16 results on '"Cheung, William K. C."'
Search Results
2. An easy and efficient inducible CRISPR/Cas9 platform with improved specificity for multiple gene targeting.
- Author
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Jian Cao, Lizhen Wu, Shang-Min Zhang, Min Lu, Cheung, William K. C., Cai, Wesley, Gale, Molly, Qi Xu, and Qin Yan
- Published
- 2016
- Full Text
- View/download PDF
3. Loss of Brain-enriched miR-124 MicroRNA Enhances Stem-like Traits and Invasiveness of Glioma Cells.
- Author
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Hongping Xia, Cheung, William K. C., Ng, Samuel S., Xiaochun Jiang, Songshan Jiang, Sze, Johnny, Leung, Gilberto K. K., Gang Lu, Chan, Danny T. M., Xiu-Wu Bian, Hsiang-fu Kung, Wai Sang Poon, and Lin, Marie C.
- Subjects
- *
MICRORNA , *GLIOMAS , *MEDULLOBLASTOMA , *BIOINFORMATICS , *CELL lines , *STEM cells - Abstract
miR-124 is a brain-enriched microRNA that plays a crucial role in neural development and has been shown to be down-regulated in glioma and medulloblastoma, suggesting its possible involvement in brain tumor progression. Here, we show that miR-124 is down-regulated in a panel of different grades of glioma tissues and in all of the human glioma cell lines we examined. By integrated bioinformatics analysis and experimental confirmation, we identified SNAI2, which is often up-regulated in glioma, as a direct functional target of miR-124. Because SNAI2 has been shown to regulate stem cell functions, we examined the roles of miR-124 and SNAI2 in glioma cell stem-like traits. The results showed that overexpression of miR-124 and knockdown of SNAI2 reduced neurosphere formation, CD133+ cell subpopulation, and stem cell marker (BMI1, Nanog, and Nestin) expression, and these effects could be rescued by re-expression of SNAI2. Furthermore, enhanced miR-124 expression significantly inhibited glioma cell invasion in vitro. Finally, stable overexpression of miR-124 and knockdown of SNAI2 inhibited the tumorigenicity and invasion of glioma cells in vivo. These findings reveal, for the first time, that the tumor suppressor activity of miR-124 could be partly due to its inhibitory effects on glioma stem-like traits and invasiveness through SNAI2. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
4. miR-200a Regulates Epithelial-Mesenchymal to Stem-like Transition via ZEB2 and β-Catenin Signaling.
- Author
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Hongping Xia, Cheung, William K. C., Sze, Johnny, Gang Lu, Songshan Jiang, Hong Yao, Xiu-Wu Bian, Wai Sang Poon, Hsiang-fu Kung, and Lin, Marie C.
- Subjects
- *
EPITHELIAL cells , *MESENCHYMAL stem cells , *MESENCHYME , *CELL populations , *LABORATORY mice - Abstract
The emerging concept of generating cancer stem cells from epithelial-mesenchymal transition has attracted great interest; however, the factors and molecular mechanisms that govern this putative tumor-initiating process remain largely elusive. We report here that miR-200a not only regulates epithelial-mesenchymal transition but also stem-like transition in nasopharyngeal carcinoma cells. We first showed that stable knockdown of miR-200a promotes the transition of epithelium-like CNE-1 cells to the mesenchymal phenotype. More importantly, it also induced several stem cell-like traits, including CD133+ side population, sphere formation capacity, in vivo tumorigenicity in nude mice, and stem cell marker expression. Consistently, stable overexpression of miR-200a switched mesenchyme-like C666-1 cells to the epithelial state, accompanied by a significant reduction of stem-like cell features. Furthermore, in vitro differentiation of the C666-1 tumor sphere resulted in diminished stem-like cell population and miR-200a induction. To investigate the molecular mechanism, we demonstrated that miR-200a controls epithelial-mesenchymal transition by targeting ZEB2, although it regulates the stem-like transition differentially and specifically by β-catenin signaling. Our findings reveal for the first time the function of miR-200a in shifting nasopharyngeal carcinoma cell states via a reversible process coined as epithelial-mesenchymal to stem-like transition through differential and specific mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
5. Makorin-2 Is a Neurogenesis Inhibitor Downstream of Phosphatidylinositol 3-Kinase/Akt (PI3K/Akt) SignaI.
- Author
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Pai-Hao Yang, Cheung, William K. C., Ying Peng, Ming-Liang He, Guo-Qing Wu, Dan Xie, Bing-Hua Jiang, Qiu-Hua Huang, Zhu Chen, Lin, Marie C. M., and Hsiang-Fu Kung
- Subjects
- *
DEVELOPMENTAL neurobiology , *ZINC-finger proteins , *NUCLEOPROTEINS , *TADPOLES , *PHENOTYPES , *OLIGONUCLEOTIDES - Abstract
Makorin-2 belongs to the makorin RING zinc finger gene family, which encodes putative ribonucleoproteins. Here we cloned the Xenopus makorin-2 (mkrn2) and characterized its function in Xenopus neurogenesis. Forced overexpression of mkrn2 produced tadpoles with dorso-posterior deficiencies and small-head/short-tail phenotype, whereas knockdown of mkrn2 by morpholino anti-sense oligonucleotides induced double axis in tadpoles. In Xenopus animal cap explant assay, mkrn2 inhibited activin, and retinoic acid induced animal cap neuralization, as evident from the suppression of a pan neural marker, neural cell adhesion molecule. Surprisingly, the anti-neurogenic activity of mkrn2 is independent of the two major neurogenesis signaling cascades, BMP-4 and Wnt8 pathways. Instead, mkrn2 works specifically through the phosphatidylinositol 3-kinase (PI3K) and Akt-mediated neurogenesis pathway. Overexpression of mkrn2 completely abrogated constitutively active PI3K- and Akt-induced, but not dominant negative glycogen synthase kinase-3β (GSK-3β)-induced, neural cell adhesion molecule expression, indicating that mkrn2 acts downstream of PI3K and Akt and upstream of GSK-3β. Moreover, mkrn2 up- regulated the mRNA and protein levels of GSK-3β. These results revealed for the first time the important role of mkrn2 as a new player in PI3K/Akt-mediated neurogenesis during Xenopus embryonic development. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
6. Extracellular Matrix Receptor Expression in Subtypes of Lung Adenocarcinoma Potentiates Outgrowth of Micrometastases.
- Author
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Stevens LE, Cheung WKC, Adua SJ, Arnal-Estapé A, Zhao M, Liu Z, Brewer K, Herbst RS, and Nguyen DX
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma of Lung, Animals, Brain Neoplasms metabolism, Brain Neoplasms secondary, Cell Line, Tumor, Extracellular Matrix genetics, Extracellular Matrix metabolism, Extracellular Matrix pathology, Extracellular Matrix Proteins genetics, Gene Expression, Humans, Hyaluronan Receptors genetics, Lung Neoplasms genetics, Male, Mice, Mice, Nude, Neoplasm Micrometastasis, Transcriptome, Tumor Microenvironment, Adenocarcinoma metabolism, Adenocarcinoma pathology, Extracellular Matrix Proteins biosynthesis, Hyaluronan Receptors biosynthesis, Lung Neoplasms metabolism, Lung Neoplasms pathology
- Abstract
Mechanisms underlying the propensity of latent lung adenocarcinoma (LUAD) to relapse are poorly understood. In this study, we show how differential expression of a network of extracellular matrix (ECM) molecules and their interacting proteins contributes to risk of relapse in distinct LUAD subtypes. Overexpression of the hyaluronan receptor HMMR in primary LUAD was associated with an inflammatory molecular signature and poor prognosis. Attenuating HMMR in LUAD cells diminished their ability to initiate lung tumors and distant metastases. HMMR upregulation was not required for dissemination in vivo , but enhanced ECM-mediated signaling, LUAD cell survival, and micrometastasis expansion in hyaluronan-rich microenvironments in the lung and brain metastatic niches. Our findings reveal an important mechanism by which disseminated cancer cells can coopt the inflammatory ECM to persist, leading to brain metastatic outgrowths. Cancer Res; 77(8); 1905-17. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
- Full Text
- View/download PDF
7. An easy and efficient inducible CRISPR/Cas9 platform with improved specificity for multiple gene targeting.
- Author
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Cao J, Wu L, Zhang SM, Lu M, Cheung WK, Cai W, Gale M, Xu Q, and Yan Q
- Subjects
- Bacterial Proteins metabolism, CRISPR-Associated Protein 9, Cell Line, Clustered Regularly Interspaced Short Palindromic Repeats, Endonucleases metabolism, Gene Expression, Gene Knockout Techniques, Gene Order, Gene Silencing, Genes, Reporter, Genetic Vectors genetics, Humans, Promoter Regions, Genetic, RNA, Guide, CRISPR-Cas Systems, Retinoblastoma-Binding Protein 2 deficiency, CRISPR-Cas Systems, Gene Targeting methods, Gene Targeting standards
- Abstract
The CRISPR/Cas9 system is a powerful genome editing tool and has been widely used for biomedical research. However, many challenges, such as off-target effects and lack of easy solutions for multiplex targeting, are still limiting its applications. To overcome these challenges, we first developed a highly efficient doxycycline-inducible Cas9-EGFP vector. This vector allowed us to track the cells for uniform temporal control and efficient gene disruption, even in a polyclonal setting. Furthermore, the inducible CRISPR/Cas9 system dramatically decreased off-target effects with a pulse exposure of the genome to the Cas9/sgRNA complex. To target multiple genes simultaneously, we established simple one-step cloning approaches for expression of multiple sgRNAs with improved vectors. By combining our inducible and multiplex genome editing approaches, we were able to simultaneously delete Lysine Demethylase (KDM) 5A, 5B and 5C efficiently in vitro and in vivo This user friendly and highly efficient toolbox provides a solution for easy genome editing with tight temporal control, minimal off-target effects and multiplex targeting., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2016
- Full Text
- View/download PDF
8. Histone demethylase RBP2 is critical for breast cancer progression and metastasis.
- Author
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Cao J, Liu Z, Cheung WK, Zhao M, Chen SY, Chan SW, Booth CJ, Nguyen DX, and Yan Q
- Subjects
- Animals, Breast Neoplasms pathology, Cell Line, Tumor, Disease Progression, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic, Histone Demethylases genetics, Humans, Male, Mammary Neoplasms, Experimental enzymology, Mammary Neoplasms, Experimental genetics, Mammary Neoplasms, Experimental pathology, Mice, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Neoplasm Metastasis, Retinol-Binding Proteins, Cellular genetics, Transfection, Breast Neoplasms enzymology, Breast Neoplasms genetics, Histone Demethylases metabolism, Retinol-Binding Proteins, Cellular metabolism
- Abstract
Metastasis is a major clinical challenge for cancer treatment. Emerging evidence suggests that aberrant epigenetic modifications contribute significantly to tumor formation and progression. However, the drivers and roles of such epigenetic changes in tumor metastasis are still poorly understood. Using bioinformatic analysis of human breast cancer gene-expression data sets, we identified histone demethylase RBP2 as a putative mediator of metastatic progression. By using both human breast cancer cells and genetically engineered mice, we demonstrated that RBP2 is critical for breast cancer metastasis to the lung in multiple in vivo models. Mechanistically, RBP2 promotes metastasis as a pleiotropic positive regulator of many metastasis genes, including TNC. In addition, RBP2 loss suppresses tumor formation in MMTV-neu transgenic mice. These results suggest that therapeutic targeting of RBP2 is a potential strategy for inhibition of tumor progression and metastasis., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
9. Control of alveolar differentiation by the lineage transcription factors GATA6 and HOPX inhibits lung adenocarcinoma metastasis.
- Author
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Cheung WK, Zhao M, Liu Z, Stevens LE, Cao PD, Fang JE, Westbrook TF, and Nguyen DX
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma of Lung, Cell Differentiation, Cell Line, Tumor, Cell Lineage, Cluster Analysis, Epithelium pathology, GATA6 Transcription Factor genetics, GATA6 Transcription Factor metabolism, Gene Expression Regulation, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Humans, Lung Neoplasms genetics, Neoplasm Invasiveness, Neoplasm Metastasis genetics, Pulmonary Alveoli cytology, Pulmonary Alveoli pathology, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Adenocarcinoma pathology, GATA6 Transcription Factor physiology, Homeodomain Proteins physiology, Lung Neoplasms pathology, Neoplasm Metastasis pathology, Tumor Suppressor Proteins physiology
- Abstract
Molecular programs that mediate normal cell differentiation are required for oncogenesis and tumor cell survival in certain cancers. How cell-lineage-restricted genes specifically influence metastasis is poorly defined. In lung cancers, we uncovered a transcriptional program that is preferentially associated with distal airway epithelial differentiation and lung adenocarcinoma (ADC) progression. This program is regulated in part by the lineage transcription factors GATA6 and HOPX. These factors can cooperatively limit the metastatic competence of ADC cells, by modulating overlapping alveolar differentiation and invasogenic target genes. Thus, GATA6 and HOPX are critical nodes in a lineage-selective pathway that directly links effectors of airway epithelial specification to the inhibition of metastasis in the lung ADC subtype., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
10. Loss of brain-enriched miR-124 microRNA enhances stem-like traits and invasiveness of glioma cells.
- Author
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Xia H, Cheung WKC, Ng SS, Jiang X, Jiang S, Sze J, Leung GKK, Lu G, Chan DTM, Bian XW, Kung HF, Poon WS, and Lin MC
- Subjects
- Animals, Antigens, Differentiation genetics, Biomarkers, Tumor genetics, Brain Neoplasms, Cell Line, Tumor, Down-Regulation genetics, Glioma genetics, Glioma pathology, Humans, Mice, Mice, Nude, MicroRNAs genetics, Neoplasm Invasiveness, Neoplastic Stem Cells pathology, Snail Family Transcription Factors, Spheroids, Cellular metabolism, Spheroids, Cellular pathology, Transcription Factors biosynthesis, Transcription Factors genetics, Up-Regulation genetics, Antigens, Differentiation metabolism, Biomarkers, Tumor metabolism, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Glioma metabolism, MicroRNAs biosynthesis, Neoplastic Stem Cells metabolism
- Abstract
miR-124 is a brain-enriched microRNA that plays a crucial role in neural development and has been shown to be down-regulated in glioma and medulloblastoma, suggesting its possible involvement in brain tumor progression. Here, we show that miR-124 is down-regulated in a panel of different grades of glioma tissues and in all of the human glioma cell lines we examined. By integrated bioinformatics analysis and experimental confirmation, we identified SNAI2, which is often up-regulated in glioma, as a direct functional target of miR-124. Because SNAI2 has been shown to regulate stem cell functions, we examined the roles of miR-124 and SNAI2 in glioma cell stem-like traits. The results showed that overexpression of miR-124 and knockdown of SNAI2 reduced neurosphere formation, CD133(+) cell subpopulation, and stem cell marker (BMI1, Nanog, and Nestin) expression, and these effects could be rescued by re-expression of SNAI2. Furthermore, enhanced miR-124 expression significantly inhibited glioma cell invasion in vitro. Finally, stable overexpression of miR-124 and knockdown of SNAI2 inhibited the tumorigenicity and invasion of glioma cells in vivo. These findings reveal, for the first time, that the tumor suppressor activity of miR-124 could be partly due to its inhibitory effects on glioma stem-like traits and invasiveness through SNAI2.
- Published
- 2012
- Full Text
- View/download PDF
11. Cell lineage specification in tumor progression and metastasis.
- Author
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Cao PD, Cheung WK, and Nguyen DX
- Subjects
- Animals, Disease Progression, Humans, Neoplasms complications, Cell Lineage physiology, Neoplasms pathology
- Abstract
Cancer has long been compared to the aberrant development of human tissues. It was in the mid-19th century writings of Rudolf Virchow and Joseph Recamier that malignant tissue was first proposed to originate from embryonal cells. More contemporary perspectives on malignant progression are founded on the tenant that tumors emerge from somatic tissues. Yet examples linking the biological properties of cancer to developmental processes, both aberrant and normal, abound. In this review, we will discuss how the developmental lineage of tumor cells can influence the course of cancer metastasis. As new molecular mechanisms that control cell fate in various tissues are being rapidly uncovered, understanding how these well orchestrated programs can be subverted in human diseases should provide intriguing avenues for fundamental biological discoveries and new therapeutic opportunities in cancer.
- Published
- 2011
12. miR-200a regulates epithelial-mesenchymal to stem-like transition via ZEB2 and beta-catenin signaling.
- Author
-
Xia H, Cheung WK, Sze J, Lu G, Jiang S, Yao H, Bian XW, Poon WS, Kung HF, and Lin MC
- Subjects
- Animals, Blotting, Western, Cell Differentiation, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Homeodomain Proteins antagonists & inhibitors, Homeodomain Proteins genetics, Immunoenzyme Techniques, Mice, Mice, Inbred BALB C, Mice, Nude, Nasopharyngeal Neoplasms metabolism, Neoplastic Stem Cells metabolism, RNA, Messenger genetics, RNA, Small Interfering genetics, Repressor Proteins antagonists & inhibitors, Repressor Proteins genetics, Reverse Transcriptase Polymerase Chain Reaction, Spheroids, Cellular metabolism, Spheroids, Cellular pathology, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Zinc Finger E-box Binding Homeobox 2, beta Catenin antagonists & inhibitors, beta Catenin genetics, Epithelial-Mesenchymal Transition, Homeodomain Proteins metabolism, MicroRNAs physiology, Nasopharyngeal Neoplasms pathology, Neoplastic Stem Cells pathology, Repressor Proteins metabolism, beta Catenin metabolism
- Abstract
The emerging concept of generating cancer stem cells from epithelial-mesenchymal transition has attracted great interest; however, the factors and molecular mechanisms that govern this putative tumor-initiating process remain largely elusive. We report here that miR-200a not only regulates epithelial-mesenchymal transition but also stem-like transition in nasopharyngeal carcinoma cells. We first showed that stable knockdown of miR-200a promotes the transition of epithelium-like CNE-1 cells to the mesenchymal phenotype. More importantly, it also induced several stem cell-like traits, including CD133(+) side population, sphere formation capacity, in vivo tumorigenicity in nude mice, and stem cell marker expression. Consistently, stable overexpression of miR-200a switched mesenchyme-like C666-1 cells to the epithelial state, accompanied by a significant reduction of stem-like cell features. Furthermore, in vitro differentiation of the C666-1 tumor sphere resulted in diminished stem-like cell population and miR-200a induction. To investigate the molecular mechanism, we demonstrated that miR-200a controls epithelial-mesenchymal transition by targeting ZEB2, although it regulates the stem-like transition differentially and specifically by β-catenin signaling. Our findings reveal for the first time the function of miR-200a in shifting nasopharyngeal carcinoma cell states via a reversible process coined as epithelial-mesenchymal to stem-like transition through differential and specific mechanisms.
- Published
- 2010
- Full Text
- View/download PDF
13. Computational identification and characterization of primate-specific microRNAs in human genome.
- Author
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Lin S, Cheung WK, Chen S, Lu G, Wang Z, Xie D, Li K, Lin MC, and Kung HF
- Subjects
- Animals, Cell Line, Chromosomes, Human, Pair 19, Chromosomes, Human, X, Embryonic Stem Cells metabolism, Evolution, Molecular, Humans, Neoplasms genetics, Primates genetics, Genome, Human, Genomics methods, MicroRNAs genetics
- Abstract
A number of microRNAs (miRNAs) that are evolutionarily conserved not beyond primate lineage have been identified. These primate-specific miRNAs (ps-miRNAs) may attribute to the difference between high-level primates and non-primate mammals or lower vertebrates. Despite of their importance, the genome-wide miRNA conservation patterns and the properties of these ps-miRNAs are largely elusive. In this study, we developed a robust classification system to assess the conservation pattern of all human mature miRNAs across 44 vertebrate genomes. By this comparative genomic analysis, a novel set of 269 ps-miRNAs were identified. We found that many ps-miRNAs were enriched in chromosome 19 and X, forming two main clusters hereafter referred as C19MC and CXMC, respectively. When comparing the seed of ps-miRNAs themselves or with non-ps-miRNAs, more than one half ps-miRNAs sharing common seeds were belonged to C19MC, 9 of which retained a unique seed that had been reported to be enriched in human embryonic stem cells (hESCs) specific miRNAs. Moreover, the most abundant ps-miRNA common seed was possessed by miR-548 family. Most ps-miRNAs had very low expression in adult tissues, which may be attributed to temporal and spatial specific transcript regulation. The ps-miRNAs with relatively high expression were mainly belonged to C19MC and CXMC, and preferentially expressed in hESCs and reproductive system. Sequence anatomy revealed that C19MC ps-miRNAs were highly conserved but not beyond primates and of great sequence similarity. Gene Ontology and KEGG pathway enrichment analyses of predicted target genes indicated that C19MC ps-miRNAs were strongly associated with developmental processes and various cancers. In conclusion, ps-miRNAs may play critical roles in differentiation and growth regulation during early development, especially in maintaining the pluripotency of hESCs. Results from this study may help explaining the differences between primates and lower vertebrates at genetic level., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
14. Identification of protein domains required for makorin-2-mediated neurogenesis inhibition in Xenopus embryos.
- Author
-
Cheung WK, Yang PH, Huang QH, Chen Z, Chen SJ, Lin MC, and Kung HF
- Subjects
- Amino Acid Motifs genetics, Animals, Conserved Sequence, Embryo, Nonmammalian metabolism, Glycogen Synthase Kinase 3 metabolism, Phosphoproteins genetics, Phosphoproteins metabolism, Phylogeny, Protein Structure, Tertiary genetics, Ribonucleoproteins classification, Ribonucleoproteins genetics, Xenopus Proteins classification, Xenopus Proteins genetics, Xenopus laevis genetics, Xenopus laevis metabolism, Zinc Fingers genetics, Neurogenesis, Ribonucleoproteins metabolism, Xenopus Proteins metabolism, Xenopus laevis embryology
- Abstract
Makorin-2, consisting of four highly conserved C(3)H zinc fingers, a Cys-His motif and a C(3)HC(4) RING zinc finger domain, is a putative ribonucleoprotein. We have previously reported that Xenopus makorin-2 (mkrn2) is a neurogenesis inhibitor acting upstream of glycogen synthase kinase-3beta (GSK-3beta) in the phosphatidylinositol 3-kinase/Akt pathway. In an effort to identify the functional domains required for its anti-neurogenic activity, we designed and constructed a series of N- and C-terminal truncation mutants of mkrn2. Concurred with the full-length mkrn2, we showed that overexpression of one of the truncation mutants mkrn2(s)-7, which consists of only the third C(3)H zinc finger, Cys-His motif and C(3)HC(4) RING zinc finger, is essential and sufficient to produce the phenotypical dorso-posterior deficiencies and small-head/short-tail phenotype in tadpoles. In animal cap explant assay, we further demonstrated that mkrn2(s)-7 not only inhibits activin and retinoic acid-induced animal cap neuralization and the expression of a pan-neural marker neural cell adhesion molecule, but also induces GSK-3beta expression. These results collectively suggest that the third C(3)H zinc finger, Cys-His motif and C(3)HC(4) RING zinc finger are indispensable for the anti-neurogenic activity of mkrn2., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
15. miR-200a-mediated downregulation of ZEB2 and CTNNB1 differentially inhibits nasopharyngeal carcinoma cell growth, migration and invasion.
- Author
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Xia H, Ng SS, Jiang S, Cheung WK, Sze J, Bian XW, Kung HF, and Lin MC
- Subjects
- Base Sequence, Carcinoma genetics, Carcinoma metabolism, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Down-Regulation, Humans, MicroRNAs genetics, Nasopharyngeal Neoplasms genetics, Nasopharyngeal Neoplasms metabolism, Neoplasm Invasiveness, Zinc Finger E-box Binding Homeobox 2, Carcinoma pathology, Cell Transformation, Neoplastic pathology, Gene Expression Regulation, Neoplastic, Homeodomain Proteins genetics, MicroRNAs physiology, Nasopharyngeal Neoplasms pathology, Repressor Proteins genetics, beta Catenin genetics
- Abstract
Nasopharyngeal carcinoma (NPC), a highly metastatic and invasive malignant tumor originating from the nasopharynx, is widely prevalent in Southeast Asia, the Middle East and North Africa. Although viral, dietary and genetic factors have been implicated in NPC, the molecular basis of its pathogenesis is not well defined. Based on a recent microRNA (miRNA) microarray study showing miR-200 downregulation in NPC, we further investigated the role of miR-200a in NPC carcinogenesis. We found that the endogenous miR-200a expression level increases with the degree of differentiation in a panel of NPC cell lines, namely undifferentiated C666-1, high-differentiated CNE-1, and low-differentiated CNE-2 and HNE1 cells. By a series of gain-of-function and loss-of-function studies, we showed that over-expression of miR-200a inhibits C666-1 cell growth, migration and invasion, whereas its knock-down stimulates these processes in CNE-1 cells. In addition, we further identified ZEB2 and CTNNB1 as the functional downstream targets of miR-200a. Interestingly, knock-down of ZEB2 solely impeded NPC cell migration and invasion, whereas CTNNB1 suppression only inhibited NPC cell growth, suggesting that the inhibitory effects of miR-200a on NPC cell growth, migration and invasion are mediated by distinct targets and pathways. Our results reveal the important role of miR-200a as a regulatory factor of NPC carcinogenesis and a potential candidate for miRNA-based therapy against NPC., (Copyright 2009 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
16. Makorin-2 is a neurogenesis inhibitor downstream of phosphatidylinositol 3-kinase/Akt (PI3K/Akt) signal.
- Author
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Yang PH, Cheung WK, Peng Y, He ML, Wu GQ, Xie D, Jiang BH, Huang QH, Chen Z, Lin MC, and Kung HF
- Subjects
- Aging physiology, Animals, Brain metabolism, Embryo, Nonmammalian cytology, Embryo, Nonmammalian embryology, Embryo, Nonmammalian metabolism, Female, Gene Expression Regulation, Developmental, Glycogen Synthase Kinase 3 genetics, Glycogen Synthase Kinase 3 metabolism, Glycogen Synthase Kinase 3 beta, Molecular Sequence Data, Neural Cell Adhesion Molecules genetics, Oocytes metabolism, Phenotype, RNA, Messenger genetics, Ribonucleoproteins genetics, Skin metabolism, Wnt Proteins metabolism, Xenopus Proteins genetics, Xenopus laevis embryology, Xenopus laevis genetics, Xenopus laevis growth & development, Xenopus laevis metabolism, Cell Differentiation, Neurons cytology, Neurons metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Ribonucleoproteins metabolism, Signal Transduction, Xenopus Proteins metabolism
- Abstract
Makorin-2 belongs to the makorin RING zinc finger gene family, which encodes putative ribonucleoproteins. Here we cloned the Xenopus makorin-2 (mkrn2) and characterized its function in Xenopus neurogenesis. Forced overexpression of mkrn2 produced tadpoles with dorso-posterior deficiencies and small-head/short-tail phenotype, whereas knockdown of mkrn2 by morpholino antisense oligonucleotides induced double axis in tadpoles. In Xenopus animal cap explant assay, mkrn2 inhibited activin, and retinoic acid induced animal cap neuralization, as evident from the suppression of a pan neural marker, neural cell adhesion molecule. Surprisingly, the anti-neurogenic activity of mkrn2 is independent of the two major neurogenesis signaling cascades, BMP-4 and Wnt8 pathways. Instead, mkrn2 works specifically through the phosphatidylinositol 3-kinase (PI3K) and Akt-mediated neurogenesis pathway. Overexpression of mkrn2 completely abrogated constitutively active PI3K- and Akt-induced, but not dominant negative glycogen synthase kinase-3beta (GSK-3beta)-induced, neural cell adhesion molecule expression, indicating that mkrn2 acts downstream of PI3K and Akt and upstream of GSK-3beta. Moreover, mkrn2 up-regulated the mRNA and protein levels of GSK-3beta. These results revealed for the first time the important role of mkrn2 as a new player in PI3K/Akt-mediated neurogenesis during Xenopus embryonic development.
- Published
- 2008
- Full Text
- View/download PDF
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