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1.
Cell Prolif ; 54(8): e13088, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34240781

RESUMO

OBJECTIVES: Breast cancer-amplified sequence 3 (BCAS3) was initially found to be amplified in human breast cancer (BRCA); however, there has been little consensus on the functions of BCAS3 in breast tumours. MATERIALS AND METHODS: We analysed BCAS3 expression in BRCA using bio-information tools. Affinity purification and mass spectrometry were employed to identify BCAS3-associated proteins. GST pull-down and ubiquitination assays were performed to analyse the interaction mechanism between BCAS3/p53 and CUL4A-RING E3 ubiquitin ligase (CRL4A) complex. BCAS3 was knocked down individually or in combination with p53 in MCF-7 cells to further explore the biological functions of the BCAS3/p53 axis. The clinical values of BCAS3 for BRCA progression were evaluated via semiquantitative immunohistochemistry (IHC) analysis and Cox regression. RESULTS: We reported that the expression level of BCAS3 in BRCA was higher than that in adjacent normal tissues. High BCAS3 expression promoted growth, inhibited apoptosis and conferred chemoresistance in breast cancer cells. Mechanistically, BCAS3 overexpression fostered BRCA cell growth by interacting with the CRL4A complex and promoting ubiquitination and proteasomal degradation of p53. Furthermore, BCAS3 could regulate cell growth, apoptosis and chemoresistance through a p53-mediated mechanism. Clinically, BCAS3 overexpression was significantly correlated with a malignant phenotype. Moreover, higher expression of BCAS3 correlates with shorter overall survival (OS) in BRCA. CONCLUSIONS: The functional characterization of BCAS3 offers new insights into the oncogenic properties and chemotherapy resistance in breast cancer.


Assuntos
Neoplasias da Mama/patologia , Proteínas de Neoplasias/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células , Proteínas Culina/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Prognóstico , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Taxa de Sobrevida , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
2.
Cell Death Differ ; 28(9): 2818-2836, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33953349

RESUMO

The biological function of PRMT5 remains poorly understood in cervical cancer metastasis. Here, we report that PRMT5 physically associates with the transcription factor Snail and the NuRD(MTA1) complex to form a transcriptional-repressive complex that catalyzes the symmetrical histone dimethylation and deacetylation. This study shows that the Snail/PRMT5/NuRD(MTA1) complex targets genes, such as TET1 and E-cadherin, which are critical for epithelial-mesenchymal transition (EMT). This complex also affects the conversion of 5mC to 5hmC. This study demonstrates that the Snail/PRMT5/NuRD(MTA1) complex promotes the invasion and metastasis of cervical cancer in vitro and in vivo. This study also shows that PRMT5 expression is upregulated in cervical cancer and various human cancers, and the PRMT5 inhibitor EPZ015666 suppresses EMT and the invasion potential of cervical cancer cells by disinhibiting the expression of TET1 and increasing 5hmC, suggesting that PRMT5 is a potential target for cancer therapy.

3.
Theranostics ; 11(5): 2058-2076, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33500709

RESUMO

Histone deacetylases (HDACs) are involved in key cellular processes and have been implicated in cancer. As such, compounds that target HDACs or drugs that target epigenetic markers may be potential candidates for cancer therapy. This study was therefore aimed to identify a potential epidrug with low toxicity and high efficiency as anti-tumor agents. Methods: We first screened an epigenetic small molecule inhibitor library to screen for an epidrug for breast cancer. The candidate was identified as PCI-24781 and was characterized for half maximal inhibitory concentration (IC50), for specificity to breast cancer cells, and for effects on carcinogenesis and metastatic properties of breast cancer cell lines in vitro. A series of in silico and in vitro analyses were further performed of PCI-24781 to identify and understand its target. Results: Screening of an epigenetic inhibitor library in MDA-MB-231 cells, a malignant cancer cell line, showed that PCI-24781 is a potential anti-tumor drug specific to breast cancer. Ca2+ related pathways were identified as a potential target of PCI-24781. Further analyses showed that PCI-24781 inhibited Gαq-PLCß3-mediated calcium signaling by activating the expression of regulator of G-protein signaling 2 (RGS2) to reduce cell proliferation, metastasis, and differentiation, resulting in cell death in breast cancer. In addition, RGS2 depletion reversed anti-tumor effect and inhibition of calcium influx induced by PCI-24781 treatment in breast cancer cells. Conclusions: We have demonstrated that PCI-24781 is an effective anti-tumor therapeutic agent that targets calcium signaling by activating RGS2. This study also provides a novel perspective into the use of HDAC inhibitors for cancer therapy.


Assuntos
Benzofuranos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Cálcio/metabolismo , Proliferação de Células , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Animais , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Aging (Albany NY) ; 13(2): 2519-2538, 2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33318294

RESUMO

Breast cancer is one of the leading causes of cancer-associated mortality in women worldwide and has become a major public health problem. Although the definitive cause of breast cancer is not known, many genes sensitive to breast cancer have been detected using advanced technologies. Our study identified 3301 differentially expressed lncRNAs and mRNAs between tumor and normal samples from The Cancer Genome Atlas database. Based on the gene expression analysis and clinical traits as well as weighted gene co-expression network analysis, the co-expression Brown module was found to be key for breast cancer prognosis. A total of 453 genes in the Brown module were used for functional enrichment, protein-protein interaction analysis, lncRNA-miRNA-mRNA ceRNA network, and lncRNA-RNA binding protein-mRNA network construction. GRM4, SSTR2, PARD6B, PRR15, COX6C, and lncRNA DSCAM-AS1 were the hub genes according to protein-protein interaction, lncRNA-miRNA-mRNA and lncRNA-RNA binding protein-mRNA network. Their high expression was found to be correlated with breast cancer development, according to multiple databases. In conclusion, this study provides a framework of the co-expression gene modules of breast cancer and identifies several important biomarkers in breast cancer development and prognosis.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Prognóstico , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Taxa de Sobrevida
5.
Sci Adv ; 6(16): eaaz0356, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32494608

RESUMO

TUDOR domain-containing proteins (TDRDs) are chiefly responsible for recognizing methyl-lysine/arginine residue. However, how TDRD dysregulation contributes to breast tumorigenesis is poorly understood. Here, we report that TUDOR domain-containing PHF20L1 as a H3K27me2 reader exerts transcriptional repression by recruiting polycomb repressive complex 2 (PRC2) and Mi-2/nucleosome remodeling and deacetylase (NuRD) complex, linking PRC2-mediated methylation and NuRD-mediated deacetylation of H3K27. Furthermore, PHF20L1 was found to serve as a potential MYC and hypoxia-driven oncogene, promoting glycolysis, proliferation, and metastasis of breast cancer cells by directly inhibiting tumor suppressors such as HIC1, KISS1, and BRCA1. PHF20L1 expression was also strongly correlated with higher histologic grades of breast cancer and markedly up-regulated in several cancers. Meanwhile, Phf20l1 deletion not only induces growth retardation and mammary ductal outgrowth delay but also inhibits tumorigenesis in vivo. Our data indicate that PHF20L1 promotes tumorigenesis, supporting the pursuit of PHF20L1 as a target for cancer therapy.

6.
Cancer Cell Int ; 20: 264, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32581654

RESUMO

Background: Stomach adenocarcinoma (STAD) is the fifth most prevalent cancer in the world and ranks third among cancer-related deaths worldwide. The tumour microenvironment (TME) plays an important role in tumorigenesis, development, and metastasis. Hence, we calculated the immune and stromal scores to find the potential prognosis-related genes in STAD using bioinformatics analysis. Methods: The ESTIMATE algorithm was used to calculate the immune/stromal scores of the STAD samples. Functional enrichment analysis, protein-protein interaction (PPI) network analysis, and overall survival analysis were then performed on differential genes. And we validated these genes using data from the Gene Expression Omnibus database. Finally, we used the Human Protein Atlas (HPA) databases to verify these genes at the protein levels by IHC. Results: Data analysis revealed correlation between stromal/immune scores and the TNM staging system. The top 10 core genes extracted from the PPI network, and primarily involved in immune responses, extracellular matrix, and cell adhesion. There are 31 genes have been validated with poor prognosis and 16 genes were upregulated in tumour tissues compared with normal tissues at the protein level. Conclusions: In summary, we identified genes associated with the tumour microenvironment with prognostic implications in STAD, which may become potential therapeutic markers leading to better clinical outcomes.

7.
Cell Death Dis ; 10(11): 832, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31685800

RESUMO

GATA3 has emerged as a prominent transcription factor required for maintaining mammary-gland homeostasis. GATA3 loss is associated with aggressive breast cancer development, but the mechanism by which breast cancer is affected by the loss of GATA3 function remains unclear. Here, we report that GATA3 expression is positively correlated with the expression of UTX, a histone H3K27 demethylase contained in the MLL4 methyltransferase complex, and that GATA3 recruits the chromatin-remodeling MLL4 complex and interacts directly with UTX, ASH2L, and RBBP5. Using RNA sequencing and chromatin immunoprecipitation and sequencing, we demonstrate that the GATA3/UTX complex synergistically regulates a cohort of genes including Dicer and UTX, which are critically involved in the epithelial-to-mesenchymal transition (EMT). Our results further show that the GATA3-UTX-Dicer axis inhibits EMT, invasion, and metastasis of breast cancer cells in vitro and the dissemination of breast cancer in vivo. Our study implicates the GATA3-UTX-Dicer axis in breast cancer metastasis and provides new mechanistic insights into the pathophysiological function of GATA3.


Assuntos
Neoplasias da Mama/metabolismo , Fator de Transcrição GATA3/metabolismo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/biossíntese , Proteínas de Neoplasias/metabolismo , Ativação Transcricional , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Fator de Transcrição GATA3/genética , Histona Desmetilases/genética , Humanos , Células MCF-7 , Metástase Neoplásica , Proteínas de Neoplasias/genética
8.
J Biol Chem ; 294(43): 15808-15825, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31492753

RESUMO

GATA3 is a basic and essential transcription factor that regulates many pathophysiological processes and is required for the development of mammary luminal epithelial cells. Loss-of-function GATA3 alterations in breast cancer are associated with poor prognosis. Here, we sought to understand the tumor-suppressive functions GATA3 normally performs. We discovered a role for GATA3 in suppressing epithelial-to-mesenchymal transition (EMT) in breast cancer by activating miR-455-3p expression. Enforced expression of miR-455-3p alone partially prevented EMT induced by transforming growth factor ß (TGF-ß) both in cells and tumor xenografts by directly inhibiting key components of TGF-ß signaling. Pathway and biochemical analyses showed that one miRNA-455-3p target, the TGF-ß-induced protein ZEB1, recruits the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex to the promotor region of miR-455 to strictly repress the GATA3-induced transcription of this microRNA. Considering that ZEB1 enhances TGF-ß signaling, we delineated a double-feedback interaction between ZEB1 and miR-455-3p, in addition to the repressive effect of miR-455-3p on TGF-ß signaling. Our study revealed that a feedback loop between these two axes, specifically GATA3-induced miR-455-3p expression, could repress ZEB1 and its recruitment of NuRD (MTA1) to suppress miR-455, which ultimately regulates TGF-ß signaling. In conclusion, we identified that miR-455-3p plays a pivotal role in inhibiting the EMT and TGF-ß signaling pathway and maintaining cell differentiation. This forms the basis of that miR-455-3p might be a promising therapeutic intervention for breast cancer.


Assuntos
Células Epiteliais/metabolismo , Fator de Transcrição GATA3/metabolismo , MicroRNAs/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Animais , Sequência de Bases , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Camundongos SCID , MicroRNAs/genética , Metástase Neoplásica , Proteínas de Neoplasias/metabolismo , Transcrição Genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
9.
Int J Oncol ; 54(5): 1747-1758, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30816447

RESUMO

Ehm2 [also known as erythrocyte membrane protein band 4.1­like protein 4B (EPB41L4B)] is a member of the NF2/ERM/4.1 superfamily. The overexpression of Ehm2 has been observed in metastatic cancer cells. Through alternative splicing, the Ehm2 gene produces two transcript variants that encode the two different isoforms, Ehm2/1 and Ehm2/2. The biological functions of these different Ehm2 transcript variants remain unclear. The present study aimed to determine the expression of the Ehm2 variants in lung adenocarcinoma and their involvement in the disease progression of the patients. The expression of Ehm2 transcript variants in human lung adenocarcinoma tissues was analyzed using immunohistochemistry and western blot analysis. Ehm2 variants were overexpressed or knocked down in A549 human lung adenocarcinoma cells. The consequent effects of the genetic modifications on the cellular functions of lung cancer cells were then examined using in vitro cell viability, invasion and migration assays. The expression of epithelial­mesenchymal transition (EMT)­related markers was evaluated by western blot analysis in the cell models. The association of Ehm2 variant expression with patient survival was analyzed using Kaplan­Meier survival analysis. The expression of Ehm2/1 was significantly decreased in lung cancers compared with the paired normal lung tissues (P<0.05), while the Ehm2/2 protein levels were higher in the tumors than in the paired normal lung tissues, although this was not statistically significant. The overexpression of Ehm2/1 exerted inhibitory effects, while the knockdown of Ehm2/1 promoted the growth, invasion and migration of A549 cells in vitro. Ehm2/2 was expressed at low levels in the A549 cells and the enforced expression of Ehm2/2 significantly increased the invasiveness and migration of the A549 cells. Immunofluorescence staining revealed that Ehm2/1 was confined to the plasma membrane, while Ehm2/2 was observed at both the plasma membrane and cytoplasm. The overexpression of Ehm2/1 resulted in the upregulation of the epithelial marker, E­cadherin, and in the decreased expression of the mesenchymal markers, N­cadherin and Snail1, while the knockdown of Ehm2/1 and the enforced expression of Ehm2/2 had the opposite effects on the protein levels of EMT­related markers. Kaplan­Meier survival analysis revealed that higher Ehm2/1 transcript levels were associated with the longer survival of patients with lung adenocarcinoma, while the lower expression of Ehm2/2 exhibited a similar association with patient survival. Taken together, the two Ehm2 variants appear to be differentially expressed in lung adenocarcinoma. Ehm2/1 may function as a putative tumor suppressor in the disease progression of lung adenocarcinoma, while Ehm2/2 may have an opposite function.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Regulação para Baixo , Neoplasias Pulmonares/metabolismo , Células A549 , Adenocarcinoma de Pulmão/genética , Adulto , Processamento Alternativo , Movimento Celular , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida
10.
Int J Oncol ; 54(1): 381-389, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30431081

RESUMO

Downstream of tyrosine kinase 7 transcript variant 1 (DOK7V1) is a docking protein mediating signal transduction between receptors and intracellular downstream molecules. Our previous study indicated that DOK7V1 was decreased in lung cancer and its lower expression was associated with a decreased survival rate. The 5­year overall survival rate for patients with lung cancer was 20.2 and 18.6% for high and low DOK7 expression, respectively; the 5­year disease­free survival rate for patients with lung cancer was 14.3 and 16.9% for high and low DOK7 expression, respectively. DOK7V1 inhibited proliferation and migration, but enhanced adhesion, of lung cancer cells. In the present study, the effect of DOK7V1 and its domains [pleckstrin homology (PH) and phosphotyrosine­binding (PTB) domain] on the malignant phenotype and associated signaling pathway in lung cancer cells was investigated. The results indicated that truncation of DOK7V1 domains (DOK7V1Δ­PH and DOK7V1Δ­PTB) inhibited the proliferation and migration of lung cancer cells which exhibited the same trend as DOK7V1, whereas DOK7V1Δ­PH and DOK7V1Δ­PTB exhibited different functions from those of DOK7V1 in cell matrix adhesion. Consistently, DOK7V1 overexpression in lung cancer cells suppressed the phosphoinositide 3­kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathways, but activated the focal adhesion kinase (FAK)/paxillin signaling pathway. Taken together, these results indicate that DOK7V1 may inhibit proliferation and migration via negatively regulating the PI3K/AKT/mTOR signaling pathway, and increase adhesion by upregulating the FAK/paxillin signaling pathway in lung cancer cells.


Assuntos
Processamento Alternativo , Regulação para Baixo , Neoplasias Pulmonares/genética , Proteínas Musculares/genética , Transdução de Sinais , Células A549 , Linhagem Celular Tumoral , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Proteínas Musculares/metabolismo , Paxilina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Análise de Sobrevida
11.
J Am Heart Assoc ; 7(21): e009167, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30571388

RESUMO

Background Vascular development, including vasculogenesis and angiogenesis, is involved in many diseases. Cystatin C ( CST 3) is a commonly used marker of renal dysfunction, and we have previously reported that its expression level is associated with variations in the gerbil circle of Willis. Thus, we hypothesized that CST 3 may affect endothelial function and angiogenic capacity. In the current study, we sought to determine the influence of CST 3 on endothelial function and explore its potential regulatory pathway. Methods and Results We analyzed CST 3 and vascular endothelial growth factor A ( VEGFA) levels in different developmental stages of gerbils using ELISA s and immunofluorescence (to examine the relationship between CST 3 and VEGFA . We used a real-time cell analyzer, cytotoxicity assays, and the chorioallantoic membrane assay to investigate the function of CST 3 in endothelial cells and the chorioallantoic membrane. Additionally, we used Western blotting to explore the downstream targets of CST 3. The expression levels of both CST 3 and VEGFA were at their highest on day 10 of the embryonic stage. CST 3 inhibited endothelial cell proliferation, migration, tube formation, and permeability, as well as vascular development in the chorioallantoic membrane. Blocking of VEGFA dose-dependently increased CST 3 expression in arterial and venous endothelial cells. Furthermore, overexpression and knockdown of CST 3 significantly affected the protein levels of p53 and CAPN10 (calpain 10), suggesting that CST 3 might play a role in vascular development through these proteins. Conclusions CST 3 may be associated with vascular development and angiogenesis, and this effect could be promoted by blocking VEGFA .


Assuntos
Membrana Corioalantoide/irrigação sanguínea , Cistatina C/biossíntese , Células Endoteliais/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Animais , Movimento Celular , Proliferação de Células , Gerbillinae , Neovascularização Patológica , Neovascularização Fisiológica
12.
Proc Natl Acad Sci U S A ; 115(22): E4980-E4989, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29760061

RESUMO

Glycosylation is a prominent strategy to optimize the pharmacokinetic and pharmacodynamic properties of drug-like small-molecule scaffolds by modulating their solubility, stability, bioavailability, and bioactivity. Glycosyltransferases applicable for "sugarcoating" various small-molecule acceptors have been isolated and characterized from plants and bacteria, but remained cryptic from filamentous fungi until recently, despite the frequent use of some fungi for whole-cell biocatalytic glycosylations. Here, we use bioinformatic and genomic tools combined with heterologous expression to identify a glycosyltransferase-methyltransferase (GT-MT) gene pair that encodes a methylglucosylation functional module in the ascomycetous fungus Beauveria bassiana The GT is the founding member of a family nonorthologous to characterized fungal enzymes. Using combinatorial biosynthetic and biocatalytic platforms, we reveal that this GT is a promiscuous enzyme that efficiently modifies a broad range of drug-like substrates, including polyketides, anthraquinones, flavonoids, and naphthalenes. It yields both O- and N-glucosides with remarkable regio- and stereospecificity, a spectrum not demonstrated for other characterized fungal enzymes. These glucosides are faithfully processed by the dedicated MT to afford 4-O-methylglucosides. The resulting "unnatural products" show increased solubility, while representative polyketide methylglucosides also display increased stability against glycoside hydrolysis. Upon methylglucosidation, specific polyketides were found to attain cancer cell line-specific antiproliferative or matrix attachment inhibitory activities. These findings will guide genome mining for fungal GTs with novel substrate and product specificities, and empower the efficient combinatorial biosynthesis of a broad range of natural and unnatural glycosides in total biosynthetic or biocatalytic formats.


Assuntos
Antineoplásicos , Descoberta de Drogas , Fungos , Glicosiltransferases , Metiltransferases , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Fungos/enzimologia , Fungos/genética , Fungos/metabolismo , Glicosilação , Glicosiltransferases/química , Glicosiltransferases/genética , Glicosiltransferases/metabolismo , Humanos , Metiltransferases/química , Metiltransferases/genética , Metiltransferases/metabolismo , Policetídeo Sintases/química , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo , Policetídeos/metabolismo , Células Vero
13.
Sci Rep ; 7(1): 5599, 2017 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-28717191

RESUMO

Neddylation is a post-translational protein modification associated with cancer development. MLN4924 is a neddylation inhibitor currently under investigation in multiple phase I studies on various malignancies, and its clincal name is Pevonedistat. It has been documented that MLN4924 blocks Cullins neddylation and inactivates CRLs and, in turn, triggers cell-cycle arrest, apoptosis, senescence and autophagy in many cancer cells. In this study, we investigated the anti-tumor effect of MLN4924 in human clear cell renal carcinoma (ccRCC). Levels of both Nedd8 activating enzyme E1 and Nedd8-conjugating enzyme E2 were higher in ccRCC tissues and RCC cancer cells than in normal. Moreover, MLN4924 treatment led to rapid inhibition of Cullin1 neddylation and notably suppressed growth and survival as well as migration in a dose-and time-dependent manner. Mechanistic studies revealed that MLN4924 induced the accumulation of a number of CRL substrates, including p21, p27 and Wee1 to trigger DNA damage and induce growth arrest at the G2/M phase. MLN4924 also induced anti-migration and anti-invasion by activating E-cadherin and repressing Vimentin. Taken together, this study provides the first evidence that neddylation pathway is overactive in ccRCC and that MLN4924 induces dose-dependent anti-proliferation, anti-migration, anti-invasion in ccRCC cells. The study thus indicates that MLN4924 has potential therapeutic value for the clinical treatment of renal cancer.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclopentanos/farmacologia , Neoplasias Renais/tratamento farmacológico , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Pirimidinas/farmacologia , Ubiquitinas/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Autofagia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Proteína NEDD8/química , Proteína NEDD8/metabolismo , Proteólise , Células Tumorais Cultivadas , Ubiquitinas/metabolismo
14.
Oncotarget ; 8(16): 26231-26244, 2017 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-28412738

RESUMO

Aberrant expression of nephroblastoma overexpressed (NOV) has been evident in certain malignancies. In the current study, we aim to investigate the role played by NOV in colorectal cancer (CRC). NOV expression was determined in a cohort of 359 CRC tissues and 174 normal colorectal tissues. Its impact on CRC cells was investigated using in vitro NOV knockdown and overexpression models. NOV transcripts were reduced in the CRC tumours compared with the paired adjacent normal colorectal tissues (p < 0.01) and was associated with distant metastases. NOV knockdown resulted in increased cell proliferation and invasion of RKO cells, whilst an opposite effect was seen in the HT115 NOV over expressing cells. A positive association between Caspase-3/-8 and NOV was seen in NOV knockdown and overexpression cell lines which contributed to the survival of serum deprived CRC cells. Further investigation showed that NOV regulated proliferation, survival and invasion through the JNK pathway. NOV knockdown in RKO cells reduced the responsiveness to 5-Fluorouracil treatment, whilst overexpression in HT115 cells exhibited a contrasting effect. Taken together, NOV is reduced in CRC tumours and this is associated with disease progression. NOV inhibits the proliferation and invasion of CRC cells in vitro. Inhibition of proliferation is mediated by a regulation of Caspase-3/-8, via the JNK pathway, which has potential for predicting and preventing chemoresistance.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Proteína Sobre-Expressa em Nefroblastoma/genética , Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Progressão da Doença , Humanos , Sistema de Sinalização das MAP Quinases , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico
15.
Oncol Rep ; 37(5): 2695-2701, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28393246

RESUMO

The downstream of tyrosine kinase 7 (DOK7) is an adaptor protein mediating signalling transduction between receptors and intracellular downstream molecules. Reduced expression of DOK7 has been observed in breast cancer. The present study aimed to investigate the role played by DOK7 in lung cancer. The expression of DOK7 at both mRNA and protein levels was evaluated in human lung cancer. A reduced expression of DOK7 transcripts was seen in lung cancers compared with normal lung tissues. Kaplan-Meier analyses showed that the reduced expression of DOK7 was associated with poorer overall survival and progression-free survival of patients with lung cancer. A further western blot analysis revealed a predominant expression of DOK7 isoform 1 (DOK7V1) in normal lung tissues, which was reduced in lung cancer. Forced overexpression of DOK7V1 in lung cancer cell lines, A549 and H3122 resulted in a decrease of in vitro cell proliferation and migration, while adhesion to extracellular matrix was enhanced following the expression. In conclusion, DOK7 was reduced in lung cancer and reduced DOK7 expression was associated with poorer survival. DOK7 isoform 1 plays an inhibitory role on the proliferation and migration of lung cancer cells in which Akt pathway may be involved.


Assuntos
Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Proteínas Musculares/metabolismo , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Musculares/genética , Fosforilação , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
16.
Oncotarget ; 8(5): 7753-7765, 2017 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-27999191

RESUMO

The oncogenic role of ectopic expression of Na+/H+ exchanger regulatory factor 1 (NHERF1) was recently suggested in colorectal cancer, where it was implicated in playing a role in the tumor hypoxia microenvironment. Here we showed that a high level expression of NHERF1 was found in colorectal cancer tissues and that the expression of NHERF1 was positively correlated with VEGFR2 expression. The prognostic value of VEGFR2 expression in colorectal cancer relied on the expression of NHERF1. The up-regulation of NHERF1 induced by the exposure to hypoxia in colon cancer cells depended on the activation of VEGFR2 signaling. NHERF1 in turn inhibited the activation of VEGFR2 signaling which could be regulated by the interaction between NHERF1 and VEGFR2, resulting in the reduction of migration and invasion of colon cancer cells. These results suggest a dynamic interplay between NHERF1 and VEGFR2 signaling in colorectal cancer, which could explain the contribution of NHERF1 to the regulation of tumor cell responses to the hypoxia microenvironment.


Assuntos
Movimento Celular , Neoplasias Colorretais/metabolismo , Fosfoproteínas/metabolismo , Transdução de Sinais , Trocadores de Sódio-Hidrogênio/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Retroalimentação Fisiológica , Humanos , Invasividade Neoplásica , Fosfolipase C gama/metabolismo , Fosfoproteínas/genética , Proteínas Proto-Oncogênicas c-akt , Trocadores de Sódio-Hidrogênio/genética , Fatores de Tempo , Hipóxia Tumoral , Microambiente Tumoral
17.
Oncol Rep ; 36(1): 3-9, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27121546

RESUMO

The junctional adhesion molecule B (JAM-B) is a multifunctional transmembrane protein, which belongs to the immunoglobulin superfamily (IgSF). JAM-B is localized to cell-cell contacts and enriched at cell junctions in epithelial and endothelial cells, as well as on the surface of erythrocytes, leukocytes, and platelets. Recent research in this field has shown that JAM-B plays an important role in numerous cellular processes, such as tight junction assembly, spermatogenesis, regulation of paracellular permeability, leukocytic transmigration, angiogenesis, tumor metastasis and cell proliferation. This study provides a new research direction for the diagnosis and treatment of relevant diseases. In this review, we briefly focus on what is currently known about the structure, function, and mechanism of JAM-B, with particular emphasis on cancer.


Assuntos
Moléculas de Adesão Celular/metabolismo , Junções Intercelulares/metabolismo , Molécula B de Adesão Juncional/metabolismo , Neoplasias/patologia , Junções Íntimas/metabolismo , Células Endoteliais/metabolismo , Células Epiteliais/metabolismo , Humanos , Estrutura Terciária de Proteína , Transdução de Sinais
18.
Anticancer Res ; 36(3): 1237-41, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26977020

RESUMO

BACKGROUND: The mitochondrial protein translocase of inner mitochondrial membrane 17 homolog A (TIMM17A) has been identified as a biomarker of breast cancer. The present study aimed to investigate the biological role of TIMM17A in human breast cancer cells. MATERIALS AND METHODS: Anti-TIMM17A transgenes were stably transfected into MDA MB-231 and MCF-7 breast cancer cell lines. The impact of TIMM17A knock-down on cell migration and invasion were evaluated using the respective cell models. RESULTS: Reducing the expression of TIMM17A in breast cancer cells resulted in reduction of cell migration using electric cell-substrate impedance sensing. It was also found that reduction of TIMM17A expression resulted in reduction of cell invasion compared to vector control. CONCLUSION: TIMM17A has a profound impact on the cellular function of breast cancer cells. A decrease of TIMM17A expression is associated with the reduction of the aggressiveness of breast cancer cells. TIMM17A, therefore, has potential in prognosis and treatment of breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Movimento Celular , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Proteínas de Transporte da Membrana Mitocondrial/genética , Invasividade Neoplásica , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Transfecção
19.
Anticancer Res ; 36(3): 1267-74, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26977024

RESUMO

BACKGROUND/AIM: The ribosomal S6 protein kinase (RSK) family is an important effector of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) that could influence tumour metastasis by phosphorylating proteins in both the nuclear and cytoplasmic compartments. Aberrant expression of RSK is evident in certain malignancies but the role played by RSK in breast cancer is still not clear. This study aimed to examine the expression of RSK in human breast cancer specimens and its role to breast cancer metastasis. MATERIALS AND METHODS: The expression of RSK1 to -3 were separately examined in human breast cancer tissues (normal, n=33; cancer, n=112) using quantitative real-time polymerase chain reaction (Q-PCR) and immunohistochemistry. Migration and adhesion of breast cancer cells treated with the RSK inhibitor SL0101 were investigated by electric cell impedance sensing (ECIS). The effect on growth and invasion of RSK1-3 was then investigated using in vitro models. RESULTS: The clinical data and immunohistochemistry revealed that expression of RSK1 and RSK3 were less in tumour tissues than normal. mRNA expression of RSK2 was negatively correlated with grade, TNM staging, and survival rate. SL0101 inhibited adhesion of the MCF-7 and MDA-231 breast cancer cell lines. SL0101 suppressed MDA-231 invasion and the alternate RSK inhibitor BRD7389 inhibited the invasion of MCF-7 and MDA-231 cells. CONCLUSION: RSK1 and 3 but not RSK2 are down-regulated in breast tumour and are associated with disease progression. RSK may be a key component in the progression and metastasis of breast cancer.


Assuntos
Neoplasias da Mama/enzimologia , Movimento Celular , Proliferação de Células , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Adesão Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Intervalo Livre de Doença , Impedância Elétrica , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Células MCF-7 , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Transdução de Sinais , Fatores de Tempo
20.
Int J Oncol ; 48(3): 929-36, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26782073

RESUMO

The junctional adhesion molecule (JAMs) family belongs to the immunoglobulin subfamily involved in the formation of tight junctions (TJ) in both endothelial and epithelial cells. Aberrant expression of JAM-2 is associated with cancer progression but little work has been carried out in discovering how this affects changes in cell behaviour. The present study aimed to examine the expression of JAM-2 in human colon cancer specimens and cell lines and its role in the development of colon cancer. JAM-2 expression in human colon cancer specimens (normal, n=75; cancer, n=94) and cell lines was analysed using quantitative real-time PCR and conventional RT-PCR. Colon cancer cells were stably transfected with a mammalian expression vector to overexpress JAM-2-Flag. The effect on growth, adhesion and migration following overexpression of JAM-2 was then investigated using in vitro models. TJ function was assessed using a trans-epithelial resistance assay (TER, with an EVOM voltammeter). JAM-2 was lowly expressed in colon cancer cells such as RKO, HT115. JAM-2 overexpression in RKO cells (RKO-JAM-2) and HT115 cells (HT115-JAM-2) showed retarded adhesion (P<0.05). An in vivo tumour model showed that RKO-JAM-2 had significantly reduced growth (P<0.05), invasion (P<0.05) and migration (P<0.05) as well as in HT115-JAM-2, except on proliferation and migration. Expression of JAM-2 resulted in a significant increase in TER and decrease in permeability of polarized monolayers (P<0.05). Further analysis of JAM-2 transcript levels against clinical aspects demonstrated that the decreasing JAM-2 expression correlated to disease progression, metastasis and poor survival. Taken together, JAM-2 may function as a putative tumour suppressor in the progression and metastasis of colorectal cancer.


Assuntos
Moléculas de Adesão Celular/fisiologia , Neoplasias Colorretais/metabolismo , Genes Supressores de Tumor , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Colo/metabolismo , Neoplasias Colorretais/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Junções Íntimas/metabolismo
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