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1.
Int J Mol Sci ; 22(19)2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34638550

RESUMO

Micro-RNA-21 (miR-21) is a vital regulator of colorectal cancer (CRC) progression and has emerged as a potential therapeutic target in CRC treatment. Our study using real-time PCR assay found that a secondary bile acid, lithocholic acid (LCA), stimulated the expression of miR21 in the CRC cell lines. Promoter activity assay showed that LCA strongly stimulated miR21 promoter activity in HCT116 cells in a time- and dose-dependent manner. Studies of chemical inhibitors and miR21 promoter mutants indicated that Erk1/2 signaling, AP-1 transcription factor, and STAT3 are major signals involved in the mechanism of LCA-induced miR21 in HCT116 cells. The elevation of miR21 expression was upstream of the phosphatase and tensin homolog (PTEN) inhibition, and CRC cell proliferation enhancement that was shown to be possibly mediated by PI3K/AKT signaling activation. This study is the first to report that LCA affects miR21 expression in CRC cells, providing us with a better understanding of the cancer-promoting mechanism of bile acids that have been described as the very first promoters of CRC progression.

2.
Front Immunol ; 12: 710750, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497608

RESUMO

Human regulatory T (Treg) cells play a central role in controlling allergic inflammation in the airways. A reduced number of peripheral Treg cells and decreased suppressive function have been previously reported in the pathogenesis of allergic asthma. However, the characteristic role of specific Treg cell subsets and their mechanisms in the pathogenesis of allergic asthma remain unclear. In this study, we examined the proportion of different Treg cell subsets in both healthy subjects and patients with allergic asthma using flow cytometry and single-cell RNA sequencing. The migration function of the cells was compared using cell sorting and Transwell experiments. Furthermore, two allergen-challenged mouse models and a cell transfer experiment were used to examine the role of these Treg subsets. We found that the proportion of CD25+Foxp3+CD127- Treg cells in the peripheral blood of patients with allergic asthma was lower than in those of healthy subjects. Furthermore, the circulating Treg cells expressed lower levels of CCR6 and IL-17 compared with healthy subjects. The chemokine from the airway mucosa, CCL20, was abundantly expressed, and Transwell experiments further proved that this chemokine promoted CCR6+ Treg cell migration in vitro. A mouse model induced by house dust mite (HDM) revealed that the number of CCR6+ Treg cells in the lung tissue increased remarkably. The incidence of allergic asthma may be related to an increase in Treg cells secreting IL-17 in the lung tissue. Recruited CCR6+ Treg cells are likely to differentiate into Th17-like cells under the Th17 environment present in the lungs. IL-17 derived from Th17-like cells could be associated with the pathology of allergic asthma by promoting Th17 responses, thereby favoring HDM-induced asthma exacerbations.

3.
Toxicol Lett ; 349: 155-164, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34171359

RESUMO

Cytochrome P450 1A1 (CYP1A1) is a member of a subfamily of enzymes involved in the metabolism of both endogenous and exogenous substrates and the chemical activation of xenobiotics to carcinogenic derivatives. Here, the effects of nicotine, a major psychoactive compound present in cigarette smoke, on CYP1A1 expression and human hepatocellular carcinoma (HepG2) cell proliferation were investigated. Nicotine stimulated CYP1A1 expression via the transcription factors, activator protein 1, nuclear factor-kappa B, and the aryl hydrocarbon receptor (AhR) signaling pathway. Pharmacological inhibition and mutagenesis studies indicated that p38 mitogen-activated protein kinase, as well as RelA (or p65), mediated the upregulation of CYP1A1 of nicotine in HepG2 cells. The antioxidant compound, N-acetyl-cysteine, abrogated nicotine-activated production of reactive oxygen species and inhibited CYP1A1 expression by nicotine. Furthermore, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was inhibited by diphenyleneiodonium (an NADPH oxidase inhibitor). Thus, these results demonstrated that AhR played an important role in nicotine-induced CYP1A1 expression. Additionally, liver hepatocellular carcinoma HepG2 cells treated with nicotine exhibited markedly enhanced proliferation via CYP1A1 expression and Akt activation.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Hepatocelular/enzimologia , Citocromo P-450 CYP1A1/biossíntese , Neoplasias Hepáticas/enzimologia , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Fator de Transcrição AP-1/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP1A1/genética , Indução Enzimática , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Transdução de Sinais , Fator de Transcrição AP-1/genética , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
4.
Front Pharmacol ; 11: 577302, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33381031

RESUMO

Urokinase-type plasminogen activator receptor (uPAR) plays a crucial role in inflammation and tumor metastasis. Docosahexaenoic acid (DHA), a representative omega-3 polyunsaturated fatty acid, has been shown to exhibit anti-inflammatory and anti-tumor properties. However, the mechanism by which DHA negatively regulates uPAR expression is not yet understood. The aim of this study was to investigate the effect of DHA on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced uPAR expression and potential role of heme oxygenase-1 (HO-1) in DHA-induced inhibition of uPAR in human endothelial ECV304 cells. Results showed that TPA induced uPAR expression in a time dependent manner, while DHA inhibited uPAR expression in a concentration-dependent manner. Moreover, treatment with DHA induced HO-1 expression in a time- and concentration-dependent manner. In addition, DHA-induced inhibition of uPAR expression and cell invasion in TPA-stimulated cells was reversed by si-HO-1 RNA. Induction of HO-1 by ferric protoporphyrin IX (FePP) inhibited TPA-induced uPAR expression, and this effect was abolished by treatment with the HO-1 inhibitor tin protoporphyrin IX (SnPP). Additionally, carbon monoxide, an HO-1 product, attenuated TPA-induced uPAR expression and cell invasion. Collectively, these data suggest a novel role of DHA-induced HO-1 in reducing uPAR expression and cell invasion in human endothelial ECV304 cells.

5.
Int J Mol Sci ; 21(10)2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32408577

RESUMO

Matrix metalloproteinase-9 (MMP-9) plays a crucial role in cell invasion and cancer metastasis. In this study, we showed that cholic acid (CA), a major primary bile acid, can induce MMP-9 expression in colon cancer HT29 and SW620 cells. CA increased reactive oxygen species (ROS) production and also activated phosphorylation of ERK1/2, JNK, and p38 MAPK. Specific inhibitors and mutagenesis studies showed that ERK1/2 and JNK functioned as upstream signals in the activation of AP-1, and p38 MAPK functioned as an upstream signal in the activation of NF-κB. N-acetyl-L-cysteine (NAC, an ROS scavenger) and diphenyleneiodonium chloride (DPI, an NADPH oxidase inhibitor) inhibited CA-induced activation of ERK1/2, JNK, and p38 MAPK, indicating that ROS production by NADPH oxidase could be the furthest upstream signal in MMP-9 expression. Colon cancer cells pretreated with CA showed remarkably enhanced invasiveness. Such enhancement was partially abrogated by MMP-9-neutralizing antibodies. These results demonstrate that CA could induce MMP-9 expression via ROS-dependent ERK1/2, JNK-activated AP-1, and p38-MAPK-activated NF-κB signaling pathways, which in turn stimulate cell invasion in human colon cancer cells.


Assuntos
Ácido Cólico/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição AP-1/metabolismo , Acetilcisteína/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Sequestradores de Radicais Livres/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Metaloproteinase 9 da Matriz/genética , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , Oniocompostos/farmacologia , Espécies Reativas de Oxigênio/metabolismo
6.
Int J Mol Sci ; 21(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31906413

RESUMO

Muscle invasive bladder carcinoma is a highly malignant cancer with a high mortality rate, due to its tendency to metastasize. The tyrosine kinase recepteur d'origine nantais (RON) promotes bladder carcinoma metastasis. Lysophosphatidic acid (LPA) is a phospholipid derivative, which acts as a signaling molecule to activate three high affinity G-protein coupled receptors, LPA1, LPA2, and LPA3. This in turn leads to cell proliferation and contributes to oncogenesis. However, little is known about the effects of LPA on invasive bladder cancer (IBC). In this study, we discovered that LPA upregulated RON expression, which in turn promoted cell invasion in bladder cancer T24 cells. As expected, we found that the LPA receptor was essential for the LPA induced increase in RON expression. More interestingly, we discovered that LPA induced RON expression via the MAPK (ERK1/2, JNK1/2), Egr-1, AP-1, and NF-κB signaling axes. These results provide experimental evidence and novel insights regarding bladder malignancy metastasis, which could be helpful for developing new therapeutic strategies for IBC treatment.


Assuntos
Movimento Celular/efeitos dos fármacos , Lisofosfolipídeos/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Neoplasias da Bexiga Urinária/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteína 1 de Resposta de Crescimento Precoce/antagonistas & inibidores , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Humanos , NF-kappa B/metabolismo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo , Fator de Transcrição AP-1/antagonistas & inibidores , Fator de Transcrição AP-1/metabolismo , Neoplasias da Bexiga Urinária/metabolismo
7.
J Cell Mol Med ; 23(8): 5360-5368, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31232516

RESUMO

Telocytes, newly discovered in the last decade, are interstitial cells found in numerous organs, with multiple proposed potential biological functions. Toll-like receptors (TLRs) play an important role in innate and adaptive immunity by recognizing pathogen-associated molecular patterns (PAMPs). However, it is still unknown whether telocytes express these innate receptors. We sought to determine the expression and role of TLRs in telocytes. In our study, we primarily detected TLR1-9 expression in telocytes. The proliferation, apoptosis and immunoregulatory activity of telocytes activated with or without TLR ligands were determined. Our results showed that purified telocytes expressed TLR2, TLR3 and TLR5. In particular, telocytes expressed high levels of TLR2 as observed using flow cytometry. When we stimulated telocytes with TLR2 or TLR3 agonists (Pam3CSK4, PolyI:C), iNOS expression was greatly increased after Pam3CSK4 treatment. Additionally, telocyte proliferation was reduced and cell apoptosis was increased after TLR agonist stimulation. A co-culture experiment showed that supernatant from telocytes pretreated with Pam3CSK4 inhibited T cell activation much more than that from untreated telocytes and this effect was mediated by iNOS. Overall, our results demonstrated TLR expression on telocytes for the first time and provided evidence of an immunoregulatory role of telocytes, indicating their clinical potential.


Assuntos
Telócitos/metabolismo , Receptores Toll-Like/metabolismo , Animais , Apoptose/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Citometria de Fluxo/métodos , Ligantes , Ativação Linfocitária/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T/metabolismo
8.
Sci Rep ; 9(1): 2003, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30765814

RESUMO

Metformin, an inexpensive, well-tolerated oral agent that is a commonly used first-line treatment for type 2 diabetes, has become the focus of intense research as a potential anticancer agent. In this study, we describe the inhibitory effect of metformin in interleukin 8 (IL-8) upregulation by lithocholic acid (LCA) in HCT116 colorectal cancer (CRC) cells. Pharmacological inhibition studies indicated that reactive oxygen species (ROS) were involved in LCA-induced IL-8 upregulation through activation of the transcription factor NF-κB. Metformin was demonstrated to block LCA-stimulated ROS production, in turn suppressing NF-κB signaling that was critical for IL-8 upregulation. An NADPH oxidase assay proved that the inhibitory effect of metformin on ROS production was derived from its strong suppression of NADPH oxidase, a key producer of ROS in cells. Compared with conditioned media (CM) derived from HCT116 cells treated with LCA, CM derived from HCT116 cells pretreated with metformin and then treated with LCA lost all stimulatory effect on endothelial cell proliferation and tubelike formation. In conclusion, metformin inhibited NADPH oxidase, which in turn suppressed ROS production and NF-κB activation to prevent IL-8 upregulation stimulated by LCA; this prevention thus obstructed endothelial cell proliferation and tubelike formation.


Assuntos
Neoplasias Colorretais/patologia , Interleucina-8/metabolismo , Ácido Litocólico/farmacologia , Metformina/farmacologia , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacos , Células HCT116 , Humanos
9.
J Cell Biochem ; 120(4): 5531-5541, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30317657

RESUMO

Interleukin-6 (IL-6), a pleiotropic cytokine, plays a key role in endothelial injury and atherosclerosis. In this study, we investigated the effects of nicotine, a major psychoactive compound in cigarette smoke, on IL-6 expression and EA.hy926 endothelial cell invasion. Nicotine stimulated IL-6 expression via the activator protein 1 (AP-1) transcription factor. Pharmacological inhibition and mutagenesis studies indicated that p38 mitogen-activated protein kinase (MAPK) mediated the IL-6-induced upregulation of nicotine in EA.hy926 cells. Furthermore, the antioxidant compound N-acetyl-cysteine eliminated the nicotine-activated production of reactive oxygen species (ROS) and inhibited signal transducer and activator of transcription 3 (STAT-3) phosphorylation; these two mechanisms mediated the upregulation of IL-6 expression by nicotine. In addition, the EA.hy926 cells treated with nicotine displayed markedly enhanced invasiveness due to IL-6 upregulation. Our data demonstrate that nicotine induced IL-6 expression, which, in turn, enhanced the invasiveness of endothelial EA.hy926 cells, via activation of the p38 MAPK/AP-1 and ROS/STAT-3 signaling pathways.


Assuntos
Fumar Cigarros/mortalidade , Células Endoteliais/metabolismo , Interleucina-6/biossíntese , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Nicotina/farmacologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição AP-1/metabolismo , Regulação para Cima/efeitos dos fármacos , Acetilcisteína/farmacologia , Linhagem Celular , Fumar Cigarros/patologia , Células Endoteliais/patologia , Humanos , Espécies Reativas de Oxigênio/metabolismo
10.
J Agric Food Chem ; 66(29): 7663-7673, 2018 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-29945448

RESUMO

The urokinase-type plasminogen activator receptor (uPAR), a glycoprotein localized on the cell surface with a glycosylphosphatidylinositol anchor, plays a crucial role in cell invasion, and the metastasis of several cancers, including bladder cancer, and its expression are significantly negatively correlated with patient survival rates. Apigenin, a naturally produced phytochemical compound found in fruits, vegetables, and plant leaves, has been shown to mediate a variety of cancer-metastasis-related molecules in various cancers. The effect of apigenin on uPAR expression is still unknown. In this study, we examined the effects of apigenin on IL-1ß-induced uPAR expression and investigated its potential mechanisms. We discovered in this study that IL-1ß could remarkably induce uPAR expression in bladder cancer T24 cells and that apigenin-inhibited IL-1ß could induce uPAR expression concentration-dependently. Interestingly, NF-κB and AP-1 transcription factors were critically required for IL-1ß-induced high uPAR expression. Apigenin suppressed the transcriptional activity of both AP-1 and NF-κB by inhibiting ERK1/2 and JNK signaling pathways. These results suggest that apigenin can exert anti-invasion effects by inhibiting uPAR expression via mediating (ERK1/2, JNK)/AP-1 and (ERK1/2, JNK)/NF-κB signaling pathways in human T24 cells. Our present study generated novel and valuable biological insight into anti-invasion through treatment with a small native compound.


Assuntos
Apigenina/farmacologia , Interleucina-1beta/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Fator de Transcrição AP-1/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/genética , NF-kappa B/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Fator de Transcrição AP-1/genética , Neoplasias da Bexiga Urinária/genética
11.
Cancer Res ; 75(6): 986-95, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25600646

RESUMO

Immune mechanisms underlying hepatocellular carcinoma (HCC) are not well understood. Here, we show that the Toll-like receptor TLR2 inhibits production of the proinflammatory cytokine IL18 and protects mice from DEN-induced liver carcinogenesis. On this protocol, Tlr2(-/-) mice exhibited more aggressive HCC development associated with impaired CD8(+) T-cell function. Furthermore, Ly6C(high)IL18Rα(+) myeloid-derived suppressor cells (MDSC) were increased in number in the livers of Tlr2(-/-) mice before tumor onset. MDSC in this setting exhibited higher iNOS levels that could inhibit IFNγ production and CD8(+) T-cell proliferation in vitro. Notably, Tlr2(-/-) hepatocytes produced more mature IL18 after DEN treatment that was sufficient to drive MDSC accumulation there. IL18 administration was sufficient to induce accumulation of MDSC, whereas hepatocyte-specific silencing of IL18 in Tlr2(-/-) mice decreased the proportion of MDSC, increased the proportion of functional CD8(+) T cells, and alleviated HCC progression. IL18 production was mediated by caspase-8 insofar as the decrease in its silencing was sufficient to attenuate levels of mature IL18 in Tlr2(-/-) mice. Furthermore, the TLR2 agonist Pam3CSK4 inhibited both caspase-8 and IL18 expression, decreasing MDSC, increasing CD8(+) T-cell function, and promoting HCC regression. Overall, our findings show how TLR2 deficiency accelerates IL18-mediated immunosuppression during liver carcinogenesis, providing new insights into immune control that may assist the design of effective immunotherapies to treat HCC.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Tolerância Imunológica , Interleucina-18/fisiologia , Neoplasias Hepáticas Experimentais/etiologia , Receptor 2 Toll-Like/fisiologia , Animais , Caspase 8/fisiologia , Neoplasias Hepáticas Experimentais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/fisiologia
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