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1.
World J Surg Oncol ; 19(1): 199, 2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34218800

RESUMO

BACKGROUND: Dysregulation of long non-coding RNAs has been implied to connect with cancer progression. This research was to decipher the mechanism of long non-coding RNA SDCBP2-AS1 in ovarian cancer (OC) through regulation of microRNA (miR)-100-5p and ependymin-related protein 1 (EPDR1). METHODS: LncRNA SDCBP2-AS1 and EPDR1 levels in OC were assessed by Gene Expression Profiling Interactive Analysis. lncRNA SDCBP2-AS1, miR-100-5p, and EPDR1 levels in OC tissues and cells were determined. SKOV3 and A2780 cells were transfected with lncRNA SDCBP2-AS1, miR-100-5p, and EPDR1-related plasmids or sequences, and then their functions in cell viability, apoptosis, migration, and invasion were evaluated. The interplay of lncRNA SDCBP2-AS1, miR-100-5p, and EPDR1 was clarified. RESULTS: LncRNA SDCBP2-AS1 and EPDR1 levels were suppressed whilst miR-100-5p level was elevated in OC. After upregulating lncRNA SDCBP2-AS1 or EPDR1, viability, migration, and invasion of OC cells were impaired, and apoptosis rate was increased. Downregulating EPDR1 or upregulating miR-100-5p partially mitigated upregulated lncRNA SDCBP2-AS1-induced impacts on the biological functions of OC cells. LncRNA SDCBP2-AS1 sponged miR-100-5p, and EPDR1 was targeted by miR-100-5p. CONCLUSION: It is illustrated that lncRNA SDCBP2-AS1 regulates EPDR1 by sponge adsorption of miR-100-5p to inhibit the progression of OC.


Assuntos
MicroRNAs , Neoplasias Ovarianas , RNA Longo não Codificante , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Neoplasias , Proteínas do Tecido Nervoso , Neoplasias Ovarianas/genética , Prognóstico
2.
Zhonghua Gan Zang Bing Za Zhi ; 29(6): 571-574, 2021 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-34225433

RESUMO

Objective: To investigate the expression of miR-495 and its effect on MHCC-97H hepatocellular carcinoma cells. Methods: Fifty-six hepatocellular carcinoma tissue specimens (HCC group) and 40 normal liver tissue specimens (control group) preserved in our hospital from January 2017 to January 2018 were selected. Reverse transcription real-time fluorescent quantitative PCR (qRT-PCR) was used for miR-495 expression detection. MHCC-97H HCC cells were randomly selected and then divide into control group, blank plasmid group and transfection group. The blank plasmid group was transfected with blank plasmid, and the transfection group was transfected with miR-495 inhibitor. The expression of miR-495 in each group of cells were detected using qRT-PCR. CCK method was used to detect each group proliferation activity. Transwell cell migration assay was used to detect each group migration ability. Analysis of variance was used for comparison between multiple groups. Furthermore, LDS-t test was used for pairwise comparison, and t -test was used for comparison between the two groups. Results: The relative expression levels of miR-495 in the HCC group was (2.043 ± 0.382), which was higher than the control group, and the difference between the two groups was statistically significant (P < 0.05). The relative expressions levels of miR-495 in patients with stage III to IV and lymph node metastasis were 2.265 ± 0.284 and 2.290 ± 0.355, which were significantly higher than those of stage I to II and no lymph node metastasis (P < 0.05). The relative expression levels of miR-495 in transfection group was 0.653 ± 0.102, which were significantly lower than control group and blank plasmid group (P < 0.05). The A values of MHCC-97H cells cultured for 24 h and 48 h in transfection group were 0.404 ± 0.106 and 0.604 ± 0.136, which were significantly lower than control group and blank plasmid group (P < 0.05). MHCC-97H cells migration number in the transfection group was (6.10 0 ± 20), which was significantly lower than that of control group and blank plasmid group (P < 0.05). Conclusion: miR-495 high expression has certain relationship with clinicopathological characteristics of HCC tissues. In addition, miR-495 has a certain effect on the proliferation and migration ability of MHCC-97H HCC cells.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , MicroRNAs/genética
3.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208313

RESUMO

Intrahepatic cholangiocarcinoma (iCCA) is a heterogeneous bile duct cancer with a poor prognosis. Integrin αvß6 (ß6) has been shown to be upregulated in iCCA and is associated with its subclassification and clinicopathological features. In the present study, two ITGB6-knockout HuCCT1 CCA cell lines (ITGB6-ko cells) were established using the clustered regulatory interspaced short palindromic repeats (CRISPR), an associated nuclease 9 (Cas9) system, and single-cell cloning. RNA sequencing analysis, real-time polymerase chain reaction (PCR), and immunofluorescent methods were applied to explore possible downstream factors. ITGB6-ko cells showed significantly decreased expression of integrin ß6 on flow cytometric analysis. Both cell lines exhibited significant inhibition of cell migration and invasion, decreased wound-healing capability, decreased colony formation ability, and cell cycle dysregulation. RNA sequencing and real-time PCR analysis revealed a remarkable decrease in podocalyxin-like protein 2 (PODXL2) expression in ITGB6-ko cells. Colocalization of PODXL2 and integrin ß6 was also observed. S100 calcium-binding protein P and mucin 1, which are associated with CCA subclassification, were downregulated in ITGB6-ko cells. These results describe the successful generation of ITGB6-ko CCA cell clones with decreased migration and invasion and downregulation of PODXL2, suggesting the utility of integrin ß6 as a possible therapeutic target or diagnostic marker candidate.


Assuntos
Movimento Celular , Colangiocarcinoma/patologia , Técnicas de Inativação de Genes , Cadeias beta de Integrinas/genética , Sialoglicoproteínas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ligação ao Cálcio/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Colangiocarcinoma/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Cadeias beta de Integrinas/metabolismo , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sialoglicoproteínas/genética , Ensaio Tumoral de Célula-Tronco , Regulação para Cima/genética
4.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206484

RESUMO

Triple-negative breast cancer (TNBC) presents an important clinical challenge, as it does not respond to endocrine therapies or other available targeting agents. FOXM1, an oncogenic transcriptional factor, has reported to be upregulated and associated with poor clinical outcomes in TNBC patients. In this study, we investigated the anti-cancer effects of FDI-6, a FOXM1 inhibitor, as well as its molecular mechanisms, in TNBC cells. Two TNBC cell lines, MDA-MB-231 and HS578T, were used in this study. The anti-cancer activities of FDI-6 were evaluated using various 2D cell culture assays, including Sulforhodamine B (SRB), wound healing, and transwell invasion assays together with 3D spheroid assays, mimicking real tumour structural properties. After treatment with FDI-6, the TNBC cells displayed a significant inhibition in cell proliferation, migration, and invasion. Increased apoptosis was also observed in the treated cells. In addition, we found that FDI-6 lead to the downregulation of FOXM1 and its key oncogenic targets, including CyclinB1, Snail, and Slug. Interestingly, we also found that the FDI-6/Doxorubicin combination significantly enhanced the cytotoxicity and apoptotic properties, suggesting that FDI-6 might improve chemotherapy treatment efficacy and reduce unwanted side effects. Altogether, FDI-6 exhibited promising anti-tumour activities and could be developed as a newly effective treatment for TNBC.


Assuntos
Antineoplásicos/farmacologia , Proteína Forkhead Box M1/antagonistas & inibidores , Piridinas/farmacologia , Tiofenos/farmacologia , Antineoplásicos/química , Caspase 3/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Piridinas/química , Tiofenos/química , Neoplasias de Mama Triplo Negativas/metabolismo
5.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206505

RESUMO

Myosins are a remarkable superfamily of actin-based motor proteins that use the energy derived from ATP hydrolysis to translocate actin filaments and to produce force. Myosins are abundant in different types of tissues and involved in a large variety of cellular functions. Several classes of the myosin superfamily are expressed in the nervous system; among them, non-muscle myosin II (NM II) is expressed in both neurons and non-neuronal brain cells, such as astrocytes, oligodendrocytes, endothelial cells, and microglia. In the nervous system, NM II modulates a variety of functions, such as vesicle transport, phagocytosis, cell migration, cell adhesion and morphology, secretion, transcription, and cytokinesis, as well as playing key roles during brain development, inflammation, repair, and myelination functions. In this review, we will provide a brief overview of recent emerging roles of NM II in resting and activated microglia cells, the principal regulators of immune processes in the central nervous system (CNS) in both physiological and pathological conditions. When stimulated, microglial cells react and produce a number of mediators, such as pro-inflammatory cytokines, free radicals, and nitric oxide, that enhance inflammation and contribute to neurodegenerative diseases. Inhibition of NM II could be a new therapeutic target to treat or to prevent CNS diseases.


Assuntos
Microglia/metabolismo , Miosina Tipo II/metabolismo , Animais , Biomarcadores , Movimento Celular/imunologia , Citoesqueleto/metabolismo , Humanos , Microglia/imunologia , Fagocitose/imunologia
6.
Stem Cell Res Ther ; 12(1): 387, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233723

RESUMO

AIMS: Neointimal hyperplasia remains a major obstacle in vascular regeneration. Sca-1-positive progenitor cells residing within the vascular adventitia play a crucial role in the assemblage of vascular smooth muscle cell (VSMC) and the formation of the intimal lesion. However, the underlying mechanisms during vascular injury are still unknown. METHODS AND RESULTS: Aneointimal formation rat model was prepared by carotid artery injury using 2F-Forgaty. After vascular injury, Meox1 expressions time-dependently increased during the neointima formation, with its levels concurrently increasing in the adventitia, media, and neointima. Meox1 was highly expressed in the adventitia on the first day after vascular injury compared to the expression levels in the media. Conversely, by the 14th day post-injury, Meox1 was extensively expressed more in the media and neointima than the adventitia. Analogous to the change of Meox1 in injured artery, Sca-1+ progenitor cells increased in the adventitia wall in a time-dependent manner and reached peak levels on the 7th day after injury. More importantly, this effect was abolished by Meox1 knockdown with shRNA. The enhanced expression of SDF-1α after vascular injury was associated with the markedly enhanced expression levels of Sca1+ progenitor cell, and these levels were relatively synchronously increased within neointima by the 7th day after vascular injury. These special effects were abolished by the knockdown of Meox1 with shRNA and inhibition of CXCR4 by its inhibitor, AMD3100. Finally, Meox1 concurrently regulated SDF-1α expressions in VSMC via activating CDC42, and CDC42 inhibition abolished these effects by its inhibitor, ZCL278. Also, Meox1 was involved in activation of the CXCR4 expression of Sca-1+ progenitor cells by CDC42. CONCLUSIONS: Spatio-temporal model of Meox1 expression regulates theSca-1+progenitor cell migration during the formation of the neointima through the synergistic effect of Rho/CDC42 and SDF-1α/CXCR4.


Assuntos
Proteínas de Homeodomínio/genética , Neointima , Células-Tronco , Fatores de Transcrição/genética , Animais , Lesões das Artérias Carótidas/genética , Movimento Celular , Células Cultivadas , Quimiocina CXCL12/genética , Miócitos de Músculo Liso , Ratos , Receptores CXCR4/genética , Proteína cdc42 de Ligação ao GTP
7.
ACS Appl Mater Interfaces ; 13(27): 31371-31378, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34196172

RESUMO

Owing to their remarkable infiltrative traits, glioblastomas develop unclear tumor margins toward the brain, hampering the complete resection. Since the remaining invasive cells tend to have resistance to therapeutics and cause recurrence around the surgical voids, this has been a major challenge for glioblastoma treatment. Thus, we design a cancer cell-sticky hydrogel (CSH) that interacts with the glioblastoma cells to impede their invasive motility by modifying the cell membrane with active thiol-enriched interfaces. Highly reactive thiols at the cell surface can make the infiltrated cancer cells adhere to the hydrogel, resulting in increased cell adhesion and decreased motility. Cotreatment with the CSH and chemical inhibitors of the major proinvasive molecules, focal adhesion kinase and hyaluronic acid synthase, maximized the invasion-inhibitory effect. In addition, a significant decrease in tumor mass was achieved via CSH implantation in mouse models. Overall, our results highlight the use of the CSH to inhibit the aggressive invasion as a novel therapeutic strategy against glioblastoma.


Assuntos
Neoplasias Encefálicas/patologia , Membrana Celular/efeitos dos fármacos , Glioblastoma/patologia , Hidrogéis/farmacologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Movimento Celular/efeitos dos fármacos , Desenho de Fármacos , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Hidrogéis/química , Invasividade Neoplásica , Compostos de Sulfidrila/química
8.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199096

RESUMO

Integrins participate in the pathogenesis and progression of tumors at many stages during the metastatic cascade. However, current evidence for the role of integrins in breast cancer progression is contradictory and seems to be dependent on tumor stage, differentiation status, and microenvironmental influences. While some studies suggest that loss of α2ß1 enhances cancer metastasis, other studies suggest that this integrin is pro-tumorigenic. However, few studies have looked at α2ß1 in the context of bone metastasis. In this study, we aimed to understand the role of α2ß1 integrin in breast cancer metastasis to bone. To address this, we utilized in vivo models of breast cancer metastasis to bone using MDA-MB-231 cells transfected with an α2 expression plasmid (MDA-OEα2). MDA cells overexpressing the α2 integrin subunit had increased primary tumor growth and dissemination to bone but had no change in tumor establishment and bone destruction. Further in vitro analysis revealed that tumors in the bone have decreased α2ß1 expression and increased osteolytic signaling compared to primary tumors. Taken together, these data suggest an inverse correlation between α2ß1 expression and bone-metastatic potential. Inhibiting α2ß1 expression may be beneficial to limit the expansion of primary tumors but could be harmful once tumors have established in bone.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Expressão Gênica , Integrina alfa2beta1/genética , Animais , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Invasividade Neoplásica , Osteólise/genética , Osteólise/metabolismo , Fenótipo
9.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200679

RESUMO

Lymphocyte migration to and sequestration in specific microenvironments plays a crucial role in their differentiation and survival. Lymphocyte trafficking and homing are tightly regulated by signaling pathways and is mediated by cytokines, chemokines, cytokine/chemokine receptors and adhesion molecules. The production of cytokines and chemokines is largely controlled by transcription factors in the context of a specific epigenetic landscape. These regulatory factors are strongly interconnected, and they influence the gene expression pattern in lymphocytes, promoting processes such as cell survival. The epigenetic status of the genome plays a key role in regulating gene expression during many key biological processes, and it is becoming more evident that dysregulation of epigenetic mechanisms contributes to cancer initiation, progression and drug resistance. Here, we review the signaling pathways that regulate lymphoma cell migration and adhesion with a focus on Mantle cell lymphoma and highlight the fundamental role of epigenetic mechanisms in integrating signals at the level of gene expression throughout the genome.


Assuntos
Linfócitos B/patologia , Adesão Celular , Movimento Celular , Epigênese Genética , Linfoma de Célula do Manto/patologia , Microambiente Tumoral/imunologia , Animais , Humanos , Linfoma de Célula do Manto/imunologia , Transdução de Sinais
10.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200891

RESUMO

Preterm labor (PTL) is one of the obstetric complications, and is known to be associated with abnormal maternal inflammatory response and intrauterine inflammation and/or infection. However, the expression of specific miRNAs associated with PTL is not clear. In this study, we performed combination analysis of miRNA array and gene array, and then selected one miRNA (miR-373-3p) and its putative target genes (CD44 and RDX) that exhibited large expression differences in term and PTL placentas with or without inflammation. Using qRT-PCR and luciferase assays, we confirmed that miR-373-3p directly targeted CD44 and RDX. Overexpression of miR-373-3p reduced the migration and invasion of trophoblast cells, while inhibition of miR-373-3p restored the migration and invasion abilities of trophoblast cells. Finally, we validated the expression of miR-373-3p and its target genes in clinical patients' blood. miR-373-3p was increased in PTL patients' blood, and was the most expressed in PTL patients' blood with inflammation. In addition, by targeting the miR-373-3p, CD44 and RDX was decreased in PTL patients' blood, and their expression were the lowest in PTL patients' blood with inflammation. Taken together, these findings suggest that miR-373-3p and its target genes can be potential biomarkers for diagnosis of PTL.


Assuntos
Movimento Celular , Proteínas do Citoesqueleto/metabolismo , Regulação da Expressão Gênica , Receptores de Hialuronatos/metabolismo , Proteínas de Membrana/metabolismo , MicroRNAs/genética , Placenta/patologia , Trofoblastos/patologia , Proliferação de Células , Proteínas do Citoesqueleto/genética , Feminino , Humanos , Receptores de Hialuronatos/genética , Proteínas de Membrana/genética , Placenta/metabolismo , Gravidez , Trofoblastos/metabolismo
11.
Int J Mol Sci ; 22(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206740

RESUMO

N-Glycosylations are an important post-translational modification of proteins that can significantly impact cell function. Terminal sialic acid in hybrid or complex N-glycans has been shown to be relevant in various types of cancer, but its role in non-malignant cells remains poorly understood. We have previously shown that the motility of human bone marrow derived mesenchymal stromal cells (MSCs) can be modified by altering N-glycoforms. The goal of this study was to determine the role of sialylated N-glycans in MSCs. Here, we show that IFN-gamma or exposure to culture media low in fetal bovine serum (FBS) increases sialylated N-glycans, while PDGF-BB reduces them. These stimuli alter mRNA levels of sialyltransferases such as ST3Gal1, ST6Gal1, or ST3Gal4, suggesting that sialylation of N-glycans is regulated by transcriptional control of sialyltransferases. We next show that 2,4,7,8,9-pentaacetyl-3Fax-Neu5Ac-CO2Me (3F-Neu5Ac) effectively inhibits sialylations in MSCs. Supplementation with 3F-Neu5Ac increases adhesion and migration of MSCs, as assessed by both videomicroscopy and wound/scratch assays. Interestingly, pre-treatment with 3F-Neu5Ac also increases the survival of MSCs in an in vitro ischemia model. We also show that pre-treatment or continuous treatment with 3F-Neu5Ac inhibits both osteogenic and adipogenic differentiation of MSCs. Finally, secretion of key trophic factors by MSCs is variably affected upon exposure to 3F-Neu5Ac. Altogether, our experiments suggest that sialylation of N-glycans is tightly regulated in response to environmental cues and that glycoengineering MSCs to reduce sialylated N-glycans could be beneficial to increase both cell migration and survival, which may positively impact the therapeutic potential of the cells.


Assuntos
Movimento Celular , Células-Tronco Mesenquimais/metabolismo , Ácido N-Acetilneuramínico/metabolismo , Polissacarídeos/metabolismo , Sialiltransferases/metabolismo , Adipócitos/metabolismo , Diferenciação Celular , Sobrevivência Celular , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Humanos , Interferon gama/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/fisiologia , Osteoblastos/citologia , Sialiltransferases/antagonistas & inibidores
12.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203850

RESUMO

Steroid receptor coactivator-1 (SRC-1) is a transcription coactivator playing a pivotal role in mediating a wide range of signaling pathways by interacting with related transcription factors and nuclear receptors. Aberrantly elevated SRC-1 activity is associated with cancer metastasis and progression, and therefore, suppression of SRC-1 is emerging as a promising therapeutic strategy. In this study, we developed a novel SRC-1 degrader for targeted degradation of cellular SRC-1. This molecule consists of a selective ligand for SRC-1 and a bulky hydrophobic group. Since the hydrophobic moiety on the protein surface could mimic a partially denatured hydrophobic region of a protein, SRC-1 could be recognized as an unfolded protein and experience the chaperone-mediated degradation in the cells through the ubiquitin-proteasome system (UPS). Our results demonstrate that a hydrophobic-tagged chimeric molecule is shown to significantly reduce cellular levels of SRC-1 and suppress cancer cell migration and invasion. Together, these results highlight that our SRC-1 degrader represents a novel class of therapeutic candidates for targeting cancer metastasis. Moreover, we believe that the hydrophobic tagging strategy would be widely applicable to develop peptide-based protein degraders with enhanced cellular activity.


Assuntos
Interações Hidrofóbicas e Hidrofílicas , Coativador 1 de Receptor Nuclear/metabolismo , Proteólise , Transativadores/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Movimento Celular , Humanos , Fator Estimulador de Colônias de Macrófagos/genética , Fator Estimulador de Colônias de Macrófagos/metabolismo , Chaperonas Moleculares/metabolismo , Invasividade Neoplásica , Peptídeos/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Estabilidade Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
13.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204945

RESUMO

A lesser known but crucially important downstream effect of Rho family GTPases is the regulation of gene expression. This major role is mediated via the cytoskeleton, the organization of which dictates the nucleocytoplasmic shuttling of a set of transcription factors. Central among these is myocardin-related transcription factor (MRTF), which upon actin polymerization translocates to the nucleus and binds to its cognate partner, serum response factor (SRF). The MRTF/SRF complex then drives a large cohort of genes involved in cytoskeleton remodeling, contractility, extracellular matrix organization and many other processes. Accordingly, MRTF, activated by a variety of mechanical and chemical stimuli, affects a plethora of functions with physiological and pathological relevance. These include cell motility, development, metabolism and thus metastasis formation, inflammatory responses and-predominantly-organ fibrosis. The aim of this review is twofold: to provide an up-to-date summary about the basic biology and regulation of this versatile transcriptional coactivator; and to highlight its principal involvement in the pathobiology of kidney disease. Acting through both direct transcriptional and epigenetic mechanisms, MRTF plays a key (yet not fully appreciated) role in the induction of a profibrotic epithelial phenotype (PEP) as well as in fibroblast-myofibroblast transition, prime pathomechanisms in chronic kidney disease and renal fibrosis.


Assuntos
Nefropatias/genética , Complexos Multiproteicos/genética , Fator de Resposta Sérica/genética , Transativadores/genética , Movimento Celular/genética , Núcleo Celular/genética , Citoesqueleto/genética , Regulação da Expressão Gênica/genética , Humanos , Nefropatias/patologia , Regiões Promotoras Genéticas/genética
14.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205118

RESUMO

During metastasis, cancer cells that originate from the primary tumor circulate in the bloodstream, extravasate, and form micrometastases at distant locations. Several lines of evidence suggest that specific interactions between cancer cells and endothelial cells, in particular tumor cell adhesion to the endothelium and transendothelial migration, play a crucial role in extravasation. Here we have studied the role of vascular endothelial (VE)-cadherin which is expressed aberrantly by breast cancer cells and might promote such interactions. By comparing different human breast cancer cell lines, we observed that the number of cancer cells that adhered to endothelium correlated with VE-cadherin expression levels. VE-cadherin silencing experiments confirmed that VE-cadherin enhances cancer cell adhesion to endothelial cells. However, in contrast, the number of cancer cells that incorporated into the endothelium was not dependent on VE-cadherin. Thus, it appears that cancer cell adhesion and incorporation are distinct processes that are governed by different molecular mechanisms. When cancer cells incorporated into the endothelial monolayer, they formed VE-cadherin positive contacts with endothelial cells. On the other hand, we also observed tumor cells that had displaced endothelial cells, reflecting either different modes of incorporation, or a temporal sequence where cancer cells first form contact with endothelial cells and then displace them to facilitate transmigration. Taken together, these results show that VE-cadherin promotes the adhesion of breast cancer cells to the endothelium and is involved in the initial phase of incorporation, but not their transmigration. Thus, VE-cadherin might be of relevance for therapeutic strategies aiming at preventing the metastatic spread of breast cancer cells.


Assuntos
Antígenos CD/genética , Neoplasias da Mama/genética , Caderinas/genética , Adesão Celular/genética , Endotélio Vascular/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Técnicas de Cocultura , Endotélio Vascular/patologia , Endotélio Vascular/ultraestrutura , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Imagem Molecular/métodos , Metástase Neoplásica
15.
Molecules ; 26(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34206998

RESUMO

BACKGROUND: N-octadecanoyl-5-hydroxytryptamide (C18-5HT) is an amide that can be obtained by the coupling of serotonin and octadecanoic acid. This study aims to characterize the in vivo and in vitro anti-inflammatory activity of C18-5HT. METHODS: A subcutaneous air pouch model (SAP) was used. The exudates were collected from SAP after carrageenan injection to assess cell migration and inflammatory mediators production. RAW 264.7 cells were used for in vitro assays. RESULTS: C18-5HT significantly inhibited leukocyte migration into the SAP as well as nitric oxide (NO) and cytokines production and protein extravasation. We also observed an reduction in some cytokines and an increase in IL-10 production. Assays conducted with RAW 264.7 cells indicated that C18-5HT inhibited NO and cytokine produced. CONCLUSIONS: Taken together, our data suggest that C18-5HT presents a significant effect in different cell types (leukocytes collected from exudate, mainly polumorphonuclear leukocytes and cell culture macrophages) and is a promising compound for further studies for the development of a new anti-inflammatory drug.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Serotonina/farmacologia , Animais , Carragenina/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-10/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Óxido Nítrico/metabolismo , Células RAW 264.7
16.
Science ; 373(6550): 111-117, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34210887

RESUMO

Spatial patterns of gene expression manifest at scales ranging from local (e.g., cell-cell interactions) to global (e.g., body axis patterning). However, current spatial transcriptomics methods either average local contexts or are restricted to limited fields of view. Here, we introduce sci-Space, which retains single-cell resolution while resolving spatial heterogeneity at larger scales. Applying sci-Space to developing mouse embryos, we captured approximate spatial coordinates and whole transcriptomes of about 120,000 nuclei. We identify thousands of genes exhibiting anatomically patterned expression, leverage spatial information to annotate cellular subtypes, show that cell types vary substantially in their extent of spatial patterning, and reveal correlations between pseudotime and the migratory patterns of differentiating neurons. Looking forward, we anticipate that sci-Space will facilitate the construction of spatially resolved single-cell atlases of mammalian development.


Assuntos
Padronização Corporal/genética , Embrião de Mamíferos/embriologia , Desenvolvimento Embrionário/genética , Perfilação da Expressão Gênica/métodos , Análise de Célula Única/métodos , Transcriptoma , Animais , Atlas como Assunto , Encéfalo/embriologia , Movimento Celular , Camundongos , Neurogênese/genética , Neurônios/citologia
17.
Braz J Med Biol Res ; 54(10): e10837, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34287578

RESUMO

Circular RNAs (circRNAs) have been extensively elucidated with regard to their significant implications in oral squamous cell carcinoma (OSCC). This study performed the functional investigation of circRNA dehydrogenase E1 and transketolase domain containing 1 (circDHTKD1) in OSCC. RNA expression levels of different molecules were measured via quantitative real-time polymerase chain reaction (qRT-PCR). Cellular behaviors were detected by 3-(4, 5-dimethylthiazol-2-y1)-2,5-diphenyl tetrazolium bromide (MTT) for cell viability, colony formation assay for clonal capacity, flow cytometry for cell apoptosis, wound healing assay for migration, and transwell assay for migration/invasion. Western blot was used for analyzing protein expression. RNA pull-down and dual-luciferase reporter assays were applied to assess the binding between targets. A xenograft tumor model was established in nude mice for in vivo experiments. Our expression analysis revealed that circDHTKD1 was upregulated in OSCC tissues and cells. circDHTKD1 knockdown was shown to impede OSCC cell growth and metastasis but motivate apoptosis. Additionally, circDHTKD1 served as a microRNA-326 (miR-326) sponge and the function of circDHTKD1 was achieved by sponging miR-326 in OSCC cells. Also, miR-326 inhibited OSCC development via targeting GRB2-associated-binding protein 1 (GAB1). circDHTKD1 could sponge miR-326 to alter GAB1 expression. Furthermore, circDHTKD1 contributed to OSCC progression in vivo via the miR-326/GAB1 axis. These data disclosed a specific circDHTKD1/miR-326/GAB1 signal axis in governing the malignant progression of OSCC, showing the considerable possibility of circDHTKD1 as a predictive and therapeutic target for clinical diagnosis and treatment of OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , MicroRNAs , Neoplasias Bucais , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Carcinoma de Células Escamosas/genética , Movimento Celular , Proliferação de Células , Camundongos , Camundongos Nus , MicroRNAs/genética , Neoplasias Bucais/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço
18.
Zhonghua Zhong Liu Za Zhi ; 43(6): 646-656, 2021 Jun 23.
Artigo em Chinês | MEDLINE | ID: mdl-34289556

RESUMO

Objective: To investigate the role of CUL4B-RING E3 ubiquitin ligase (CRL4B) complex in pancreatic tumorigenesis and the molecular mechanism. Methods: Pancreatic cells were divided into control group (transfected with negative control lentivirus), shCUL4B group (transfected with CUL4B lentivirus), shDDB1 group [transfected with DNA damage binding protein 1 (DDB1) lentivirus], and shCUL4B+ siSFRP1 group (transfected with CUL4B lentivirus and SFRP1-siRNA). RNA-seq was performed in pancreatic cancer cell lines with CUL4B and DDB1 knocked down respectively, to identify the target genes regulated by CRL4B complex. Real-time fluorescent quantitative polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression levels of target genes. Chromatin immunoprecipitation (ChIP) assay was used to identify the target genes directly regulated by CUL4B and DDB1. Western blot was used to detect the protein expression levels of the epithelial-mesenchymal transition (EMT) markers. The EdU cell proliferation test was used to detect cell proliferation ability. The scratch repair test and Transwell cell invasion test were used to detect cell migration and invasion ability. Finally, the sequencing data of pancreatic cancer-related tumor samples and normal samples in GEO, TCGA and GTEx databases were used to analyze the expression correlations of CUL4B, DDB1 and their downstream target genes. Results: RNA-seq results showed that target genes regulated by CRL4B complex involved in a number of malignant tumor-related signaling pathways. qRT-PCR results verified that the mRNA expression levels of the target genes of CUL4B or DDB1 knockdown groups were higher than those of the control group, and the difference was statistically significant (P<0.05). ChIP-PCR results showed that CRL4B complex directly bound to the promoter regions of the target genes, NME1 and SFRP1, and the enrichment of monoubiquitination of lysine at 119 of histone H2A (H2AK119ub1) in the promoter region of target gene was reduced after CUL4B knockdown. The proliferation rate in PANC-1 cell line of the control group was (32.10±3.58)%, higher than (13.95±1.66)% in the shCUL4B group and (22.38±0.77)% in the shCUL4B+ siSFRP1 group (P<0.05). The proliferation rate in AsPC-1 cell line of the control group was (35.47±7.80)%, higher than (19.60±3.58)% in the shCUL4B group and (30.09±0.81)% in the shCUL4B+ siSFRP1 group (P<0.05). The scratch repair experiment showed that the migration rate of PANC-1 cell line control group was (53.18±3.70)%, higher than that (17.46±2.62)% in the shCUL4B group and (44.99±9.18)% in the shCUL4B + siSFRP1 group (P<0.05). Western blot showed the expression levels of epithelial markers including α-catenin and γ-catenin in the control group were 1.00±0.03 and 1.01±0.11, respectively, lower than 1.44±0.01 and 1.21±0.06 in the shCUL4B group (P<0.05). The expression levels of mesenchymal markers including fibronectin and vimentin in the control group were 1.01±0.14 and 1.02±0.18, respectively, higher than 1.53±0.13 and 1.22±0.07 in the shCUL4B+ siSFRP1 group (P<0.05). The cell metastasis rate of the control group was (100.00±3.96)%, higher than the (35.49±0.34)% in the shCUL4B group and (107.06±2.77)% in the shCUL4B+ siSFRP1 group, the difference was statistically significant (P<0.05). The expressions of CUL4B and DDB1 were significantly upregulated in the pancreatic cancer tissues, and were negatively correlated with the expression of SFRP1 (r=-0.342 and r=-0.264, respectively). Conclusions: CRL4B complex inhibits the transcription of target gene SFRP1 and promotes the development of pancreatic cancer. Moreover, CRL4B complex is upregulated in pancreatic cancer, which provide a potential of therapeutic target for pancreatic cancer.


Assuntos
Proteínas Culina , Neoplasias Pancreáticas , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteínas Culina/genética , Proteínas Culina/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Pancreáticas/genética
19.
Zhonghua Zhong Liu Za Zhi ; 43(7): 762-768, 2021 Jul 23.
Artigo em Chinês | MEDLINE | ID: mdl-34289570

RESUMO

Objective: To investigate the effects of long-chain non-coding RNA ASB16 antisense RNA1 (ASB16-AS1) on the proliferation, migration and invasion of esophageal cancer cells by targeting microRNA (miR )-1258. Methods: Forty pairs of esophageal cancer tissues and matched adjacent tissues (distance of tumor margin>3 cm) resected in Xinxiang Central Hospital from May 2016 to July 2017 were collected. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expressions of ASB16-AS1 and miR-1258 in esophageal cancer tissues and adjacent tissues. The small interfering RNA negative control (si-NC), ASB16-AS1 small interfering RNA (si-ASB16-AS1), miR-negative control mimics (miR-NC), miR-1258 mimics (miR-1258), si-ASB16-AS1 and anti-miR-NC, si-ASB16-AS1 and anti-miR-1258, si-ASB16-AS1 and anti-miR-1258 were transfected into Eca109 cells, respectively. Methyl thiazolyl tetrazolium (MTT) was utilized to detect the cell viability. Transwell assays were applied to detect cell migration and invasion. Double luciferase reporting experiment and qRT-PCR were used to confirm the relationship between ASB16-AS1 and miR-1258. Results: The expression levels of ASB16-AS1 and miR-1258 in esophageal cancer tissues were 2.95±0.27 and 0.62±0.06, respectively. Compared with 1.00±0.06 and 1.00±0.07 in adjacent tissues, the difference was statistically significant (P<0.05). The cell viability of the si-NC group at 48 h and 72 h were 0.81±0.07 and 1.15±0.11, while those of si-ASB16-AS1 group were 0.46±0.04 and 0.62±0.06 (P<0.05). The numbers of cell migration and invasion in the si-NC group were 86.32±8.24 and 71.29±7.15, respectively, while those of si-ASB16-AS1 group were 43.22±4.31 and 32.36±3.58, respectively, the differences were statistically significant (P<0.05). The cell viability of the miR-NC group at 48 h and 72 h were 0.84±0.08, 1.18±0.12, while those of miR-1258 group were 0.55±0.05, 0.71±0.07 (P<0.05). The migration and invasion numbers of the miR-NC group were (83.15±8.31) and (75.33±7.51), while those of miR-1258 group were (49.58±4.23) and (38.42±3.84), respectively, the differences were statistically significant (P<0.05). The cell viability of the si-ASB16-AS1+ anti-miR-NC group at 48 h and 72 h were 0.45±0.04, 0.61±0.06, while those of si-ASB16-AS1+ anti-miR-1258 group were 0.72±0.07, 0.98±0.08; The migration and invasion numbers of cells in the si-ASB16-AS1+ anti-miR-NC group were 44.36±4.41 and 31.69±3.85, respectively, while those of si-ASB16-AS1+ anti-miR-1258 group were 72.65±7.27 and 61.22±6.14, respectively, and the differences were statistically significant (P<0.05). ASB16-AS1 targeted negative regulation of miR-1258 expression. Conclusions: ASB16-AS1 upregulates in esophageal cancer. ASB16-AS1 promotes the proliferation, migration and invasion of esophageal cancer cells by targeting miR-1258.


Assuntos
Neoplasias Esofágicas , MicroRNAs , RNA Longo não Codificante , Movimento Celular , Proliferação de Células , Neoplasias Esofágicas/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , RNA Bacteriano , RNA Longo não Codificante/genética
20.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(6): 628-636, 2021 Jun 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34275932

RESUMO

The long intergic non-protein coding RNA 460 (LINC00460) is abnormally highly expressed in gastrointestinal tumors and plays an important role in promoting tumor formation and development. LINC00460 is mainly distributed in cytoplasm and has many abnormal gene variants of single nucleotide polymorphism in tumors. LINC00460 can promote the proliferation, metastasis, angiogenesis, radiotherapy and chemotherapy resistance, inhibit the apoptosis of tumor cells, and further promote the malignant progression of tumors via involving in chromatin state maintenance, methylation modification, endogenous competition and transcriptional regulation. It may serve as a valuable tumor marker and therapeutic target.


Assuntos
Neoplasias Gastrointestinais , RNA Longo não Codificante , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Gastrointestinais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , RNA Longo não Codificante/genética
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