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1.
Nature ; 577(7789): 204-208, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31915394

RESUMO

Graphene films grown by chemical vapour deposition have unusual physical and chemical properties that offer promise for applications such as flexible electronics and high-frequency transistors1-10. However, wrinkles invariably form during growth because of the strong coupling to the substrate, and these limit the large-scale homogeneity of the film1-4,11,12. Here we develop a proton-assisted method of chemical vapour deposition to grow ultra-flat graphene films that are wrinkle-free. Our method of proton penetration13-17 and recombination to form hydrogen can also reduce the wrinkles formed during traditional chemical vapour deposition of graphene. Some of the wrinkles disappear entirely, owing to the decoupling of van der Waals interactions and possibly an increase in distance from the growth surface. The electronic band structure of the as-grown graphene films shows a V-shaped Dirac cone and a linear dispersion relation within the atomic plane or across an atomic step, confirming the decoupling from the substrate. The ultra-flat nature of the graphene films ensures that their surfaces are easy to clean after a wet transfer process. A robust quantum Hall effect appears even at room temperature in a device with a linewidth of 100 micrometres. Graphene films grown by proton-assisted chemical vapour deposition should largely retain their intrinsic performance, and our method should be easily generalizable to other nanomaterials for strain and doping engineering.

2.
Nat Mater ; 18(6): 602-607, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30858568

RESUMO

Two-dimensional transition metal selenides (TMSs) possess fascinating physical properties. However, many as-prepared TMSs are environmentally unstable and limited in sample size, which greatly hinder their wide applications in high-performance electrical devices. Here we develop a general two-step vapour deposition method and successfully grow different TMS films with controllable thickness, wafer size and high quality. The superconductivity of the grown NbSe2 film is comparable with sheets exfoliated from bulk materials, and can maintain stability after a variety of harsh treatments, which are ascribed to the absence of oxygen during the whole growth process. Such environmental stability can greatly simplify the fabrication procedure for device applications, and should be of both fundamental and technological significance in developing TMS-based devices.

3.
Mol Cell Biochem ; 443(1-2): 169-180, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29159771

RESUMO

Claudin-6 (CLDN6), a critical tight junction protein acting as a tumor suppressor in breast cancer, is also considered to be a stem cell marker. Triple-negative breast cancer (TNBC) is a subtype of claudin-low and stem cell-like breast cancer which is chemoresistant to multiple anti-cancer drugs. The aim of our study was to determine whether CLDN6 plays a role in chemoresistance of TNBC. We found that overexpression of CLDN6 in TNBC cell line MDAMB231 significantly inhibited cell growth, migration, and invasion. The expression of CLDN6 increased the IC50 of adriamycin (ADM) and promoted the clonogenic survival. CLDN6 inhibited ADM-induced apoptosis and senescence in MDAMB231 cells. However, P-gp, a resistance-related protein highly associated with chemoresistance, was downregulated by CLDN6 overexpression in MDAMB231 cells. Epithelial mesenchymal transition (EMT) marker E-cadherin was increased, and vimentin was decreased by CLDN6. In addition, stem cell markers OCT4, SOX2, and Nanog were dramatically increased. CLDN6 colocalized and interacted with AF-6. Overexpression of CLDN6 increased the expression of afadin (AF-6) and hampered the activation of ERK signaling. PMA, a specific ERK activator, reversed the expression of EMT and stem cell markers, and decreased chemoresistance of MDAMB231 cells to ADM with a decreased IC50 and an increased apoptosis resulting from CLDN6. Together, we conclude that CLDN6 enhances the chemoresistance to ADM via activating the AF-6/ERK signaling pathway and up-regulating cancer stem cell characters in MDAMB231 cells.


Assuntos
Claudinas/metabolismo , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Cinesina/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Miosinas/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Claudinas/genética , Feminino , Humanos , Cinesina/genética , Miosinas/genética , Proteínas de Neoplasias/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
4.
Int J Mol Sci ; 18(9)2017 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-28867761

RESUMO

The downregulation of tight junction protein CLDN6 promotes breast cancer cell migration and invasion; however, the exact mechanism underlying CLDN6 downregulation remains unclear. CLDN6 silence is associated with DNA methyltransferase 1 (DNMT1) mediated DNA methylation, and DNMT1 is regulated by the transforming growth factor beta (TGFß)/SMAD pathway. Therefore, we hypothesized that TGFß/SMAD pathway, specifically SMAD2, may play a critical role for CLDN6 downregulation through DNA methyltransferase 1 (DNMT1) mediated DNA methylation. To test this hypothesis, we blocked the SMAD2 pathway with SB431542 in two human breast cancer cell lines (MCF-7 and SKBR-3). Our results showed that treatment with SB431542 led to a decrease of DNMT1 expression and the binding activity for CLDN6 promoter. The methylation level of CLDN6 promoter was decreased, and simultaneously CLDN6 protein expression increased. Upregulation of CLDN6 inhibited epithelial to mesenchymal transition (EMT) and reduced the migration and invasion ability of both MCF-7 and SKBR-3 cells. Furthermore, knocked down of CLDN6 abolished SB431542 effects on suppression of EMT associated gene expression and inhibition of migration and invasion. Thus, we demonstrated that the downregulation of CLDN6 is regulated through promoter methylation by DNMT1, which depends on the SMAD2 pathway, and that CLDN6 is a key regulator in the SMAD2/DNMT1/CLDN6 pathway to inhibit EMT, migration and invasion of breast cancer cells.


Assuntos
Neoplasias da Mama/genética , Claudinas/genética , Proteína Smad2/genética , Neoplasias da Mama/patologia , Movimento Celular/genética , Proliferação de Células/genética , Claudinas/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferase 1/genética , Metilação de DNA/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Células MCF-7 , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Transdução de Sinais/genética
5.
Oncol Rep ; 38(2): 875-885, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28656265

RESUMO

Claudin-6 (CLDN6) is an integral component of the tight junction proteins in polarized epithelial and endothelial cells and plays a crucial role in maintaining cell integrity. Deregulation of CLDN6 expression and distribution in tumor tissues have been widely documented and correlated with cancer progression and metastasis. However, a complete mechanistic understanding of CLDN6 regulation and function remains to be studied. Herein, we show new potential properties of CLDN6 regulation and functions from bioinformatics analysis. Using numerous algorithms to characterize the CLDN6 gene promoter elements and the CLDN6 protein structure, physio-chemical and localization properties, and its evolutionary relationships. CLDN6 is regulated by a diverse set of transcription factors (SP1, SPR, AML-1a, CdxA, CRE-BP and CREB) and associated with the levels of methylation of CpG islands in promoters. The structural properties of CLDN6 indicate that it promotes cancer cell behavior via the ASK1-p38/JNK MAPK secretory signaling pathway. In conclusion, this information from bioinformatics analysis will help future attempts to better understand CLDN6 regulation and functions.


Assuntos
Claudinas/genética , Neoplasias/genética , Proteínas de Junções Íntimas/genética , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Humanos , MAP Quinase Quinase Quinase 5/genética , Neoplasias/patologia , Regiões Promotoras Genéticas , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genética
6.
Molecules ; 21(11)2016 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-27834930

RESUMO

TTF1-NP (5,2',4'-trihydroxy-6,7,5'-trimethoxyflavone nanoparticles), derived from the traditional Changbai Mountain medicinal plant Sorbaria sorbifolia (SS), has been showed its anti-cancer effect in various liver cancer cell types and tissues. The present study was designed to evaluate the antitumor mechanism of the TTF1-NP against HepG2 hepatoma cells and HepG2 cells-induced hepatocarcinoma (HCC) in nude mouse model. Here we demonstrated that TTF1-NP inhibits tube formation of HUVECs and HepG2 cell migration and invasion, and inhibits tumor growth in nude mice implanted with HepG2 cells through the downregulation of STAT3 protein and activation, along with VEGF, KDR, bFGF, MMP2 and MMP9 levels. We further revealed that TTF1-NP decreased the DNA-binding capacity of STAT3. Together our results provide a mechanism by which TTF1-NP suppresses cancer cell migration, invasion and angiogenesis through the action of STAT3 and suggests TTF1-NP as a potential therapy for hepatocellular cancer treatment.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/metabolismo , Movimento Celular/efeitos dos fármacos , Flavonas/administração & dosagem , Neoplasias Hepáticas/metabolismo , Nanopartículas , Fator de Transcrição STAT3/metabolismo , Inibidores da Angiogênese/química , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Flavonas/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Modelos Biológicos , Nanopartículas/química , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/genética , Ligação Proteica
7.
J Exp Clin Cancer Res ; 35(1): 120, 2016 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-27461117

RESUMO

BACKGROUND: Claudin-6 (CLDN6), a member of claudin transmembrane protein family, has recently been reported to be undetectable or at low levels in human breast cancer cell lines and tissues and plays a role in suppression of migration and invasion in breast cancer cells. In addition, it is reported that CLDN6 expression is regulated by DNA methylation in various human cancers and cell lines. However, it is unclear how DNA methylation regulates CLDN6 expression. Here we show the mechanism by which DNA methylation regulates CLDN6 expression in human breast cancer cell line MCF-7. METHODS: RT-PCR, Western blot and immunofluorescent staining were utilized to investigate CLDN6 expression in breast cancer tissues and MCF-7 cells. Methylation-Specific PCR (MSP) was applied to determine DNA methylation status in CLDN6 gene promoter region. Wound-healing assay and invasion assay were utilized to test mobility of MCF-7 cells treated with 5-aza-dC (DNA methyltransferase inhibitor). MeCP2 binding, H3Ac and H4Ac in CLDN6 promoter region were analyzed by ChIP assay. Nuclease accessibility assay was performed for analysis of the chromatin conformation of CLDN6 gene. To study the role of CLDN6 in malignant progression, we used RNAi to knockdown CLDN6 expression in MCF-7 cells treated with 5-aza-dC, and examined the mobility of MCF-7 cells by wound-healing assay and invasion assay. RESULTS: 5-aza-dC and TSA (histone deacetylase inhibitor) application induced CLDN6 expression in MCF-7 cells respectively and synergistically. 5-aza-dC treatment induced CLDN6 demethylation, inhibited MeCP2 binding to CLDN6 promoter and increased H3Ac and H4Ac in the promoter. In addition, TSA increased H4Ac, not H3Ac in the promoter. The chromatin structure of CLDN6 gene became looser than the control group after treating with 5-aza-dC in MCF-7 cells. 5-aza-dC up-regulated CLDN6 expression and suppressed migration and invasion in MCF-7 cells, whereas CLDN6 silence restored tumor malignance in MCF-7 cells. CONCLUSIONS: DNA methylation down-regulates CLDN6 expression through MeCP2 binding to the CLDN6 promoter, deacetylating H3 and H4, and altering chromatin structure, consequently promoting migratory and invasive phenotype in MCF-7 cells.


Assuntos
Neoplasias da Mama/genética , Claudinas/genética , Claudinas/metabolismo , Metilação de DNA , Histonas/metabolismo , Proteína 2 de Ligação a Metil-CpG/metabolismo , Acetilação/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Azacitidina/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Feminino , Humanos , Ácidos Hidroxâmicos/farmacologia , Células MCF-7 , Pessoa de Meia-Idade , Invasividade Neoplásica , Regiões Promotoras Genéticas , Adulto Jovem
8.
Int J Oncol ; 48(6): 2435-44, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27035750

RESUMO

Claudin 6 (CLDN6), a member of tight junction protein claudin (CLDN) family, inhibits proliferation and induces apoptosis of MCF-7 breast cancer cells. However, these molecular mechanisms of CLDN6-induced apoptosis remain largely elusive. We previously found that restoration of human CLDN6 gene expression was correlated with the expression level of apoptosis signal-regulating kinase 1 (ASK1) using cDNA array and bioinformatics analysis. ASK1, a mitogen-activated protein kinase kinase kinase, is involved in environmental stress-activation of the c-jun N-terminal kinase (JNK) and p38 pathways, which contribute to apoptosis-associated tumor cell death. In the present study, we show that the restoration of CLDN6 gene expression in MCF-7 cells marhedly decreased ASK1 phosphorylation at Ser967. Activated ASK1ser967 further induced the activation of downstream targets, JNK and p38 kinase. MCF-7/CLDN6 stable transfection cell clone treated with TRX1, an ASK1 inhibitor, showed suppressed JNK and p38 activation, and showed substantially increased survival and colony formation and reduced percent of apoptotic cells using TUNEL staining and DNA ladder. Furthermore, TRX1 treatment increased Bcl-2/Bax ratio and reduced caspase-3 cleavage in MCF-7/CLDN6 stable transfection cell clone. Therefore, these data show that CLDN6 mediates ASK1-p38/JNK apoptotic signaling in MCF-7 cells, and it is correlated with constitutive deregulation of the balance of Bcl-2 family proteins and activation of caspase-3.


Assuntos
Neoplasias da Mama/metabolismo , Claudinas/metabolismo , MAP Quinase Quinase Quinase 5/metabolismo , Apoptose , Caspase 3/metabolismo , Feminino , Humanos , Sistema de Sinalização das MAP Quinases , Células MCF-7 , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Serina/metabolismo
9.
Int J Clin Exp Pathol ; 8(5): 5535-41, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26191261

RESUMO

In our previous work, apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase (MAPK) kinase family has been proved to be associated with the pro-apoptosis effect of tight junction protein claudin-6 in breast cancer. However, its expression in cervical carcinoma has not been reported. The ASK1 and claudin-6 expression in cervical carcinoma tissues and adjacent non-neoplastic tissues was examined by immunohistochemistry. The mRNA and protein expression of ASK1 and claudin-6 in cervical cancer carcinoma cells was detected by reverse transcription (RT)-PCR and western blot. The expression level of ASK1 was down-regulated in cervical carcinoma tissues compared with the adjacent non-neoplastic tissues and positively correlated with the level of claudin-6 in cervical carcinoma cells and tissues. Our present study reveals that ASK1 protein expression altered between human cervical carcinoma and adjacent non-neoplastic tissues. The expression of ASK1 is correlated with the level of claudin-6 in cervical carcinoma cells and tissues.


Assuntos
Adenocarcinoma/enzimologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/enzimologia , Claudinas/análise , MAP Quinase Quinase Quinase 5/metabolismo , RNA Mensageiro/metabolismo , Neoplasias do Colo do Útero/enzimologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Western Blotting , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Claudinas/genética , Regulação para Baixo , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Imuno-Histoquímica , MAP Quinase Quinase Quinase 5/genética , Pessoa de Meia-Idade , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
10.
Med Oncol ; 32(5): 148, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25822939

RESUMO

Claudin-6, a member of claudin family integral membrane proteins, has recently been reported to be a tumor suppressor for breast cancer. However, whether it plays a role in other types of cancer remains unclear. In the present study, we showed that the expression of claudin-6 is down-regulated in cervical carcinoma tissues as revealed by immunohistochemistry. Through over-expressing claudin-6 in HeLa and C33A cervical carcinoma cells, we found that claudin-6 is localized at plasma membrane and it increases transepithelial electrical resistance of the cells. Gain of claudin-6 expression suppresses cell proliferation, colony formation in vitro, and tumor growth in vivo. The effects are accompanied and potentially caused by promotion of tumor cell apoptosis. Taken together, these results suggest that claudin-6 may function as a tumor suppressor and loss of claudin-6 contributes to enhanced tumorigenic properties of cervical carcinoma cells.


Assuntos
Apoptose/genética , Carcinoma/genética , Proliferação de Células/genética , Claudinas/genética , Junções Íntimas/genética , Neoplasias do Colo do Útero/genética , Carcinoma/patologia , Linhagem Celular Tumoral , Regulação para Baixo/genética , Feminino , Células HeLa , Humanos , Neoplasias do Colo do Útero/patologia
11.
Mol Cell Biochem ; 388(1-2): 113-21, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24293287

RESUMO

To research the effects of silencing transcription factor SNAI1 on the in vitro biological phenotypes of breast cancer cell line MCF-7, based on the gene sequence of SNAI1, we linked shRNA with the green fluorescent protein-expressing eukaryotic expression vector pGCsilencer™ U6/Neo/GFP, and transfected it into MCF-7 cells. The SNAI1 gene-silencing effect was authenticated by RT-PCR and immunofluorescence. We then examined the effect of gene silencing on the expression of epithelial and mesenchymal markers and on their biological phenotypes of the target cells. Finally, we explained that SNAI1 was bound to E-cadherin in MCF-7 cells by ChIP. Silencing SNAI1 upregulated the expression of epithelial markers claudin-4, claudin-7, and E-cadherin, while expression of the mesenchymal marker matrix metalloproteinase-2 was downregulated. The capacity for proliferation, migration, and invasion was diminished. SNAI1 binds to the E-cadherin gene promoter and inhibits its transcription. We can conclude that silencing gene SNAI1 inhibits expression of properties that are associated with the malignant phenotype of MCF-7 cells and reverses the epithelial-mesenchymal transition process by regulating relevant target gene E-cadherin.


Assuntos
Neoplasias da Mama/genética , Caderinas/genética , Transição Epitelial-Mesenquimal/genética , Invasividade Neoplásica/genética , Fatores de Transcrição/genética , Células 3T3 , Animais , Biomarcadores Tumorais/genética , Neoplasias da Mama/classificação , Caderinas/biossíntese , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Claudina-4/biossíntese , Claudinas/biossíntese , Feminino , Proteínas de Fluorescência Verde/genética , Humanos , Células MCF-7 , Metaloproteinase 2 da Matriz/biossíntese , Camundongos , Fenótipo , Regiões Promotoras Genéticas , Interferência de RNA , RNA Interferente Pequeno , Fatores de Transcrição da Família Snail
12.
Diagn Pathol ; 8: 190, 2013 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-24245968

RESUMO

BACKGROUND: Tight junctions (TJs) are mainly composed of claudins, occludin, and tight junction adhesion molecules (JAM). The invasive and metastatic phenotype of highly invasive cancer cells has been related to abnormal structure and function of TJs, and with expression of activated matrix metalloproteinases (MMPs). The relevance of these mechanisms responsible for the invasion and metastasis of ovarian carcinoma is unclear. Similarly, it is not known if the expression of claudin-6, occludin and MMP2 is related with the clinical properties of these tumors. METHODS: Expression of claudin-6, occludin, and MMP2 was detected in samples of human ovarian cancer tissues by immunohistochemistry and correlated with the clinical properties of the tumors. RESULTS: The positive expression rates of claudin-6 and MMP-2 were higher in ovarian papillary serous carcinomas than n ovarian serous adenomas (P < 0.05). There were no differences in the expression of occludin (P > 0.05). The expression of claudin-6 and occludin in ovarian cancer was not correlated with patient age, pathological grade, clinical stage, and metastasis (P > 0.05). MMP-2 expression was enhanced with increased clinical stage and metastasis (P < 0.05), but was unrelated to patient age or tumor grade (P > 0.05). There were no apparent correlations between expression of claudin-6, occludin and MMP-2 in ovarian cancer tissue (P > 0.05). CONCLUSIONS: Our data suggest, for the first time, that the claudin-6 and MMP-2 are up-regulated in ovarian papillary serous carcinomas, MMP-2 expression was enhanced with increased clinical stage and metastasis. Claudin-6 and MMP-2 may play a positive role in the invasion and metastasis of ovarian cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1775628454106511.


Assuntos
Biomarcadores Tumorais/metabolismo , Claudinas/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Metaloproteinase 2 da Matriz/metabolismo , Ocludina/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Adenoma/metabolismo , Adenoma/patologia , Adenoma/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Papilar/metabolismo , Carcinoma Papilar/patologia , Carcinoma Papilar/fisiopatologia , Claudinas/genética , Progressão da Doença , Feminino , Humanos , Metaloproteinase 2 da Matriz/genética , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Estadiamento de Neoplasias , Ocludina/genética , Neoplasias Ovarianas/fisiopatologia , Estudos Retrospectivos , Junções Íntimas/patologia , Regulação para Cima/fisiologia , Adulto Jovem
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