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Jin Y, Xie X, Li H, Zhang M. The role of homeobox gene Six1 in cancer progression and its potential as a therapeutic target: A review. Int J Biol Macromol 2025; 308:142666. [PMID: 40164243 DOI: 10.1016/j.ijbiomac.2025.142666] [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: 11/04/2024] [Revised: 03/19/2025] [Accepted: 03/28/2025] [Indexed: 04/02/2025]
Abstract
The sine oculis homeobox gene 1 (Six1), a member of the Six transcription factor family, specifically binds to defined DNA regions, regulates target gene expression, and plays a crucial role in various tissue and organ development processes. Moreover, Six1 is a critical factor in cancer progression and prognosis making it a central focus in cancer research. Consequently, a comprehensive review of involvement of the Six1 gene in cancer research has a high relevance. This review synthesizes findings from other researches, examines the gene structure and protein functionality of Six1, summarizes its relationship with various cancers, elucidates its mechanisms in promoting tumor progression and development, explores potential possibilities for targeting Six1 as a therapeutic approach for cancer treatment. Six1 is correlated with tumor malignancy and poor prognosis, plays a critical role in promoting tumor cell proliferation, invasion, metastasis, and energy metabolism. Targeting Six1 degradation or expression can potentially suppress tumor progression. This review aims to enhance our understanding of the function and significance of Six1 in cancers while providing a valuable reference for Six1-based cancer diagnosis, prognosis, and therapeutic interventions. This knowledge will facilitate more in-depth oncology research related to Six1, particularly in identifying drug resistance mechanisms and developing precision-targeted therapies.
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Affiliation(s)
- Yong Jin
- Department of Rheumatology and Immunology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China; Inner Mongolia Key Laboratory for Pathogenesis and Diagnosis of Rheumatic and Autoimmune Diseases, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Xinran Xie
- School of Basic Medicine sciences, Inner Mongolia Medical University, Hohhot, China
| | - Hongbin Li
- Department of Rheumatology and Immunology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China; Inner Mongolia Key Laboratory for Pathogenesis and Diagnosis of Rheumatic and Autoimmune Diseases, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China.
| | - Manling Zhang
- Department of Rheumatology and Immunology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China; Inner Mongolia Key Laboratory for Pathogenesis and Diagnosis of Rheumatic and Autoimmune Diseases, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China.
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Lan YZ, Wu Z, Chen WJ, Yu XN, Wu HT, Liu J. Sine oculis homeobox homolog family function in gastrointestinal cancer: Progression and comprehensive analysis. World J Clin Oncol 2025; 16:97163. [PMID: 39867730 PMCID: PMC11528897 DOI: 10.5306/wjco.v16.i1.97163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 09/20/2024] [Accepted: 10/20/2024] [Indexed: 10/30/2024] Open
Abstract
The sine oculis homeobox homolog (SIX) family, a group of transcription factors characterized by a conserved DNA-binding homology domain, plays a critical role in orchestrating embryonic development and organogenesis across various organisms, including humans. Comprising six distinct members, from SIX1 to SIX6, each member contributes uniquely to the development and differentiation of diverse tissues and organs, underscoring the versatility of the SIX family. Dysregulation or mutations in SIX genes have been implicated in a spectrum of developmental disorders, as well as in tumor initiation and progression, highlighting their pivotal role in maintaining normal developmental trajectories and cellular functions. Efforts to target the transcriptional complex of the SIX gene family have emerged as a promising strategy to inhibit tumor development. While the development of inhibitors targeting this gene family is still in its early stages, the significant potential of such interventions holds promise for future therapeutic advances. Therefore, this review aimed to comprehensively explore the advancements in understanding the SIX family within gastrointestinal cancers, focusing on its critical role in normal organ development and its implications in gastrointestinal cancers, including gastric, pancreatic, colorectal cancer, and hepatocellular carcinomas. In conclusion, this review deepened the understanding of the functional roles of the SIX family and explored the potential of utilizing this gene family for the diagnosis, prognosis, and treatment of gastrointestinal cancers.
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Affiliation(s)
- Yang-Zheng Lan
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Zheng Wu
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Xin-Ning Yu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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Zhou X, Hang S, Wang Q, Xu L, Wang P. Decoding the Role of O-GlcNAcylation in Hepatocellular Carcinoma. Biomolecules 2024; 14:908. [PMID: 39199296 PMCID: PMC11353135 DOI: 10.3390/biom14080908] [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: 06/25/2024] [Revised: 07/16/2024] [Accepted: 07/22/2024] [Indexed: 09/01/2024] Open
Abstract
Post-translational modifications (PTMs) influence protein functionality by modulating protein stability, localization, and interactions with other molecules, thereby controlling various cellular processes. Common PTMs include phosphorylation, acetylation, ubiquitination, glycosylation, SUMOylation, methylation, sulfation, and nitrosylation. Among these modifications, O-GlcNAcylation has been shown to play a critical role in cancer development and progression, especially in hepatocellular carcinoma (HCC). This review outlines the role of O-GlcNAcylation in the development and progression of HCC. Moreover, we delve into the underlying mechanisms of O-GlcNAcylation in HCC and highlight compounds that target O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) to improve treatment outcomes. Understanding the role of O-GlcNAcylation in HCC will offer insights into potential therapeutic strategies targeting OGT and OGA, which could improve treatment for patients with HCC.
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Affiliation(s)
- Xinyu Zhou
- Department of Surgery, Zhejiang Chinese Medical University, Hangzhou 310053, China; (X.Z.); (S.H.)
| | - Sirui Hang
- Department of Surgery, Zhejiang Chinese Medical University, Hangzhou 310053, China; (X.Z.); (S.H.)
| | - Qingqing Wang
- Department of Hepatobiliary Surgery, The First Hospital of Jiaxing, Jiaxing 314051, China;
| | - Liu Xu
- Department of Hepatobiliary Surgery, The First Hospital of Jiaxing, Jiaxing 314051, China;
| | - Peter Wang
- Department of Medicine, Zhejiang Zhongwei Medical Research Center, Hangzhou 310000, China
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Bian Z, Benjamin MM, Bialousow L, Tian Y, Hobbs GA, Karan D, Choo YM, Hamann MT, Wang X. Targeting sine oculis homeoprotein 1 (SIX1): A review of oncogenic roles and potential natural product therapeutics. Heliyon 2024; 10:e33204. [PMID: 39022099 PMCID: PMC11252760 DOI: 10.1016/j.heliyon.2024.e33204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 06/16/2024] [Accepted: 06/17/2024] [Indexed: 07/20/2024] Open
Abstract
Sine oculis homeoprotein 1 (SIX1), a prominent representative of the homeodomain transcription factors within the SIX family, has attracted significant interest owing to its role in tumorigenesis, cancer progression, and prognostic assessments. Initially recognized for its pivotal role in embryonic development, SIX1 has emerged as a resurgent factor across a diverse set of mammalian cancers. Over the past two decades, numerous investigations have emphasized SIX1's dual significance as a developmental regulator and central player in oncogenic processes. A mounting body of evidence links SIX1 to the initiation of diverse cancers, encompassing enhanced cellular metabolism and advancement. This review provides an overview of the multifaceted roles of SIX1 in both normal development and oncogenic processes, emphasizing its importance as a possible therapeutic target and prognostic marker. Additionally, this review discusses the natural product agents that inhibit various pro-oncogenic mechanisms associated with SIX1.
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Affiliation(s)
- Zhiwei Bian
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Menny M. Benjamin
- Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Lucas Bialousow
- Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Yintai Tian
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - G. Aaron Hobbs
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA
| | - Dev Karan
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Yeun-Mun Choo
- Chemistry Department, Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Mark T. Hamann
- Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Xiaojuan Wang
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, Gansu, China
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Lin J, Li B, Xu Q, Liu YS, Kang YL, Wang X, Wang Y, Lei Y, Bai YL, Li XM, Zhou J. DACH1 attenuated PA-induced renal tubular injury through TLR4/MyD88/NF-κB and TGF-β/Smad signalling pathway. J Endocrinol Invest 2024; 47:1531-1544. [PMID: 38147289 DOI: 10.1007/s40618-023-02253-7] [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: 08/09/2023] [Accepted: 11/20/2023] [Indexed: 12/27/2023]
Abstract
BACKGROUND Palmitic acid (PA), the major saturated fatty acid in the blood, often induces the initiation and progression of diabetic kidney disease (DKD). However, the underlying mechanism remains unclear. DACH1 is an important regulator of kidney functions. Herein, we investigated the roles of DACH1 in PA-induced kidney injury. METHODS Clinical data from the NHANES database were subjected to analyse the association between serum PA (sPA), blood glucose and kidney function. Molecular docking of PA was performed with DACH1. Immunohistochemistry, cell viability, annexin V/7-AAD double staining, TUNEL assay, immunofluorescent staining, autophagic flux analysis, qRT-PCR and western blot were performed. RESULTS Clinical data confirmed that sPA was increased significantly in the pathoglycemia individuals compared with controls and correlated negatively with renal function. Our findings suggested that PA could dock with DACH1. DACH1 enhances cell viability by inhibiting apoptosis and attenuating autophagy blockage induced by PA. Furthermore, the results demonstrated that DACH1 ameliorated inflammation and fibrosis through TLR4/MyD88/NF-κB and TGF-β/Smad signalling pathway in PA-treated renal tubular epithelial cell line (HK-2). CONCLUSIONS This study proved that sPA presents a risk factor for kidney injuries and DACH1 might serve as a protective target against renal function deterioration in diabetic patients.
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Affiliation(s)
- J Lin
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, No.127 Changle West Road, Xi'an, 710032, China
| | - B Li
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, No.127 Changle West Road, Xi'an, 710032, China
| | - Q Xu
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, No.127 Changle West Road, Xi'an, 710032, China
| | - Y S Liu
- Department of Pharmacology, Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medical of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Air Force Medical University, Xi'an, 710032, China
| | - Y L Kang
- Department of Microbiology and Pathogen Biology, School of Preclinical Medicine, Air Force Medical University, Xi'an, 710032, China
| | - X Wang
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, No.127 Changle West Road, Xi'an, 710032, China
| | - Y Wang
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, No.127 Changle West Road, Xi'an, 710032, China
| | - Y Lei
- The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, 712099, China
| | - Y L Bai
- Department of Microbiology and Pathogen Biology, School of Preclinical Medicine, Air Force Medical University, Xi'an, 710032, China.
| | - X M Li
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, No.127 Changle West Road, Xi'an, 710032, China.
| | - J Zhou
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, No.127 Changle West Road, Xi'an, 710032, China.
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Guo M, Zhuang Y, Wu Y, Zhang C, Cheng X, Xu D, Zhang Z. The cell fate regulator DACH1 modulates ferroptosis through affecting P53/SLC25A37 signaling in fibrotic disease. Hepatol Commun 2024; 8:e0396. [PMID: 38437058 PMCID: PMC10914241 DOI: 10.1097/hc9.0000000000000396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 01/11/2024] [Indexed: 03/06/2024] Open
Abstract
BACKGROUND Dachshund homolog 1 (DACH1) is widely acknowledged for its involvement in regulating diverse cell fates, but its precise regulatory mechanism in ferroptosis remains elusive. In this study, we investigated whether DACH1 modulates ferroptosis through affecting P53/solute carrier family 25 member 37 (SLC25A37) signaling in hepatic fibrogenesis. METHODS CRISPR-Cas9 system was used to knockout DACH1 in HSC to determine the effect of DACH1 on ferroptosis. Immunoprecipitation, pulldown, and mouse model of hepatic fibrogenesis were used to analyze the potential molecular mechanism of ferroptosis regulation by DACH1. RESULTS We found that ferroptosis inducers increased the protein expression of DACH1 by suppressing the ubiquitin-proteasome signaling. DACH1 knockout can resist ferroptosis, whereas DACH1 knockin can enhance it. Interestingly, the upregulation of DACH1 resulted in the mitochondrial translocation of p53 by inducing phosphorylation at serine 392. The mutation of serine 392 can prevent the combination of DACH1 and p53, the mitochondrial translocation of p53, and DACH1-mediated ferroptosis. Moreover, SLC25A37 was identified as a candidate target for mitochondrial p53. The binding of p53 to SLC25A37 can enhance the iron uptake capacity of SLC25A37, which may cause an overload of iron in the mitochondria and hyperactive mitochondrial electron transport chain. Knockdown of SLC25A37 can impair p53-mediated mitochondrial iron overload and ferroptosis. Furthermore, treatment with erastin can induce HSC ferroptosis and relieve fibrotic lesion damage in the mouse model of hepatic fibrogenesis. HSC-specific knockdown of DACH1, p53, and SLC25A37 can abolish the induction of HSC ferroptosis and reversal of hepatic fibrogenesis by erastin treatment. CONCLUSIONS Our findings suggest that the DACH1/P53/SLC25A37 signaling pathway is a promising target for fibrotic disorders and reveals new regulatory mechanisms of ferroptosis.
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Affiliation(s)
- Mei Guo
- School of Nursing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yanshuang Zhuang
- Taizhou Hospital of Traditional Chinese Medicine, Taizhou, China
| | - Yang Wu
- Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chun Zhang
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xudong Cheng
- Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Dong Xu
- Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zili Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
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Jourdeuil K, Neilson KM, Cousin H, Tavares ALP, Majumdar HD, Alfandari D, Moody SA. Zmym4 is required for early cranial gene expression and craniofacial cartilage formation. Front Cell Dev Biol 2023; 11:1274788. [PMID: 37854072 PMCID: PMC10579616 DOI: 10.3389/fcell.2023.1274788] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 09/18/2023] [Indexed: 10/20/2023] Open
Abstract
Introduction: The Six1 transcription factor plays important roles in the development of cranial sensory organs, and point mutations underlie craniofacial birth defects. Because Six1's transcriptional activity can be modulated by interacting proteins, we previously screened for candidate interactors and identified zinc-finger MYM-containing protein 4 (Zmym4) by its inclusion of a few domains with a bona fide cofactor, Sine oculis binding protein (Sobp). Although Zmym4 has been implicated in regulating early brain development and certain cancers, its role in craniofacial development has not previously been described. Methods: We used co-immunoprecipitation and luciferase-reporter assays in cultured cells to test interactions between Zmym4 and Six1. We used knock-down and overexpression of Zmym4 in embryos to test for its effects on early ectodermal gene expression, neural crest migration and craniofacial cartilage formation. Results: We found no evidence that Zmym4 physically or transcriptionally interacts with Six1 in cultured cells. Nonetheless, knockdown of endogenous Zmym4 in embryos resulted in altered early cranial gene expression, including those expressed in the neural border, neural plate, neural crest and preplacodal ectoderm. Experimentally increasing Zmym4 levels had minor effects on neural border or neural plate genes, but altered the expression of neural crest and preplacodal genes. At larval stages, genes expressed in the otic vesicle and branchial arches showed reduced expression in Zmym4 morphants. Although we did not detect defects in neural crest migration into the branchial arches, loss of Zmym4 resulted in aberrant morphology of several craniofacial cartilages. Discussion: Although Zmym4 does not appear to function as a Six1 transcriptional cofactor, it plays an important role in regulating the expression of embryonic cranial genes in tissues critical for normal craniofacial development.
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Affiliation(s)
- Karyn Jourdeuil
- Department of Anatomy and Cell Biology, George Washington University, School of Medicine and Health Sciences, Washington, DC, United States
| | - Karen M. Neilson
- Department of Anatomy and Cell Biology, George Washington University, School of Medicine and Health Sciences, Washington, DC, United States
| | - Helene Cousin
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, United States
| | - Andre L. P. Tavares
- Department of Anatomy and Cell Biology, George Washington University, School of Medicine and Health Sciences, Washington, DC, United States
| | - Himani D. Majumdar
- Department of Anatomy and Cell Biology, George Washington University, School of Medicine and Health Sciences, Washington, DC, United States
| | - Dominique Alfandari
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, United States
| | - Sally A. Moody
- Department of Anatomy and Cell Biology, George Washington University, School of Medicine and Health Sciences, Washington, DC, United States
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Ma Y, Wei J, Song J, Hu Z, Zhang R, Li Z, Sun Y. The DACH1 Gene Transcriptional Activation and Protein Degradation Mediated by Transactivator Tas of Prototype Foamy Virus. Viruses 2023; 15:1899. [PMID: 37766305 PMCID: PMC10534306 DOI: 10.3390/v15091899] [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: 08/11/2023] [Revised: 09/02/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
Foamy viruses are members of the Retroviridae family's Spumaretrovirinae subfamily. They induce cell vacuolation and exhibit a foamy pathogenic impact after infecting cells. DACH1 (dachshund family transcription factor 1) is a crucial cytokine linked to tumor development, and is associated with the growth of many different malignant tumor cells. Additionally, DACH1 suppresses pancreatic cell proliferation and is involved in diabetes insulin signaling. Prototype foamy viruses (PFVs) were used for the investigation of the regulatory mechanism of FVs on cellular DACH1 expression. The results show that DACH1 expression in PFV-infected cells was inconsistent at both the transcriptional and protein levels. At the transcriptional level, DACH1 was significantly activated by PFV transactivator Tas, and dual-luciferase reporter gene tests, EMSA, and ChIP assays found a Tas response element of 21 nucleotides in the DACH1 promoter. PFV and Tas did not boost the levels of DACH1 protein in a manner consistent with the high levels of DACH1 transcription expression. It was noted that Tas increased the expression of the Ser/Thr protein phosphatase PPM1E, causing PPM1E-mediated post-translational SUMOylation alterations of DACH1 to prompt DACH1 to degrade. The reason for DACH1 protein degradation is that DACH1 inhibits PFV replication. To sum up, these findings show that PFV upregulated the transcription of DACH1, while urging its protein into PPM1E-mediated SUMOylation, to eliminate the adverse effect of DACH1 overexpression of host cells on viral replication and promote virus survival.
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Affiliation(s)
- Yongping Ma
- College of Life Science, Shaanxi Normal University, Xi’an 710119, China
- College of Biological Science and Engineering, North Minzu University, Yinchuan 750021, China
| | - Jie Wei
- College of Life Science, Shaanxi Normal University, Xi’an 710119, China
- College of Environment and Life Sciences, Weinan Normal University, Weinan 714099, China
| | - Jing Song
- College of Life Science, Shaanxi Normal University, Xi’an 710119, China
| | - Zhongxiang Hu
- College of Life Science, Shaanxi Normal University, Xi’an 710119, China
| | - Ruifen Zhang
- College of Life Science, Shaanxi Normal University, Xi’an 710119, China
| | - Zhi Li
- College of Life Science, Shaanxi Normal University, Xi’an 710119, China
| | - Yan Sun
- College of Life Science, Shaanxi Normal University, Xi’an 710119, China
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Zhu S, Li W, Zhang H, Yan Y, Mei Q, Wu K. Retinal determination gene networks: from biological functions to therapeutic strategies. Biomark Res 2023; 11:18. [PMID: 36750914 PMCID: PMC9906957 DOI: 10.1186/s40364-023-00459-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 01/28/2023] [Indexed: 02/09/2023] Open
Abstract
The retinal determinant gene network (RDGN), originally discovered as a critical determinator in Drosophila eye specification, has become an important regulatory network in tumorigenesis and progression, as well as organogenesis. This network is not only associated with malignant biological behaviors of tumors, such as proliferation, and invasion, but also regulates the development of multiple mammalian organs. Three members of this conservative network have been extensively investigated, including DACH, SIX, and EYA. Dysregulated RDGN signaling is associated with the initiation and progression of tumors. In recent years, it has been found that the members of this network can be used as prognostic markers for cancer patients. Moreover, they are considered to be potential therapeutic targets for cancer. Here, we summarize the research progress of RDGN members from biological functions to signaling transduction, especially emphasizing their effects on tumors. Additionally, we discuss the roles of RDGN members in the development of organs and tissue as well as their correlations with the pathogenesis of chronic kidney disease and coronary heart disease. By summarizing the roles of RDGN members in human diseases, we hope to promote future investigations into RDGN and provide potential therapeutic strategies for patients.
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Affiliation(s)
- Shuangli Zhu
- grid.412793.a0000 0004 1799 5032Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Wanling Li
- grid.412793.a0000 0004 1799 5032Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China ,grid.470966.aCancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032 China
| | - Hao Zhang
- grid.412793.a0000 0004 1799 5032Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Yuheng Yan
- grid.412793.a0000 0004 1799 5032Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Qi Mei
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. .,Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.
| | - Kongming Wu
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China. .,Cancer Center, Tongji hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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10
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Lu Y, Tang K, Wang S, Tian Z, Fan Y, Li B, Wang M, Zhao J, Xie J. Dach1 deficiency drives alveolar epithelium apoptosis in pulmonary fibrosis via modulating C-Jun/Bim activity. Transl Res 2023; 257:54-65. [PMID: 36754276 DOI: 10.1016/j.trsl.2023.01.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 01/10/2023] [Accepted: 01/30/2023] [Indexed: 02/08/2023]
Abstract
Dysregulation of type II alveolar epithelial cells (AECII) plays a vital role in the initiation and development of pulmonary fibrosis (PF). Dachshund homolog 1 (Dach1), frequently expressed in epithelial cells with stem cell potential, controls cell proliferation, apoptosis, and cell cycle in tissue development and disease process. In this study, we demonstrated that the lungs collected from PF patients and mice of Bleomycin (BLM)-treated were characterized by low expression of Dachshund homolog 1 (Dach1), especially in AECII. Dach1 deficiency in the alveolar epithelium exacerbated PF in BLM-treated mice, as evidenced by reduced pulmonary function and increased expression of fibrosis markers. Rather, treatment with lung-specific overexpression of Dach1 alleviated histopathological damage, lung compliance, and fibrosis in BLM-treated mice. Moreover, overexpression of Dach1 could inhibit epithelial apoptosis in vitro. Conversely, primary AECII with Dach1 depletion were more susceptible to apoptosis in vivo. Mechanically, Dach1 combined with C-Jun protooncogene selectively bound to the promoter of B-cell lymphoma 2 interacting mediators of cell death (Bim), by which it repressed Bim expression and alleviated epithelial apoptosis. Taken together, our data support that Dach1 in AECII contributes to the progression of PF and may be a viable target for the prevention and treatment of PF.
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Affiliation(s)
- Yanjiao Lu
- Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Kum Tang
- Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Shanshan Wang
- Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhen Tian
- Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yan Fan
- Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Boyu Li
- Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Meijia Wang
- Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jianping Zhao
- Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Jungang Xie
- Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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11
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Zhang HY, Zong RQ, Wu FX, Li YR. Bioinformatics Analysis Identifies ASCL1 as the Key Transcription Factor in Hepatocellular Carcinoma Progression. DISEASE MARKERS 2023; 2023:3560340. [PMID: 36755802 PMCID: PMC9902118 DOI: 10.1155/2023/3560340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/12/2022] [Accepted: 11/25/2022] [Indexed: 01/31/2023]
Abstract
Methods Differentially transcription factors (DETFs) were identified from differentially expressed genes (DEGs) in GSE62232 and transcription factors. Then, they were analyzed by regulatory networks, prognostic risk model, and overall survival analyses to identify the key DETF. Combined with the regulatory networks and binding site analysis, the target mRNA of key DETF was determined, and its prognostic value in HCC was evaluated by survival, clinical characteristics analyses, and experiments. Finally, the expressions and functions of the key DETF on the DEmRNAs were investigated in HCC cells. Results Through multiple bioinformatics analyses, ASCL1 was identified as the key DETF, and SLC6A13 was predicted to be its target mRNA with the common binding site of CCAGCAACTGGCC, both downregulated in HCC. In survival analysis, high SLC6A13 was related to better HCC prognosis, and SLC6A13 was differentially expressed in HCC patients with clinical characteristics. Furthermore, cell experiments showed the mRNA expressions of ASCL1 and SLC6A13 were both reduced in HCC, and their overexpressions suppressed the growth, invasion, and migration of HCC cells. Besides, over-ASCL1 could upregulate SLC6A13 expression in HCC cells. Conclusion This study identifies two suppressor genes in HCC progression, ASCL1 and SLC6A13, and the key transcription factor ASCL1 suppresses HCC progression by targeting SLC6A13 mRNA. They are both potential treatment targets and prognostic biomarkers for HCC patients, which provides new clues for HCC research.
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Affiliation(s)
- Hong-yan Zhang
- Department of Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Rui-qing Zong
- Department of Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Fei-xiang Wu
- Department of Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Yi-ran Li
- Department of Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai, China
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12
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SIX3 function in cancer: progression and comprehensive analysis. Cancer Gene Ther 2022; 29:1542-1549. [PMID: 35764712 DOI: 10.1038/s41417-022-00488-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 05/02/2022] [Accepted: 05/27/2022] [Indexed: 02/04/2023]
Abstract
The homeobox gene family encodes transcription factors that are essential for cell growth, proliferation, and differentiation, and its dysfunction is linked to tumor initiation and progression. Sine oculis homeobox (SIX) belongs to the homeobox gene family, with SIX3 being a core member. Recent studies indicate that SXI3 functions as a cancer suppressor or promoter, which is mainly dependent on SIX3's influence on the signal pathways that promote or inhibit cancer in cells. The low expression of SIX3 in most malignant tumors was confirmed by detailed studies, which could promote the cell cycle, proliferation, migration, and angiogenesis. The recovery or upregulation of SIX3 expression to suppress cancer is closely related to the direct or indirect inhibition of the Wnt pathway. However, in some malignancies, such as esophageal cancer and gastric cancer, SIX3 is a tumor-promoting factor, and repressing SIX3 improves patients' prognosis. This review introduces the research progress of SIX3 in tumors and gives a comprehensive analysis, intending to explain why SIX3 plays different roles in different cancers and provide new cancer therapy strategies.
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13
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Hardy S, Choo YM, Hamann M, Cray J. Manzamine-A Alters In Vitro Calvarial Osteoblast Function. Mar Drugs 2022; 20:647. [PMID: 36286470 PMCID: PMC9604769 DOI: 10.3390/md20100647] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/07/2022] [Accepted: 10/14/2022] [Indexed: 11/17/2022] Open
Abstract
Manzamine-A is a marine-derived alkaloid which has anti-viral and anti-proliferative properties and is currently being investigated for its efficacy in the treatment of certain viruses (malaria, herpes, HIV-1) and cancers (breast, cervical, colorectal). Manzamine-A has been found to exert effects via modulation of SIX1 gene expression, a gene critical to craniofacial development via the WNT, NOTCH, and PI3K/AKT pathways. To date little work has focused on Manzamine-A and how its use may affect bone. We hypothesize that Manzamine-A, through SIX1, alters bone cell activity. Here, we assessed the effects of Manzamine-A on cells that are responsible for the generation of bone, pre-osteoblasts and osteoblasts. PCR, qrtPCR, MTS cell viability, Caspase 3/7, and functional assays were used to test the effects of Manzamine-A on these cells. Our data suggests Six1 is highly expressed in osteoblasts and their progenitors. Further, osteoblast progenitors and osteoblasts exhibit great sensitivity to Manzamine-A treatment exhibited by a significant decrease in cell viability, increase in cellular apoptosis, and decrease in alkaline phosphatase activity. In silico binding experiment showed that manzamine A potential as an inhibitor of cell proliferation and survival proteins, i.e., Iκb, JAK2, AKT, PKC, FAK, and Bcl-2. Overall, our data suggests Manzamine-A may have great effects on bone health overall and may disrupt skeletal development, homeostasis, and repair.
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Affiliation(s)
- Samantha Hardy
- Department of Biomedical Education and Anatomy, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Yeun-Mun Choo
- Chemistry Department, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Mark Hamann
- Departments of Drug Discovery and Biomedical Sciences and Public Health, Colleges of Pharmacy and Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - James Cray
- Department of Biomedical Education and Anatomy, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- Division of Biosciences, The Ohio State College of Dentistry, Columbus, OH 43210, USA
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14
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Zhang J, Xun M, Li C, Chen Y. The O-GlcNAcylation and its promotion to hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer 2022; 1877:188806. [PMID: 36152903 DOI: 10.1016/j.bbcan.2022.188806] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 09/15/2022] [Accepted: 09/17/2022] [Indexed: 11/27/2022]
Abstract
O-GlcNAcylation is a posttranslational modification that attaches O-linked β-N-acetylglucosamine (O-GlcNAc) to the serine and threonine residues of proteins. Such a glycosylation would alter the activities, stabilities, and interactions of target proteins that are functional in a wide range of biological processes and diseases. Accumulating evidence indicates that O-GlcNAcylation is tightly associated with hepatocellular carcinoma (HCC) in its onset, growth, invasion and metastasis, drug resistance, and stemness. Here we summarize the discoveries of the role of O-GlcNAcylation in HCC and its function mechanism, aiming to deepen our understanding of HCC pathology, generate more biomarkers for its diagnosis and prognosis, and offer novel molecular targets for its treatment.
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Affiliation(s)
- Jie Zhang
- Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 410001, China
| | - Min Xun
- Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 410001, China
| | - Chaojie Li
- Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 410001, China
| | - Yuping Chen
- Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 410001, China.
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15
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Dai K, Liu C, Guan G, Cai J, Wu L. Identification of immune infiltration-related genes as prognostic indicators for hepatocellular carcinoma. BMC Cancer 2022; 22:496. [PMID: 35513781 PMCID: PMC9074323 DOI: 10.1186/s12885-022-09587-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 04/18/2022] [Indexed: 12/29/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has a high degree of malignancy and a poor prognosis. Immune infiltration-related genes have shown good predictive value in the prognosis of many solid tumours. In this study, we established and verified prognostic biomarkers consisting of immune infiltration-related genes in HCC. Gene expression data and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. Differential gene expression analysis, univariate Cox regression analysis and the least absolute shrinkage and selection operator (LASSO) regression algorithm were used to screen prognostic immune infiltration-related genes and to construct a risk scoring model. Kaplan-Meier (KM) survival plots and receiver operating characteristic (ROC) curve analysis were used to evaluate the prognostic performance of the risk scoring model in the TCGA-HCC cohort. In addition, a nomogram model with a risk score was established, and its predictive performance was verified by ROC analysis and calibration plot analysis in the TCGA-HCC cohort. Gene set enrichment analysis (GSEA) identified pathways and biological processes that may be enriched in the high-risk group. Finally, immune infiltration analysis was used to explore the characteristics of the tumour microenvironment related to the risk score. We identified 17 immune infiltration-related genes with prognostic value and constructed a risk scoring model. ROC analysis showed that the risk scoring model can accurately predict the 1-year, 3-year, and 5-year overall survival (OS) of HCC patients in the TCGA-HCC cohort. KM analysis showed that the OS of the high-risk group was significantly lower than that of the low-risk group (P < 0.001). The nomogram model effectively predicted the OS of HCC patients in the TCGA-HCC cohort. GSEA indicated that the immune infiltration-related genes may be involved in biological processes such as amino acid and lipid metabolism, matrisome and small molecule transportation, immune system regulation, and hepatitis virus infection. Immune infiltration analysis showed that the level of immune cell infiltration in the high-risk group was low, and the risk score was negatively correlated with infiltrating immune cells. Our prognostic model based on immune infiltration-related genes in HCC could help the prognostic assessment of HCC patients and provide potential targets for HCC inhibition.
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Affiliation(s)
- Kunfu Dai
- Liver Disease Center, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266003, China
| | - Chao Liu
- Liver Disease Center, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266003, China
| | - Ge Guan
- Liver Disease Center, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266003, China
| | - Jinzhen Cai
- Liver Disease Center, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266003, China
| | - Liqun Wu
- Liver Disease Center, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266003, China.
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16
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Xie K, Yan Z, Wang W, Luo R, Gao X, Wang P, Yang Q, Huang X, Zhang J, Yang J, Gun S. ssc-microRNA-132 targets DACH1 to exert anti-inflammatory and anti-apoptotic effects in Clostridium perfringens beta2 toxin-treated porcine intestinal epithelial cells. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2022; 127:104270. [PMID: 34582881 DOI: 10.1016/j.dci.2021.104270] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/24/2021] [Accepted: 09/24/2021] [Indexed: 06/13/2023]
Abstract
Clostridium perfringens (C. perfringens) type C (CPC) is one of the chief pathogens that causes diarrhea in piglets, and C. perfringens beta2 (CPB2) toxin is the main virulence factor of CPC. Our previous research demonstrated that ssc-microR-132 was differentially expressed in ileal tissues of CPC-mediated diarrheic piglets and healthy piglets, which implied a potential role of ssc-microR-132 in this process. Here, we found that ssc-microR-132 was notably down-regulated in CPB2-exposed intestinal porcine epithelial cells (IPEC-J2), which was consistent with the ileal tissue expression. Moreover, ssc-microR-132 upregulation alleviated CPB2-induced inflammatory damage and apoptosis in IPEC-J2, whereas ssc-microR-132 knockdown presented the opposite effects. Furthermore, the dual-luciferase reporter assay indicated that ssc-microR-132 directly targeted Dachshund homolog 1 (DACH1). Moreover, DACH1 overexpression intensified CPB2-induced inflammatory injury and apoptosis in IPEC-J2. Remarkably, the introduction of DACH1 weakened the anti-inflammatory and anti-apoptotic effects of ssc-microR-132 in CPB2-exposed IPEC-J2. Overall, the results reveal that ssc-microR-132 targeted DACH1 to alleviate CPB2-mediated inflammation and apoptosis in IPEC-J2.
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Affiliation(s)
- Kaihui Xie
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Zunqiang Yan
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Wei Wang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Ruirui Luo
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Xiaoli Gao
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Pengfei Wang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Qiaoli Yang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Xiaoyu Huang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Juanli Zhang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Jiaojiao Yang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Shuangbao Gun
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China; Gansu Research Center for Swine Production Engineering and Technology, Lanzhou, Gansu, 730070, China.
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17
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Hamidi AA, Zangoue M, Kashani D, Zangouei AS, Rahimi HR, Abbaszadegan MR, Moghbeli M. MicroRNA-217: a therapeutic and diagnostic tumor marker. Expert Rev Mol Diagn 2021; 22:61-76. [PMID: 34883033 DOI: 10.1080/14737159.2022.2017284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Cancer as one of the most common causes of death has always been one of the major health challenges globally. Since, the identification of tumors in the early tumor stages can significantly reduce mortality rates; it is required to introduce novel early detection tumor markers. MicroRNAs (miRNAs) have pivotal roles in regulation of cell proliferation, migration, apoptosis, and tumor progression. Moreover, due to the higher stability of miRNAs than mRNAs in body fluids, they can be considered as non-invasive diagnostic or prognostic markers in cancer patients. AREAS COVERED In the present review we have summarized the role of miR-217 during tumor progressions. The miR-217 functions were categorized based on its target molecular mechanisms and signaling pathways. EXPERT OPINION It was observed that miR-217 mainly exerts its function by regulation of the transcription factors during tumor progressions. The WNT, MAPK, and PI3K/AKT signaling pathways were also important molecular targets of miR-217 in different cancers. The present review clarifies the molecular biology of miR-217 and paves the way of introducing miR-217 as a non-invasive diagnostic marker and therapeutic target in cancer therapy.
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Affiliation(s)
- Amir Abbas Hamidi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Malihe Zangoue
- Department of Anesthesiology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Daniel Kashani
- Department of Internal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
| | - Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Reza Rahimi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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18
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Meurer L, Ferdman L, Belcher B, Camarata T. The SIX Family of Transcription Factors: Common Themes Integrating Developmental and Cancer Biology. Front Cell Dev Biol 2021; 9:707854. [PMID: 34490256 PMCID: PMC8417317 DOI: 10.3389/fcell.2021.707854] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 06/28/2021] [Indexed: 01/19/2023] Open
Abstract
The sine oculis (SIX) family of transcription factors are key regulators of developmental processes during embryogenesis. Members of this family control gene expression to promote self-renewal of progenitor cell populations and govern mechanisms of cell differentiation. When the function of SIX genes becomes disrupted, distinct congenital defects develops both in animal models and humans. In addition to the embryonic setting, members of the SIX family have been found to be critical regulators of tumorigenesis, promoting cell proliferation, epithelial-to-mesenchymal transition, and metastasis. Research in both the fields of developmental biology and cancer research have provided an extensive understanding of SIX family transcription factor functions. Here we review recent progress in elucidating the role of SIX family genes in congenital disease as well as in the promotion of cancer. Common themes arise when comparing SIX transcription factor function during embryonic and cancer development. We highlight the complementary nature of these two fields and how knowledge in one area can open new aspects of experimentation in the other.
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Affiliation(s)
- Logan Meurer
- Department of Basic Sciences, NYIT College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR, United States
| | - Leonard Ferdman
- Department of Basic Sciences, NYIT College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR, United States
| | - Beau Belcher
- Department of Biological Sciences, Arkansas State University, Jonesboro, AR, United States
| | - Troy Camarata
- Department of Basic Sciences, NYIT College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR, United States
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19
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Zhang X, Guo J, Jabbarzadeh Kaboli P, Zhao Q, Xiang S, Shen J, Zhao Y, Du F, Wu X, Li M, Ji H, Yang X, Xiao Z, Wen Q. Analysis of Key Genes Regulating the Warburg Effect in Patients with Gastrointestinal Cancers and Selective Inhibition of This Metabolic Pathway in Liver Cancer Cells. Onco Targets Ther 2020; 13:7295-7304. [PMID: 32801756 PMCID: PMC7394593 DOI: 10.2147/ott.s257944] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 07/03/2020] [Indexed: 12/24/2022] Open
Abstract
Objective The Warburg effect, also known as aerobic glycolysis, plays a dominant role in the development of gastrointestinal (GI) cancers. In this study, we analyzed the expression of key genes involved in the Warburg effect in GI cancers and investigated the effect of suppressing the Warburg effect in vitro in liver cancer cell lines. Methods The Cancer Genome Atlas (TCGA) RNA-Seq data were used to determine gene expression levels, which were analyzed with GraphPad Prism 7.00. Genetic alterations were queried with cBioPortal. The influence of the Warburg effect on liver cancer cell viability, migration and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity was determined by means of MTT, transwell and GAPDH activity assays. Results The levels of expression of genes associated with the Warburg effect were increased in tumors. To our knowledge, this is the first report of upregulated expression of CUEDC2, HMGB2, PFKFB4, PFKP and SIX1 in liver cancer. Clinically, overexpression of these genes was associated with significantly worse overall survival of liver cancer patients. In vitro, selective inhibition of GADPH suppressed the growth and metastasis of Huh-7, Bel7404 and Hep3B hepatocellular carcinoma cell lines. Conclusion The Warburg effect may play an important role in GI cancers, especially in liver cancer.
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Affiliation(s)
- Xinyue Zhang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,Academician (Expert) Workstation of Sichuan Province, Luzhou, Sichuan, People's Republic of China
| | - Jinan Guo
- The Department of Urology, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen Urology Minimally Invasive Engineering Center, Shenzhen, Guangdong, People's Republic of China.,Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Shenzhen, Guangdong, People's Republic of China
| | - Parham Jabbarzadeh Kaboli
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, People's Republic of China
| | - Qijie Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Shixin Xiang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, People's Republic of China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, People's Republic of China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, People's Republic of China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, People's Republic of China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, People's Republic of China
| | - Huijiao Ji
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, People's Republic of China
| | - Xiao Yang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, People's Republic of China
| | - Qinglian Wen
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,Academician (Expert) Workstation of Sichuan Province, Luzhou, Sichuan, People's Republic of China
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20
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Chu Y, Jiang M, Wu N, Xu B, Li W, Liu H, Su S, Shi Y, Liu H, Gao X, Fu X, Chen D, Li X, Wang W, Liang J, Nie Y, Fan D. O-GlcNAcylation of SIX1 enhances its stability and promotes Hepatocellular Carcinoma Proliferation. Am J Cancer Res 2020; 10:9830-9842. [PMID: 32863962 PMCID: PMC7449927 DOI: 10.7150/thno.45161] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 06/17/2020] [Indexed: 12/14/2022] Open
Abstract
It is universally accepted that aberrant metabolism facilitates tumor growth. However, how cancer cells coordinate glucose metabolism and tumor proliferation is largely unknown. Sine oculis homeobox homolog 1 (SIX1) is a transcription factor that belongs to the SIX family and is believed to play an important role in the regulation of the Warburg effect in tumors. However, whether the role of SIX1 and the molecular mechanisms that regulate its activity are similar in hepatocellular carcinoma (HCC) still needs further investigation. Methods: Western blotting was performed to determine the levels of SIX1 and O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) in HCC tissues. Cell Counting Kit 8 (CCK8), colony formation and mouse tumor model assays were used to establish the role of SIX1 and O-GlcNAcylation in HCC processes. Mass spectrometry, immunoprecipitation and site-directed mutagenesis were performed to confirm the O-GlcNAcylation of SIX1. Results: Here, we demonstrated that SIX1, the key transcription factor regulating the Warburg effect in cancer, promotes HCC growth in vitro and in vivo. Furthermore, we revealed that SIX1 could also enhance the levels of a posttranslational modification called O-GlcNAcylation. Importantly, we found that SIX1 was also highly modified by O-GlcNAcylation and that O-GlcNAcylation inhibited the ubiquitination degradation of SIX1. In addition, site-directed mutagenesis at position 276 (T276A) decreased the O-GlcNAcylation level and reversed the protumor effect of SIX1. Conclusions: We conclude that O-GlcNAcylation of SIX1 enhances its stability and promotes HCC proliferation. Our findings illustrate a novel feedback loop of SIX1 and O-GlcNAcylation and show that O-GlcNAcylation of SIX1 is an important way to coordinate glucose metabolism and tumor progression.
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21
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Wang R, Shen J, Su N, Wang Q, Zhang M, Liu C. MiR-645 regulates the proliferation and apoptosis of diffuse large B-cell lymphoma by targeting DACH1. Hum Cell 2020; 33:1091-1098. [PMID: 32529465 DOI: 10.1007/s13577-020-00321-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 01/02/2020] [Indexed: 10/24/2022]
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of malignant non-Hodgkin lymphoma cases. An increasing body of evidence has indicated the critical roles of microRNAs (miRNAs) in regulating the progression of DLBCL. In this study, we found that miR-645 was up-regulated in DLBCL tissues and cell lines. Down-regulation of miR-645 significantly inhibited the proliferation, cell cycle progression and promoted the apoptosis of DLBCL cells. Experimental study identified Dachshund family transcription factor 1 (DACH1) as a target of miR-645. MiR-645 bound the 3'-untranslated region of DACH1 and reduced the expression of DACH1 in DLBCL cells. Decreased expression of DACH1 was inversely correlated with that of miR-645 in DLBCL tissues. The promoting effect of miR-645 on the proliferation of DLBCL cells was attenuated with the overexpression of DACH1. These results demonstrated the novel mechanism of miR-645 in DLBCL, which indicated miR-645 as a potential target for the diagnosis and prognostics of DLBCL.
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Affiliation(s)
- Ruihuan Wang
- The Second Hematology Department, Cangzhou Central Hospital, No. 16 Xinhua West Street, Cangzhou, 061001, Hebei, China.
| | - Jie Shen
- The Second Hematology Department, Cangzhou Central Hospital, No. 16 Xinhua West Street, Cangzhou, 061001, Hebei, China
| | - Na Su
- The CDC of Xinhua District, Cangzhou, 061000, Hebei, China
| | - Qing Wang
- The Second Hematology Department, Cangzhou Central Hospital, No. 16 Xinhua West Street, Cangzhou, 061001, Hebei, China
| | - Minjuan Zhang
- The Second Hematology Department, Cangzhou Central Hospital, No. 16 Xinhua West Street, Cangzhou, 061001, Hebei, China
| | - Chunyan Liu
- The Second Hematology Department, Cangzhou Central Hospital, No. 16 Xinhua West Street, Cangzhou, 061001, Hebei, China
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22
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Hu X, Zhang L, Li Y, Ma X, Dai W, Gao X, Rao X, Fu G, Wang R, Pan M, Guo Q, Xu X, Zhou Y, Gao J, Zhang Z, Cai S, Peng J, Hua G. Organoid modelling identifies that DACH1 functions as a tumour promoter in colorectal cancer by modulating BMP signalling. EBioMedicine 2020; 56:102800. [PMID: 32512510 PMCID: PMC7281795 DOI: 10.1016/j.ebiom.2020.102800] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 04/28/2020] [Accepted: 04/29/2020] [Indexed: 12/22/2022] Open
Abstract
Background Dachshund homologue 1 (DACH1) is highly expressed in LGR5+ intestinal stem cells and colorectal tumours. However, the roles of DACH1 in intestinal cell stemness and colorectal tumorigenesis remain largely undefined. Methods We used immunohistochemistry, western blotting and quantitative real-time PCR to analyse DACH1 expression in colorectal cancer (CRC) samples. CRISPR/Cas9 gene editing and lentiviral vector-mediated overexpression and shRNA-mediated knockdown of DACH1 were utilized to modulate DACH1 expression in cell lines and organoids. An intestinal organoid-based functional model was analysed, and cancer cell colony formation, sphere formation assays and murine xenotransplants were performed to reveal the role of DACH1 in CRC cell proliferation, stemness and tumorigenesis. Immunofluorescence, co-immunoprecipitation, RNA interference and microarray data analyses were conducted to demonstrate the association between DACH1 and the bone morphogenetic protein (BMP) signalling pathway. Findings DACH1 is specifically expressed in discrete crypt base cells, and increased DACH1 expression was found in all stages of CRC. Moreover, the high expression of DACH1 independently predicted poor prognosis. In colon cancer cells, shRNA-mediated suppression of DACH1 inhibited cell growth in vitro and in vivo. By studying the intestinal organoid-based functional model, we found that depletion of DACH1 reduced the organoid formation efficiency and tumour organoid size. DACH1 overexpression stimulated both colonsphere formation and tumour organoid formation in the context of dysregulated BMP signalling. Mechanistic characterizations indicated that overexpression of DACH1 affects a subset of stem cell signature genes implicated in stem cell proliferation and maintenance through the suppression of BMP signalling via SMAD4. Interpretation Together, our study highlights DACH1 as an integral regulator of BMP signalling during intestinal tumorigenesis, and DACH1 could be a potential prognostic marker and therapeutic target for colorectal cancer patients.
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Affiliation(s)
- Xiang Hu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Long Zhang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Cancer institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
| | - Yaqi Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xiaoji Ma
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Weixing Dai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xiaoxue Gao
- Institute of Radiation Medicine, and Cancer institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
| | - Xinxin Rao
- Institute of Radiation Medicine, and Cancer institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
| | - Guoxiang Fu
- Institute of Radiation Medicine, and Cancer institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
| | - Renjie Wang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Mengxue Pan
- Institute of Radiation Medicine, and Cancer institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
| | - Qiang Guo
- Institute of Radiation Medicine, and Cancer institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
| | - Xiaoya Xu
- Institute of Radiation Medicine, and Cancer institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
| | - Yi Zhou
- Institute of Radiation Medicine, and Cancer institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
| | - Jianjun Gao
- Institute of Radiation Medicine, and Cancer institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
| | - Zhen Zhang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
| | - Sanjun Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Cancer institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China.
| | - Junjie Peng
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Guoqiang Hua
- Institute of Radiation Medicine, and Cancer institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China.
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Riley D, Miller R, Nicholson K, Gill C, Herring A, Riggs P, Sawyer J, Savell J, Sanders J. Genome association of carcass and palatability traits from Bos indicus-Bos taurus crossbred steers within electrical stimulation status and correspondence with steer temperament 1. Carcass. Livest Sci 2019. [DOI: 10.1016/j.livsci.2019.09.021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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24
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Chen H, Xu J, Wang P, Shu Q, Huang L, Guo J, Zhang X, Zhang H, Wang Y, Shen Z, Chen X, Zhang Q. Protein phosphatase 2 regulatory subunit B''Alpha silencing inhibits tumor cell proliferation in liver cancer. Cancer Med 2019; 8:7741-7753. [PMID: 31647192 PMCID: PMC6912040 DOI: 10.1002/cam4.2620] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Revised: 09/29/2019] [Accepted: 10/06/2019] [Indexed: 12/24/2022] Open
Abstract
Aim To explore the effects of protein phosphatase 2 regulatory subunit B''Alpha (PPP2R3A) on the proliferation and migration of liver cancer cells. Methods Expression of PPP2R3A in tumor tissues of hepatocellular carcinoma (HCC) patients was detected by immunohistochemistry and western blotting. In two liver cancer cell lines (HepG2 and HuH7), PPP2R3A expression was silenced and then overexpression with PPP2R3A lentiviral vectors, and the effects of PPP2R3A knockdown or overexpression on the proliferation, cell cycle, migration, and invasion of HCC cells were determined in vitro. In a xenograft cancer model in nude mice, the in vivo effects of PPP2R3A knockdown on tumor growth and cancer cell proliferation were evaluated. Results PPP2R3A expression was found in tumor foci in six of eight HCC samples, at a level higher than that in the adjacent para‐tumor tissues. PPP2R3A expression was observed primarily in the cytoplasm of the cancer cells. Knockdown of PPP2R3A resulted in significant inhibition of hepatoma cell proliferation (P < .05), migration (P < .01), and invasion (P < .01) as well as a significant delay in the G1/S transition in both liver cancer lines (P < .05) and increased p53 expression. Conversely, overexpression of PPP2R3A promoted the proliferation (P < .05) and altered cell cycle progression (P < .05) of both liver cancer cell lines. In vivo, PPP2R3A knockdown in liver cancer cells led to significant reductions in the tumor volume (P < .001) and the expression of Ki‐67 in tumor tissues (P < .05). Conclusion PPP2R3A may play a role in liver cancer via the regulation of tumor cell proliferation and invasion.
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Affiliation(s)
- Huijuan Chen
- Department of Liver Transplantation, The Third Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing, China.,Graduate School, Anhui Medical University, Hefei, China
| | - Jing Xu
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China
| | - Peixiao Wang
- Department of Gastroenterology, Henan Children's Hospital, Zhengzhou, China
| | - Qingming Shu
- Pathology Department, The Third Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing, China
| | - Lihong Huang
- Medical Department, The Third Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing, China
| | - Jing Guo
- Medical Department, The Third Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing, China
| | - Xuyi Zhang
- Medical Department, The Third Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing, China
| | - Hongying Zhang
- Medical Department, The Third Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing, China
| | - Ying Wang
- Department of Liver Transplantation, The Third Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing, China
| | - Zhongyang Shen
- Department of Liver Transplantation, The Third Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing, China.,Department of Transplantation Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Xinguo Chen
- Department of Liver Transplantation, The Third Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing, China
| | - Qing Zhang
- Department of Liver Transplantation, The Third Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing, China
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25
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Wan J, Yang J, Qiao C, Sun X, Di A, Zhang L, Wang D, Zhao G. MicroRNA-362 Inhibits Cell Proliferation and Invasion by Directly Targeting SIX1 in Colorectal Cancer. Yonsei Med J 2019; 60:414-422. [PMID: 31016902 PMCID: PMC6479121 DOI: 10.3349/ymj.2019.60.5.414] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 02/27/2019] [Accepted: 03/07/2019] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Colorectal cancer (CRC) is the third most common cancer in China and poses high morbidity and mortality. In recent years, increasing evidence has indicated that microRNAs played important functions in the occurrence and development of tumors. The purpose of this study was to identify the biological mechanisms of miR-362 in CRC. MATERIALS AND METHODS Quantitative real-time PCR was carried out to assess the expression of miR-362 and SIX1. The Kaplan-Meier method was employed to evaluate the 5-year overall survival of CRC patients. The proliferative and invasive abilities of CRC cells were assessed by MTT and transwell assays. RESULTS miR-362 was significantly decreased in CRC tissues and cell lines, compared to the normal tissues and normal cells. A significant connection was confirmed between the overall survival of 53 CRC patients and low expression of miR-362. Downregulation of miR-362 inhibited the proliferation and invasion through binding to the 3'-UTR of SIX1 mRNA in CRC. Additionally, we discovered that SIX1 was a direct target gene of miR-362 and that the expression of miR-362 had a negative connection with SIX1 expression in CRC. SIX1 could reverse partial functions in the proliferation and invasion in CRC cells. CONCLUSION miR-362 may be a prognostic marker in CRC and suppress CRC cell proliferation and invasion in part through targeting the 3'-UTR of SIX1 mRNA. The newly identified miR-362/SIX1 axis provides insight into the progression of CRC.
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Affiliation(s)
- Jin'e Wan
- Department of Hyperbaric Oxygen, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jian Yang
- Department of Oncology, Zouping Centre Hospital, Binzhou, China
| | - Cuixia Qiao
- Department of Anorectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaomei Sun
- Department of Anorectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Aiting Di
- Department of Anorectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lize Zhang
- Department of Anorectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Dandan Wang
- Department of Anorectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Gang Zhao
- Department of Anorectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.
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26
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Song W, Ma J, Lei B, Yuan X, Cheng B, Yang H, Wang M, Feng Z, Wang L. Sine oculis homeobox 1 promotes proliferation and migration of human colorectal cancer cells through activation of Wnt/β-catenin signaling. Cancer Sci 2019; 110:608-616. [PMID: 30548112 PMCID: PMC6361609 DOI: 10.1111/cas.13905] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 11/29/2018] [Accepted: 12/02/2018] [Indexed: 12/11/2022] Open
Abstract
Sine oculis homeobox 1 (Six1) is a homeodomain transcription factor that is aberrantly expressed in a variety of human cancers, including colorectal cancer (CRC). Six1 has been reported to play a key role in the proliferation and migration of CRC cells but the underlying molecular mechanisms are still poorly characterized. In the present study, we found that Six1 overexpression promoted the proliferation and migration of CRC cells. Consistently, Six1 knockdown (KD) significantly inhibited proliferation and migration of CRC cells. In addition, we showed that Six1 promoted proliferation and migration of CRC cells through activation of Wnt/β‐catenin signaling, as evidenced by promotion of nuclear localization of β‐catenin. Silencing of β‐catenin expression with siRNA or inhibiting Wnt signaling with a specific inhibitor, xav939, significantly blocked Six1‐induced nuclear localization of β‐catenin and mitigated Six1‐promoted proliferation and migration of CRC cells. We further confirmed the involvement of β‐catenin in Six1‐promoted proliferation and migration of CRC cells by activation of Wnt signaling with lithium chloride (LiCl) in Six1 KD CRC cells and results showed that LiCl restores defective β‐catenin nuclear localization and proliferation and migration of CRC cells. Taken together, these results suggest that Six1 homeoprotein promotes the proliferation and migration of CRC cells by activating the Wnt/β‐catenin signaling pathway, and strategies targeting Six1 may be promising for the treatment of CRC.
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Affiliation(s)
- Wenxin Song
- School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, China.,Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Jian Ma
- School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, China
| | - Bingbing Lei
- School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, China
| | - Xin Yuan
- School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, China
| | - Binfeng Cheng
- School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, China
| | - Haijie Yang
- School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, China
| | - Mian Wang
- School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, China
| | - Zhiwei Feng
- School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, China.,Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Lei Wang
- School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, China
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27
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Kingsbury TJ, Kim M, Civin CI. Regulation of cancer stem cell properties by SIX1, a member of the PAX-SIX-EYA-DACH network. Adv Cancer Res 2019; 141:1-42. [PMID: 30691681 DOI: 10.1016/bs.acr.2018.12.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The PAX-SIX-EYA-DACH network (PSEDN) is a central developmental transcriptional regulatory network from Drosophila to humans. The PSEDN is comprised of four conserved protein families; including paired box (PAX), sine oculis (SIX), eyes absent (EYA), and dachshund (DACH). Aberrant expression of PSEDN members, particularly SIX1, has been observed in multiple human cancers, where SIX1 expression correlates with increased aggressiveness and poor prognosis. In conjunction with its transcriptional activator EYA, the SIX1 transcription factor increases cancer stem cell (CSC) numbers and induces epithelial-mesenchymal transition (EMT). SIX1 promotes multiple hallmarks and enabling characteristics of cancer via regulation of cell proliferation, senescence, apoptosis, genome stability, and energy metabolism. SIX1 also influences the tumor microenvironment, enhancing recruitment of tumor-associated macrophages and stimulating angiogenesis, to promote tumor development and progression. EYA proteins are multifunctional, possessing a transcriptional activation domain and tyrosine phosphatase activity, that each contributes to cancer stem cell properties. DACH proteins function as tumor suppressors in solid cancers, opposing the actions of SIX-EYA and reducing CSC prevalence. Multiple mechanisms can lead to increased SIX1 expression, including loss of SIX1-targeting tumor suppressor microRNAs (miRs), whose expression correlates inversely with SIX1 expression in cancer patient samples. In this review, we discuss the major mechanisms by which SIX1 confers CSC and EMT features and other important cancer cell characteristics. The roles of EYA and DACH in CSCs and cancer progression are briefly highlighted. Finally, we summarize the clinical significance of SIX1 in cancer to emphasize the potential therapeutic benefits of effective strategies to disrupt PSEDN protein interactions and functions.
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Lu GF, Geng F, Xiao Z, Chen YS, Han Y, You CY, Gong NL, Xie ZM, Pan M. MicroRNA-6807-3p promotes the tumorigenesis of glioma by targeting downstream DACH1. Brain Res 2018; 1708:47-57. [PMID: 30527681 DOI: 10.1016/j.brainres.2018.12.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Revised: 11/16/2018] [Accepted: 12/04/2018] [Indexed: 01/08/2023]
Abstract
Accumulated evidence reveals that microRNAs play vital roles in various tumors, including gliomas. MiRNAs have been shown to participate in multiple cellular functions, including cell proliferation, migration and apoptosis. Here, we investigate the potential role of a novel miRNA, miR-6807-3p, in glioma. A quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and western blot were applied to detect the expression of miR-6807-3p and its target molecule in glioma specimens and cultured cells. The direct targets of miR-6807-3p were predicted by bioinformatics software and were further verified by a luciferase reporter assay. The effects of miR-6807-3p on glioma cell proliferation, migration, cell apoptosis and the cell cycle of glioma cells were analyzed by the Cell-Counting Kit-8 (CCK-8) assay, a cell migration assay and flow cytometry assays. MiR-6807-3p was found to promote tumor growth and migration and inhibits apoptosis and cell cycle arrest in vitro, thus playing a tumor oncogenic role in the progression of glioma. Expression levels of miR-6807-3p were greatly upregulated in glioma specimens, and dachshund homolog 1 (DACH1) was ascertained as a direct target of miR-6807-3p, modulated by the expression of miR-6807-3p in glioma cells. Aberrant expression of DACH1 was associated with the clinical survival of glioma patients. Furthermore, overexpression of DACH1 rescued the promotive effects of miR-6807-3p in glioma. Based on these findings, a novel miR-6807-3p may act as a glioma enhancer by targeting DACH1.
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Affiliation(s)
- Gui-Feng Lu
- Department of Pathophysiology, Zunyi Medical University, Zunyi 563003, China
| | - Fei Geng
- Department of Physiology, Zunyi Medical University, Zunyi 563003, China.
| | - Zhi Xiao
- Department of Physiology, Zunyi Medical University, Zunyi 563003, China
| | - Yuan-Shou Chen
- Department of Physiology, Zunyi Medical University, Zunyi 563003, China
| | - Yong Han
- Department of Physiology, Zunyi Medical University, Zunyi 563003, China
| | - Chun-Yue You
- Department of Neurosurgery, The Affiliated Hospital of Zunyi Medical University, Zunyi 563003, China
| | - Nan-Ling Gong
- Department of Physiology, Zunyi Medical University, Zunyi 563003, China
| | - Ze-Mei Xie
- Department of Physiology, Zunyi Medical University, Zunyi 563003, China
| | - Min Pan
- Department of Physiology, Zunyi Medical University, Zunyi 563003, China
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