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For:
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Arab K, Smith LT, Gast A, Weichenhan D, Huang JPH, Claus R, Hielscher T, Espinosa AV, Ringel MD, Morrison CD, Schadendorf D, Kumar R, Plass C. Epigenetic deregulation of TCF21 inhibits metastasis suppressor KISS1 in metastatic melanoma. Carcinogenesis 2011;32:1467-73. [PMID: 21771727 DOI: 10.1093/carcin/bgr138] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open |
Supplementary Information
The online version contains supplementary material available at 10.1186/s12964-021-00783-2.
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Affiliation(s)
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Cited by Other Article(s) |
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1
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Nadhan R, Isidoro C, Song YS, Dhanasekaran DN. LncRNAs and the cancer epigenome: Mechanisms and therapeutic potential. Cancer Lett 2024; 605:217297. [PMID: 39424260 DOI: 10.1016/j.canlet.2024.217297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 09/30/2024] [Accepted: 10/08/2024] [Indexed: 10/21/2024]
Abstract
Long non-coding RNAs (lncRNAs) have emerged as critical regulators of epigenome, modulating gene expression through DNA methylation, histone modification, and/or chromosome remodeling. Dysregulated lncRNAs act as oncogenes or tumor suppressors, driving tumor progression by shaping the cancer epigenome. By interacting with the writers, readers, and erasers of the epigenetic script, lncRNAs induce epigenetic modifications that bring about changes in cancer cell proliferation, apoptosis, epithelial-mesenchymal transition, migration, invasion, metastasis, cancer stemness and chemoresistance. This review analyzes and discusses the multifaceted role of lncRNAs in cancer pathobiology, from cancer genesis and progression through metastasis and therapy resistance. It also explores the therapeutic potential of targeting lncRNAs through innovative diagnostic, prognostic, and therapeutic strategies. Understanding the dynamic interplay between lncRNAs and epigenome is crucial for developing personalized therapeutic strategies, offering new avenues for precision cancer medicine.
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Affiliation(s)
- Revathy Nadhan
- Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
| | - Ciro Isidoro
- Laboratory of Molecular Pathology and NanoBioImaging, Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy.
| | - Yong Sang Song
- Department of Obstetrics and Gynecology, Cancer Research Institute, College of Medicine, Seoul National University, Seoul, 151-921, South Korea.
| | - Danny N Dhanasekaran
- Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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2
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Elsayed AMA, Oweda M, Abushady AM, Alhelf M, Khalil SRM, Tawfik MS, Al-Atabany W, El-Hadidi M. Identification of Differentially Expressed Genes in Human Colorectal Cancer Using RNASeq Data Validated on the Molecular Level with Real-Time PCR. Biochem Genet 2024; 62:3260-3284. [PMID: 38097858 PMCID: PMC11289010 DOI: 10.1007/s10528-023-10593-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 11/08/2023] [Indexed: 07/31/2024]
Abstract
Colorectal cancer (CRC) is a prevalent cancer with high morbidity and mortality rates worldwide. Late diagnosis is a significant contributor to low survival rates in a minority of cases. The study aimed to perform a robust pipeline using integrated bioinformatics tools that will enable us to identify potential diagnostic and prognostic biomarkers for early detection of CRC by exploring differentially expressed genes (DEGs). In addition to, testing the capability of replacing chemotherapy with plant extract in CRC treatment by validating it using real-time PCR. RNA-seq data from cancerous and adjacent normal tissues were pre-processed and analyzed using various tools such as FastQC, Kallisto, DESeq@ R package, g:Profiler, GNEMANIA-CytoScape and CytoHubba, resulting in the identification of 1641 DEGs enriched in various signaling routes. MMP7, TCF21, and VEGFD were found to be promising diagnostic biomarkers for CRC. An in vitro experiment was conducted to examine the potential anticancer properties of 5-fluorouracile, Withania somnifera extract, and their combination. The extract was found to exhibit a positive trend in gene expression and potential therapeutic value by targeting the three genes; however, further trials are required to regulate the methylation promoter. Molecular docking tests supported the findings by revealing a stable ligand-receptor complex. In conclusion, the study's analysis workflow is precise and robust in identifying DEGs in CRC that may serve as biomarkers for diagnosis and treatment. Additionally, the identified DEGs can be used in future research with larger sample sizes to analyze CRC survival.
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Affiliation(s)
- Aya M A Elsayed
- School of Biotechnology, Nile University, Giza, Egypt
- School of Information Technology and Computer Science, Nile University, Giza, Egypt
- Department of Agricultural, Forest and Food Sciences, University of Torino, Turin, Italy
| | - Mariam Oweda
- Bioinformatics Group, Center for Informatics Sciences (CIS), School of Information Technology and Computer Science (ITCS), Nile University, Giza, Egypt
| | - Asmaa M Abushady
- School of Biotechnology, Nile University, Giza, Egypt
- Genetic Department, Faculty of Agriculture, Ain Shams University, Cairo, Egypt
| | - Maha Alhelf
- School of Biotechnology, Nile University, Giza, Egypt
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Shaimaa R M Khalil
- Oil Crops Biotechnology Lab, Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research Center (ARC), 9 Gamaa Street, Giza, 12619, Egypt
| | - Mohamed S Tawfik
- Oil Crops Biotechnology Lab, Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research Center (ARC), 9 Gamaa Street, Giza, 12619, Egypt
| | - Walid Al-Atabany
- Bioinformatics Group, Center for Informatics Sciences (CIS), School of Information Technology and Computer Science (ITCS), Nile University, Giza, Egypt
| | - Mohamed El-Hadidi
- Bioinformatics Group, Center for Informatics Sciences (CIS), School of Information Technology and Computer Science (ITCS), Nile University, Giza, Egypt.
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham Dubai Campus, Dubai, United Arab Emirates.
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3
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Janin M, Davalos V, Esteller M. Cancer metastasis under the magnifying glass of epigenetics and epitranscriptomics. Cancer Metastasis Rev 2023; 42:1071-1112. [PMID: 37369946 PMCID: PMC10713773 DOI: 10.1007/s10555-023-10120-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023]
Abstract
Most of the cancer-associated mortality and morbidity can be attributed to metastasis. The role of epigenetic and epitranscriptomic alterations in cancer origin and progression has been extensively demonstrated during the last years. Both regulations share similar mechanisms driven by DNA or RNA modifiers, namely writers, readers, and erasers; enzymes responsible of respectively introducing, recognizing, or removing the epigenetic or epitranscriptomic modifications. Epigenetic regulation is achieved by DNA methylation, histone modifications, non-coding RNAs, chromatin accessibility, and enhancer reprogramming. In parallel, regulation at RNA level, named epitranscriptomic, is driven by a wide diversity of chemical modifications in mostly all RNA molecules. These two-layer regulatory mechanisms are finely controlled in normal tissue, and dysregulations are associated with every hallmark of human cancer. In this review, we provide an overview of the current state of knowledge regarding epigenetic and epitranscriptomic alterations governing tumor metastasis, and compare pathways regulated at DNA or RNA levels to shed light on a possible epi-crosstalk in cancer metastasis. A deeper understanding on these mechanisms could have important clinical implications for the prevention of advanced malignancies and the management of the disseminated diseases. Additionally, as these epi-alterations can potentially be reversed by small molecules or inhibitors against epi-modifiers, novel therapeutic alternatives could be envisioned.
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Affiliation(s)
- Maxime Janin
- Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), IJC Building, Germans Trias I Pujol, Ctra de Can Ruti, Cami de Les Escoles S/N, 08916 Badalona, Barcelona, Spain
- Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain
| | - Veronica Davalos
- Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), IJC Building, Germans Trias I Pujol, Ctra de Can Ruti, Cami de Les Escoles S/N, 08916 Badalona, Barcelona, Spain
| | - Manel Esteller
- Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), IJC Building, Germans Trias I Pujol, Ctra de Can Ruti, Cami de Les Escoles S/N, 08916 Badalona, Barcelona, Spain.
- Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain.
- Institucio Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
- Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain.
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4
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Wang JG, Jin XF, Huang YM, Xu ZF, Huang SJ, Zhu Y, Ai L, Hang T. TCF21 rs2327429 and TCF21 rs12190287 are associated with colorectal cancer in a Chinese population. Biomark Med 2023; 17:693-699. [PMID: 38197316 DOI: 10.2217/bmm-2022-0750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2024] Open
Abstract
Aims: TCF21 is considered a tumor suppressor gene. This work was designed to explore the associations between TCF21 polymorphisms and colorectal cancer (CRC) susceptibility. Methods: A case-control study was designed with 421 patients with CRC and 469 non-CRC controls. Six tagging single-nucleotide polymorphisms (rs2327429 T>C, rs2327430 T>C, rs2327433 A>G, rs12190287 C>G, rs7766238 G>A and rs4896011 T>A) were genotyped by ligase detection reaction of PCR. Results: TCF21 rs2327429 and rs12190287 polymorphisms were associated with CRC susceptibility in a Chinese Han population. Conclusion: rs2327429 and rs12190287 polymorphisms may be predictive of CRC susceptibility in Chinese Han populations.
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Affiliation(s)
- Jian-Guo Wang
- Jiaxing Women & Children's Hospital, Wenzhou Medical University, Jiaxing, Zhejiang, 314000, China
| | - Xia-Fang Jin
- Jiaxing Women & Children's Hospital, Wenzhou Medical University, Jiaxing, Zhejiang, 314000, China
| | - Yi-Min Huang
- Jiaxing Women & Children's Hospital, Wenzhou Medical University, Jiaxing, Zhejiang, 314000, China
| | - Zheng-Fen Xu
- Jiaxing Women & Children's Hospital, Wenzhou Medical University, Jiaxing, Zhejiang, 314000, China
| | - Shou-Ju Huang
- Zhejiang Chinese Medical University, Hangzhou, 310000, China
| | - Yingjie Zhu
- Joint Training Base of Jiaxing College of Zhejiang Chinese Medical University, Jiaxing, 314000, China
| | - Ling Ai
- Jiaxing Women & Children's Hospital, Wenzhou Medical University, Jiaxing, Zhejiang, 314000, China
| | - Tian Hang
- Jiaxing Women & Children's Hospital, Wenzhou Medical University, Jiaxing, Zhejiang, 314000, China
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5
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Harihar S, Welch DR. KISS1 metastasis suppressor in tumor dormancy: a potential therapeutic target for metastatic cancers? Cancer Metastasis Rev 2023; 42:183-196. [PMID: 36720764 PMCID: PMC10103016 DOI: 10.1007/s10555-023-10090-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 01/25/2023] [Indexed: 02/02/2023]
Abstract
Present therapeutic approaches do not effectively target metastatic cancers, often limited by their inability to eliminate already-seeded non-proliferative, growth-arrested, or therapy-resistant tumor cells. Devising effective approaches targeting dormant tumor cells has been a focus of cancer clinicians for decades. However, progress has been limited due to limited understanding of the tumor dormancy process. Studies on tumor dormancy have picked up pace and have resulted in the identification of several regulators. This review focuses on KISS1, a metastasis suppressor gene that suppresses metastasis by keeping tumor cells in a state of dormancy at ectopic sites. The review explores mechanistic insights of KISS1 and discusses its potential application as a therapeutic against metastatic cancers by eliminating quiescent cells or inducing long-term dormancy in tumor cells.
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Affiliation(s)
- Sitaram Harihar
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu 603203, India
| | - Danny R. Welch
- Department of Cancer Biology, The Kansas University Medical Center, Kansas City, USA
- The University of Kansas Comprehensive Cancer Center, 3901 Rainbow Blvd. Kansas City, Kansas City, KS 66160, USA
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6
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Anestopoulos I, Kyriakou S, Tragkola V, Paraskevaidis I, Tzika E, Mitsiogianni M, Deligiorgi MV, Petrakis G, Trafalis DT, Botaitis S, Giatromanolaki A, Koukourakis MI, Franco R, Pappa A, Panayiotidis MI. Targeting the epigenome in malignant melanoma: Facts, challenges and therapeutic promises. Pharmacol Ther 2022; 240:108301. [PMID: 36283453 DOI: 10.1016/j.pharmthera.2022.108301] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 10/03/2022] [Accepted: 10/19/2022] [Indexed: 11/16/2022]
Abstract
Malignant melanoma is the most lethal type of skin cancer with high rates of mortality. Although current treatment options provide a short-clinical benefit, acquired-drug resistance highlights the low 5-year survival rate among patients with advanced stage of the disease. In parallel, the involvement of an aberrant epigenetic landscape, (e.g., alterations in DNA methylation patterns, histone modifications marks and expression of non-coding RNAs), in addition to the genetic background, has been also associated with the onset and progression of melanoma. In this review article, we report on current therapeutic options in melanoma treatment with a focus on distinct epigenetic alterations and how their reversal, by specific drug compounds, can restore a normal phenotype. In particular, we concentrate on how single and/or combinatorial therapeutic approaches have utilized epigenetic drug compounds in being effective against malignant melanoma. Finally, the role of deregulated epigenetic mechanisms in promoting drug resistance to targeted therapies and immune checkpoint inhibitors is presented leading to the development of newly synthesized and/or improved drug compounds capable of targeting the epigenome of malignant melanoma.
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Affiliation(s)
- I Anestopoulos
- Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
| | - S Kyriakou
- Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
| | - V Tragkola
- Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
| | - I Paraskevaidis
- Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
| | - E Tzika
- Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
| | | | - M V Deligiorgi
- Laboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, Athens, Greece
| | - G Petrakis
- Saint George Hospital, Chania, Crete, Greece
| | - D T Trafalis
- Laboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, Athens, Greece
| | - S Botaitis
- Department of Surgery, Alexandroupolis University Hospital, Democritus University of Thrace School of Medicine, Alexandroupolis, Greece
| | - A Giatromanolaki
- Department of Pathology, Democritus University of Thrace, University General Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - M I Koukourakis
- Radiotherapy / Oncology, Radiobiology & Radiopathology Unit, Department of Medicine, School of Health Sciences, Democritus University of Thrace, Alexandroupolis, Greece
| | - R Franco
- Redox Biology Centre, University of Nebraska-Lincoln, Lincoln, NE, USA; School of Veterinary Medicine & Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, USA
| | - A Pappa
- Department of Molecular Biology & Genetics, Democritus University of Thrace, Alexandroupolis, Greece
| | - M I Panayiotidis
- Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
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7
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Fang L, Gao Y, Wang Z, Li Y, Yan Y, Wu Z, Cheng JC, Sun YP. EGF stimulates human trophoblast cell invasion by downregulating ID3-mediated KISS1 expression. Cell Commun Signal 2021; 19:101. [PMID: 34620174 PMCID: PMC8499481 DOI: 10.1186/s12964-021-00783-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 08/30/2021] [Indexed: 11/24/2022] Open
Abstract
Background During pregnancy, trophoblast cell invasion needs to be finely controlled. Aberrant trophoblast cell invasion is associated with placental diseases. Epidermal growth factor (EGF) and its receptor, EGFR, are expressed in trophoblast cells. Although the pro-invasive effect of EGF on trophoblast cells has been reported, the underlying mechanism remains largely unknown. Results In the present study, we conducted an RNA sequencing (RNA-seq) to HTR-8/SVneo human trophoblast cells in response to EGF and identified KISS1 as a target gene of EGF. The human KISS1 gene encodes kisspeptin, also known as metastin, which can suppress tumor metastasis. Our results showed that EGF treatment downregulated KISS1 expression and secretion by activating the EGFR-mediated PI3K/AKT signaling pathway. In addition, the expression of inhibitor of DNA-binding protein 3 (ID3) was downregulated by EGF and that was required for the EGF-suppressed KISS1 expression. Functionally, transwell invasion assays demonstrated that EGF stimulated human trophoblast cell invasion by downregulating KISS1 expression. Preeclampsia (PE) is a placental disease characterized by insufficient trophoblast cell invasion. Our clinical results revealed that serum levels of EGF were downregulated while serum and placental levels of KISS1 were upregulated in PE patients. Conclusions This study demonstrates that downregulation of EGF can lead to poor trophoblast cell invasion by increasing KISS1 expression which subsequently contributes to the pathogenesis of PE.
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Video Abstract
- Lanlan Fang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, 40, Daxue Road, Zhengzhou, 450052, Henan, China
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- Yibo Gao
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, 40, Daxue Road, Zhengzhou, 450052, Henan, China
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- Zhen Wang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, 40, Daxue Road, Zhengzhou, 450052, Henan, China
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- Yuxi Li
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, 40, Daxue Road, Zhengzhou, 450052, Henan, China
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- Yang Yan
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, 40, Daxue Road, Zhengzhou, 450052, Henan, China
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- Ze Wu
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, 40, Daxue Road, Zhengzhou, 450052, Henan, China
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- Jung-Chien Cheng
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, 40, Daxue Road, Zhengzhou, 450052, Henan, China.
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- Ying-Pu Sun
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, 40, Daxue Road, Zhengzhou, 450052, Henan, China.
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Bona Fide Tumor Suppressor Genes Hypermethylated in Melanoma: A Narrative Review.
Int J Mol Sci 2021;
22:ijms221910674. [PMID:
34639015 PMCID:
PMC8508892 DOI:
10.3390/ijms221910674]
[Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/27/2021] [Accepted: 09/30/2021] [Indexed: 12/17/2022] Open
Abstract
Loss-of-function events in tumor suppressor genes (TSGs) contribute to the development and progression of cutaneous malignant melanoma (CMM). Epigenetic alterations are the major mechanisms of TSG inactivation, in particular, silencing by promoter CpG-island hypermethylation. TSGs are valuable tools in diagnosis and prognosis and, possibly, in future targeted therapy. The aim of this narrative review is to outline bona fide TSGs affected by promoter CpG-island hypermethylation and their functional role in the progression of CMM. We conducted a systematic literature review to identify studies providing evidence of bona fide TSGs by cell line or animal experiments. We performed a broad first search and a gene-specific second search, supplemented by reference checking. We included studies describing bona fide TSGs in CMM with promoter CpG-island hypermethylation in which inactivating mechanisms were reported. We extracted data about protein role, pathway, experiments conducted to meet the bona fide criteria and hallmarks of cancer acquired by TSG inactivation. A total of 24 studies were included, describing 24 bona fide TSGs silenced by promoter CpG-island hypermethylation in CMM. Their effect on cell proliferation, apoptosis, growth, senescence, angiogenesis, migration, invasion or metastasis is also described. These data give further insight into the role of TSGs in the progression of CMM.
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Kremer JL, Auricino TB, Dos Santos Passaia B, Lotfi CFP. Upregulation of TCF21 inhibits migration of adrenocortical carcinoma cells.
Discov Oncol 2021;
12:23. [PMID:
35201460 PMCID:
PMC8777580 DOI:
10.1007/s12672-021-00417-6]
[Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/13/2021] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND
Adrenocortical carcinomas (ACC) are rare and aggressive cancer. Our previous study has revealed that the transcription factor 21, TCF21, is downregulated in ACC and regulates steroidogenic factor 1 (SF-1) binding to the SF-1 E-box promoter. In addition, it could be found that TCF21 is a predictor of overall survival (OS) in adult carcinomas.
METHODS
In this study, it was investigated the correlation between TCF21 expression and the promoter methylation status in adrenocortical tumor cells, carcinomas and adenoma. The biological function and potential molecular mechanism of TCF21 restoration in migration and invasion of ACC cells was examined.
RESULTS
We could be demonstrated a negative correlation between the level of TCF21 expression and methylation of its promoter in adenoma and carcinoma cells indicating the epigenetic control of TCF21 expression. It was also demonstrated that the expression of TCF21 inhibits migration and invasion in the ACC cell line, H295R cells, using plasmid transfection to express TCF21. Furthermore, it could be investigated the TCF21 function as tumor suppressor probably through Kisspeptin 1 (KISS-1) expression and epithelial-mesenchymal transition (EMT) reversion, as well as the modulation of several metalloproteinases in ACC cells.
CONCLUSIONS
Our results suggest that enhancement of TCF21 expression levels may be a potential strategy to revert invasive abilities in adrenocortical carcinomas.
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Affiliation(s)
- Jean Lucas Kremer
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
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- Thais Barabba Auricino
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
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Lotfi CFP, Passaia BS, Kremer JL. Role of the bHLH transcription factor TCF21 in development and tumorigenesis.
ACTA ACUST UNITED AC 2021;
54:e10637. [PMID:
33729392 PMCID:
PMC7959166 DOI:
10.1590/1414-431x202010637]
[Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 11/17/2020] [Indexed: 01/12/2023]
Abstract
Transcription factors control, coordinate, and separate the functions of distinct network modules spatially and temporally. In this review, we focus on the transcription factor 21 (TCF21) network, a highly conserved basic-helix-loop-helix (bHLH) protein that functions to integrate signals and modulate gene expression. We summarize the molecular and biological properties of TCF21 control with an emphasis on molecular and functional TCF21 interactions. We suggest that these interactions serve to modulate the development of different organs at the transcriptional level to maintain growth homeostasis and to influence cell fate. Importantly, TCF21 expression is epigenetically inactivated in different types of human cancers. The epigenetic modification or activation and/or loss of TCF21 expression results in an imbalance in TCF21 signaling, which may lead to tumor initiation and, most likely, to progression and tumor metastasis. This review focuses on research on the roles of TCF21 in development and tumorigenesis systematically considering the physiological and pathological function of TCF21. In addition, we focus on the main molecular bases of its different roles whose importance should be clarified in future research. For this review, PubMed databases and keywords such as TCF21, POD-1, capsulin, tumors, carcinomas, tumorigenesis, development, and mechanism of action were utilized. Articles were selected within a historical context as were a number of citations from journals with relevant impact.
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Affiliation(s)
- C F P Lotfi
- Instituto de Ciências Biomédicas, Departamento de Anatomia, Universidade de São Paulo, São Paulo, SP, Brasil
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- B S Passaia
- Instituto de Ciências Biomédicas, Departamento de Anatomia, Universidade de São Paulo, São Paulo, SP, Brasil
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- J L Kremer
- Instituto de Ciências Biomédicas, Departamento de Anatomia, Universidade de São Paulo, São Paulo, SP, Brasil
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11
Varankar SS, More M, Abraham A, Pansare K, Kumar B, Narayanan NJ, Jolly MK, Mali AM, Bapat SA. Functional balance between Tcf21-Slug defines cellular plasticity and migratory modalities in high grade serous ovarian cancer cell lines.
Carcinogenesis 2020;
41:515-526. [PMID:
31241128 DOI:
10.1093/carcin/bgz119]
[Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 04/26/2019] [Accepted: 06/21/2019] [Indexed: 12/21/2022] Open
Abstract
Cellular plasticity and transitional phenotypes add to complexities of cancer metastasis that can be initiated by single cell epithelial to mesenchymal transition (EMT) or cooperative cell migration (CCM). Our study identifies novel regulatory cross-talks between Tcf21 and Slug in mediating phenotypic and migration plasticity in high-grade serous ovarian adenocarcinoma (HGSC). Differential expression and subcellular localization associate Tcf21, Slug with epithelial, mesenchymal phenotypes, respectively; however, gene manipulation approaches identify their association with additional intermediate phenotypic states, implying the existence of a multistep epithelial-mesenchymal transition program. Live imaging further associated distinct migratory modalities with the Tcf21/Slug status of cell systems and discerned proliferative/passive CCM, active CCM and EMT modes of migration. Tcf21-Slug balance identified across a phenotypic spectrum in HGSC cell lines, associated with microenvironment-induced transitions and the emergence of an epithelial phenotype following drug exposure. Phenotypic transitions and associated functionalities following drug exposure were affirmed to ensue from occupancy of Slug promoter E-box sequences by Tcf21. Our study effectively provides a framework for understanding the relevance of ovarian cancer plasticity as a function of two transcription factors.
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Affiliation(s)
- Sagar S Varankar
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune, India
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- Madhuri More
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune, India
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- Ancy Abraham
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune, India
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- Kshama Pansare
- Institute for Plasma Research & Tata Memorial Centre, Kharghar, Navi-Mumbai, India
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- Brijesh Kumar
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune, India
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- Nivedhitha J Narayanan
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune, India
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- Mohit Kumar Jolly
- Center for Theoretical Biological Physics, Rice University, Houston, TX, USA
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- Avinash M Mali
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune, India
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- Sharmila A Bapat
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune, India
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12
Rajan N, Khanal T, Ringel MD. Progression and dormancy in metastatic thyroid cancer: concepts and clinical implications.
Endocrine 2020;
70:24-35. [PMID:
32779092 PMCID:
PMC7530083 DOI:
10.1007/s12020-020-02453-8]
[Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 08/01/2020] [Indexed: 02/07/2023]
Abstract
Distant metastasis classically has been defined as a late-stage event in cancer progression. However, it has become clear that metastases also may occur early in the "lifetime" of a cancer and that they may remain stable at distant sites. This stability of metastatic cancer deposits has been termed "metastatic dormancy" or, as we term it, "metastatic progression dormancy" as the progression either may reflect growth of already existing metastases or new cancer spread. Biologically, dormancy is the presence of nongrowing, static metastatic cells that survive over time. Clinically, dormancy is defined by stability in tumor markers, imaging, and clinical course. Metastatic well-differentiated thyroid cancer offers an excellent tumor type to understand these processes for several reasons: (1) primary therapy often includes removal of the entire gland with ablation of residual normal tissue thereby removing one source for new metastases; (2) the presence of a sensitive biochemical and radiographic monitoring tests enabling monitoring of metastasis throughout the progression process; and (3) its tendency toward prolonged clinical dormancy that can last for years or decades be followed by progression. This latter factor provides opportunities to define therapeutic targets and/or markers of progression. In this review, we will discuss concepts of metastatic progression dormancy and the factors that drive both long-term stability and loss of dormancy with a focus on thyroid cancer.
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Affiliation(s)
- Neel Rajan
- Division of Endocrinology, Diabetes, and Metabolism, Arthur G. James Comprehensive Center, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
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- Tilak Khanal
- Division of Endocrinology, Diabetes, and Metabolism, Arthur G. James Comprehensive Center, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
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- Matthew D Ringel
- Division of Endocrinology, Diabetes, and Metabolism, Arthur G. James Comprehensive Center, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA.
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13
Abstract
The significance of KISS1 goes beyond its original discovery as a metastasis suppressor. Its function as a neuropeptide involved in diverse physiologic processes is more well studied. Enthusiasm regarding KISS1 has cumulated in clinical trials in multiple fields related to reproduction and metabolism. But its cancer therapeutic space is unsettled. This review focuses on collating data from cancer and non-cancer fields in order to understand shared and disparate signaling that might inform clinical development in the cancer therapeutic and biomarker space. Research has focused on amino acid residues 68-121 (kisspeptin 54), binding to the KISS1 receptor and cellular responses. Evidence and counterevidence regarding this canonical pathway require closer look at the covariates so that the incredible potential of KISS1 can be realized.
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Affiliation(s)
- Thuc Ly
- Department of Cancer Biology, Kansas University Medical Center, 3901 Rainbow Blvd. - MS1071, Kansas City, KS, 66160, USA
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- Sitaram Harihar
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603203, India
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- Danny R Welch
- Department of Cancer Biology, Kansas University Medical Center, 3901 Rainbow Blvd. - MS1071, Kansas City, KS, 66160, USA.
- University of Kansas Cancer Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA.
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14
TCF21: a critical transcription factor in health and cancer.
J Mol Med (Berl) 2020;
98:1055-1068. [DOI:
10.1007/s00109-020-01934-7]
[Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 05/07/2020] [Accepted: 06/03/2020] [Indexed: 02/07/2023]
15
Liu Z, Wan Y, Qiu Y, Qi X, Yang M, Huang J, Zhang Q. Development and validation of a novel immune-related prognostic model in lung squamous cell carcinoma.
Int J Med Sci 2020;
17:1393-1405. [PMID:
32624696 PMCID:
PMC7330657 DOI:
10.7150/ijms.47301]
[Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 05/23/2020] [Indexed: 12/12/2022] Open
Abstract
Background: The immune system plays an important role in the development of lung squamous cell carcinoma (LUSC). Therefore, immune-related genes (IRGs) expression may be an important predictor of LUSC prognosis. However, a prognostic model based on IRGs that can systematically assess the prognosis of LUSC patients is still lacking. This study aimed to construct a LUSC immune-related prognostic model by using IRGs. Methods: Gene expression data about LUSC were obtained from The Cancer Genome Atlas (TCGA). Differential expression analysis and univariate Cox regression analysis were performed to identify prognostic differentially expressed IRGs. A prognostic model was constructed using the Lasso and multivariate Cox regression analyses. Then we validated the performance of the prognostic model in training and test cohorts. Furthermore, associations with clinical variables and immune infiltration were also analyzed. Results: 593 differentially expressed IRGs were identified, and 8 of them were related to prognosis. Then a transcription factor regulatory network was established. A prognostic model consisted of 4 immune-related genes was constructed by using Lasso and multivariate Cox regression analyses. The prognostic value of this model was successfully validated in training and test cohorts. Further analysis showed that the prognostic model could be used independently to predict the prognosis of LUSC patients. The relationships between the risk score and immune cell infiltration indicated that the model could reflect the status of the tumor immune microenvironment. Conclusions: We constructed a risk model using four PDIRGs that can accurately predict the prognosis of LUSC patients. The risk score generated by this model can be used as an independent prognostic indicator. Moreover, the model can predict the infiltration of immune cells in patients, which is conducive to the prediction of patient sensitivity to immunotherapy.
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Affiliation(s)
- Zeyu Liu
- Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
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- Yuxiang Wan
- Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
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- Yuqin Qiu
- Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
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- Xuewei Qi
- Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
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- Ming Yang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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- Jinchang Huang
- Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
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- Qiaoli Zhang
- Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
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16
Harihar S, Ray S, Narayanan S, Santhoshkumar A, Ly T, Welch DR. Role of the tumor microenvironment in regulating the anti-metastatic effect of KISS1.
Clin Exp Metastasis 2020;
37:209-223. [PMID:
32088827 PMCID:
PMC7339126 DOI:
10.1007/s10585-020-10030-6]
[Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 02/19/2020] [Indexed: 12/29/2022]
Abstract
KISS1, a metastasis suppressor gene, has been shown to block metastasis without affecting primary tumor formation. Loss of KISS1 leads to invasion and metastasis in multiple cancers, which is the leading cause of cancer morbidity and mortality. The discovery of KISS1 has provided a ray of hope for early clinical diagnosis and for designing effective treatments targeting metastatic cancer. However, this goal requires greater holistic understanding of its mechanism of action. In this review, we go back into history and highlight some key developments, from the discovery of KISS1 to its role in regulating multiple physiological processes including cancer. We discuss key emerging roles for KISS1, specifically interactions with tissue microenvironment to promote dormancy and regulation of tumor cell metabolism, acknowledged as some of the key players in tumor progression and metastasis. We finally discuss strategies whereby KISS1 might be exploited clinically to treat metastasis.
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Affiliation(s)
- Sitaram Harihar
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India.
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- Srijit Ray
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
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- Samyukta Narayanan
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
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- Anirudh Santhoshkumar
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
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- Thuc Ly
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
- The University Kansas Cancer Center, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
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- Danny R Welch
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
- The University Kansas Cancer Center, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
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17
Wong KM, Song J, Saini V, Wong YH. Small Molecules as Drugs to Upregulate Metastasis Suppressors in Cancer Cells.
Curr Med Chem 2019;
26:5876-5899. [PMID:
29788870 DOI:
10.2174/0929867325666180522090842]
[Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 03/20/2018] [Accepted: 05/18/2018] [Indexed: 12/26/2022]
Abstract
It is well-recognized that the majority of cancer-related deaths is attributed to metastasis, which can arise from virtually any type of tumor. Metastasis is a complex multistep process wherein cancer cells must break away from the primary tumor, intravasate into the circulatory or lymphatic systems, extravasate, proliferate and eventually colonize secondary sites. Since these molecular processes involve the coordinated actions of numerous proteins, targeted disruptions of key players along these pathways represent possible therapeutic interventions to impede metastasis formation and reduce cancer mortality. A diverse group of proteins with demonstrated ability to inhibit metastatic colonization have been identified and they are collectively known as metastasis suppressors. Given that the metastasis suppressors are often downregulated in tumors, drug-induced re-expression or upregulation of these proteins represents a promising approach to limit metastasis. Indeed, over 40 compounds are known to exhibit efficacy in upregulating the expression of metastasis suppressors via transcriptional or post-transcriptional mechanisms, and the most promising ones are being evaluated for their translational potentials. These small molecules range from natural products to drugs in clinical use and they apparently target different molecular pathways, reflecting the diverse nature of the metastasis suppressors. In this review, we provide an overview of the different classes of compounds known to possess the ability to upregulate one or more metastasis suppressors, with an emphasis on their mechanisms of action and therapeutic potentials.
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Affiliation(s)
- Ka Ming Wong
- Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
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- Jiaxing Song
- Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
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- Vasu Saini
- Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
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- Yung H Wong
- Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.,State Key Laboratory of Molecular Neuroscience, and the Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.,Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen, China
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18
Lu W, Yang C, Du P, Zhang JL, Zhang JC. Expression tendency and prognostic value of TCF21 in hepatocellular carcinoma.
ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019;
47:1466-1470. [PMID:
31014118 DOI:
10.1080/21691401.2019.1601102]
[Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND
Transcription factor 21 (TCF21) is identified as a tumor suppressor in a variety of human tumors. The purpose of the study was to examine its expression tendency and prognostic value in hepatocellular carcinoma (HCC).
METHODS
Relative expression of TCF21 mRNA in tissue samples from HCC patients and healthy volunteers were detected through quantitative real-time polymerase chain reaction (qRT-PCR) while its protein level was examined via immunohistochemistry analysis. Chi-square test was adopted to assess the association of TCF21 expression with the clinicopathological characteristic of the patients. Then Kaplan-Meier analysis was employed to analyze the function of TCF21 expression on overall survival among HCC patients.
RESULTS
Both the mRNA and protein levels of TCF21 were significantly reduced in HCC tissue samples compared with healthy controls (p < .05). Also, its expression was obviously affected by the classification of tissue pathology, metastasis, T stage, N stage and pathological grading. According to Kaplan-Meier analysis, patients with higher expression of TCF21 experienced dramatically longer overall survival time than those with lower expression (log rank test, p < .001).
CONCLUSIONS
TCF21 expression was decreased in HCC patients and it could act as a prognostic marker.
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Affiliation(s)
- Wei Lu
- a Department of Interventional Medicine , Chinese PLA General Hospital-Sixth Medical Center , Beijing , China
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- Chao Yang
- a Department of Interventional Medicine , Chinese PLA General Hospital-Sixth Medical Center , Beijing , China
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- Peng Du
- a Department of Interventional Medicine , Chinese PLA General Hospital-Sixth Medical Center , Beijing , China
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- Jun-Li Zhang
- a Department of Interventional Medicine , Chinese PLA General Hospital-Sixth Medical Center , Beijing , China
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- Jia-Cheng Zhang
- a Department of Interventional Medicine , Chinese PLA General Hospital-Sixth Medical Center , Beijing , China
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19
Zhang P, Zhang M, Yu D, Liu W, Hu L, Zhang B, Zhou Q, Cao Z. Lycorine inhibits melanoma cell migration and metastasis mainly through reducing intracellular levels of β-catenin and matrix metallopeptidase 9.
J Cell Physiol 2019;
234:10566-10575. [PMID:
30565685 DOI:
10.1002/jcp.27732]
[Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 10/18/2018] [Indexed: 12/19/2022]
Abstract
Metastatic melanoma accounts for 60% of death for skin cancer. Although great efforts have been made to treat the disease, effective drugs against metastatic melanoma still lack at the clinical setting. In the current study, we found that lycorine, a small molecule of isoquinoline alkaloid, significantly suppressed melanoma cell migration and invasion in vitro, and decreased the metastasis of melanoma cells to lung tissues in tumor-bearing mice, resulting in significant prolongation of the survival of the mice without obvious toxicity. Molecular mechanistic studies revealed that lycorine significantly reduced intracellular levels of β-catenin protein through degradation of the protein via the ubiquitin-proteasome pathway, and decreased the expression of β-catenin downstream prometastatic matrix metallopeptidase 9 and Axin2 genes. Collectively, our findings support the notion that targeting the oncogenic β-catenin by lycorine is a new option to inhibit melanoma cell metastasis, providing a good drug candidate potential for development novel therapeutics against metastatic melanoma.
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Affiliation(s)
- Pan Zhang
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, P. R. China
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- Mengli Zhang
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, P. R. China
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- Di Yu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
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- Wenming Liu
- State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China
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- Lin Hu
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
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- Bin Zhang
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, P. R. China
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- Quansheng Zhou
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, P. R. China
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- Zhifei Cao
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, P. R. China
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20
Gu Y, Zhou JD, Xu ZJ, Zhang TJ, Wen XM, Ma JC, Ji RB, Yuan Q, Zhang W, Chen Q, Lin J, Qian J. Promoter methylation of the candidate tumor suppressor gene TCF21 in myelodysplastic syndrome and acute myeloid leukemia.
Am J Transl Res 2019;
11:3450-3460. [PMID:
31312357 PMCID:
PMC6614633]
[Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 05/12/2019] [Indexed: 06/10/2023]
Abstract
Transcription factor 21 (TCF21) has been identified as a candidate tumor suppressor gene which was epigenetically inactivated in a variety of human cancers. However, TCF21 methylation pattern remains unknown in hematologic malignancies. The aim of this study was to investigate TCF21 methylation and its clinical relevance in myelodysplastic syndrome (MDS) and non-M3 acute myeloid leukemia (AML). A total cohort of 33 MDS patients, 100 non-M3 AML patients and 25 healthy donors were enrolled in the study. Targeted bisulfite sequencing assay was performed to identify the methylation pattern of CpG islands within the promoter of TCF21 gene. The bioinformatics analyses were based on The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO). The results showed that there were significant differences in the methylation levels of TCF21 between MDS, non-M3 AML and controls (P = 0.003 and < 0.001, respectively). TCF21 hypermethylation might be served as a promising biomarker which could distinguish MDS/AML from normal controls (P < 0.001 and = 0.003, respectively). There was a significant difference in cytogenetic risk categories between TCF21 hypermethylation and non-hypermethylation AML patients (P = 0.032). Notably, TCF21 hypermethylation occurred frequently in AML patients with adverse risk category, compared with those with favorable and intermediate categories, respectively (67% vs 44% and 29%). TCF21 non-hypermethylation AML patients showed a higher probability of normal karyotype than abnormal karyotype (P = 0.003). The rate of DNMT3A gene mutation was significantly higher in the non-hypermethylation AML patients than that in the hypermethylation (8/44 vs 0/34, P = 0.020). These results suggested that aberrant DNA promoter methylation of TCF21 was frequent event in MDS and non-M3 AML, and TCF21 hypermathylation was associated with adverse risk karyotype in AML.
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Affiliation(s)
- Yu Gu
- Department of Hematology, Affiliated People’s Hospital of Jiangsu UniversityZhenjiang, Jiangsu, People’s Republic of China
- Zhenjiang Clinical Research Center of HematologyZhenjiang, Jiangsu, People’s Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang CityZhenjiang, Jiangsu, People’s Republic of China
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- Jing-Dong Zhou
- Department of Hematology, Affiliated People’s Hospital of Jiangsu UniversityZhenjiang, Jiangsu, People’s Republic of China
- Zhenjiang Clinical Research Center of HematologyZhenjiang, Jiangsu, People’s Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang CityZhenjiang, Jiangsu, People’s Republic of China
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- Zi-Jun Xu
- Laboratory Center, Affiliated People’s Hospital of Jiangsu UniversityZhenjiang, Jiangsu, People’s Republic of China
- Zhenjiang Clinical Research Center of HematologyZhenjiang, Jiangsu, People’s Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang CityZhenjiang, Jiangsu, People’s Republic of China
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- Ting-Juan Zhang
- Department of Hematology, Affiliated People’s Hospital of Jiangsu UniversityZhenjiang, Jiangsu, People’s Republic of China
- Zhenjiang Clinical Research Center of HematologyZhenjiang, Jiangsu, People’s Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang CityZhenjiang, Jiangsu, People’s Republic of China
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- Xiang-Mei Wen
- Laboratory Center, Affiliated People’s Hospital of Jiangsu UniversityZhenjiang, Jiangsu, People’s Republic of China
- Zhenjiang Clinical Research Center of HematologyZhenjiang, Jiangsu, People’s Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang CityZhenjiang, Jiangsu, People’s Republic of China
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- Ji-Chun Ma
- Laboratory Center, Affiliated People’s Hospital of Jiangsu UniversityZhenjiang, Jiangsu, People’s Republic of China
- Zhenjiang Clinical Research Center of HematologyZhenjiang, Jiangsu, People’s Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang CityZhenjiang, Jiangsu, People’s Republic of China
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- Ren-Bi Ji
- Zhenjiang Clinical Research Center of HematologyZhenjiang, Jiangsu, People’s Republic of China
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- Qian Yuan
- Laboratory Center, Affiliated People’s Hospital of Jiangsu UniversityZhenjiang, Jiangsu, People’s Republic of China
- Zhenjiang Clinical Research Center of HematologyZhenjiang, Jiangsu, People’s Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang CityZhenjiang, Jiangsu, People’s Republic of China
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- Wei Zhang
- Department of Hematology, Affiliated People’s Hospital of Jiangsu UniversityZhenjiang, Jiangsu, People’s Republic of China
- Zhenjiang Clinical Research Center of HematologyZhenjiang, Jiangsu, People’s Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang CityZhenjiang, Jiangsu, People’s Republic of China
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- Qin Chen
- Laboratory Center, Affiliated People’s Hospital of Jiangsu UniversityZhenjiang, Jiangsu, People’s Republic of China
- Zhenjiang Clinical Research Center of HematologyZhenjiang, Jiangsu, People’s Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang CityZhenjiang, Jiangsu, People’s Republic of China
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- Jiang Lin
- Laboratory Center, Affiliated People’s Hospital of Jiangsu UniversityZhenjiang, Jiangsu, People’s Republic of China
- Zhenjiang Clinical Research Center of HematologyZhenjiang, Jiangsu, People’s Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang CityZhenjiang, Jiangsu, People’s Republic of China
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- Jun Qian
- Department of Hematology, Affiliated People’s Hospital of Jiangsu UniversityZhenjiang, Jiangsu, People’s Republic of China
- Zhenjiang Clinical Research Center of HematologyZhenjiang, Jiangsu, People’s Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang CityZhenjiang, Jiangsu, People’s Republic of China
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21
Sun W, Li S, Yu Y, Jin H, Xie Q, Hua X, Wang S, Tian Z, Zhang H, Jiang G, Huang C, Huang H. MicroRNA-3648 Is Upregulated to Suppress TCF21, Resulting in Promotion of Invasion and Metastasis of Human Bladder Cancer.
MOLECULAR THERAPY. NUCLEIC ACIDS 2019;
16:519-530. [PMID:
31071528 PMCID:
PMC6506626 DOI:
10.1016/j.omtn.2019.04.006]
[Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 04/07/2019] [Indexed: 12/30/2022]
Abstract
Although microRNAs (miRNAs) are well-known for their potential in cancer, the function and mechanisms of miR-3648 have barely been explored in any type of cancer. We show here that miR-3648 is upregulated in human BC tissues in comparison with adjacent non-tumor tissues. Functional studies showed that inhibition of miR-3648 expression in the human invasive BC UMUC3 and T24T cell lines decreased migration and invasion in vitro and suppressed lung metastasis in vivo, whereas miR-3648 overexpression promoted BC cell migration and invasion. A bioinformatics screen and mRNA 3' UTR luciferase reporter assay showed that transcription factor 21 (TCF21) was a direct target of miR-3648, and the results obtained from using a miR-3648 inhibitor revealed that miR-3648 inhibited TCF21 protein expression by reduction of its mRNA stability. Further, Kisspeptin 1 (KISS1) was identified as a TCF21 downstream effector responsible for miR-3648-mediated BC invasion and lung metastasis. Collectively, the present results suggest that miR-3648 is overexpressed and plays an oncogenic role in mediation of BC invasion and metastasis through directing the TCF21/KISS1 axis, revealing miR-3648 as a potential biomarker for BC prognosis and a target for BC therapy.
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Affiliation(s)
- Wenrui Sun
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Xi'an GaoXin Hospital, Shannxi, Xi'an 710000, China
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- Shi Li
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
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- Yuan Yu
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
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- Honglei Jin
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
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- Qipeng Xie
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
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- Xiaohui Hua
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
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- Shuai Wang
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
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- Zhongxian Tian
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
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- Huxiang Zhang
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
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- Guosong Jiang
- Department of Urology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, China.
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- Chuanshu Huang
- Department of Environmental Medicine, New York University School of Medicine, 431 East 25(th) Street, New York, NY 10010, USA.
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- Haishan Huang
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
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22
Duan HX, Li BW, Zhuang X, Wang LT, Cao Q, Tan LH, Qu GF, Xiao S. TCF21 inhibits tumor-associated angiogenesis and suppresses the growth of cholangiocarcinoma by targeting PI3K/Akt and ERK signaling.
Am J Physiol Gastrointest Liver Physiol 2019;
316:G763-G773. [PMID:
30920845 DOI:
10.1152/ajpgi.00264.2018]
[Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Tumor-associated angiogenesis plays a critical role in the pathogenesis of cholangiocarcinoma (CCA). In this study, we examined the biological effects and molecular mechanisms of transcription factor 21 (TCF21) on CCA-associated angiogenesis. TCF21 expression was compared between 15 pairs of peritumor normal tissues and CCA tissues and also between normal bile duct epithelial cells and two CCA cell lines (QBC-939 and TFK-1) using real-time PCR and Western blot. With the use of both CCA cell lines as the model system, we stably expressed TCF21 by lentiviral transduction (Lv-TCF21). In vivo, we monitored xenograft growth from different CCA cells, measured tumor-associated angiogenesis by histological analysis, and determined the expressions and circulatory levels of VEGFA and PDGF-BB by immunohistochemistry and ELISA, respectively. In vitro, we assessed the effects of conditioned medium collected from different CCA cells on the viability, migration, and tube formation of endothelial cells and explored the significance of phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), as well as ERK1/2 signaling in this process. TCF21 was significantly downregulated in CCA tissues or cell lines. Ectopic expression of TCF21 in CCA cells inhibited xenograft growth or tumor-associated angiogenesis in vivo and targeted the expression and secretion of proangiogenic factors, VEGFA and PDGF-BB. In vitro, the conditioned medium collected from Lv-TCF21 CCA cells significantly reduced the viability, migration, and tube formation of endothelial cells. On the molecular level, the targeting of PI3K/Akt and ERK1/2 signaling mediated the anti-angiogenic activity of TCF21. TCF21 presents growth-inhibitory and anti-angiogenic activities, and thus the elevation of TCF21 expression may provide therapeutic benefits for CCA. NEW & NOTEWORTHY Transcription factor 21 (TCF21) is downregulated in cholangiocarcinoma (CCA) tissues or cells. TCF21 inhibits the growth of xenografts derived from CCA cells. TCF21 suppresses in vivo tumor-associated angiogenesis. TCF21 targets expression and production of proangiogenic factors from CCA cells. The targeting of phosphatidylinositol 3-kinase/protein kinase B and ERK1/2 signaling mediates the anti-angiogenesis of TCF21.
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Affiliation(s)
- Hua-Xin Duan
- Department of Oncology, Hunan Provincial People's Hospital and the First Affiliated Hospital of Hunan Normal University , Changsha , People's Republic of China; and Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Changsha, Hunan, People's Republic of China
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- Bo-Wen Li
- Department of Oncology, Hunan Provincial People's Hospital and the First Affiliated Hospital of Hunan Normal University , Changsha , People's Republic of China; and Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Changsha, Hunan, People's Republic of China
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- Xin Zhuang
- Department of Oncology, Hunan Provincial People's Hospital and the First Affiliated Hospital of Hunan Normal University , Changsha , People's Republic of China; and Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Changsha, Hunan, People's Republic of China
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- Lu-Ting Wang
- Department of Oncology, Hunan Provincial People's Hospital and the First Affiliated Hospital of Hunan Normal University , Changsha , People's Republic of China; and Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Changsha, Hunan, People's Republic of China
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- Qian Cao
- Department of Oncology, Hunan Provincial People's Hospital and the First Affiliated Hospital of Hunan Normal University , Changsha , People's Republic of China; and Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Changsha, Hunan, People's Republic of China
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- Ling-Hua Tan
- Department of Oncology, Hunan Provincial People's Hospital and the First Affiliated Hospital of Hunan Normal University , Changsha , People's Republic of China; and Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Changsha, Hunan, People's Republic of China
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- Gui-Fang Qu
- Department of Oncology, Hunan Provincial People's Hospital and the First Affiliated Hospital of Hunan Normal University , Changsha , People's Republic of China; and Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Changsha, Hunan, People's Republic of China
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- Shuang Xiao
- Department of Oncology, Hunan Provincial People's Hospital and the First Affiliated Hospital of Hunan Normal University , Changsha , People's Republic of China; and Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Changsha, Hunan, People's Republic of China
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23
Zhang N, Wang H, Xie Q, Cao H, Wu F, Di Wu DB, Wan Y. Identification of potential diagnostic and therapeutic target genes for lung squamous cell carcinoma.
Oncol Lett 2019;
18:169-180. [PMID:
31289486 PMCID:
PMC6539486 DOI:
10.3892/ol.2019.10300]
[Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 03/19/2019] [Indexed: 12/19/2022] Open
Abstract
The purpose of this study was to identify potential molecular markers of lung squamous cell carcinoma (LUSC). Three datasets containing LUSC mRNA sequencing data were downloaded from the Gene Expression Omnibus, The Cancer Genome Atlas and the Gene Expression Profiling Interactive Analysis databases. These datasets were used to identify significantly differentially expressed genes (DEGs) in LUSC. A protein-protein interaction network of the DEGs was constructed followed by Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and overall survival analyses of the DEGs. A total of 37 DEGs between LUSC and normal tissues were identified, including 26 downregulated genes and 11 upregulated genes. Biological Process enrichment analysis revealed that the DEGs were mainly enriched in ‘cell adhesion’, ‘cell-matrix adhesion’, ‘anatomical structure morphogenesis’, ‘ECM-receptor interaction’ and ‘focal adhesion’. Overall survival analysis demonstrated that transcription factor 21, α-2-macroglobulin, acyl-CoA synthetase long chain family member 5, integrin subunit β8, meiotic nuclear divisions 1 and secretoglobin family 1A member 1 were significantly associated with the occurrence and development of lung cancer, and these genes were selected as hub genes. The results obtained in the present study may aid the elucidation of the molecular mechanisms involved in the development of LUSC and may provide potential targets for LUSC treatment.
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Affiliation(s)
- Nana Zhang
- Department of Respiration, Second Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
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- Hong Wang
- Department of Respiration, Second Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
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- Qiqi Xie
- Department of Orthopaedics, Second Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
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- Hua Cao
- Department of Respiration, Second Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
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- Fanqi Wu
- Department of Respiration, Second Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
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- Dan Bei Di Wu
- Department of Respiration, Second Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
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- Yixin Wan
- Department of Respiration, Second Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
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24
KiSS1 in regulation of metastasis and response to antitumor drugs.
Drug Resist Updat 2019;
42:12-21. [DOI:
10.1016/j.drup.2019.02.001]
[Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 02/03/2019] [Accepted: 02/06/2019] [Indexed: 12/15/2022]
25
Wu PL, Zhou Y, Zeng C, Li X, Dong ZT, Zhou YF, Bulun SE, Xue Q. Transcription factor 21 regulates expression of ERβ and SF-1 via upstream stimulatory factor-2 in endometriotic tissues.
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2018;
1861:706-717. [PMID:
30018006 DOI:
10.1016/j.bbagrm.2018.06.008]
[Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 06/07/2018] [Accepted: 06/21/2018] [Indexed: 11/19/2022]
Abstract
Steroidogenic factor-1 (SF-1, encoded by NR5A1) and estrogen receptor beta (ERβ, encoded by ESR2), which are highly expressed in endometriotic stromal cells (ESCs), contribute to the pathogenesis of endometriosis, but the regulation mechanism remains largely unknown. Transcription factor 21 (TCF21) belongs to the helix-loop-helix (bHLH) family characterized by regulating gene expression via binding to E-box element. Here, we attempted to determine the molecular mechanism of TCF21 on SF-1 and ERβ expression in endometriosis. We found that TCF21 expression in ESCs was higher than that in endometrial stromal cells (EMs), and positively correlated with SF-1 and ERβ expression in ESCs. Since the importance of E-box element for NR5A1 promoter activity has been previously reported, we performed site-mutation and luciferase assay, revealing that the E-box sequence in the ESR2 promoter is also a critical element modulating ERβ expression. Upstream stimulatory factor 2 (USF2) is another bHLH factor implicated in transcriptional regulation. Further analyses elucidated that it is not TCF21, but USF2 exhibited higher binding affinities in ESCs to NR5A1 and ESR2 promoters than in EMs. Additionally, TCF21 knockdown significantly decreased the binding activities of USF2 to NR5A1 and ESR2 promoters via disruption of the TCF21-USF2 complex. Meanwhile, manipulating TCF21 expression significantly affected MMP9 and cyclinD1 expression, as wells as proliferation and invasion of ESCs. Moreover, TCF21 depletion in endometriotic xenografts reduced SF-1 and ERβ expression, abrogating ectopic lesion growth in mice. Cumulatively, a critical role of TCF21 in the pathogenesis of endometriosis is demonstrated, suggesting a potential druggable target for future therapy.
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Affiliation(s)
- Pei-Li Wu
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing 100034, China
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- Yan Zhou
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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- Cheng Zeng
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing 100034, China
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- Xin Li
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing 100034, China
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- Zhao-Tong Dong
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing 100034, China
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- Ying-Fang Zhou
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing 100034, China
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- Serdar E Bulun
- Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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- Qing Xue
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing 100034, China.
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26
Jiang X, Yang Z. Multiple biological functions of transcription factor 21 in the development of various cancers.
Onco Targets Ther 2018;
11:3533-3539. [PMID:
29950858 PMCID:
PMC6016277 DOI:
10.2147/ott.s164033]
[Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Transcription factor 21 (TCF21) is a basic helix–loop–helix transcription factor that binds to DNA and regulates cell differentiation and cell fate specification through mesenchymal–epithelial transition during development. The TCF21 gene is epigenetically inactivated in many types of human cancers and exerts a wide variety of functions, including the regulation of epithelial–mesenchymal transition, invasion, metastasis, cell cycle, and autophagy. This review focuses on research progress in relation to the roles of TCF21 in tumor development. We systematically consider multiple pathological functions of TCF21 in various cancers, revealing the molecular bases of its diverse biological roles and providing new directions for future research.
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Affiliation(s)
- Xiaodi Jiang
- Department of Infectious Disease, The Shengjing Hospital of China Medical University, Shenyang, China
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- Zhi Yang
- Department of Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
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27
Chen Y, Zhang C, Chen J, Zhang B, Zhang H, Yang X, Liu J, Wu Q. Expression of Transcription Factor 21 (TCF21) and Upregulation Its Level Inhibits Invasion and Metastasis in Esophageal Squamous Cell Carcinoma.
Med Sci Monit 2018;
24:4128-4136. [PMID:
29909422 PMCID:
PMC6038723 DOI:
10.12659/msm.909138]
[Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background
Transcription factor 21 (TCF21), a member of the class A of basic helix-loop-helix family, has been widely identified as a tumor suppressor. Growing evidence has demonstrated the downregulation of TCF21 in distinct cancers. The aim of this study was to explore the expression and biological functions of TCF21 in esophageal squamous cell carcinoma (ESCC).
Material/Methods
TCF21 expression in esophageal cancer cell lines and carcinomas tissues were detected, and its associations with clinical characteristics were analyzed. We carried out this study of biological functions and underlying mechanisms using TE10 and KYSE510 cell lines.
Results
TCF21 mRNA and protein expression were both downregulated in esophageal cancer tissues compared with adjacent normal tissues. Low expression of TCF21 was closely correlated with N stage. In Kaplan-Meier survival analysis, patients with lower TCF21 expression had poorer prognosis. Overexpression of TCF21 greatly inhibited the proliferation, migration, and invasion in both TE10 and KYSE510 cell lines. Furthermore, mechanistic studies showed that with TCF21 gene overexpressed, the expression of tumor suppressor Kiss-1 was upregulated and epithelial-mesenchymal transition (EMT) related proteins (E-cadherin, N-cadherin, Snail, Twist, and Vimentin) which participate in cancer cell invasion and metastasis, were reversed.
Conclusions
TCF21 is downregulated in ESCC, and its low expression is closely correlated with N stage and predicts a poor prognosis. TCF21 functions as a tumor suppressor in ESCC progression, and enhancement of its expression levels may be partly through promoting Kiss-1 expression to reverse EMT by modulating EMT-related gene expression. Thus, TCF21 can potentially be used as a treatment target for ESCC.
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Affiliation(s)
- Yue Chen
- Department of Cardiothoracic Surgery, The First Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing, China (mainland)
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- Cheng Zhang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing, China (mainland)
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- Jing Chen
- Department of Medical Statistics, College of Public Health, Chongqing Medical University, Yuzhong, Chongqing, China (mainland)
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- Bohan Zhang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing, China (mainland)
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- Hongqi Zhang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing, China (mainland)
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- Xuetao Yang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing, China (mainland)
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- Jingshu Liu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing, China (mainland)
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- Qingchen Wu
- Department of Cardiothoracic Surgery, The First Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing, China (mainland)
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28
Ao X, Li S, Xu Z, Yang Y, Chen M, Jiang X, Wu H. Sumoylation of TCF21 downregulates the transcriptional activity of estrogen receptor-alpha.
Oncotarget 2018;
7:26220-34. [PMID:
27028856 PMCID:
PMC5041976 DOI:
10.18632/oncotarget.8354]
[Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 03/06/2016] [Indexed: 12/18/2022] Open
Abstract
Aberrant estrogen receptor-α (ERα) signaling is recognized as a major contributor to the development of breast cancer. However, the molecular mechanism underlying the regulation of ERα in breast cancer is still inconclusive. In this study, we showed that the transcription factor 21 (TCF21) interacted with ERα, and repressed its transcriptional activity in a HDACs-dependent manner. We also showed that TCF21 could be sumoylated by the small ubiquitin-like modifier SUMO1, and this modification could be reversed by SENP1. Sumoylation of TCF21 occurred at lysine residue 24 (K24). Substitution of K24 with arginine resulted in complete abolishment of sumoylation. Sumoylation stabilized TCF21, but did not affect its subcellular localization. Sumoylation of TCF21 also enhanced its interaction with HDAC1/2 without affecting its interaction with ERα. Moreover, sumoylation of TCF21 promoted its repression of ERα transcriptional activity, and increased the recruitment of HDAC1/2 to the pS2 promoter. Consistent with these observations, sumoylation of TCF21 could inhibit the growth of ERα-positive breast cancer cells and decreased the proportion of S-phase cells in the cell cycle. These findings suggested that TCF21 might act as a negative regulator of ERα, and its sumoylation inhibited the transcriptional activity of ERα through promoting the recruitment of HDAC1/2.
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Affiliation(s)
- Xiang Ao
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, People's Republic of China
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- Shujing Li
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, People's Republic of China
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- Zhaowei Xu
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, People's Republic of China
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- Yangyang Yang
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, People's Republic of China
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- Min Chen
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, People's Republic of China
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- Xiao Jiang
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, People's Republic of China
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- Huijian Wu
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, People's Republic of China.,School of Life Science and Medicine, Dalian University of Technology, Panjin 114221, Liaoning, People's Republic of China
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29
Alteration of Epigenetic Regulation by Long Noncoding RNAs in Cancer.
Int J Mol Sci 2018;
19:ijms19020570. [PMID:
29443889 PMCID:
PMC5855792 DOI:
10.3390/ijms19020570]
[Citation(s) in RCA: 123] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 02/13/2018] [Accepted: 02/13/2018] [Indexed: 02/06/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) are important regulators of the epigenetic status of the human genome. Besides their participation to normal physiology, lncRNA expression and function have been already associated to many diseases, including cancer. By interacting with epigenetic regulators and by controlling chromatin topology, their misregulation may result in an aberrant regulation of gene expression that may contribute to tumorigenesis. Here, we review the functional role and mechanisms of action of lncRNAs implicated in the aberrant epigenetic regulation that has characterized cancer development and progression.
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30
Gooskens SL, Klasson TD, Gremmels H, Logister I, Pieters R, Perlman EJ, Giles RH, van den Heuvel-Eibrink MM. TCF21 hypermethylation regulates renal tumor cell clonogenic proliferation and migration.
Mol Oncol 2017;
12:166-179. [PMID:
29080283 PMCID:
PMC5792742 DOI:
10.1002/1878-0261.12149]
[Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 09/12/2017] [Accepted: 10/07/2017] [Indexed: 01/06/2023] Open
Abstract
We recently identified hypermethylation at the gene promoter of transcription factor 21 (TCF21) in clear cell sarcoma of the kidney (CCSK), a rare pediatric renal tumor. TCF21 is a transcription factor involved in tubular epithelial development of the kidney and is a candidate tumor suppressor. As there are no in vitro models of CCSK, we employed a well-established clear cell renal cell carcinoma (ccRCC) cell line, 786-O, which also manifests high methylation at the TCF21 promoter, with consequent low TCF21 expression. The tumor suppressor function of TCF21 has not been functionally addressed in ccRCC cells; we aimed to explore the functional potential of TCF21 expression in ccRCC cells in vitro. 786-O clones stably transfected with either pBABE-TCF21-HA construct or pBABE vector alone were functionally analyzed. We found that ectopic expression of TCF21 in 786-O cells results in a trend toward decreased cell proliferation (not significant) and significantly decreased migration compared with mock-transfected 786-O cells. Although the number of colonies established in colony formation assays was not different between 786-O clones, colony size was significantly reduced in 786-O cells expressing TCF21. To investigate whether the changes in migration were due to epithelial-to-mesenchymal transition changes, we interrogated the expression of selected epithelial and mesenchymal markers. Although we observed upregulation of mRNA and protein levels of epithelial marker E-cadherin in clones overexpressing TCF21, this did not result in surface expression of E-cadherin as measured by fluorescence-activated cell sorting and immunofluorescence. Furthermore, mRNA expression of the mesenchymal markers vimentin (VIM) and SNAI1 was not significantly decreased in TCF21-expressing 786-O cells, while protein levels of VIM were markedly decreased. We conclude that re-expression of TCF21 in renal cancer cells that have silenced their endogenous TCF21 locus through hypermethylation results in reduced clonogenic proliferation, reduced migration, and reduced mesenchymal-like characteristics, suggesting a tumor suppressor function for transcription factor 21.
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Affiliation(s)
- Saskia L Gooskens
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.,Department of Pediatric Hematology and Oncology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands
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- Timothy D Klasson
- Department of Nephrology and Hypertension, University Medical Center Utrecht, University of Utrecht, The Netherlands
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- Hendrik Gremmels
- Department of Nephrology and Hypertension, University Medical Center Utrecht, University of Utrecht, The Netherlands
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- Ive Logister
- Department of Nephrology and Hypertension, University Medical Center Utrecht, University of Utrecht, The Netherlands
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- Robert Pieters
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
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- Elizabeth J Perlman
- Department of Pathology, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University's Feinberg School of Medicine and Robert H. Lurie Cancer Center, IL, USA
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- Rachel H Giles
- Department of Nephrology and Hypertension, University Medical Center Utrecht, University of Utrecht, The Netherlands
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31
Promoter methylation of TCF21 may repress autophagy in the progression of lung cancer.
J Cell Commun Signal 2017;
12:423-432. [PMID:
29086202 DOI:
10.1007/s12079-017-0418-2]
[Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 10/12/2017] [Indexed: 02/04/2023] Open
Abstract
Lung cancer is a leading cause of cancer mortality worldwide. Promoter methylation of transcription factor 21 (TCF21) was frequently observed in the early stage of non-small cell lung cancer (NSCLC). However, clinical relevance and molecular functions of TCF21 in NSCLC progression remain unclear. In this study, we analyzed the associations between TCF21 expression and clinicopathological features in 100 patients with NSCLC and revealed the underlying molecular mechanisms of TCF21 methylation on cell viability, apoptosis and invasion of H1299 cells. We found that the expression of TCF21 was significantly regulated by its methylation level in patients with NSCLC and was associated with tumor stage, metastasis and invasion. Demethylation of H1299 cells by 5-aza-2'-deoxycytine (5-Aza) demonstrated that a higher level of TCF21 expression led to remarkable decreases of cell viability and invasion ability but an increase of cell apoptosis. Accordingly, TCF21 knockdown showed converse results to high expression of TCF21. TCF21 knockdown cells exhibited significantly upregulated ATG-9, BECLIN-1, and LC3-I/II expressions but decreased p62 expression compared to wildtype cells. Inhibition of autophagy by 3-methyladenine (3-MA) elevated TCF21 expression and increased cell apoptosis. TCF21 expression is clinically related to the progress of lung cancer and may inhibit autophagy by suppressing ATG-9 and BECLIN-1. In turn, autophagy may also play an important role in regulation TCF21 expression.
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32
Jiang Z, Zhang W, Chen Z, Shao J, Chen L, Wang Z. Transcription Factor 21 (TCF21) rs12190287 Polymorphism is Associated with Osteosarcoma Risk and Outcomes in East Chinese Population.
Med Sci Monit 2017;
23:3185-3191. [PMID:
28663539 PMCID:
PMC5503230 DOI:
10.12659/msm.905595]
[Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Background
The transcription factor 21 (TCF21) gene is believed to be a tumor suppressor gene. TCF21 gene polymorphisms were found to play a role in the tumorigenesis of some solid malignancies. We raised a hypothesis that genetic polymorphisms of TCF21 were correlated with risk and prognosis of osteosarcoma.
Material/Methods
We recruited 225 young osteosarcoma individuals and 250 cancer-free controls. Five tagging SNPs (TCF21 rs2327429 T>C, rs2327433 A>G, rs2327433 A>G, rs12190287 C>G, and rs4896011 T>A) were genotyped. Preserved DNA samples from blood underwent PCR analysis for genotyping.
Results
rs12190287 C>G is a good predictor of osteosarcoma risk and outcomes. The CG and GG genotypes of rs12190287 predict elevated risk of osteosarcoma. Besides, rs12190287 CG and GG genotypes are associated with Enneking stage and potential in forming metastasis of osteosarcoma.
Conclusions
Genetic polymorphisms of TCF21 are potentially predictive for osteosarcoma risk and outcomes.
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Affiliation(s)
- Zhenghui Jiang
- Department of Orthopaedics, The First People's Hospital of Wenling, Wenling, Zhejiang, China (mainland)
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- Weikang Zhang
- Department of Orthopaedics, The First People's Hospital of Wenling, Wenling, Zhejiang, China (mainland)
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- Zhikang Chen
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China (mainland)
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- Jinxiang Shao
- Department of Orthopaedics, The First People's Hospital of Wenling, Wenling, Zhejiang, China (mainland)
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- Liqiu Chen
- Department of Orthopaedics, The First People's Hospital of Wenling, Wenling, Zhejiang, China (mainland)
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- Zhaohui Wang
- Department of Orthopaedics, The First People's Hospital of Wenling, Zhejiang, China (mainland)
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33
Wouters J, Vizoso M, Martinez-Cardus A, Carmona FJ, Govaere O, Laguna T, Joseph J, Dynoodt P, Aura C, Foth M, Cloots R, van den Hurk K, Balint B, Murphy IG, McDermott EW, Sheahan K, Jirström K, Nodin B, Mallya-Udupi G, van den Oord JJ, Gallagher WM, Esteller M. Comprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma.
BMC Med 2017;
15:101. [PMID:
28578692 PMCID:
PMC5458482 DOI:
10.1186/s12916-017-0851-3]
[Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 04/03/2017] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND
Cutaneous melanoma is the deadliest skin cancer, with an increasing incidence and mortality rate. Currently, staging of patients with primary melanoma is performed using histological biomarkers such as tumor thickness and ulceration. As disruption of the epigenomic landscape is recognized as a widespread feature inherent in tumor development and progression, we aimed to identify novel biomarkers providing additional clinical information over current factors using unbiased genome-wide DNA methylation analyses.
METHODS
We performed a comprehensive DNA methylation analysis during all progression stages of melanoma using Infinium HumanMethylation450 BeadChips on a discovery cohort of benign nevi (n = 14) and malignant melanoma from both primary (n = 33) and metastatic (n = 28) sites, integrating the DNA methylome with gene expression data. We validated the discovered biomarkers in three independent validation cohorts by pyrosequencing and immunohistochemistry.
RESULTS
We identified and validated biomarkers for, and pathways involved in, melanoma development (e.g., HOXA9 DNA methylation) and tumor progression (e.g., TBC1D16 DNA methylation). In addition, we determined a prognostic signature with potential clinical applicability and validated PON3 DNA methylation and OVOL1 protein expression as biomarkers with prognostic information independent of tumor thickness and ulceration.
CONCLUSIONS
Our data underscores the importance of epigenomic regulation in triggering metastatic dissemination through the inactivation of central cancer-related pathways. Inactivation of cell-adhesion and differentiation unleashes dissemination, and subsequent activation of inflammatory and immune system programs impairs anti-tumoral defense pathways. Moreover, we identify several markers of tumor development and progression previously unrelated to melanoma, and determined a prognostic signature with potential clinical utility.
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Affiliation(s)
- Jasper Wouters
- Translational Cell and Tissue Research, KU Leuven (University of Leuven), Leuven, Belgium
- OncoMark Ltd, NovaUCD, Dublin 4, Ireland
- Laboratory of Computational Biology, VIB Center for Brain & Disease Research, Leuven, Belgium
- Department of Human Genetics, KU Leuven (University of Leuven), Leuven, Belgium
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- Miguel Vizoso
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
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- Anna Martinez-Cardus
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
| |
- F Javier Carmona
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
| |
- Olivier Govaere
- Translational Cell and Tissue Research, KU Leuven (University of Leuven), Leuven, Belgium
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- Teresa Laguna
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
- Institute of Molecular Biology (IMB), Mainz, Germany
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- Claudia Aura
- Translational Cell and Tissue Research, KU Leuven (University of Leuven), Leuven, Belgium
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- Mona Foth
- OncoMark Ltd, NovaUCD, Dublin 4, Ireland
- Cancer Research UK, Beatson Institute, Glasgow, G61 1BD, UK
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- Roy Cloots
- OncoMark Ltd, NovaUCD, Dublin 4, Ireland
- Department of Pathology, Maastricht University Medical Centre, Maastricht, The Netherlands
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- Karin van den Hurk
- OncoMark Ltd, NovaUCD, Dublin 4, Ireland
- Department of Pathology, Maastricht University Medical Centre, Maastricht, The Netherlands
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- Balazs Balint
- OncoMark Ltd, NovaUCD, Dublin 4, Ireland
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
| |
- Ian G Murphy
- Department of Surgery, St. Vincent's University Hospital, Dublin 4, Ireland
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- Enda W McDermott
- Department of Surgery, St. Vincent's University Hospital, Dublin 4, Ireland
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- Kieran Sheahan
- Department of Pathology and Laboratory Medicine, St. Vincent's University Hospital, Dublin 4, Ireland
| |
- Karin Jirström
- Department of Clinical Sciences, Division of Pathology, Lund University, Skåne University Hospital, 221 85, Lund, Sweden
| |
- Bjorn Nodin
- Department of Clinical Sciences, Division of Pathology, Lund University, Skåne University Hospital, 221 85, Lund, Sweden
| |
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- Joost J van den Oord
- Translational Cell and Tissue Research, KU Leuven (University of Leuven), Leuven, Belgium
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- William M Gallagher
- OncoMark Ltd, NovaUCD, Dublin 4, Ireland.
- UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin 4, Ireland.
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- Manel Esteller
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
- Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain.
- Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
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34
França MM, Lerario AM, Fragoso MCBV, Lotfi CFP. New evidences on the regulation of SF-1 expression by POD1/TCF21 in adrenocortical tumor cells.
Clinics (Sao Paulo) 2017;
72:391-394. [PMID:
28658440 PMCID:
PMC5463254 DOI:
10.6061/clinics/2017(06)10]
[Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Accepted: 02/14/2017] [Indexed: 01/22/2023] Open
Abstract
OBJECTIVES:
Transcription Factor 21 represses steroidogenic factor 1, a nuclear receptor required for gonadal development, sex determination and the regulation of adrenogonadal steroidogenesis. The aim of this study was to investigate whether silencing or overexpression of the gene Transcription Factor 21 could modulate the gene and protein expression of steroidogenic factor 1 in adrenocortical tumors.
METHODS:
We analyzed the gene expression of steroidogenic factor 1 using qPCR after silencing endogenous Transcription Factor 21 in pediatric adrenal adenoma-T7 cells through small interfering RNA. In addition, using overexpression of Transcription Factor 21 in human adrenocortical carcinoma cells, we analyzed the protein expression of steroidogenic factor 1 using Western blotting.
RESULTS:
Transcription Factor 21 knockdown increased the mRNA expression of steroidogenic factor 1 by 5.97-fold in pediatric adrenal adenoma-T7 cells. Additionally, Transcription Factor 21 overexpression inhibited the protein expression of steroidogenic factor 1 by 0.41-fold and 0.64-fold in two different adult adrenocortical carcinoma cell cultures, H295R and T36, respectively.
CONCLUSIONS:
Transcription Factor 21 is downregulated in adrenocortical carcinoma cells. Taken together, these findings support the hypothesis that Transcription Factor 21 is a regulator of steroidogenic factor 1 and is a tumor suppressor gene in pediatric and adult adrenocortical tumors.
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Affiliation(s)
- Monica Malheiros França
- Departamento de Anatomia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP, BR
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- Antonio M Lerario
- Laboratorio de Hormonio e Genetica Molecular (LIM-42), Unidade Adrenal, Divisao de Endocrinologia, Faculdade de Medicine, Universidade de Sao Paulo, Sao Paulo, SP, BR
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- Maria Candida B V Fragoso
- Laboratorio de Hormonio e Genetica Molecular (LIM-42), Unidade Adrenal, Divisao de Endocrinologia, Faculdade de Medicine, Universidade de Sao Paulo, Sao Paulo, SP, BR
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35
Xiao J, Liu A, Lu X, Chen X, Li W, He S, He B, Chen Q. Prognostic significance of TCF21 mRNA expression in patients with lung adenocarcinoma.
Sci Rep 2017;
7:2027. [PMID:
28515486 PMCID:
PMC5435710 DOI:
10.1038/s41598-017-02290-2]
[Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 04/10/2017] [Indexed: 12/16/2022] Open
Abstract
Several prognostic indicators have shown inconsistencies in patients of different genders with lung adenocarcinoma, indicating that these variations may be due to the different genetic background of males and females with lung adenocarcinoma. In this study, we first used the Gene-Cloud of Biotechnology Information (GCBI) bioinformatics platform to identify differentially expressed genes (DEGs) that eliminated gender differences between lung adenocarcinoma and normal lung tissues. Then, we screened out that transcription factor 21 (TCF21) is a hub gene among these DEGs by creating a gene co-expression network on the GCBI platform. Furthermore, we used the comprehensive survival analysis platforms Kaplan-Meier plotter and PrognoScan to assess the prognostic value of TCF21 expression in lung adenocarcinoma patients. Finally, we concluded that decreased mRNA expression of TCF21 is a predictor for poor prognosis in patients with lung adenocarcinoma.
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Affiliation(s)
- Jian Xiao
- Department of Geriatrics, Respiratory Medicine, Xiangya Hospital of Central South University, Changsha, China
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- Aibin Liu
- Department of Geriatrics, Xiangya Hospital of Central South University, Changsha, China
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- Xiaoxiao Lu
- Department of Geriatrics, Respiratory Medicine, Xiangya Hospital of Central South University, Changsha, China
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- Xi Chen
- Department of Respiratory Medicine, Xiangya Hospital of Central South University, Changsha, China
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- Wei Li
- Department of Geriatrics, Clinical Laboratory, Xiangya Hospital of Central South University, Changsha, China
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- Shuya He
- Department of Biochemistry & Biology, University of South China, Hengyang, China
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- Bixiu He
- Department of Geriatrics, Respiratory Medicine, Xiangya Hospital of Central South University, Changsha, China
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- Qiong Chen
- Department of Geriatrics, Respiratory Medicine, Xiangya Hospital of Central South University, Changsha, China.
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36
Wei J, Zhang L, Li J, Zhu S, Tai M, Mason CW, Chapman JA, Reynolds EA, Weiner CP, Zhou HH. MicroRNA-205 promotes cell invasion by repressing TCF21 in human ovarian cancer.
J Ovarian Res 2017;
10:33. [PMID:
28476165 PMCID:
PMC5420089 DOI:
10.1186/s13048-017-0328-1]
[Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 04/24/2017] [Indexed: 01/06/2023] Open
Abstract
Background
Ovarian cancer is the leading lethal, gynecological malignancy in the United States. No doubt, the continued morbidity and mortality of ovarian cancer reflects a poor understanding of invasive mechanisms. Recent studies reveal that ovarian cancers express aberrant microRNAs (miRNAs or miRs), some of which have oncogenic or tumor suppressor properties. Several studies suggested that miR-205 is involved in tumorigenesis. Presently, we investigate the molecular mechanisms and target of miR-205 in ovarian cancer.
Methods
Quantitative real-time polymerase chain reaction and western blot were performed to assess miR-205 and transcription factor 21 (TCF21) expression in ovarian cancer and normal ovary samples. The effect of miR-205 on TCF21 was determined by luciferase reporter assay and western blot. The effect of miR-205 and TCF21 on cell invasion was quantitated using transwell invasion assay.
Result
miR-205 expression was increased in ovarian cancer and it promoted the invasive behavior of ovarian cancer cell lines (OVCAR-5, OVCAR-8 and SKOV-3). miR-205 directly targeted TCF21, which was significantly decreased in ovarian cancer tissue. miR-205 inhibited TCF21 expression and as a consequence blunted the inhibitory effect of TCF21 on cell invasion. Matrix Metalloproteinases (MMPs) play an important role in cancer invasion and metastasis. TCF21 inhibited MMP-2 and MMP-10 and decreased ovarian cancer cell invasion. Co-transfection of TCF21 expression plasmid with miR-205 mimic diminished the inhibitory effect of TCF21 on MMP-2 and MMP-10 in ovarian cancer cells.
Conclusion
miR-205 appears to have an important role in the spread of ovarian cancer by targeting TCF21. These findings offer a new mechanism of ovarian cancer tumorigenesis, which could be useful for the development of new therapeutic approaches to ovarian cancer treatment.
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Affiliation(s)
- Jun Wei
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, Kansas, 66160, USA
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- Lahong Zhang
- Department of Clinical Laboratory, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, 310036, People's Republic of China
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- Jennifer Li
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, Kansas, 66160, USA
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- Shuguang Zhu
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, Kansas, 66160, USA
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- Minghui Tai
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, Kansas, 66160, USA
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- Clifford W Mason
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, Kansas, 66160, USA
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- Julia A Chapman
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, Kansas, 66160, USA
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- Evelyn A Reynolds
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, Kansas, 66160, USA
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- Carl P Weiner
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, Kansas, 66160, USA
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- Helen H Zhou
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, Kansas, 66160, USA.
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37
Kim JB, Pjanic M, Nguyen T, Miller CL, Iyer D, Liu B, Wang T, Sazonova O, Carcamo-Orive I, Matic LP, Maegdefessel L, Hedin U, Quertermous T. TCF21 and the environmental sensor aryl-hydrocarbon receptor cooperate to activate a pro-inflammatory gene expression program in coronary artery smooth muscle cells.
PLoS Genet 2017;
13:e1006750. [PMID:
28481916 PMCID:
PMC5439967 DOI:
10.1371/journal.pgen.1006750]
[Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 05/22/2017] [Accepted: 04/07/2017] [Indexed: 01/31/2023] Open
Abstract
Both environmental factors and genetic loci have been associated with coronary artery disease (CAD), however gene-gene and gene-environment interactions that might identify molecular mechanisms of risk are not easily studied by human genetic approaches. We have previously identified the transcription factor TCF21 as the causal CAD gene at 6q23.2 and characterized its downstream transcriptional network that is enriched for CAD GWAS genes. Here we investigate the hypothesis that TCF21 interacts with a downstream target gene, the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that mediates the cellular response to environmental contaminants, including dioxin and polycyclic aromatic hydrocarbons (e.g., tobacco smoke). Perturbation of TCF21 expression in human coronary artery smooth muscle cells (HCASMC) revealed that TCF21 promotes expression of AHR, its heterodimerization partner ARNT, and cooperates with these factors to upregulate a number of inflammatory downstream disease related genes including IL1A, MMP1, and CYP1A1. TCF21 was shown to bind in AHR, ARNT and downstream target gene loci, and co-localization was noted for AHR-ARNT and TCF21 binding sites genome-wide in regions of HCASMC open chromatin. These regions of co-localization were found to be enriched for GWAS signals associated with cardio-metabolic as well as chronic inflammatory disease phenotypes. Finally, we show that similar to TCF21, AHR gene expression is increased in atherosclerotic lesions in mice in vivo using laser capture microdissection, and AHR protein is localized in human carotid atherosclerotic lesions where it is associated with protein kinases with a critical role in innate immune response. These data suggest that TCF21 can cooperate with AHR to activate an inflammatory gene expression program that is exacerbated by environmental stimuli, and may contribute to the overall risk for CAD.
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Affiliation(s)
- Juyong Brian Kim
- Division of Cardiovascular Medicine, Stanford University, Stanford, California, United States of America
- Cardiovascular Institute, Stanford University, Stanford, California, United States of America
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- Milos Pjanic
- Division of Cardiovascular Medicine, Stanford University, Stanford, California, United States of America
- Cardiovascular Institute, Stanford University, Stanford, California, United States of America
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- Trieu Nguyen
- Division of Cardiovascular Medicine, Stanford University, Stanford, California, United States of America
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- Clint L. Miller
- Division of Cardiovascular Medicine, Stanford University, Stanford, California, United States of America
- Cardiovascular Institute, Stanford University, Stanford, California, United States of America
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- Dharini Iyer
- Division of Cardiovascular Medicine, Stanford University, Stanford, California, United States of America
- Cardiovascular Institute, Stanford University, Stanford, California, United States of America
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- Boxiang Liu
- Department of Biology, Stanford University, Stanford, California, United States of America
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- Ting Wang
- Division of Cardiovascular Medicine, Stanford University, Stanford, California, United States of America
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- Olga Sazonova
- Division of Cardiovascular Medicine, Stanford University, Stanford, California, United States of America
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- Ivan Carcamo-Orive
- Division of Cardiovascular Medicine, Stanford University, Stanford, California, United States of America
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- Lars Maegdefessel
- Department of Molecular Medicine and Surgery, Karolinska Institute, Solna, Sweden
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- Ulf Hedin
- Department of Molecular Medicine and Surgery, Karolinska Institute, Solna, Sweden
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- Thomas Quertermous
- Division of Cardiovascular Medicine, Stanford University, Stanford, California, United States of America
- Cardiovascular Institute, Stanford University, Stanford, California, United States of America
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38
Dai Y, Duan H, Duan C, Zhu H, Zhou R, Pei H, Shen L. TCF21 functions as a tumor suppressor in colorectal cancer through inactivation of PI3K/AKT signaling.
Onco Targets Ther 2017;
10:1603-1611. [PMID:
28352192 PMCID:
PMC5359128 DOI:
10.2147/ott.s118151]
[Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Colorectal cancer (CRC) has become a major public health problem, ranking as the third most common type of cancer. Our previous study has revealed that TCF21 is frequently silenced by promoter hypermethylation in both CRC cell lines and primary CRC, with TCF21 methylation being significantly correlated with lymph node invasion. In this study, we further analyze the expression of TCF21 in CRC tissues and investigate the role of TCF21 in CRC in vitro and in vivo. We also explore the possible pathway regulated by TCF21. We thus demonstrate that decreased levels of TCF21 are associated with the pathological stage, clinical stage and lymph node metastasis, indicating a poor prognosis in CRC patients; overexpression of TCF21 inhibits cell proliferation, migration and invasion in the colorectal cell lines HCT116 and HT29. Furthermore, TCF21 functions as a tumor suppressor probably through inactivation of PI3K/AKT signaling and inhibition of MMPs. Our results suggest that enhancement of TCF21 levels may be a potential strategy to facilitate the prevention and treatment of CRC in the clinic.
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Affiliation(s)
- Youyi Dai
- Department of Oncology, Xiangya Hospital, Central South University
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- Huaxin Duan
- Department of Oncology, Hunan Provincial People's Hospital; Department of Oncology, The First Affiliated Hospital of Hunan Normal University
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- Chaojun Duan
- Institute of Medical Sciences, Xiangya Hospital, Central South University
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- Hong Zhu
- Department of Oncology, Xiangya Hospital, Central South University
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- Rongrong Zhou
- Department of Oncology, Xiangya Hospital, Central South University
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- Haiping Pei
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
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- Liangfang Shen
- Department of Oncology, Xiangya Hospital, Central South University
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39
Feng N, Wang Y, Zheng M, Yu X, Lin H, Ma RN, Shi O, Zheng X, Gao M, Yu H, Garmire L, Qian B. Genome-wide analysis of DNA methylation and their associations with long noncoding RNA/mRNA expression in non-small-cell lung cancer.
Epigenomics 2017;
9:137-153. [PMID:
28111977 DOI:
10.2217/epi-2016-0120]
[Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
AIM
The goal of this study is to identify differentially methylated (DM) loci associated with long noncoding RNA (lncRNA)/mRNA expression in non-small-cell lung cancer (NSCLC).
MATERIALS & METHODS
Microarrays were used to interrogate genome-wide methylation and expression of lncRNA/mRNA in NSCLC.
RESULTS
We identified 113,644 DM loci between tumors and adjacent tissues. Among them, 26,310 DM loci were associated with 1685 differentially expressed genes, and 839 genes had significant correlations between methylation and expression, of which 26 hypermethylated loci in transcription start site 200 were correlated with low gene expression. We validated the correlations between methylation and expression in five genes (CDO1, C2orf40, SCARF1, ZFP106 and IFFO1) using pyrosequencing and quantitative polymerase chain reaction. We also found significant correlations between lncRNAs and mRNAs, and validated four of the correlations with quantitative polymerase chain reaction.
CONCLUSION
Integrated analysis of genome-wide DNA methylation and lncRNA/mRNA expression allows us to identify new DM loci-correlated with gene expression in NSCLC.
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Affiliation(s)
- Nannan Feng
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital & Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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- Yu Wang
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital & Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Tianjin Key Laboratory of Cancer Prevention & Therapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, China
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- Min Zheng
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital & Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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- Xiao Yu
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital & Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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- Hongyan Lin
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital & Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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- Rong-Na Ma
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital & Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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- Oumin Shi
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital & Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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- Xiangqian Zheng
- Tianjin Key Laboratory of Cancer Prevention & Therapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, China
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- Ming Gao
- Tianjin Key Laboratory of Cancer Prevention & Therapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, China
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- Herbert Yu
- Cancer Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI 96813, USA
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- Lana Garmire
- Cancer Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI 96813, USA
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- Biyun Qian
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital & Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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40
Xin J, Xu R, Lin S, Xin M, Cai W, Zhou J, Fu C, Zhen G, Lai J, Li Y, Zhang P. Clinical potential of
TCF21 methylation in the diagnosis of renal cell carcinoma.
Oncol Lett 2016;
12:1265-1270. [PMID:
27446425 PMCID:
PMC4950740 DOI:
10.3892/ol.2016.4748]
[Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 02/24/2016] [Indexed: 01/06/2023] Open
Abstract
The aim of the present study was to investigate the clinical potential of transcription factor (TCF) 21 methylation in the diagnosis of renal cell carcinoma (RCC). TCF21 methylation levels were quantified in renal tissues (55 cases of RCC tissue and 22 cases of normal tissue) and urine samples (33 cases of urine samples with RCC and 15 cases of normal urine samples) using pyrosequencing. Spearman's rank correlation coefficient was used to investigate the correlation between TCF21 methylation levels and clinical parameters (gender, age, smoking history, Fuhrman grade and clinical stage). The receiver operating characteristic (ROC) curve was utilized to evaluate the accuracy of predictive diagnosis of RCC. TCF21 methylation levels were significantly increased in RCC samples compared with normal renal tissues and urine samples. The Spearman's correlation analysis revealed that the TCF21 methylation level was positively associated with age (P=0.002), smoking (P=0.017) and Fuhrman grade (P=0.045) in RCC tissues and was positively associated with tumor size (P<0.001), Fuhrman grade (P=0.017) and clinical stage (P=0.017) in urine samples. ROC curves revealed that the cut-off value, sensitivity and specificity were 23.61, 89.00 and 61.90%, respectively in tissue samples, and 26.84, 79 and 100%, respectively in urine samples. Furthermore, there were significant differences in the area under the curve between the tissue and urine samples (P=0.004). The results of the present study indicate that TCF21 may be used as a biomarker for diagnosing RCC, and TCF21 methylation levels in urine samples may be a useful means of diagnosing RCC.
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Affiliation(s)
- Jun Xin
- Department of Urology, The First Hospital of Quanzhou Affiliated Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
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- Rong Xu
- Department of Pharmacy, Quanzhou Medical College, Quanzhou, Fujian 362011, P.R. China
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- Shaokun Lin
- Department of Urology, The First Hospital of Quanzhou Affiliated Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
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- Minghua Xin
- Department of Urology, The First Hospital of Quanzhou Affiliated Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
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- Wenjie Cai
- Department of Urology, The First Hospital of Quanzhou Affiliated Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
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- Jin Zhou
- Department of Urology, The First Hospital of Quanzhou Affiliated Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
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- Changde Fu
- Department of Urology, The First Hospital of Quanzhou Affiliated Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
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- Guangfu Zhen
- Department of Urology, General Hospital of the People's Liberation Army, Beijing 100853, P.R. China
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- Jinjin Lai
- Department of Urology, The First Hospital of Quanzhou Affiliated Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
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- Yue Li
- Xiamen Xinchuang Bio-Technology Co. Ltd, Xiamen, Fujian 361021, P.R. China
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- Pengfeng Zhang
- Xiamen Xinchuang Bio-Technology Co. Ltd, Xiamen, Fujian 361021, P.R. China
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41
Tandon P, Wilczewski CM, Williams CE, Conlon FL. The Lhx9-integrin pathway is essential for positioning of the proepicardial organ.
Development 2016;
143:831-40. [PMID:
26811386 DOI:
10.1242/dev.129551]
[Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 01/15/2016] [Indexed: 12/15/2022]
Abstract
The development of the vertebrate embryonic heart occurs by hyperplastic growth as well as the incorporation of cells from tissues outside of the initial heart field. Amongst these tissues is the epicardium, a cell structure that develops from the precursor proepicardial organ on the right side of the septum transversum caudal to the developing heart. During embryogenesis, cells of the proepicardial organ migrate, adhere and envelop the maturing heart, forming the epicardium. The cells of the epicardium then delaminate and incorporate into the heart giving rise to cardiac derivatives, including smooth muscle cells and cardiac fibroblasts. Here, we demonstrate that the LIM homeodomain protein Lhx9 is transiently expressed in Xenopus proepicardial cells and is essential for the position of the proepicardial organ on the septum transversum. Utilizing a small-molecule screen, we found that Lhx9 acts upstream of integrin-paxillin signaling and consistently demonstrate that either loss of Lhx9 or disruption of the integrin-paxillin pathway results in mis-positioning of the proepicardial organ and aberrant deposition of extracellular matrix proteins. This leads to a failure of proepicardial cell migration and adhesion to the heart, and eventual death of the embryo. Collectively, these studies establish a requirement for the Lhx9-integrin-paxillin pathway in proepicardial organ positioning and epicardial formation.
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Affiliation(s)
- Panna Tandon
- Department of Biology, UNC at Chapel Hill, Chapel Hill, NC 27599-3280, USA Department of Genetics, UNC at Chapel Hill, Chapel Hill, NC 27599-3280, USA Integrative Program for Biological and Genome Sciences, UNC at Chapel Hill, Chapel Hill, NC 27599-3280, USA
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- Caralynn M Wilczewski
- Department of Genetics, UNC at Chapel Hill, Chapel Hill, NC 27599-3280, USA Integrative Program for Biological and Genome Sciences, UNC at Chapel Hill, Chapel Hill, NC 27599-3280, USA
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- Clara E Williams
- Integrative Program for Biological and Genome Sciences, UNC at Chapel Hill, Chapel Hill, NC 27599-3280, USA
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- Frank L Conlon
- Department of Biology, UNC at Chapel Hill, Chapel Hill, NC 27599-3280, USA Department of Genetics, UNC at Chapel Hill, Chapel Hill, NC 27599-3280, USA Integrative Program for Biological and Genome Sciences, UNC at Chapel Hill, Chapel Hill, NC 27599-3280, USA University of North Carolina McAllister Heart Institute, UNC at Chapel Hill, Chapel Hill, NC 27599-3280, USA
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42
Down-regulation of TCF21 by hypermethylation induces cell proliferation, migration and invasion in colorectal cancer.
Biochem Biophys Res Commun 2015;
469:430-6. [PMID:
26435499 DOI:
10.1016/j.bbrc.2015.09.109]
[Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 09/21/2015] [Indexed: 01/22/2023]
Abstract
Epigenetic alteration induced loss function of the transcription factor 21 (TCF21) has been associated with different types of human cancers. However, the epigenetic regulation and molecular functions of TCF21 in colorectal cancer (CRC) remain unknown. In this study, TCF21 expression levels and methylation status of its promoter region in CRC cell lines (n = 5) and CRC tissues (n = 151) as well as normal colorectal mucosa (n = 30) were assessed by RTq-PCR and methylation analysis (methylation specific PCR, MSP and bisulfite sequencing PCR, BSP), respectively. The cellular functions of TCF21 on CRC cell proliferation, apoptosis, invasion and migration were investigated in vitro. Our data revealed that TCF21 was frequently silenced by promoter hypermethylation in both tested CRC cell lines and primary CRC, and correlation analysis between methylation status and clinicopathologic parameters found that TCF21 methylation was significantly correlated with lymph node invasion (P = 0.013), while no significant correlation was found in other parameters. In addition, demethylation treatment resulted in re-expression of TCF21 in CRC cell lines, and cellular function experiments revealed that restoration of TCF21 inhibited CRC cell proliferation, promoted apoptosis and suppressed cell invasion and migration, suggesting that TCF21 may function as a tumor suppressor gene, which is downregulated through promoter hypermethylation in CRC development.
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43
POD-1/TCF21 Reduces SHP Expression, Affecting LRH-1 Regulation and Cell Cycle Balance in Adrenocortical and Hepatocarcinoma Tumor Cells.
BIOMED RESEARCH INTERNATIONAL 2015;
2015:841784. [PMID:
26421305 PMCID:
PMC4572413 DOI:
10.1155/2015/841784]
[Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2015] [Revised: 06/12/2015] [Accepted: 06/24/2015] [Indexed: 01/09/2023]
Abstract
POD-1/TCF21 may play a crucial role in adrenal and gonadal homeostasis and represses Sf-1/SF-1 expression in adrenocortical tumor cells. SF-1 and LRH-1 are members of the Fzt-F1 subfamily of nuclear receptors. LRH-1 is involved in several biological processes, and both LRH-1 and its repressor SHP are involved in many types of cancer. In order to assess whether POD-1 can regulate LRH-1 via the same mechanism that regulates SF-1, we analyzed the endogenous mRNA levels of POD-1, SHP, and LRH-1 in hepatocarcinoma and adrenocortical tumor cells using qRT-PCR. Hereafter, these tumor cells were transiently transfected with pCMVMycPod-1, and the effect of POD-1 overexpression on E-box elements in the LRH-1 and SHP promoter region were analyzed by ChIP assay. Also, Cyclin E1 protein expression was analyzed to detect cell cycle progression. We found that POD-1 overexpression significantly decreased SHP/SHP mRNA and protein levels through POD-1 binding to the E-box sequence in the SHP promoter. Decreased SHP expression affected LRH-1 regulation and increased Cyclin E1. These findings show that POD-1/TCF21 regulates SF-1 and LRH-1 by distinct mechanisms, contributing to the understanding of POD-1 involvement and its mechanisms of action in adrenal and liver tumorigenesis, which could lead to the discovery of relevant biomarkers.
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44
Gooskens SL, Gadd S, Guidry Auvil JM, Gerhard DS, Khan J, Patidar R, Meerzaman D, Chen QR, Hsu CH, Yan C, Nguyen C, Hu Y, Mullighan CG, Ma J, Jennings LJ, de Krijger RR, van den Heuvel-Eibrink MM, Smith MA, Ross N, Gastier-Foster JM, Perlman EJ. TCF21 hypermethylation in genetically quiescent clear cell sarcoma of the kidney.
Oncotarget 2015;
6:15828-41. [PMID:
26158413 PMCID:
PMC4599240 DOI:
10.18632/oncotarget.4682]
[Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 06/07/2015] [Indexed: 01/31/2023] Open
Abstract
Clear Cell Sarcoma of the Kidney (CCSK) is a rare childhood tumor whose molecular pathogenesis remains poorly understood. We analyzed a discovery set of 13 CCSKs for changes in chromosome copy number, mutations, rearrangements, global gene expression and global DNA methylation. No recurrent segmental chromosomal copy number changes or somatic variants (single nucleotide or small insertion/deletion) were identified. One tumor with t(10;17)(q22;p13) involving fusion of YHWAE with NUTM2B was identified. Integrated analysis of expression and methylation data identified promoter hypermethylation and low expression of the tumor suppressor gene TCF21 (Pod-1/capsulin/epicardin) in all CCSKs except the case with t(10;17)(q22;p13). TARID, the long noncoding RNA responsible for demethylating TCF21, was virtually undetectable in most CCSKs. TCF21 hypermethylation and decreased TARID expression were validated in an independent set of CCSK tumor samples. The presence of significant hypermethylation of TCF21, a transcription factor known to be active early in renal development, supports the hypothesis that hypermethylation of TCF21 and/or decreased TARID expression lies within the pathogenic pathway of most CCSKs. Future studies are needed to functionally verify a tumorigenic role of TCF21 down-regulation and to tie this to the unique gene expression pattern of CCSK.
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Affiliation(s)
- Saskia L. Gooskens
- Department of Pediatric Hematology and Oncology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands
- Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
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- Samantha Gadd
- Department of Pathology, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University's Feinberg School of Medicine and Robert H. Lurie Cancer Center, Chicago, IL, USA
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- Javed Khan
- Genetics Branch, Oncogenomics section, National Cancer Institute, Bethesda, MD, USA
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- Rajesh Patidar
- Genetics Branch, Oncogenomics section, National Cancer Institute, Bethesda, MD, USA
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- Daoud Meerzaman
- Computational Genomics Research Group, Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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- Qing-Rong Chen
- Computational Genomics Research Group, Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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- Chih Hao Hsu
- Computational Genomics Research Group, Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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- Chunhua Yan
- Computational Genomics Research Group, Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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- Cu Nguyen
- Computational Genomics Research Group, Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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- Ying Hu
- Computational Genomics Research Group, Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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- Charles G. Mullighan
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
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- Jing Ma
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
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- Lawrence J. Jennings
- Department of Pathology, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University's Feinberg School of Medicine and Robert H. Lurie Cancer Center, Chicago, IL, USA
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- Ronald R. de Krijger
- Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands
- Department of Pathology, Reinier de Graaf Hospital, Delft, The Netherlands
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- Malcolm A. Smith
- Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA
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- Nicole Ross
- Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, OH, USA
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- Julie M. Gastier-Foster
- Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, OH, USA
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- Elizabeth J. Perlman
- Department of Pathology, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University's Feinberg School of Medicine and Robert H. Lurie Cancer Center, Chicago, IL, USA
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45
Nurnberg ST, Cheng K, Raiesdana A, Kundu R, Miller CL, Kim JB, Arora K, Carcamo-Oribe I, Xiong Y, Tellakula N, Nanda V, Murthy N, Boisvert WA, Hedin U, Perisic L, Aldi S, Maegdefessel L, Pjanic M, Owens GK, Tallquist MD, Quertermous T. Coronary Artery Disease Associated Transcription Factor TCF21 Regulates Smooth Muscle Precursor Cells That Contribute to the Fibrous Cap.
PLoS Genet 2015;
11:e1005155. [PMID:
26020946 PMCID:
PMC4447275 DOI:
10.1371/journal.pgen.1005155]
[Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Accepted: 03/18/2015] [Indexed: 01/10/2023] Open
Abstract
Recent genome wide association studies have identified a number of genes that contribute to the risk for coronary heart disease. One such gene, TCF21, encodes a basic-helix-loop-helix transcription factor believed to serve a critical role in the development of epicardial progenitor cells that give rise to coronary artery smooth muscle cells (SMC) and cardiac fibroblasts. Using reporter gene and immunolocalization studies with mouse and human tissues we have found that vascular TCF21 expression in the adult is restricted primarily to adventitial cells associated with coronary arteries and also medial SMC in the proximal aorta of mouse. Genome wide RNA-Seq studies in human coronary artery SMC (HCASMC) with siRNA knockdown found a number of putative TCF21 downstream pathways identified by enrichment of terms related to CAD, including “vascular disease,” “disorder of artery,” and “occlusion of artery,” as well as disease-related cellular functions including “cellular movement” and “cellular growth and proliferation.” In vitro studies in HCASMC demonstrated that TCF21 expression promotes proliferation and migration and inhibits SMC lineage marker expression. Detailed in situ expression studies with reporter gene and lineage tracing revealed that vascular wall cells expressing Tcf21 before disease initiation migrate into vascular lesions of ApoE-/- and Ldlr-/- mice. While Tcf21 lineage traced cells are distributed throughout the early lesions, in mature lesions they contribute to the formation of a subcapsular layer of cells, and others become associated with the fibrous cap. The lineage traced fibrous cap cells activate expression of SMC markers and growth factor receptor genes. Taken together, these data suggest that TCF21 may have a role regulating the differentiation state of SMC precursor cells that migrate into vascular lesions and contribute to the fibrous cap and more broadly, in view of the association of this gene with human CAD, provide evidence that these processes may be a mechanism for CAD risk attributable to the vascular wall.
Coronary artery disease (CAD) is responsible for the majority of deaths in the Western world, and is due in part to environmental and metabolic factors. However, half of the risk for developing heart disease is genetically predetermined. Genome-wide association studies in human populations have identified over 100 sites in the genome that appear to be associated with CAD, however, the mechanisms by which variation in these regions are responsible for predisposition to CAD remain largely unknown. We have begun to study a gene that contributes to CAD risk, the TCF21 gene. Through genomic studies we show that this gene is involved in processes related to alterations in vascular gene expression, and in particular those related to the smooth muscle cell biology. With cell culture models, we show that TCF21 regulates the differentiation state of this cell type, which is believed critical for vascular disease. Using mouse genetic models of atherosclerotic vascular disease we provide evidence that this gene is expressed in precursor cells that migrate into the disease lesions and contribute to the formation of the fibrous cap that is believed to stabilize these lesions and prevent heart attacks.
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Affiliation(s)
- Sylvia T. Nurnberg
- Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America
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- Karen Cheng
- Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America
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- Azad Raiesdana
- Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America
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- Ramendra Kundu
- Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America
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- Clint L. Miller
- Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America
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- Juyong B. Kim
- Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America
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- Komal Arora
- Department of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America
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- Ivan Carcamo-Oribe
- Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America
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- Yiqin Xiong
- Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America
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- Nikhil Tellakula
- Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America
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- Vivek Nanda
- Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America
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- Nikitha Murthy
- Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America
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- William A. Boisvert
- Department of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America
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- Ulf Hedin
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
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- Ljubica Perisic
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
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- Silvia Aldi
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
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- Milos Pjanic
- Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America
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- Gary K. Owens
- Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America
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- Michelle D. Tallquist
- Department of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America
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- Thomas Quertermous
- Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America
- * E-mail:
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46
Yang Z, Li DM, Xie Q, Dai DQ. Protein expression and promoter methylation of the candidate biomarker TCF21 in gastric cancer.
J Cancer Res Clin Oncol 2015;
141:211-20. [PMID:
25156819 DOI:
10.1007/s00432-014-1809-x]
[Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Accepted: 08/04/2014] [Indexed: 01/18/2023]
Abstract
PURPOSE
Transcription factor 21 (TCF21) has been identified as a candidate tumor suppressor at 6q23-q24 that is epigenetically inactivated in many types of human cancers. This study aimed to determine the expression of TCF21 mRNA and protein in gastric cancer cell lines and tissue specimens and then investigate the prognostic impact of TCF21 expression in gastric cancer and analyze the relationship between TCF21 expression and methylation level.
METHODS
We used real-time PCR and immunohistochemical staining to detect the expression of TCF21 and used methylation-specific-PCR to determine the methylation status of TCF21 in gastric cancer samples and gastric cancer cell lines.
RESULTS
The results showed that TCF21 expression level in gastric cancer samples was significantly lower than in normal adjacent tissue samples. The Kaplan-Meier survival analysis demonstrated that TCF21 was a significant prognosticator of cancer-specific survival (p = 0.001). Furthermore, the methylation level of TCF21 in gastric cancer samples was much higher than the samples in normal adjacent tissue. Treatment with the DNA methyltransferase inhibitor 5-Aza-2'-deoxy-cytidine can upregulate the expression of TCF21 in gastric cancer cells.
CONCLUSIONS
These results suggest that the low expression of TCF21 was an independent prognostic factor for poor survival in patients with gastric cancer. Aberrant methylation was an important reason for the downregulation of TCF21 and may be associated with tumorigenesis in gastric cancer.
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Affiliation(s)
- Z Yang
- Cancer Center, The Fourth Hospital of China Medical University, Shenyang, China
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47
Chen SQ, Chen ZH, Lin SY, Dai QB, Fu LX, Chen RQ.
KISS1 methylation and expression as predictors of disease progression in colorectal cancer patients.
World J Gastroenterol 2014;
20:10071-10081. [PMID:
25110434 PMCID:
PMC4123336 DOI:
10.3748/wjg.v20.i29.10071]
[Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 02/07/2014] [Accepted: 03/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the effect of aberrant methylation of the KISS1 promoter on the development of colorectal cancer (CRC) and to investigate reversing aberrant methylation of the KISS1 promoter as a potential therapeutic target.
METHODS: KISS1 promoter methylation, mRNA expression and protein expression were detected by methylation-specific polymerase chain reaction (PCR), real-time quantitative PCR and Western blotting, respectively, in 126 CRC tissues and 142 normal colorectal tissues. Human CRC cells with KISS1 promoter hypermethylation and poor KISS1 expression were treated in vitro with 5-aza-2’-deoxycytidine (5-Aza-CdR). After treatment, KISS1 promoter methylation, KISS1 mRNA and protein expression and cell migration and invasion were evaluated.
RESULTS: Hypermethylation of KISS1 occurred frequently in CRC samples (83.1%, 105/126), but was infrequent in normal colorectal tissues (6.34%, 9/142). Moreover, KISS1 methylation was associated with tumor differentiation, the depth of invasion, lymph node metastasis and distant metastasis (P < 0.001). KISS1 methylation was also associated with low KISS1 expression (P < 0.001). Furthermore, we observed re-expression of the KISS1 gene and decreased cell migration after 5-Aza-CdR treatment in a CRC cell line.
CONCLUSION: These data suggest that KISS1 is down-regulated in cancer tissues via promoter hypermethylation and therefore may represent a candidate target for treating metastatic CRC.
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48
Arab K, Park YJ, Lindroth AM, Schäfer A, Oakes C, Weichenhan D, Lukanova A, Lundin E, Risch A, Meister M, Dienemann H, Dyckhoff G, Herold-Mende C, Grummt I, Niehrs C, Plass C. Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A.
Mol Cell 2014;
55:604-14. [PMID:
25087872 DOI:
10.1016/j.molcel.2014.06.031]
[Citation(s) in RCA: 215] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 05/14/2014] [Accepted: 06/24/2014] [Indexed: 12/26/2022]
Abstract
DNA methylation is a dynamic and reversible process that governs gene expression during development and disease. Several examples of active DNA demethylation have been documented, involving genome-wide and gene-specific DNA demethylation. How demethylating enzymes are targeted to specific genomic loci remains largely unknown. We show that an antisense lncRNA, termed TARID (for TCF21 antisense RNA inducing demethylation), activates TCF21 expression by inducing promoter demethylation. TARID interacts with both the TCF21 promoter and GADD45A (growth arrest and DNA-damage-inducible, alpha), a regulator of DNA demethylation. GADD45A in turn recruits thymine-DNA glycosylase for base excision repair-mediated demethylation involving oxidation of 5-methylcytosine to 5-hydroxymethylcytosine in the TCF21 promoter by ten-eleven translocation methylcytosine dioxygenase proteins. The results reveal a function of lncRNAs, serving as a genomic address label for GADD45A-mediated demethylation of specific target genes.
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Affiliation(s)
- Khelifa Arab
- Institute of Molecular Biology (IMB), 55128 Mainz, Germany; Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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- Yoon Jung Park
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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- Anders M Lindroth
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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- Andrea Schäfer
- Institute of Molecular Biology (IMB), 55128 Mainz, Germany
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- Christopher Oakes
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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- Dieter Weichenhan
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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- Annekatrin Lukanova
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Medical Biosciences, Department of Pathology, Umea University, 90185 Umea, Sweden
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- Eva Lundin
- Medical Biosciences, Department of Pathology, Umea University, 90185 Umea, Sweden
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- Angela Risch
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), 69120 Heidelberg, Germany
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- Michael Meister
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), 69120 Heidelberg, Germany; Translational Research Unit, Thoraxklinik-Heidelberg gGmbH University of Heidelberg, 69120 Heidelberg, Germany
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- Hendrik Dienemann
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), 69120 Heidelberg, Germany; Department of Thoracic Surgery, Thoraxklinik-Heidelberg gGmbH, University of Heidelberg, 69120 Heidelberg, Germany
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- Gerhard Dyckhoff
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, 69120 Heidelberg, Germany
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- Christel Herold-Mende
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, 69120 Heidelberg, Germany; Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, 69120 Heidelberg, Germany
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- Ingrid Grummt
- Division of Molecular Biology of the Cell II, DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
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- Christof Niehrs
- Institute of Molecular Biology (IMB), 55128 Mainz, Germany; Division of Molecular Embryology, DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
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- Christoph Plass
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; The German Cancer Consortium, 69120 Heidelberg, Germany.
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49
Hu S, Yang N, Chen M, Guo J, Xian L. [Effects of tumor suppressor gene TCF21 on the proliferation, migration and apoptosis of A549 cells].
ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2014;
17:302-7. [PMID:
24758904 PMCID:
PMC6000019 DOI:
10.3779/j.issn.1009-3419.2014.04.03]
[Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
背景与目的
转录因子21（transcription factor 21, TCF21）是新近发现的抑癌基因，其在多种肿瘤中具有抑癌功能，本研究旨在探讨TCF21基因对人肺癌A549细胞增殖、迁移和凋亡的影响。
方法
利用慢病毒转染技术在肺癌A549细胞中高表达TCF21基因，以荧光定量PCR、Western blot分析目的基因的表达，并采用Transwell、MTT法、流式细胞术检测TCF21高表达对A549迁移、增殖、凋亡的影响。
结果
成功在肺癌细胞株A549中高表达TCF21，且高表达TCF21后A549的细胞生长和迁移能力受抑制、凋亡率增高。
结论
抑癌基因TCF21可抑制A549细胞的增殖和迁移、诱导凋亡。
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Affiliation(s)
- Song Hu
- Department of Cardiothoracic Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
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- Nuo Yang
- Department of Cardiothoracic Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
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- Mingwu Chen
- Department of Cardiothoracic Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
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- Jianji Guo
- Department of Cardiothoracic Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
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- Lei Xian
- Department of Cardiothoracic Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
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50
Miller CL, Haas U, Diaz R, Leeper NJ, Kundu RK, Patlolla B, Assimes TL, Kaiser FJ, Perisic L, Hedin U, Maegdefessel L, Schunkert H, Erdmann J, Quertermous T, Sczakiel G. Coronary heart disease-associated variation in TCF21 disrupts a miR-224 binding site and miRNA-mediated regulation.
PLoS Genet 2014;
10:e1004263. [PMID:
24676100 PMCID:
PMC3967965 DOI:
10.1371/journal.pgen.1004263]
[Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Accepted: 02/11/2014] [Indexed: 01/28/2023] Open
Abstract
Genome-wide association studies (GWAS) have identified chromosomal loci that affect risk of coronary heart disease (CHD) independent of classical risk factors. One such association signal has been identified at 6q23.2 in both Caucasians and East Asians. The lead CHD-associated polymorphism in this region, rs12190287, resides in the 3′ untranslated region (3′-UTR) of TCF21, a basic-helix-loop-helix transcription factor, and is predicted to alter the seed binding sequence for miR-224. Allelic imbalance studies in circulating leukocytes and human coronary artery smooth muscle cells (HCASMC) showed significant imbalance of the TCF21 transcript that correlated with genotype at rs12190287, consistent with this variant contributing to allele-specific expression differences. 3′ UTR reporter gene transfection studies in HCASMC showed that the disease-associated C allele has reduced expression compared to the protective G allele. Kinetic analyses in vitro revealed faster RNA-RNA complex formation and greater binding of miR-224 with the TCF21 C allelic transcript. In addition, in vitro probing with Pb2+ and RNase T1 revealed structural differences between the TCF21 variants in proximity of the rs12190287 variant, which are predicted to provide greater access to the C allele for miR-224 binding. miR-224 and TCF21 expression levels were anti-correlated in HCASMC, and miR-224 modulates the transcriptional response of TCF21 to transforming growth factor-β (TGF-β) and platelet derived growth factor (PDGF) signaling in an allele-specific manner. Lastly, miR-224 and TCF21 were localized in human coronary artery lesions and anti-correlated during atherosclerosis. Together, these data suggest that miR-224 interaction with the TCF21 transcript contributes to allelic imbalance of this gene, thus partly explaining the genetic risk for coronary heart disease associated at 6q23.2. These studies implicating rs12190287 in the miRNA-dependent regulation of TCF21, in conjunction with previous studies showing that this variant modulates transcriptional regulation through activator protein 1 (AP-1), suggests a unique bimodal level of complexity previously unreported for disease-associated variants.
Both genetic and environmental factors cumulatively contribute to coronary heart disease risk in human populations. Large-scale meta-analyses of genome-wide association studies have now leveraged common genetic variation to identify multiple sites of disease susceptibility; however, the causal mechanisms for these associations largely remain elusive. One of these disease-associated variants, rs12190287, resides in the 3′untranslated region of the vascular developmental transcription factor, TCF21. Intriguingly, this variant is shown to disrupt the seed binding sequence for microRNA-224, and through altered RNA secondary structure and binding kinetics, leads to dysregulated TCF21 gene expression in response to disease-relevant stimuli. Importantly TCF21 and miR-224 expression levels were perturbed in human atherosclerotic lesions. Along with our previous reports on the transcriptional regulatory mechanisms altered by this variant, these studies shed new light on the complex heritable mechanisms of coronary heart disease risk that are amenable to therapeutic intervention.
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Affiliation(s)
- Clint L. Miller
- Department of Medicine, Division of Cardiovascular Medicine, and Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America
- * E-mail: (CLM); (TQ); (GS)
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- Ulrike Haas
- Institut für Molekulare Medizin, Universität zu Lübeck, Lübeck, Germany
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- Roxanne Diaz
- Department of Medicine, Division of Cardiovascular Medicine, and Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America
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- Nicholas J. Leeper
- Department of Medicine, Division of Cardiovascular Medicine, and Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America
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- Ramendra K. Kundu
- Department of Medicine, Division of Cardiovascular Medicine, and Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America
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- Bhagat Patlolla
- Department of Medicine, Division of Cardiothoracic Surgery, and Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America
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- Themistocles L. Assimes
- Department of Medicine, Division of Cardiovascular Medicine, and Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America
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- Frank J. Kaiser
- Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany
- DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lubeck/Kiel, Lubeck, Germany
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- Ljubica Perisic
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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- Ulf Hedin
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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- Lars Maegdefessel
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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- Heribert Schunkert
- Deutsches Herzzentrum München, Technische Universität München, Munich, DZHK, partner site Munich Heart Alliance, Munich, Germany
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- Jeanette Erdmann
- DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lubeck/Kiel, Lubeck, Germany
- Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany
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- Thomas Quertermous
- Department of Medicine, Division of Cardiovascular Medicine, and Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America
- * E-mail: (CLM); (TQ); (GS)
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- Georg Sczakiel
- Institut für Molekulare Medizin, Universität zu Lübeck, Lübeck, Germany
- DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lubeck/Kiel, Lubeck, Germany
- * E-mail: (CLM); (TQ); (GS)
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