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1.
DNA Cell Biol ; 38(9): 1013-1021, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31386568

RESUMO

Increasing evidence has indicated that long noncoding RNAs (lncRNAs) could participate in diverse cancers. Among these, lymphoid enhancer-binding factor 1 antisense RNA 1 (LEF1-AS1) was recently identified as an oncogenic lncRNA, but little is known about its function in non-small-cell lung cancer (NSCLC). In the present study, we found that LEF1-AS1 was markedly upregulated in lung cancer tissues and could promote NSCLC cell proliferation and migration in vivo and in vitro. LEF1-AS1 could bind with miR-489 and further negatively regulate miR-489 to promote SRY-related HMG box transcription factor 4 (SOX4) expression. In conclusion, these data suggested that LEF1-AS1 promoted NSCLC tumorigenesis dependent on the miR-489-SOX4 axis and implicated the potential application of LEF1-AS1 for the prognosis and treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Fator 1 de Ligação ao Facilitador Linfoide/genética , RNA Antissenso/genética , RNA Longo não Codificante/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo , Regulação para Cima
2.
J Exp Clin Cancer Res ; 38(1): 304, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296250

RESUMO

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the most difficult subtype of esophageal cancer to treat due to the paucity of effective targeted therapy. ESCC is believed to arise from cancer stem cells (CSCs) that contribute to metastasis and chemoresistance. Despite advances in diagnosis and treatment, the prognosis of ESCC patients remains poor. METHODS: In this study, we applied western blot, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry, RNA-Seq analysis, luciferase reporter assay, Chip-qPCR, bioinformatics analysis, and a series of functional assays to show the potential role of LEF1 in regulating esophageal CSCs. RESULTS: We found that the overexpression of LEF1 was associated with aberrant clinicopathological characteristics and the poor prognosis of ESCC patients. In addition, the elevated expression of LEF1 and OV6 was significantly associated with aberrant clinicopathological features, and poor patient prognosis. Moreover, the overexpression of LEF1 was observed in esophageal CSCs purified by the magnetic sorting of adherent and spheroidal ESCC cells. The increased level of LEF1 in CSCs facilitated the expression of CSC markers, stem cell-like properties, resistance to chemotherapy, and tumorigenicity and increased the percentage of CSCs in ESCC samples. Conversely, the knockdown of LEF1 significantly diminished the self-renewal properties of ESCC. We showed that LEF1 played an important mechanical role in activating the TGF-ß signaling pathway by directly binding to the ID1 gene promoter. A positive association between LEF1 and ID1 expression was also observed in clinical ESCC samples. CONCLUSION: Our results indicate that the overexpression of LEF1 promotes a CSC-like phenotype in and the tumorigenicity of ESCC by activating the TGF-ß signaling pathway. The inhibition of LEF1 might therefore be a novel therapeutic target to inactivate CSCs and inhibit tumor progression.


Assuntos
Transformação Celular Neoplásica/metabolismo , Carcinoma de Células Escamosas do Esôfago/etiologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos de Diferenciação/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Modelos Animais de Doenças , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/terapia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto
3.
PLoS Genet ; 15(5): e1007895, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31116734

RESUMO

XX and XY fetal gonads are initially bipotential, poised between the ovary and testis fate. Multiple lines of evidence suggest that commitment to testis fate requires the repression of genes associated with ovary fate. It was previously shown that loss of CBX2, the subunit of the Polycomb Repressive Complex 1 (PRC1) that binds H3K27me3 and mediates silencing, leads to ovary development in XY mice and humans. While it had been proposed that CBX2 is an activator of the testis-determining gene Sry, we investigated the alternative possibility that CBX2 has a direct role as a repressor of the antagonistic ovary-promoting pathway. To investigate this possibility, we developed a quantitative genome-wide profile of the repressive histone mark H3K27me3 and its active counterpart H3K4me3 in isolated XY and XX gonadal supporting cells before and after sex determination. We show that testis and ovary sex-determining (SD) genes are bivalent before sex determination, providing insight into how the bipotential state of the gonad is established at the epigenetic level. After sex determination, many SD genes of the alternate pathway remain bivalent, possibly contributing to the ability of these cells to transdifferentiate even in adults. The finding that many genes in the Wnt signaling pathway were targeted for H3K27me3-mediated repression in Sertoli cells led us to test whether deletion of Wnt4 could rescue testis development in Cbx2 mutants. We show that Sry expression and testis development were rescued in XY Cbx2-/-;Wnt4-/- mice. Furthermore, we show that CBX2 directly binds the downstream Wnt signaler Lef1, an ovary-promoting gene that remains bivalent in Sertoli cells. Our results suggest that stabilization of the testis fate requires CBX2-mediated repression of bivalent ovary-determining genes, which would otherwise block testis development.


Assuntos
Epigênese Genética , Ovário/metabolismo , Complexo Repressor Polycomb 1/genética , Processos de Determinação Sexual , Testículo/metabolismo , Via de Sinalização Wnt/genética , Animais , Embrião de Mamíferos , Feminino , Fator 9 de Crescimento de Fibroblastos/genética , Fator 9 de Crescimento de Fibroblastos/metabolismo , Proteína Forkhead Box L2/genética , Proteína Forkhead Box L2/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Histonas/genética , Histonas/metabolismo , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/genética , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Masculino , Camundongos , Ovário/citologia , Ovário/crescimento & desenvolvimento , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Complexo Repressor Polycomb 1/deficiência , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Diferenciação Sexual , Testículo/citologia , Testículo/crescimento & desenvolvimento , Proteína Wnt4/genética , Proteína Wnt4/metabolismo
4.
Int J Oncol ; 54(4): 1282-1294, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30968150

RESUMO

Accumulating evidence indicates that microRNAs (miRNAs) have a critical role in cell proliferation and metastasis in hepatocellular carcinoma (HCC). However, the effect of miR­300 on the development and progression of HCC remains unclear. In the present study, it was observed that miRNA (miR)­300 expression was significantly decreased in HCC cell lines compared with normal liver cells. Furthermore, we detected the effects of miR­300 on cell proliferation and apoptosis, cell cycle, migration and invasion by using MTT, colony formation assay, wound healing, Transwell assay and flow cytometry methods, respectively. The results demonstrated that miR­300 overexpression inhibited proliferation, induced apoptosis and G1/S cell cycle arrest, and suppressed migration and invasion in Huh­7 cells, whereas miR­300 silencing promoted the proliferation, migration and invasion of Hep3B cells. Mechanistically, the transcription factor lymphoid enhancer­binding factor 1 (LEF­1), which was verified as a direct target gene of miR­300, promoted cell proliferation, migration and invasion and mediates the effects of miR­300 on HCC cells. In addition, low expression of miR­300 and high expression of LEF­1 in HCC tissues were found to be associated with poor prognosis of patients with HCC. These findings indicate that miR­300 may be a potential prognostic predictor and therapeutic target for patients with HCC.


Assuntos
Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Fator 1 de Ligação ao Facilitador Linfoide/genética , MicroRNAs/metabolismo , Adulto , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Prognóstico , RNA Interferente Pequeno/metabolismo , Análise de Sobrevida , Regulação para Cima
5.
J Immunol ; 202(8): 2296-2306, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30814306

RESUMO

NK cells are innate-like lymphocytes that eliminate virally infected and cancerous cells, but the mechanisms that control NK cell development and cytotoxicity are incompletely understood. We identified roles for sclerostin domain-containing-1 (Sostdc1) in NK cell development and function. Sostdc1-knockout (Sostdc1 -/-) mice display a progressive accumulation of transitional NK cells (tNKs) (CD27+CD11b+) with age, indicating a partial developmental block. The NK cell Ly49 repertoire in Sostdc1 -/- mice is also changed. Lower frequencies of Sostdc1 -/- splenic tNKs express inhibitory Ly49G2 receptors, but higher frequencies express activating Ly49H and Ly49D receptors. However, the frequencies of Ly49I+, G2+, H+, and D+ populations were universally decreased at the most mature (CD27-CD11b+) stage. We hypothesized that the Ly49 repertoire in Sostdc1 -/- mice would correlate with NK killing ability and observed that Sostdc1-/- NK cells are hyporesponsive against MHC class I-deficient cell targets in vitro and in vivo, despite higher CD107a surface levels and similar IFN-γ expression to controls. Consistent with Sostdc1's known role in Wnt signaling regulation, Tcf7 and Lef1 levels were higher in Sostdc1 -/- NK cells. Expression of the NK development gene Id2 was decreased in Sostdc1-/- immature NK and tNK cells, but Eomes and Tbx21 expression was unaffected. Reciprocal bone marrow transplant experiments showed that Sostdc1 regulates NK cell maturation and expression of Ly49 receptors in a cell-extrinsic fashion from both nonhematopoietic and hematopoietic sources. Taken together, these data support a role for Sostdc1 in the regulation of NK cell maturation and cytotoxicity, and identify potential NK cell niches.


Assuntos
Proteínas Morfogenéticas Ósseas/imunologia , Imunidade Celular , Células Matadoras Naturais/imunologia , Via de Sinalização Wnt/imunologia , Animais , Proteínas Morfogenéticas Ósseas/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/imunologia , Proteína 2 Inibidora de Diferenciação/genética , Proteína 2 Inibidora de Diferenciação/imunologia , Células Matadoras Naturais/citologia , Fator 1 de Ligação ao Facilitador Linfoide/genética , Fator 1 de Ligação ao Facilitador Linfoide/imunologia , Camundongos , Camundongos Knockout , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Via de Sinalização Wnt/genética
6.
EMBO J ; 38(9)2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30886049

RESUMO

Mutations in Lef1 occur in human and mouse sebaceous gland (SG) tumors, but their contribution to carcinogenesis remains unclear. Since Gata6 controls lineage identity in SG, we investigated the link between these two transcription factors. Here, we show that Gata6 is a ß-catenin-independent transcriptional target of mutant Lef1. During epidermal development, Gata6 is expressed in a subset of Sox9-positive Lef1-negative hair follicle progenitors that give rise to the upper SG Overexpression of Gata6 by in utero lentiviral injection is sufficient to induce ectopic sebaceous gland elements. In mice overexpressing mutant Lef1, Gata6 ablation increases the total number of skin tumors yet decreases the proportion of SG tumors. The increased tumor burden correlates with impaired DNA mismatch repair and decreased expression of Mlh1 and Msh2 genes, defects frequently observed in human sebaceous neoplasia. Gata6 specifically marks human SG tumors and also defines tumors with elements of sebaceous differentiation, including a subset of basal cell carcinomas. Our findings reveal that Gata6 controls sebaceous gland development and cancer.


Assuntos
Fator de Transcrição GATA6/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/fisiologia , Neoplasias das Glândulas Sebáceas/patologia , Neoplasias Cutâneas/patologia , Células-Tronco/patologia , Animais , Proliferação de Células , Dano ao DNA , Feminino , Folículo Piloso/metabolismo , Folículo Piloso/patologia , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/genética , Masculino , Camundongos , Camundongos Knockout , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Mutação , Neoplasias das Glândulas Sebáceas/genética , Neoplasias das Glândulas Sebáceas/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Células-Tronco/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
7.
Ann Surg Oncol ; 26(5): 1401-1411, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30706227

RESUMO

BACKGROUND: Treatment-resistance genes limiting anticancer therapy have not been well clarified in colorectal cancer (CRC). We explored gene expression profiles to identify biomarkers for predicting treatment resistance to an anticancer drug in CRC. METHODS: Six CRC cell lines were treated with phenylbutyrate (PB). The gene expression profiles were then compared using microarrays (harboring 54,675 genes), and genes associated with PB resistance were identified. Candidate genes were functionally examined in cell lines and clinically validated for treatment resistance in clinical samples. RESULTS: Both DLD1 and HCT15 cells were PB resistant, while HCT116 cells were identified as PB sensitive. On microarray analysis, among the PB resistance-related genes, the expression of the genes ASCL2, LEF1, and TSPAN8 was clearly associated with PB resistance. PB-sensitive cells transfected with one of these three genes exhibited significant (P < 0.001) augmentation of PB resistance; ASCL2 induced expression of both LEF1 and TSPAN8, while neither LEF1 nor TSPAN8 induced ASCL2. RNA interference via ASCL2 knockdown made PB-resistant cells sensitive to PB and inhibited both genes. ASCL2 knockdown also played a critical role in sensitivity to treatment by 5-fluorouracil and radiotherapy in addition to PB. Finally, ASCL2 expression was significantly correlated with histological grade of rectal cancer with preoperative chemoradiation therapy. CONCLUSIONS: ASCL2 was identified as a causative gene involved in therapeutic resistance against anticancer treatments in CRC.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Hepáticas/genética , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Fenilbutiratos/farmacologia , Tetraspaninas/metabolismo , Antineoplásicos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Biomarcadores Tumorais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Fator 1 de Ligação ao Facilitador Linfoide/genética , Prognóstico , Transdução de Sinais , Taxa de Sobrevida , Tetraspaninas/genética , Células Tumorais Cultivadas
8.
Genet Test Mol Biomarkers ; 23(3): 197-203, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30767676

RESUMO

BACKGROUND: Epithelial-mesenchymal transition (EMT) of the medial edge epithelium (MEE) occurs through fusion of the palatal shelves and is a crucial step in palatogenesis. The key genes, however, and the related signaling pathway of EMT are not yet fully understood. Therefore, the aim of this study was to reveal the key genes and the related signaling pathway of EMT during palatal fusion. MATERIALS AND METHODS: C57BL/6J mice at embryonic gestation day 14.5 (E14.5; n = 6) were used to establish the cleft palate model for mRNA-Seq (HiSeq X Ten). The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed for functional annotations of the differentially expressed genes. Quantitative polymerase chain reaction (qPCR) assays were used to validate the RNAseq data. RESULTS: A total of 936 differentially expressed genes, including 558 upregulated and 378 downregulated genes were identified in cases versus controls, respectively. Among these genes, the GO analysis showed that Lymphoid Enhancer-Binding Factor 1 (LEF1) and SMAD Family Member 3 (SMAD3) significantly enriched biological processes, which were EMT related. The KEGG analysis showed that these genes regulated EMT through the Hippo signaling pathway. LEF1 and SMAD3 were downregulated, and the qPCR results corroborated the RNA-seq data. CONCLUSIONS: These results demonstrate that LEF1 and SMAD3 inhibits EMT at the MEE through the Hippo signaling pathway; and that this could contribute to cleft palate formation in embryonic palatal fusion at E 14.5.


Assuntos
Fator 1 de Ligação ao Facilitador Linfoide/genética , Palato/embriologia , Proteína Smad3/genética , Animais , Fissura Palatina/genética , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Perfilação da Expressão Gênica , Fator 1 de Ligação ao Facilitador Linfoide/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Organogênese , Proteínas Serina-Treonina Quinases/fisiologia , RNA Mensageiro/metabolismo , Análise de Sequência de RNA , Transdução de Sinais/genética , Proteína Smad3/fisiologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta3/genética , Regulação para Cima
9.
J Microbiol Biotechnol ; 29(2): 321-329, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30609881

RESUMO

Hair loss, also known as alopecia, is a common dermatological condition of psychosocial significance; development of therapeutic candidates for the treatment of this condition is, hence, important. Silibinin, a secondary metabolite from Silybum marianum, is an effective antioxidant that also prevents various cutaneous problems. In this study, we have investigated the effect of silibinin on hair induction using three-dimensional (3D) cultured, human dermal papilla (DP) spheroids. Silibinin was found to significantly increase viability through AKT serine/threonine kinase (AKT) activation in 3D DP spheroids. This was correlated with an increase in the diameter of the 3D DP spheroids. The activation of the wingless and INT-1 (Wnt)/ß-catenin signaling pathway, which is associated with hair growth induction in the DP, was evaluated using the T cell-specific transcription factor and lymphoid enhancer-binding factor (TCF/LEF) transcription factor reporter assay; results indicated significantly increased luciferase activity. In addition, we were able to demonstrate increased expression of the target genes, WNT5a and LEF1, using quantitative real-time PCR assay. Lastly, significantly elevated expression of signature genes associated with hair induction was demonstrated in the 3D DP spheroids treated with silibinin. These results suggest that silibinin promotes proliferation and hair induction through the AKT and Wnt/ß-catenin signaling pathways in 3D DP spheroids. Silibinin can be a potential candidate to promote hair proliferation.


Assuntos
Antioxidantes/farmacologia , Derme/efeitos dos fármacos , Folículo Piloso/efeitos dos fármacos , Folículo Piloso/crescimento & desenvolvimento , Proteínas Proto-Oncogênicas c-akt/metabolismo , Silibina/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Derme/citologia , Derme/crescimento & desenvolvimento , Derme/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Folículo Piloso/citologia , Folículo Piloso/metabolismo , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/genética , Fosforilação , Esferoides Celulares/citologia , Esferoides Celulares/efeitos dos fármacos , Proteína Wnt-5a/genética
10.
Oral Dis ; 25(1): 164-173, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30270548

RESUMO

OBJECTIVE: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease affecting exocrine glands, thereby causing dry mouth and eyes (sicca). Our objective was to determine the expression of pSS pathogenic biomarker MMP9 and its putative transcription factors ETS1 and LEF1, in labial salivary glands of pSS patients. METHODS: Sicca patients were assigned to three groups based on focus score (FS): non-pSS sicca (i.e., GR1 [FS = 0] and GR2 [0 < FS < 1]) and pSS (i.e., GR3 [FS ≥ 1]). We determined the mRNA and protein expression of MMP9, ETS1, and LEF1 in salivary gland biopsies. Also, ETS1-CD4 and LEF1-CD4 co-expression analyses were performed. RESULTS: The mRNA expression of MMP9, ETS1, and LEF1 was upregulated in GR3 compared to GR1 (p < 0.01). Most GR3 salivary gland areas had moderate to high MMP9, ETS1, and LEF1 protein expression compared to GR1 and GR2. Further, ETS1-CD4 and LEF1-CD4 dual staining demonstrated that both salivary gland epithelial cells and lymphocytic infiltrates had increased levels of ETS1 and LEF1. Moreover, there was a strong correlation between ETS1(+)-CD4(-) and LEF1(+)-CD4(-) cells. CONCLUSION: These results suggest, for the first time, a concerted increase in ETS1 and LEF1 expression in salivary gland epithelial cells of pSS patients that is reflective of the etiopathogenesis of pSS.


Assuntos
Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Proteína Proto-Oncogênica c-ets-1/metabolismo , Glândulas Salivares Menores/metabolismo , Síndrome de Sjogren/metabolismo , Linfócitos T CD4-Positivos , Células Epiteliais , Feminino , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/genética , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Proteína Proto-Oncogênica c-ets-1/genética , Síndrome de Sjogren/genética
11.
IUBMB Life ; 71(2): 223-234, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30452118

RESUMO

Progesterone is often used to protect the endometrium and prevent endometrial cancer. An intensive study on its molecular mechanism in endometrial cancer would contribute to the development of more promising therapies. Relevant lncRNAs and mRNAs expression data in endometrial cancer cell line Ishikawa pretreated and post-treated with progesterone were derived from Gene Expression Omnibus (accession no. GSE29435), and then we analyzed long noncoding RNAs and mRNAs with differential expressions in two different conditions. The Cytoscape software, TargetScan, miRanda, and Human microRNA Disease Database (HMDD) websites were employed. Gene set enrichment analysis (GSEA) was used to determine related Kyoto Encyclopedia of Genes and Genomes pathways alteration in Ishikawa cells treated with progesterone. In addition to bioinformatics analysis, Reverse Transcription-Polymerase Chain Reaction (RT-PCR), Western blot, and dual-luciferase reporter assays were performed. The impact of progesterone on cell propagation and cell cycle was testified by colony formation and flow cytometry analysis. LncRNA nuclear enriched abundant transcript 1 (NEAT1) was the most significantly downregulated lncRNA in endometrial cancer cells treated with progesterone. Lymphoid enhancing factor 1 (LEF1) was positively associated with NEAT1, and eventually hsa_miR-146b-5p was validated to target both LEF1 and NEAT1. Wnt/ß-catenin signaling pathway was identified to involve in endometrial cancer. NEAT1 or LEF1 was overexpressed in endometrial cancer cells while downregulated following post-treatment with progesterone. Conversely, miR-146b-5p was notably decreased in Ishikawa cells while upregulated after treatment with progesterone. Downstream gene c-myc or MMP9 regulated by upstream gene LEF1 in Wnt/ß-catenin signaling pathway was remarkably increased in Ishikawa cells and positively related with NEAT1. Progesterone inhibited cell cycle and viability through regulating NEAT1/miR-146b-5p axis via Wnt/ß-catenin signaling pathway. Progesterone exerted suppressive influence on endometrial cancer progression via regulation of lncRNA NEAT1/miR-146b-5p-mediated Wnt/ß-catenin signaling pathway, which might reveal new strategies for developing more effective therapeutics. © 2018 IUBMB Life, 71(1):223-234, 2019.


Assuntos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Progesterona/farmacologia , RNA Longo não Codificante/genética , Via de Sinalização Wnt/genética , beta Catenina/genética , Sequência de Bases , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Endométrio/patologia , Feminino , Ontologia Genética , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/genética , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , MicroRNAs/metabolismo , Anotação de Sequência Molecular , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Longo não Codificante/metabolismo , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia , beta Catenina/metabolismo
12.
Biofactors ; 45(1): 24-34, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30521071

RESUMO

The effects of radiation are known to be potentiated by N-3 polyunsaturated fatty acids, which modulate several signaling pathways, but the molecular mechanisms through which these fatty acids enhance the anticancer effects of irradiation in colorectal cancer (CRC) treatment remain poorly elucidated. Here, we aimed to ascertain whether the fatty acid docosahexaenoic acid (DHA) exerts a modulating effect on the response elicited by radiation treatment (RT). Two CRC cell lines, Caco-2 and HT-29, were exposed to RT, DHA, or both (DHA + RT) for various times, and then cell viability, proliferation, and clonogenicity were assessed. Moreover, cell cycle, apoptosis, and necrosis were analyzed using flow cytometry, and the involvement of WNT/ß-catenin signaling was investigated by immunofluorescence to determine nuclear ß-catenin, GSK3ß phosphorylation status, and TCF/LEF-activity reporter. DHA and RT applied separately diminished the viability of both HT-29 and Caco-2 cells, and DHA + RT caused a further reduction in proliferation mainly in HT-29 cells, particularly in terms of colony formation. Concomitantly, our results verified cell cycle arrest in G0/G1 phase, a reduction of cyclin D1 expression, and a decrease in GSK3ß phosphorylation after the combined treatment. Furthermore, immunofluorescence quantification revealed that nuclear ß-catenin was increased in RT-exposed cells, but this effect was abrogated in cells exposed to DHA + RT, and the results of TCF/LEF-activity assays confirmed that DHA attenuated the increase in nuclear ß-catenin activity induced by irradiation. Our finding shows that DHA applied in combination with RT enhanced the antitumor effects of irradiation on CRC cells, and that the underlying mechanism involved the WNT/ß-catenin pathway. © 2018 BioFactors, 45(1):24-34, 2019.


Assuntos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/farmacologia , Raios gama , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , beta Catenina/genética , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Células CACO-2 , Pontos de Checagem do Ciclo Celular/genética , Pontos de Checagem do Ciclo Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Ensaio de Unidades Formadoras de Colônias , Ciclina D1/genética , Ciclina D1/metabolismo , Relação Dose-Resposta a Droga , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HT29 , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/genética , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Fosforilação/efeitos dos fármacos , Fosforilação/efeitos da radiação , Fator 1 de Transcrição de Linfócitos T/genética , Fator 1 de Transcrição de Linfócitos T/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo
13.
Pathol Oncol Res ; 25(1): 377-389, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29138985

RESUMO

This study was conducted in order to elucidate the role microRNA-708 (miR-708) plays between proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) involving melanoma cells by targeting using LEF1 through the Wnt signaling pathway. Male Kunming mice were selected and subsequently divided into normal and model groups to take part in this study. Following cell line selection, the B16 cells with the highest miR-708 expression were selected and assigned into the control, blank, negative control (NC), miR-708 mimic, miR-708 inhibitor, siRNA-LEF1, and miR-708 inhibitor + siRNA-LEF1 groups. A Bioinformatics Web service and dual-luciferase reporter assay were conducted in order to determine the relationship between LEF1 and miR-708. The RT-qPCR method was performed in order to detect the miR-708 expression and mRNA expressions of LEF1, ß-catenin, Wnt3a, N-cadherin, Bcl-2, Bax, Caspase3, E-cadherin, and western blotting was used in order to detect the protein expressions of these genes. MTT assay, scratch test, Transwell assay, and flow cytometry were all conducted in order to detect the cell proliferation, migration, invasion, and cycle/apoptosis, respectively. LEF1 was verified as the target gene of miR-708. In comparison with the normal group, the model group had reduced expressions of miR-708, Bax, Caspase3, and E-cadherin, while showing elevated expressions of LEF1, ß-catenin, Bcl-2, Wnt3a, and N-cadherin. In comparison to the blank and control groups, the miR-708, mimic, and siRNA-LEF1 groups had elevated expressions of Bax, Caspase3, and E-cadherin, while also showing enhanced cell apoptosis. The miR-708, mimic, and siRNA-LEF1 groups also had decreased expressions of LEF1, ß-catenin, Bcl-2, Wnt3a, and N-cadherin, and reduced optical density value 48 h and 72 h after transfection. Besides, these two groups showed declined cell migration and invasion, as well as lengthened G0/G1 phase (increased cell number) and shortened S phase (decreased cell number). Our findings demonstrated that an overexpressed miR-708 inhibits the proliferation, invasion, migration, and EMT, but also promotes the apoptosis of melanoma cells by targeting LEF1 through the suppression of the Wnt signaling pathway.


Assuntos
Apoptose , Proliferação de Células , Transição Epitelial-Mesenquimal , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Melanoma Experimental/patologia , MicroRNAs/genética , Proteínas Wnt/metabolismo , Animais , Movimento Celular , Fator 1 de Ligação ao Facilitador Linfoide/antagonistas & inibidores , Fator 1 de Ligação ao Facilitador Linfoide/genética , Masculino , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Camundongos , RNA Interferente Pequeno/genética , Células Tumorais Cultivadas , Proteínas Wnt/genética
14.
Cell Physiol Biochem ; 51(2): 961-978, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30466106

RESUMO

BACKGROUND/AIMS: Interferon consensus sequence-binding protein 8 (IRF8) belongs to a family of interferon (IFN) regulatory factors that modulates various important physiological processes including carcinogenesis. As reported by others and our group, IRF8 expression is silenced by DNA methylation in both human solid tumors and hematological malignancies. However, the role of IRF8 in lung carcinoma remains elusive. In this study, we determined IRF8 epigenetic regulation, biological functions, and the signaling pathway involved in non-small cell lung cancer (NSCLC). METHODS: IRF8 expression were determined by Q- PCR. MSP and A+T determined promotor methylation. MTS, clonogenic, Transwell assay, Flow cytometry, three-dimensional culture and AO/EB stain verified cell function. In vivo tumorigenesis examed the in vivo effects. By Chip-QPCR, RT-PCR, Western blot and Immunofluorescence staining, the mechanisms were studied. RESULTS: IRF8 was significantly downregulated in lung tumor tissues compared with adjacent non-cancerous tissues. Furthermore, methylation-specific PCR analyses revealed that IRF8 methylation in NSCLC was a common event, and demethylation reagent treatment proved that downregulation of IRF8 was due to its promoter CpG hypermethylation. Clinical data showed that the IRF8 methylation was associated with tumor stage, lymph node metastasis status, patient outcome, and tumor histology. Exogenous expression of IRF8 in the silenced or downregulated lung cancer cell lines A549 and H1299 at least partially restored the sensitivity of lung cancer cells to apoptosis, and arrested cells at the G0/G1 phase. Cell viability, clonogenicity, and cell migration and invasive abilities were strongly inhibited by restored expression of IRF8. A three-dimensional culture system demonstrated that IRF8 changed the cells to a more spherical phenotype. Moreover, ectopic expression of IRF8 enhanced NSCLC chemosensitivity to cisplatin. Furthermore, as verified by Chip-qPCR, immunofluorescence staining, and western blotting, IRF8 bound to the T-cell factor/lymphoid enhancer factor (TCF /LEF) promoter, thus repressing ß-catenin nuclear translocation and its activation. IRF8 significantly disrupted the effects of Wnt agonist, bml284, further suggesting its involvement in the Wnt/ß-catenin pathway. CONCLUSION: IRF8 acted as a tumor suppressor gene through the transcriptional repression of ß-catenin-TCF/LEF in NSCLC. IRF8 methylation may serve as a potential biomarker in NSCLC prognosis.


Assuntos
Fatores Reguladores de Interferon/metabolismo , Via de Sinalização Wnt , Idoso , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular/efeitos dos fármacos , Cisplatino/farmacologia , Metilação de DNA , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Fatores Reguladores de Interferon/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Fator 1 de Ligação ao Facilitador Linfoide/química , Fator 1 de Ligação ao Facilitador Linfoide/genética , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Regiões Promotoras Genéticas , Proteínas Wnt/agonistas , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo
15.
Croat Med J ; 59(5): 213-223, 2018 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-30394013

RESUMO

AIM: To identify the involvement of Secreted Frizzled Related Protein 1 (SFRP1) promoter hypermethylation in different malignancy grades of astrocytoma and assess its association with beta-catenin, lymphoid-enhancer factor 1, and T-cell factor 1. METHODS: Twenty-six astrocytoma samples were collected from 2008-2015. Promoter hypermethylation was evaluated by methylation-specific polymerase-chain-reaction and protein expression by immunohistochemistry and stereological analysis. The staining intensity was scored by comparing immunoreactivity with normal tissue and by using 10% and 50% cut-offs. RESULTS: SFRP1 promoter methylation was found in 32% of astrocytomas. The number of hypermethylated samples increased in higher astrocytoma grades and was the highest in glioblastoma (P=0.042 compared to other astrocytoma grades). There was 45.8% of samples with the lack of or weak expression of SFRP1 protein and 29.2% with strong expression. Samples with methylated promoter expressed significantly less SFRP1 than samples with unmethylated promoter (P=0.031). Beta-catenin expression levels were elevated. Yet, glioblastomas with unmethylated SFRP1 promoter had significantly less beta-catenin (P=0.033). Strong expression of lymphoid-enhancer factor 1 was associated to higher astrocytoma grades (P=0.006). CONCLUSION: SFRP1 gene was epigenetically silenced in glioblastomas when compared to low astrocytoma grades, which may suggest that the lack of its protein is involved in astrocytoma progression.


Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Metilação de DNA , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Regiões Promotoras Genéticas , Adulto , Idoso , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Análise Mutacional de DNA , DNA de Neoplasias/genética , Epigenômica , Éxons , Feminino , Inativação Gênica , Humanos , Imuno-Histoquímica , Fator 1 de Ligação ao Facilitador Linfoide/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Fator 1 de Transcrição de Linfócitos T/genética , Adulto Jovem , beta Catenina/genética
16.
Int J Mol Sci ; 19(12)2018 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-30477246

RESUMO

Wingless-type mouse mammary tumor virus (MMTV) integration site (Wnt) signaling is one of the most critical pathways in developing and adult tissues. In the brain, Wnt signaling contributes to different neurodevelopmental aspects ranging from differentiation to axonal extension, synapse formation, neurogenesis, and neuroprotection. Canonical Wnt signaling is mediated mainly by the multifunctional ß-catenin protein which is a potent co-activator of transcription factors such as lymphoid enhancer factor (LEF) and T-cell factor (TCF). Accumulating evidence points to dysregulation of Wnt/ß-catenin signaling in major neurodegenerative disorders. This review highlights a Wnt/ß-catenin/glial connection in Parkinson's disease (PD), the most common movement disorder characterized by the selective death of midbrain dopaminergic (mDAergic) neuronal cell bodies in the subtantia nigra pars compacta (SNpc) and gliosis. Major findings of the last decade document that Wnt/ß-catenin signaling in partnership with glial cells is critically involved in each step and at every level in the regulation of nigrostriatal DAergic neuronal health, protection, and regeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, focusing on Wnt/ß-catenin signaling to boost a full neurorestorative program in PD.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Neurogênese/genética , Transtornos Parkinsonianos/genética , Regeneração/genética , Transdução de Sinais/genética , Proteínas Wnt/genética , beta Catenina/genética , Animais , Sobrevivência Celular , Terapia Baseada em Transplante de Células e Tecidos/métodos , Modelos Animais de Doenças , Neurônios Dopaminérgicos/patologia , Regulação da Expressão Gênica , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/genética , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Camundongos , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/terapia , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
17.
Biomed Pharmacother ; 108: 817-827, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30372893

RESUMO

Pulmonary arterial hypertension (PAH) has been known to result in progressive pulmonary artery pressures (PAP), pulmonary vascular resistance, and right ventricular failure. Emerging evidence has highlighted the function lymphoid enhancer-binding factor 1 (LEF-1) exerts in human diseases along with its potential participation in PAH. Herein, the present study aims to investigate the mechanisms by which LEF-1 affects the pulmonary vascular remodeling in rat models of PAH via the ß-catenin signaling pathway. Both pulmonary vascular remodeling and PAP in the rat pulmonary arterioles were observed by using blood gas analysis as well as plasma NO level detection. Cells from the rats were then treated using monocrotaline (MCT) with PM2.5 also being treated with either shLEF-1, HU-308 (agonist of ß-catenin signaling pathway) or shLEF-1 + HU-308. Expressions of the following: LEF-1, GSK-3ß, ß-catenin, PCNA, Caspase-3, survivin, and Bax were all determined by employing both RT-qPCR and Western blot. Cell proliferation, senescence, and apoptosis calculations were all measured by using the CCK-8 assay, SA ß-Gal and flow cytometry methods, respectively. Rats that were treated with the combination of MCT + PM2.5, afterwards presented with a noticeably higher degree of pulmonary vascular remodeling and PAP, and reduced plasma levels of NO; besides, the expressions of LEF-1, GSK-3ß, ß-catenin, PCNA, and survivin were all elevated, while the expressions of both Caspase-3 and Bax were reduced. Following treatment of HU-308, cell senescence, and apoptosis were all inhibited, while cell proliferation had been contrarily enhanced; the transfection of shLEF-1. reversed the tendency. These results suggested demonstrate that LEF-1 gene silencing inhibited the activation of ß-catenin signaling pathway, thereby suppressing both the occurrence and pulmonary vascular remodeling of PAH. Therefore, LEF-1 gene silencing may become a novel target for PAH treatment.


Assuntos
Inativação Gênica/fisiologia , Pulmão/fisiologia , Fator 1 de Ligação ao Facilitador Linfoide/genética , Artéria Pulmonar/fisiologia , Transdução de Sinais/genética , Remodelação Vascular/genética , beta Catenina/genética , Animais , Apoptose/genética , Caspase 3/genética , Proliferação de Células/genética , Glicogênio Sintase Quinase 3 beta/genética , Hipertensão Pulmonar/genética , Proteínas Inibidoras de Apoptose/genética , Masculino , Ratos , Ratos Sprague-Dawley
18.
Gene ; 679: 150-159, 2018 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-30193961

RESUMO

Molecular alterations that occur in cancer have the potential to be considered as either cancer biomarkers or targeted therapies or even both. In the presented study, we aimed to elucidate the gene regulatory network of metastatic colorectal cancer using data acquired from microarrays to reach the most common DEGs in colorectal cancer metastasis and find their possible regulatory mechanism by DETFs and DEmiRs. In this regards, seven microarray datasets were employed to assess the most important DEGs, DETFs and DEmiRs in colorectal cancer metastasis. Afterward, GRN based on DETFs and DEmiRs were constructed. Also ARACNE algorithm was used to construct an accurate GRN. GRN was analyzed structurally and then, two DETFs (LEF1 and ETV4) and a less-well known DEG (FABP6) by real time qRT-PCR in 50 patients with colorectal cancer were quantified. The constructed GRN highlighted the importance of some DETFs and DEmiRs in colorectal cancer metastasis. Interestingly the gene expression analysis by qRT-PCR on three candidate genes (LEF1, ETV4 and FABP6) indicated that the three genes were co-expressed in tumor samples, and were significantly associated with metastasis in colorectal cancer. Therefore, our experimental results proved a part of our comprehensive data analysis and system biology results. In summary, according to our empirical study we found the importance of three candidate genes as the potent prognostic factors in colorectal cancer metastasis. Also our study in a holistic insight on gene regulatory mechanism revealed the importance of some gene regulatory factors (DETFs and DEmiRs) and their potential as prognostic factors and/or targets in molecular targeted therapies in colorectal cancer.


Assuntos
Proteínas E1A de Adenovirus/genética , Neoplasias Colorretais/genética , Biologia Computacional/métodos , Proteínas de Ligação a Ácido Graxo/genética , Hormônios Gastrointestinais/genética , Perfilação da Expressão Gênica/métodos , Fator 1 de Ligação ao Facilitador Linfoide/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas/genética , Algoritmos , Biomarcadores Tumorais/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Metástase Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Prognóstico , Mapas de Interação de Proteínas
19.
J Exp Clin Cancer Res ; 37(1): 238, 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30253791

RESUMO

BACKGROUND: Aberrant activation of Wnt/ß-catenin signaling pathway is considered to be an important issue in progression and metastasis of various human cancers, especially in colorectal cancer (CRC). MiR-452 could activate of Wnt/ß-catenin signaling. But the mechanism remains unclear. METHODS: The expression of miR-452 in CRC and normal tissues was detected by real-time quantitative PCR. The effect of miR-452 on CRC growth and invasion was conducted by functional experiments in vitro and in vivo. Bioinformatics and cell luciferase function studies verified the direct regulation of miR-452 on the 3'-UTR of the GSK3ß, which leads to the activation of Wnt/ß-catenin signaling. RESULTS: MiR-452 was upregulated in CRC compared with normal tissues and was correlated with clinical significance. The luciferase reporter system studies affirmed the direct regulation of miR-452 on the 3'-UTR of the GSK3ß, which activate the Wnt/ß-catenin signaling. The ectopic upregulation of miR-452 significantly inhibited the expression of GSK3ß and enhanced CRC proliferation and invasion in vitro and in vivo. Meanwhile, knockdown of miR-452 significantly recovered the expression of GSK3ß and attenuated Wnt/ß-catenin-mediated cell metastasis and proliferation. More important, T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors, which are crucial downstream molecules of the Wnt/ß-catenin signaling pathway was verified as a valid transcription factor of miR-452's promoter. CONCLUSIONS: Our findings first demonstrate that miR-452-GSK3ß-LEF1/TCF4 positive feedback loop induce CRC proliferation and migration.


Assuntos
Proliferação de Células/genética , Neoplasias Colorretais/genética , Glicogênio Sintase Quinase 3 beta/genética , MicroRNAs/genética , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HCT116 , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fenótipo , Regiões Promotoras Genéticas , Fator de Transcrição 4/genética , Via de Sinalização Wnt/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Exp Dermatol ; 27(11): 1237-1244, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30099770

RESUMO

DECORIN is a prototypical member of the small leucine-rich proteoglycan (SLRP) family that plays important roles in numerous biological processes and cellular biological pathways. We previously showed that Decorin expression was highly enhanced in mouse dorsal hair follicles (HFs) during the anagen phase and was reduced during the catagen and telogen phases, suggesting that Decorin might modulate follicular cycling and morphogenesis. In this study, to further clarify the effects of DECORIN on hair cells and the cycling transition, an in vitro overexpression strategy and Decorin-null (Dcn-/- ) mice were used to investigate the effects of DECORIN on outer root sheath (ORS) keratinocytes. DECORIN overexpression significantly enhanced proliferation and migration in ORS keratinocytes in vitro. Moreover, DECORIN overexpression upregulated the mRNA and protein expression levels of WNT10b, ß-CATENIN and LEF1. The DECORIN overexpression-induced increase in the proliferation and migration of ORS keratinocytes was partially inhibited by a Wnt/ß-catenin inhibitor. Furthermore, Dcn-/- mice had a shortened anagen phase and lower levels of ß-catenin expression than were observed in wild-type mice in imaging and histological analyses. Taken together, these findings suggest that DECORIN promotes the proliferation and migration of ORS keratinocytes in vitro and maintains hair anagen in mice.


Assuntos
Movimento Celular/genética , Proliferação de Células/genética , Decorina/genética , Folículo Piloso/fisiopatologia , Queratinócitos/fisiologia , Adulto , Animais , Células Cultivadas , Decorina/metabolismo , Regulação para Baixo , Feminino , Expressão Gênica/genética , Folículo Piloso/citologia , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/genética , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Biossíntese de Proteínas/genética , RNA Mensageiro/metabolismo , Transfecção , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/genética , Cicatrização , Adulto Jovem , beta Catenina/genética , beta Catenina/metabolismo
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