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Nam Hee Kim,
Hyun Sil Kim,
Xiao-Yan Li,
Inhan Lee,
Hyung-Seok Choi,
Shi Eun Kang,
So Young Cha,
Joo Kyung Ryu,
Dojun Yoon,
Eric R Fearon,
R Grant Rowe,
Sanghyuk Lee,
Christopher A Maher,
Stephen J Weiss, Jong In Yook
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Nam Hee Kim,
Yong Hoon Cha,
Shi Eun Kang,
Yoon Mi Lee,
Inhan Lee,
So Young Cha,
Joo Kyung Ryu,
Jung Min Na,
Changbum Park,
Ho-Geun Yoon,
Gyeong-Ju Park, Jong In Yook,
Hyun Sil Kim
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ABSTRACT: p53 is a bona fide tumor suppressor gene whose loss of function marks the most common genetic alteration in human malignancy. Although the causal link between loss of p53 function and tumorigenesis has been clearly demonstrated, the mechanistic links by which loss of p53 potentiates oncogenic signaling are not fully understood. Recent evidence indicates that the microRNA-34 (miR-34) family, a transcriptional target of the p53, directly suppresses a set of canonical Wnt genes and Snail, resulting in p53-mediated suppression of Wnt signaling and the EMT process. In this study, we report that p53 regulates GSK-3β nuclear localization via miR-34-mediated suppression of Axin2 in colorectal cancer. Exogenous miR-34a decreases Axin2 UTR-reporter activity through multiple binding sites within the 5' and 3' UTR of Axin2. Suppression of Axin2 by p53 or miR-34 increases nuclear GSK-3β abundance and leads to decreased Snail expression in colorectal cancer cells. Conversely, expression of the non-coding UTR of Axin2 causes depletion of endogenous miR-34 via the miR-sponge effect together with increased Axin2 function, supporting that the RNA-RNA interactions with Axin2 transcripts act as an endogenous decoy for miR-34. Further, RNA transcripts of miR-34 target were correlated with Axin2 in clinical data set of colorectal cancer patients. Although the biological relevance of nuclear GSK-3 level has not been fully studied, our results demonstrate that the tumor suppressor p53/miR-34 axis plays a role in regulating nuclear GSK-3 levels and Wnt signaling through the non-coding UTR of Axin2 in colorectal cancer.
Cell cycle (Georgetown, Tex.) 04/2013; 12(10). · 5.36 Impact Factor
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Ismail Ahmed Ismail,
Hye Sook Kang,
Heon-Jin Lee,
Hyeyoun Chang,
Jieun Yun,
Chang Woo Lee,
Nam Hee Kim,
Hyun Sil Kim, Jong In Yook,
Su-Hyung Hong,
Byoung-Mog Kwon
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ABSTRACT: Since epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression and in maintaining cancer stem cell properties, EMT is emerging as a therapeutic target for inhibiting the metastatic progression of cancer cells. 2'-Hydroxycinnamaldehyde (HCA) and its derivative, 2'-benzoyloxycinnamaldehyde, have recently been suggested as promising therapeutic candidates for cancer treatment. The purpose of this study is to investigate the anti-metastatic effect of HCA on breast cancer and the molecular mechanisms by which HCA regulates the transcriptional program during EMT. HCA induces epithelial reversion at nanomolar concentrations by suppressing Snail via the nuclear translocalization of GSK-3β, which results in the transcriptional upregulation of E-cadherin. HCA also activates the transcription factor KLF17, which suppresses Id-1, indicating that HCA inhibits EMT by multiple transcriptional programs. Further, HCA treatment significantly inhibits lung metastasis in a mouse orthotopic breast cancer model. This study demonstrates the anti-metastatic effect of the non-toxic natural compound HCA through attenuation of EMT in a breast cancer model.
Breast Cancer Research and Treatment 01/2013; · 4.43 Impact Factor
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Oral surgery, oral medicine, oral pathology and oral radiology. 01/2013; 115(1):2-8.
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ABSTRACT: We report smart nanoprobe, hyaluronic acid (HA)-based nanocontainers containing miR-34a beacons (bHNCs), for the intracellular recognition of miR-34a levels in metastatic breast cancer cells, which is distinct from the imaging of biomarkers such of cell membrane receptors such as HER2. In this study, we demonstrate that a nanoscale vesicle that couples a targeting endocytic route, CD44, and a molecular imaging probe enables the efficient detection of specific miRNAs. Furthermore, bHNCs showed no cytotoxicity and high stability due to the anchored HA molecules on the surface of nanocontainers, and enables the targeted delivery of beacons via CD44 receptor-mediated endocytosis. In vitro and in vivo optical imaging using bHNCs also allow the measurement of miR-34a expression levels due to the selective recognition of the beacons released from the internalized bHNCs. We believe that the technique described herein can be further developed as a cancer diagnostic as well as a miRNA-based therapy of metastatic cancer.
ACS Nano 09/2012; 6(10):8525-35. · 10.77 Impact Factor
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ABSTRACT: Previously, we reported that high PKCK2 activity could protect cancer cells from death receptor–mediated
apoptosis through phosphorylation of procaspase-2. Because anoikis is another form of apoptosis, we asked whether PKCK2 could similarly confer resistance to anoikis on cancer cells. Human esophageal squamous cancer cell lines with high PKCK2 activity (HCE4 and HCE7) were anoikis-resistant, whereas cell lines with low PKCK2 activity (TE2 and TE3) were anoikis-sensitive. Because the cells showed different sensitivity to anoikis, we compared the expression of cell adhesion molecules between anoikis-sensitive TE2 and anoikis-resistant HCE4 cells using cDNA microarray. We found that E-cadherin is expressed only in TE2 cells; whereas N-cadherin is expressed instead of E-cadherin in HCE4 cells. To examine whether PKCK2 activity could determine the type of cadherin expressed, we first increased intracellular PKCK2 activity in TE2 cells by overexpressing the PKCK2a catalytic subunit using lentivirus and found that high PKCK2 activity could switch cadherin expression from type E to N and confer anoikis resistance. Conversely, a decrease in PKCK2 activity in HCE4 cells by knockdown of PKCK2a catalytic subunit using shRNA induced N- to E-cadherin switching and the anoikis-resistant cells became sensitive. In addition, N- cadherin expression correlated with PKB/Akt activation and increased invasiveness. We conclude that high intracellular PKCK2 activity confers anoikis resistance on esophageal cancer cells by inducing E- to N-cadherin switching.
Molecular Cancer Research 07/2012; 46. · 4.29 Impact Factor
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ABSTRACT: Aberrant expression of casein kinase 2 (CK2) is associated with tumor progression; however, the molecular mechanism by which CK2 modulates tumorigenesis is incompletely understood. In this paper, we show that CK2α phosphorylates the C-terminal domain of the nuclear receptor corepressor (NCoR) at Ser-2436 to stabilize the NCoR against the ubiquitin-dependent proteasomal degradation pathway. Importantly, NCoR promoted the invasion of esophageal cancer cells in a CK2-dependent manner. By using cyclic DNA microarray analysis, we identified CXCL10/IP-10 as a novel CK2α-NCoR cascade-regulated gene. The depletion of both NCoR and HDAC3 commonly derepressed IP-10 transcription, demonstrating the functional engagement of the NCoR-HDAC3 axis in IP-10 transcriptional repression. Furthermore, chromatin immunoprecipitation assays showed that c-Jun recruits NCoR-HDAC3 corepressor complexes to the (AP1 site of IP-10, leading to histone hypoacetylation and IP-10 down-regulation. Collectively these data suggest that the CK2α-NCoR cascade selectively represses the transcription of IP-10 and promotes oncogenic signaling in human esophageal cancer cells.
Molecular biology of the cell 06/2012; 23(15):2943-54. · 5.98 Impact Factor
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Gyudo Lee,
Kilho Eom,
Joseph Park,
Jaemoon Yang,
Seungjoo Haam,
Yong-Min Huh,
Joo Kyung Ryu,
Nam Hee Kim, Jong In Yook,
Sang Woo Lee,
Dae Sung Yoon,
Taeyun Kwon
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ABSTRACT: Good vibrations: A bioassay using a resonant peptide-functionalized microcantilever enables the quantitative characterization of the proteolytic activity of membrane type-1 matrix metalloproteinase (MT1-MMP). In this assay, shifts in the frequency of the cantilever after specific proteolytic cleavage of the target peptides by MT1-MMP are measured.
Angewandte Chemie International Edition 05/2012; 51(24):5837-41. · 13.45 Impact Factor
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ABSTRACT: Though tumor suppressor p53 and the canonical Wnt cascade have been extensively studied for the last 30 years, due to their important physiological roles, the two signaling pathways have been largely considered independent. Recently, the miR-34 family was found to directly link p53 and Wnt, revealing the tight connection between loss of tumor suppressor function and activation of oncogenic signaling. These observations demonstrate that miR-34, known to be directly downstream of p53, targets a set of highly conserved sites in the UTR of Wnt and EMT genes, specifically WNT1, WNT3, LRP6, AXIN2, β-catenin, LEF1 and Snail, resulting in suppression of TCF/LEF transcriptional activity and the EMT program. The loss of p53 function increases Wnt activities and promotes the Snail-dependent EMT program at multiple levels in a miR-34/UTR-specific manner. The TCF/LEF transcriptional signature was closely associated with functionality of p53 and miR-34 in clinical samples, suggesting the pervasive impact of miR-34 loss on the oncogenic pathway in human cancer. Here, we review recent findings on ceRNA in light of novel data to elucidate the physiological relevance of the p53-miR-34-Wnt network, which encompasses sets of genes and directions of signaling. As loss of wt-p53 or hyperactivation of Wnt is critical in maintaining cancer stem cell properties and in establishing the metastatic program, these observations indicate a mechanism of miR-mediated quasi-sufficiency which connects tumor suppressor and oncogenic signaling pathways, supporting a continuum model of human cancer.
Cell cycle (Georgetown, Tex.) 04/2012; 11(7):1273-81. · 5.36 Impact Factor
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Joseph Park,
Jaemoon Yang,
Eun-Kyung Lim,
Eunjung Kim,
Jihye Choi,
Joo Kyung Ryu,
Nam Hee Kim,
Jin-Suck Suh, Jong In Yook,
Yong-Min Huh,
Seungjoo Haam
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ABSTRACT: Activatable nanoprobe: A dual-function nanoprobe has been developed that detects membrane type 1-matrix metalloproteinase (MT1-MMP) activity by a dual-signal increase in complementary fluorescence imaging (FI) and magnetic resonance imaging (MRI). MNCs=magnetic nanocrystals, Q=quencher, F=fluorescence dye.
Angewandte Chemie International Edition 12/2011; 51(4):945-8. · 13.45 Impact Factor
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Nam Hee Kim,
Hyun Sil Kim,
Xiao-Yan Li,
Inhan Lee,
Hyung-Seok Choi,
Shi Eun Kang,
So Young Cha,
Joo Kyung Ryu,
Dojun Yoon,
Eric R Fearon,
R Grant Rowe,
Sanghyuk Lee,
Christopher A Maher,
Stephen J Weiss, Jong In Yook
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ABSTRACT: Snail1 is a zinc finger transcriptional repressor whose pathological expression has been linked to cancer cell epithelial-mesenchymal transition (EMT) programs and the induction of tissue-invasive activity, but pro-oncogenic events capable of regulating Snail1 activity remain largely uncharacterized. Herein, we demonstrate that p53 loss-of-function or mutation promotes cancer cell EMT by de-repressing Snail1 protein expression and activity. In the absence of wild-type p53 function, Snail1-dependent EMT is activated in colon, breast, and lung carcinoma cells as a consequence of a decrease in miRNA-34 levels, which suppress Snail1 activity by binding to highly conserved 3' untranslated regions in Snail1 itself as well as those of key Snail1 regulatory molecules, including β-catenin, LEF1, and Axin2. Although p53 activity can impact cell cycle regulation, apoptosis, and DNA repair pathways, the EMT and invasion programs initiated by p53 loss of function or mutation are completely dependent on Snail1 expression. These results identify a new link between p53, miR-34, and Snail1 in the regulation of cancer cell EMT programs.
The Journal of Cell Biology 10/2011; 195(3):417-33. · 10.26 Impact Factor
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ABSTRACT: Dysregulation of Wnt signaling has been implicated in tumorigenesis. The role of Transducin β-like proteins TBL1-TBLR1 in the promotion of Wnt/β-catenin-mediated oncogenesis has recently been emphasized; however, the molecular basis of activation of Wnt signaling by the corepressor TBL1-TBLR1 is incompletely understood. Here, we show that both TBL1 and TBLR1 are SUMOylated in a Wnt signaling-dependent manner, and that this modification is selectively reversed by SUMO-specific protease I (SENP1). SUMOylation dismissed TBL1-TBLR1 from the nuclear hormone receptor corepressor (NCoR) complex, increased recruitment of the TBL1-TBLR1-β-catenin complex to the promoter of Wnt target genes, and consequently led to activation of Wnt signaling. Conversely, SENP1 decreased formation of the TBL1-TBLR1-β-catenin complex, leading to inhibition of β-catenin-mediated transcription. Importantly, inhibition of SUMOylation significantly decreased the tumorigenicity of SW480 colon cancer cells. Thus, our data reveal a mechanism for activation of Wnt signaling via the SUMOylation-dependent disassembly of the corepressor complex.
Molecular cell 07/2011; 43(2):203-16. · 14.61 Impact Factor
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Nam Hee Kim,
Hyun Sil Kim,
Nam-Gyun Kim,
Inhan Lee,
Hyung-Seok Choi,
Xiao-Yan Li,
Shi Eun Kang,
So Young Cha,
Joo Kyung Ryu,
Jung Min Na,
Changbum Park,
Kunhong Kim,
Sanghyuk Lee,
Barry M Gumbiner, Jong In Yook,
Stephen J Weiss
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ABSTRACT: Although loss of p53 function and activation of canonical Wnt signaling cascades are frequently coupled in cancer, the links between these two pathways remain unclear. We report that p53 transactivated microRNA-34 (miR-34), which consequently suppressed the transcriptional activity of β-catenin-T cell factor and lymphoid enhancer factor (TCF/LEF) complexes by targeting the untranslated regions (UTRs) of a set of conserved targets in a network of genes encoding elements of the Wnt pathway. Loss of p53 function increased canonical Wnt signaling by alleviating miR-34-specific interactions with target UTRs, and miR-34 depletion relieved p53-mediated Wnt repression. Gene expression signatures reflecting the status of β-catenin-TCF/LEF transcriptional activity in breast cancer and pediatric neuroblastoma patients were correlated with p53 and miR-34 functional status. Loss of p53 or miR-34 contributed to neoplastic progression by triggering the Wnt-dependent, tissue-invasive activity of colorectal cancer cells. Further, during development, miR-34 interactions with the β-catenin UTR affected Xenopus body axis polarity and the expression of Wnt-dependent patterning genes. These data provide insight into the mechanisms by which a p53-miR-34 network restrains canonical Wnt signaling cascades in developing organisms and human cancer.
Science Signaling 01/2011; 4(197):ra71. · 7.50 Impact Factor
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Sang Yoon Park,
Hyun Sil Kim,
Nam Hee Kim,
Suena Ji,
So Young Cha,
Jeong Gu Kang,
Ichiro Ota,
Keiji Shimada,
Noboru Konishi,
Hyung Wook Nam,
Soon Won Hong,
Won Ho Yang,
Jürgen Roth, Jong In Yook,
Jin Won Cho
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ABSTRACT: Protein O-phosphorylation often occurs reciprocally with O-GlcNAc modification and represents a regulatory principle for proteins. O-phosphorylation of serine by glycogen synthase kinase-3β on Snail1, a transcriptional repressor of E-cadherin and a key regulator of the epithelial-mesenchymal transition (EMT) programme, results in its proteasomal degradation. We show that by suppressing O-phosphorylation-mediated degradation, O-GlcNAc at serine112 stabilizes Snail1 and thus increases its repressor function, which in turn attenuates E-cadherin mRNA expression. Hyperglycaemic condition enhances O-GlcNAc modification and initiates EMT by transcriptional suppression of E-cadherin through Snail1. Thus, dynamic reciprocal O-phosphorylation and O-GlcNAc modification of Snail1 constitute a molecular link between cellular glucose metabolism and the control of EMT.
The EMBO Journal 10/2010; 29(22):3787-96. · 9.20 Impact Factor
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ABSTRACT: Osteoblasts originate from mesenchymal stem cells by the coordinated activities of different signaling pathways that regulate the expression of osteoblast-specific genes. Runt-related transcription factor 2 (Runx2) is the master transcription factor for osteoblast differentiation. Despite the importance of Runx2 in the developing skeleton, how Runx2 expression is regulated remains a pivotal question. Snail, a zinc finger transcription factor, is essential for triggering epithelial-to-mesenchymal transitions (EMTs) during embryonic development and tumor progression. Here, we report that Runx2 expression is significantly up- or down-regulated relative to Snail expression. We demonstrate that Snail binds to the Runx2 promoter and that repression of Runx2 transcription by Snail is dependent on specific E-box sequence within the promoter. With antisense morpholino oligonucleotide (MO)-mediated knockdown of Snail expression in zebrafish, we observed alterations in osteogenic potential. These results indicate that Snail plays a crucial role in osteogenic differentiation by acting as a direct Runx2 repressor.
Bone 03/2010; 46(6):1498-507. · 4.02 Impact Factor
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Jeong Gu Kang,
Sang Yoon Park,
Suena Ji,
Insook Jang,
Sujin Park,
Hyun Sil Kim, Sung-Min Kim, Jong In Yook,
Yong-Il Park,
Jürgen Roth,
Jin Won Cho
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ABSTRACT: When cellular glucose concentrations fall below normal levels, in general the extent of protein O-GlcNAc modification (O-GlcNAcylation) decreases. However, recent reports demonstrated increased O-GlcNAcylation by glucose deprivation in HepG2 and Neuro-2a cells. Here, we report increased O-GlcNAcylation in non-small cell lung carcinoma A549 cells and various other cells in response to glucose deprivation. Although the level of O-GlcNAc transferase was unchanged, the enzyme contained less O-GlcNAc, and its activity was increased. Moreover, O-GlcNAcase activity was reduced. The studied cells contain glycogen, and we show that its degradation in response to glucose deprivation provides a source for UDP-GlcNAc required for increased O-GlcNAcylation under this condition. This required active glycogen phosphorylase and resulted in increased glutamine:fructose-6-phosphate amidotransferase, the first and rate-limiting enzyme in the hexosamine biosynthetic pathway. Interestingly, glucose deprivation reduced the amount of phosphofructokinase 1, a regulatory glycolytic enzyme, and blocked ATP synthesis. These findings suggest that glycogen is the source for increased O-GlcNAcylation but not for generating ATP in response to glucose deprivation and that this may be useful for cancer cells to survive.
Journal of Biological Chemistry 10/2009; 284(50):34777-84. · 4.77 Impact Factor
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ABSTRACT: Artemisinin is of special biological interest because of its outstanding antimalarial activity. Recently, it was reported that artemisinin has antitumor activity. Its derivatives, artesunate, arteether, and artemeter, also have antitumor activity against melanoma, breast, ovarian, prostate, CNS, and renal cancer cell lines. Recently, monomer, dimer, and trimer derivatives were synthesized from deoxoartemisinin, and the dimers and the trimers were found to have much more potent antitumor activity than the monomers.
We evaluated the antitumor activity of artemisinin and its various derivatives (dihydroartemisinin, dihydroartemisinin 12-benzoate, 12-(2'-hydroxyethyl) deoxoartemisinin, 12-(2'-ethylthio) deoxoartemisinin dimer, deoxoartemisinin trimer) in comparison with paclitaxel (Taxol), 5-fluorouracil (5-FU), cisplatin in vitro.
In this study, the deoxoartemisinin trimer had the most potent antitumor effect (IC(50) = 6.0 microM), even better than paclitaxel (IC(50) = 13.1 microM), on oral cancer cell line (YD-10B). In addition, it induced apoptosis through a caspase-3-dependent mechanism.
The deoxoartemisinin trimer was found to have greater antitumor effect on tumor cells than other commonly used chemotherapeutic drugs, such as 5-FU, cisplatin, and paclitaxel. Furthermore, the ability of artemisinin and its derivatives to induce apoptosis highlights their potential as chemotherapeutic agents, for many anticancer drugs achieve their antitumor effects by inducing apoptosis in tumor cells.
Head & Neck 05/2007; 29(4):335-40. · 2.40 Impact Factor
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ABSTRACT: The E-cadherin transcriptional repressor, Snail, plays a critical role in driving the epithelial-mesenchymal transition programs that mark gastrulation as well as invasion of cancer cells. Recent data suggest that Snail is phosphorylated by GSK3-beta, resulting in beta-TRCP-mediated ubiquitination and proteasomal degradation. Accordingly, Wnt signaling inhibits Snail phosphorylation, and consequently increases Snail protein levels. In the present study, we examine the function of nuclear localization motifs embedded within the Snail sequence. A typical bipartite nuclear localization signal (NLS) motif is located at the N-terminal of Snail, where it overlaps with the SNAG domain (residues 8-16), while a basic cluster NLS motif is found proximal to zinc finger domains (residues 151-152). Mutational inactivation of these NLS signals resulted in decreased levels of nuclear and total Snail protein as well as attenuated Snail repressor activity on an E-cadherin promoter construct, suggesting that NLS motifs are essential for proper function. In the presence of GSK3 inhibitor LiCl, the cytoplasmic levels of the NLS mutants increased, suggesting that cytosolic Snail undergoes rapid phosphorylation and degradation. Given the highly conserved nature of the Snail NLS motifs (from Xenopus to human), these results indicate that nuclear localization signals regulate Snail expression and subcellular localization via GSK3-beta-dependent phosphorylation.
Cells Tissues Organs 02/2007; 185(1-3):66-72. · 2.20 Impact Factor
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Jong In Yook,
Xiao-Yan Li,
Ichiro Ota,
Casey Hu,
Hyun Sil Kim,
Nam Hee Kim,
So Young Cha,
Joo Kyung Ryu,
Yoon Jung Choi,
Jin Kim,
Eric R Fearon,
Stephen J Weiss
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ABSTRACT: Accumulating evidence indicates that hyperactive Wnt signalling occurs in association with the development and progression of human breast cancer. As a consequence of engaging the canonical Wnt pathway, a beta-catenin-T-cell factor (TCF) transcriptional complex is generated, which has been postulated to trigger the epithelial-mesenchymal transition (EMT) that characterizes the tissue-invasive phenotype. However, the molecular mechanisms by which the beta-catenin-TCF complex induces EMT-like programmes remain undefined. Here, we demonstrate that canonical Wnt signalling engages tumour cell dedifferentiation and tissue-invasive activity through an Axin2-dependent pathway that stabilizes the Snail1 zinc-transcription factor, a key regulator of normal and neoplastic EMT programmes. Axin2 regulates EMT by acting as a nucleocytoplasmic chaperone for GSK3beta, the dominant kinase responsible for controlling Snail1 protein turnover and activity. As dysregulated Wnt signalling marks a diverse array of cancerous tissue types, the identification of a beta-catenin-TCF-regulated Axin2-GSK3beta-Snail1 axis provides new mechanistic insights into cancer-associated EMT programmes.
Nature Cell Biology 01/2007; 8(12):1398-406. · 19.49 Impact Factor
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ABSTRACT: Although the head and neck region is recognized as the most common location for peripheral nerve sheath tumors, central involvement, particularly in the jaw bones, is quite unusual. Neurofibroma is one of the most common nerve sheath tumors occurring in the soft tissue and generally appears in neurofibromatosis 1 (NF1 or von Recklinghausen's disease). Malignant peripheral nerve sheath tumors (MPNSTs) are uncommon sarcomas that almost always arise in the soft tissue. Here, we report four cases of intraosseous peripheral nerve sheath tumors occurring in the jaw bones and compare the clinical, radiologic, and pathologic findings in order to make a differential diagnosis.
Yonsei Medical Journal 05/2006; 47(2):264-70. · 1.14 Impact Factor
