, Germany
| | - F. Klemm
- Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany
| | - E. Rietkötter
- Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany
| | - Chr. Wegner
- Department of Neuropathology, University Medical Center Göttingen, 37099 Göttingen, Germany
| | - F. Kramer
- Department of Medical Statistics, University Medical Center Göttingen, 37099 Göttingen, Germany
| | - T. Beissbarth
- Department of Medical Statistics, University Medical Center Göttingen, 37099 Göttingen, Germany
| | - C. Binder
- Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany
| | - Chr. Stadelmann
- Department of Neuropathology, University Medical Center Göttingen, 37099 Göttingen, Germany
| | - T. Pukrop
- Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany
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Shelton DN, Fornalik H, Neff T, Park SY, Bender D, DeGeest K, Liu X, Xie W, Meyerholz DK, Engelhardt JF, Goodheart MJ. The role of LEF1 in endometrial gland formation and carcinogenesis. PLoS One 2012; 7:e40312. [PMID: 22792274 PMCID: PMC3391280 DOI: 10.1371/journal.pone.0040312] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Accepted: 06/05/2012] [Indexed: 12/28/2022] Open
Abstract
Endometrial carcinoma is the most common gynecologic cancer, yet the mechanisms underlying this disease process are poorly understood. We hypothesized that Lef1 is required for endometrial gland formation within the uterus and is overexpressed in endometrial cancer. Using Lef1 knockout (KO) mice, we compared uterine gland development to wild-type (WT) controls, with respect to both morphology and expression of the Lef1 targets, cyclin D1 and MMP7. We characterized the dynamics of Lef1 protein expression during gland development and the mouse estrus cycle, by immunostaining and Western blot. Finally, we investigated the roles of cyclin D1 and MMP7 in gland and cancer formation in the mouse, and assessed the relevance of Lef1 to human cancer by comparing expression levels in cancerous and normal endometrial tissues. Lef1 upregulation in mouse endometrium correlates with the proliferative stages of the estrus cycle and gland development during the neonatal period. WT mice endometrial glands began to develop by day 5 and were easily identified by day 9, whereas Lef1 KO mice endometrial glands had not developed by day 9 although the endometrial lining was intact. We found that during gland development cyclin D1 is elevated and localized to the gland buds, and that this requires the presence of Lef1. We also noted that Lef1 protein was expressed at higher levels in endometrial cancers within mice and humans when compared to normal endometrium. Our loss-of-function data indicate that Lef1 is required for the formation of endometrial glands in the mouse uterus. Lef1 protein elevation corresponds to gland formation during development, and varies cyclically with the mouse estrus cycle, in parallel with gland regeneration. Finally, Lef1 is overexpressed in human and mouse endometrial tumors, consistent with it playing a role in gland proliferation.
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Affiliation(s)
- Dawne N. Shelton
- Department of Obstetrics and Gynecology, Holden Comprehensive Cancer Center, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America
| | - Hubert Fornalik
- Department of Obstetrics and Gynecology, Holden Comprehensive Cancer Center, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America
| | - Traci Neff
- Department of Obstetrics and Gynecology, Holden Comprehensive Cancer Center, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America
| | - Soo Yeun Park
- Department of Obstetrics and Gynecology, Holden Comprehensive Cancer Center, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America
| | - David Bender
- Department of Obstetrics and Gynecology, Holden Comprehensive Cancer Center, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America
| | - Koen DeGeest
- Department of Obstetrics and Gynecology, Holden Comprehensive Cancer Center, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America
| | - Xiaoming Liu
- Department of Anatomy and Cell Biology, The University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America
| | - Weiliang Xie
- Department of Anatomy and Cell Biology, The University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America
| | - David K. Meyerholz
- Department of Pathology, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America
| | - John F. Engelhardt
- Department of Anatomy and Cell Biology, The University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America
| | - Michael J. Goodheart
- Department of Obstetrics and Gynecology, Holden Comprehensive Cancer Center, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America
- * E-mail:
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MiR-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor LEF1. Oncol Rep 2012; 28:1013-21. [PMID: 22766851 DOI: 10.3892/or.2012.1902] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Accepted: 05/18/2012] [Indexed: 01/24/2023] Open
Abstract
The invasive behavior of glioblastoma multiforme (GBM) cells is one of the most important reasons for the poor prognosis of this cancer. For invasion, tumor cells must acquire an ability to digest the extracellular matrix and infiltrate the normal tissue bordering the tumor. Preventing this by altering effector molecules can significantly improve a patient's prognosis. Accumulating evidence suggests that miRNAs are involved in multiple biological functions, including cell invasion, by altering the expression of multiple target genes. The expression levels of miR-218 correlate with the invasive potential of GBM cells. In this study, we found that miR-218 expression was low in glioma tissues, especially in GBM. The data showed an inverse correlation in 60 GBM tissues between the levels of miR-218 and MMP mRNAs (MMP-2, -7 and -9). Additionally, ectopic expression of miR-218 suppressed the invasion of GBM cells whereas inhibition of miR-218 expression enhanced the invasive ability. Numerous members of the MMP family are downstream effectors of the Wnt/LEF1 pathway. Target prediction databases and luciferase data showed that LEF1 is a new direct target of miR-218. Importantly, western blot assays demonstrated that miR-218 can reduce protein levels of LEF1 and MMP-9. We, therefore, hypothesize that miR-218 directly targets LEF1, resulting in reduced synthesis of MMP-9. Results suggest that miR-218 is involved in the invasive behavior of GBM cells and by targeting LEF1 and blocking the invasive axis, miR-218-LEF1-MMPs, it may be useful for developing potential clinical strategies.
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Huang FI, Chen YL, Chang CN, Yuan RH, Jeng YM. Hepatocyte growth factor activates Wnt pathway by transcriptional activation of LEF1 to facilitate tumor invasion. Carcinogenesis 2012; 33:1142-8. [PMID: 22436613 DOI: 10.1093/carcin/bgs131] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Hepatocyte growth factor (HGF) is a secretory protein that plays important roles in cancer growth and metastasis. Lymphoid-enhancing factor 1 (LEF1) is a transcription factor mediating Wnt/β-catenin signaling. Using microarray analysis, we found HGF induced expression of LEF1 in liver and breast cancer cell lines. HGF induced expression of LEF1 through phosphatidylinositol 3-kinase/Akt and nuclear factor-kappa B (NF-κB) signaling. Multiple NF-κB-binding sites were mapped within 3 kb upstream of LEF1 transcription initiation site. NF-κB binding to a site 2 kb upstream of LEF1 transcription initiation site was confirmed by chromatin immunoprecipitation assay. Knockdown of LEF1 inhibited the expression of Slug and Zinc finger E-box-binding homeobox 2 (ZEB2) and markedly attenuated HGF-induced tumor migration and invasion. Using immunohistochemical staining, we found LEF1 was frequently expressed in multiple types of carcinoma but not in the non-tumorous epithelial cells. Our finding suggest that transcriptional activation of LEF1 is a mechanism of cross talk between HGF/c-Met and Wnt/β-catenin pathways and is essential for HGF-induced tumor invasion.
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Affiliation(s)
- Fang-I Huang
- Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan
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Kendziorra E, Ahlborn K, Spitzner M, Rave-Fränk M, Emons G, Gaedcke J, Kramer F, Wolff HA, Becker H, Beissbarth T, Ebner R, Ghadimi BM, Pukrop T, Ried T, Grade M. Silencing of the Wnt transcription factor TCF4 sensitizes colorectal cancer cells to (chemo-) radiotherapy. Carcinogenesis 2011; 32:1824-31. [PMID: 21983179 DOI: 10.1093/carcin/bgr222] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
A considerable percentage of rectal cancers are resistant to standard preoperative chemoradiotherapy. Because patients with a priori-resistant tumors do not benefit from multimodal treatment, understanding and overcoming this resistance remains of utmost clinical importance. We recently reported overexpression of the Wnt transcription factor TCF4, also known as TCF7L2, in rectal cancers that were resistant to 5-fluorouracil-based chemoradiotherapy. Because Wnt signaling has not been associated with treatment response, we aimed to investigate whether TCF4 mediates chemoradioresistance. RNA interference-mediated silencing of TCF4 was employed in three colorectal cancer (CRC) cell lines, and sensitivity to (chemo-) radiotherapy was assessed using a standard colony formation assay. Silencing of TCF4 caused a significant sensitization of CRC cells to clinically relevant doses of X-rays. This effect was restricted to tumor cells with high T cell factor (TCF) reporter activity, presumably in a β-catenin-independent manner. Radiosensitization was the consequence of (i) a transcriptional deregulation of Wnt/TCF4 target genes, (ii) a silencing-induced G(2)/M phase arrest, (iii) an impaired ability to adequately halt cell cycle progression after radiation and (iv) a compromised DNA double strand break repair as assessed by γH2AX staining. Taken together, our results indicate a novel mechanism through which the Wnt transcription factor TCF4 mediates chemoradioresistance. Moreover, they suggest that TCF4 is a promising molecular target to sensitize resistant tumor cells to (chemo-) radiotherapy.
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Affiliation(s)
- Emil Kendziorra
- Department of General and Visceral Surgery, University Medical Center, Göttingen 37075, Germany
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Dawson MI, Xia Z. The retinoid X receptors and their ligands. Biochim Biophys Acta Mol Cell Biol Lipids 2011; 1821:21-56. [PMID: 22020178 DOI: 10.1016/j.bbalip.2011.09.014] [Citation(s) in RCA: 269] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2011] [Revised: 08/23/2011] [Accepted: 09/23/2011] [Indexed: 12/12/2022]
Abstract
This chapter presents an overview of the current status of studies on the structural and molecular biology of the retinoid X receptor subtypes α, β, and γ (RXRs, NR2B1-3), their nuclear and cytoplasmic functions, post-transcriptional processing, and recently reported ligands. Points of interest are the different changes in the ligand-binding pocket induced by variously shaped agonists, the communication of the ligand-bound pocket with the coactivator binding surface and the heterodimerization interface, and recently identified ligands that are natural products, those that function as environmental toxins or drugs that had been originally designed to interact with other targets, as well as those that were deliberately designed as RXR-selective transcriptional agonists, synergists, or antagonists. Of these synthetic ligands, the general trend in design appears to be away from fully aromatic rigid structures to those containing partial elements of the flexible tetraene side chain of 9-cis-retinoic acid. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
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Affiliation(s)
- Marcia I Dawson
- Cancer Center, Sanford-Burn Medical Research Institute, 10901 North Torrey Pines Rd., La Jolla, CA 93207, USA.
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Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nat Genet 2011; 43:964-968. [PMID: 21892161 DOI: 10.1038/ng.936] [Citation(s) in RCA: 252] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2011] [Accepted: 08/11/2011] [Indexed: 02/06/2023]
Abstract
Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma and have surveyed exons of protein-coding genes for mutations in 11 affected individuals. Here we report whole-genome sequencing from nine individuals with colorectal cancer, including primary colorectal tumors and matched adjacent non-tumor tissues, at an average of 30.7× and 31.9× coverage, respectively. We identify an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with β-catenin in colorectal carcinogenesis, the fusion lacks the TCF4 β-catenin-binding domain. We found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interference-mediated knockdown. This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events.
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Eichhoff OM, Weeraratna A, Zipser MC, Denat L, Widmer DS, Xu M, Kriegl L, Kirchner T, Larue L, Dummer R, Hoek KS. Differential LEF1 and TCF4 expression is involved in melanoma cell phenotype switching. Pigment Cell Melanoma Res 2011; 24:631-42. [PMID: 21599871 DOI: 10.1111/j.1755-148x.2011.00871.x] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Recent observations suggest that melanoma cells drive disease progression by switching back and forth between phenotypic states of proliferation and invasion. Phenotype switching has been linked to changes in Wnt signalling, and we therefore looked for cell phenotype-specific differences in the levels and activity of β-catenin and its LEF/TCF co-factors. We found that while cytosolic β-catenin distribution is phenotype-specific (membrane-associated in proliferative cells and cytosolic in invasive cells), its nuclear distribution and activity is not. Instead, the expression patterns of two β-catenin co-factors, LEF1 and TCF4, are both phenotype-specific and inversely correlated. LEF1 is preferentially expressed by differentiated/proliferative phenotype cells and TCF4 by dedifferentiated/invasive phenotype cells. Knock-down experiments confirmed that these co-factors are important for the phenotype-specific expression of M-MITF, WNT5A and other genes and that LEF1 suppresses TCF4 expression independently of β-catenin. Our data show that melanoma cell phenotype switching behaviour is regulated by differential LEF1/TCF4 activity.
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Affiliation(s)
- Ossia M Eichhoff
- Department of Dermatology, University Hospital of Zürich, Zürich, Switzerland
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T-cell factor 4 functions as a tumor suppressor whose disruption modulates colon cell proliferation and tumorigenesis. Proc Natl Acad Sci U S A 2011; 108:4914-9. [PMID: 21383188 DOI: 10.1073/pnas.1102300108] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The Wnt/β-catenin pathway plays multiple and diverse roles in development by regulating gene expression via T-cell factor/Lymphoid enhancer-binding factor (Tcf/Lef) DNA binding factors. Misregulation of this pathway is thought to initiate colon adenoma formation. It is controversial whether Tcf4 (Tcf7L2) functions as an oncogene or tumor suppressor gene in colon carcinogenesis. We show here that Tcf4 haploinsufficiency results in colon tumor formation in a mouse tumor model that normally only develops small intestinal tumors. Further, we show that loss of Tcf4 early in development and in adult colon results in increased cell proliferation. These findings strongly suggest that Tcf4 normally modulates proliferation of the colonic epithelium and that disruption of Tcf4 activity increases proliferation, leading to colon tumorigenesis. Taken together, our in vivo studies favor a tumor suppressor function for Tcf4.
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