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1.
Genes Cells ; 28(8): 573-584, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37248626

RESUMEN

Tumor-derived G-CSF is a well-known factor to aggravate disease progression in various types of cancers. In this study, we investigated a role of G-CSF in squamous cell carcinoma (SCC). High expression of G-CSF in the tumor tissues of esophageal SCC (ESCC) patients correlated with poor prognosis. Murine SCC NR-S1M cells produce considerable amount of G-CSF, which expression is correlated with its metastatic potentials. Deletion of G-CSF in NR-S1M cells mitigated tumor growth and metastasis to lymph node and lung of subcutaneous NR-S1M tumors in the mice. Mechanistically, G-CSF enhanced cell proliferation in autocrine manner in vitro, whereas in NR-S1M tumor-bearing mice, accumulation of plasma G-CSF was associated with expansion of peripheral neutrophils, which led to a decreased proportion of CD8+ T cells. Antibody depletion of neutrophils restored the number of CD8+ T cells and modestly suppressed tumor outgrowth, albeit no changes in distant metastasis. We propose that G-CSF produced by NR-S1M cells facilitates tumor progression in mice through bi-functional effects to promote neutrophil recruitment and tumor cell proliferation, which may render poor prognosis to the ESCC patients with high G-CSF expression.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Animales , Ratones , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Factor Estimulante de Colonias de Granulocitos/metabolismo , Infiltración Neutrófila , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas/genética , Proliferación Celular , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica
2.
Oncogene ; 41(50): 5319-5330, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36335283

RESUMEN

Metastasis predicts poor prognosis in cancer patients. It has been recognized that specific tumor microenvironment defines cancer cell metastasis, whereas the underlying mechanisms remain elusive. Here we show that Galectin-7 is a crucial mediator of metastasis associated with immunosuppression. In a syngeneic mouse squamous cell carcinoma (SCC) model of NR-S1M cells, we isolated metastasized NR-S1M cells from lymph nodes in tumor-bearing mice and established metastatic NR-S1M cells in in vitro culture. RNA-seq analysis revealed that interferon gene signature was markedly downregulated in metastatic NR-S1M cells compared with parental cells, and in vivo NR-S1M tumors heterogeneously developed focal immunosuppressive areas featured by deficiency of anti-tumor immune cells. Spatial transcriptome analysis (Visium) for the NR-S1M tumors revealed that various pro-metastatic genes were significantly upregulated in immunosuppressive areas when compared to immunocompetent areas. Notably, Galectin-7 was identified as a novel metastasis-driving factor. Galectin-7 expression was induced during tumorigenesis particularly in the microenvironment of immunosuppression, and extracellularly released at later stage of tumor progression. Deletion of Galectin-7 in NR-S1M cells significantly suppressed lymph node and lung metastasis without affecting primary tumor growth. Therefore, Galectin-7 is a crucial mediator of tumor metastasis of SCC, which is educated in the immune-suppressed tumor areas, and may be a potential target of cancer immunotherapy.


Asunto(s)
Carcinoma de Células Escamosas , Galectinas , Neoplasias Pulmonares , Microambiente Tumoral , Animales , Ratones , Carcinoma de Células Escamosas/patología , Galectinas/genética , Galectinas/metabolismo , Tolerancia Inmunológica/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ganglios Linfáticos/patología , Microambiente Tumoral/genética
3.
PLoS One ; 17(7): e0270920, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35867642

RESUMEN

Angiotensin-converting enzyme 2 (ACE2) is the carboxypeptidase to degrade angiotensin II (Ang II) to angiotensin 1-7 (Ang 1-7) and improves the pathologies of cardiovascular disease and acute respiratory distress syndrome (ARDS)/acute lung injury. B38-CAP is a bacteria-derived ACE2-like carboxypeptidase as potent as human ACE2 and ameliorates hypertension, heart failure and SARS-CoV-2-induced lung injury in mice. Recombinant B38-CAP is prepared with E. coli protein expression system more efficiently than recombinant soluble human ACE2. Here we show therapeutic effects of B38-CAP on abdominal sepsis- or acid aspiration-induced acute lung injury. ACE2 expression was downregulated in the lungs of mice with cecal ligation puncture (CLP)-induced sepsis or acid-induced lung injury thereby leading to upregulation of Ang II levels. Intraperitoneal injection of B38-CAP significantly decreased Ang II levels while upregulated angiotensin 1-7 levels. B38-CAP improved survival rate of the mice under sepsis. B38-CAP suppressed the pathologies of lung inflammation, improved lung dysfunction and downregulated elevated cytokine mRNA levels in the mice with acute lung injury. Thus, systemic treatment with an ACE2-like enzyme might be a potential therapeutic strategy for the patients with severe sepsis or ARDS.


Asunto(s)
Lesión Pulmonar Aguda , COVID-19 , Síndrome de Dificultad Respiratoria , Sepsis , Lesión Pulmonar Aguda/patología , Angiotensina II/metabolismo , Enzima Convertidora de Angiotensina 2 , Animales , Carboxipeptidasas/metabolismo , Escherichia coli/metabolismo , Humanos , Pulmón/patología , Ratones , Peptidil-Dipeptidasa A/metabolismo , Sistema Renina-Angiotensina , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , SARS-CoV-2 , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Sepsis/metabolismo
4.
Surgery ; 171(6): 1535-1542, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35000783

RESUMEN

BACKGROUND: The mechanism underlying cancer cell metastasis from the tumor to regional lymph nodes is not yet fully understood. We hypothesized that peritumoral neutrophil accumulation promotes regional lymph node metastasis in thoracic esophageal squamous cell cancer. METHODS: Between 2010 and 2019, 126 thoracic esophageal squamous cell cancer patients received curative (R0) esophagectomy without preoperative treatment in our hospital. Using paraffin-embedded resected tumors, we performed immunohistochemical analysis of CD16b-positive neutrophil accumulation in the peritumoral area, which was defined as a 1-mm region centered on the border separating the malignant cell nests from the host tissue. The relationship between the density of peritumoral CD16b staining and pathological lymph node metastasis or 5-year overall survival was evaluated. RESULTS: Although the clinicopathological characteristics of CD16b-high and CD16b-low patients did not differ, greater pathological lymph node metastasis (P < .001) and lymphatic invasion by the tumor (P = .024) and a poorer 5-year survival (P = .010) were seen in CD16b-high patients. Moreover, CD16b-positive neutrophil density was generally higher in the peritumoral area than within the tumor itself. Univariate and multivariate analyses showed that CD16b-positive neutrophil accumulation was an independent factor for lymph node metastasis with an odds ratio >25 (P < .001). On the other hand, blood neutrophil counts did not correlate with lymph node metastasis. CONCLUSION: Peritumoral accumulation of CD16b-positive neutrophils is an independent factor strongly correlated with lymph node metastasis in thoracic esophageal squamous cell cancer.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Células Epiteliales/patología , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/cirugía , Esofagectomía , Humanos , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Estadificación de Neoplasias , Neutrófilos , Estudios Retrospectivos
5.
Nat Commun ; 12(1): 6791, 2021 11 23.
Artículo en Inglés | MEDLINE | ID: mdl-34815389

RESUMEN

Angiotensin-converting enzyme 2 (ACE2) is a receptor for cell entry of SARS-CoV-2, and recombinant soluble ACE2 protein inhibits SARS-CoV-2 infection as a decoy. ACE2 is a carboxypeptidase that degrades angiotensin II, thereby improving the pathologies of cardiovascular disease or acute lung injury. Here we show that B38-CAP, an ACE2-like enzyme, is protective against SARS-CoV-2-induced lung injury. Endogenous ACE2 expression is downregulated in the lungs of SARS-CoV-2-infected hamsters, leading to elevation of angiotensin II levels. Recombinant Spike also downregulates ACE2 expression and worsens the symptoms of acid-induced lung injury. B38-CAP does not neutralize cell entry of SARS-CoV-2. However, B38-CAP treatment improves the pathologies of Spike-augmented acid-induced lung injury. In SARS-CoV-2-infected hamsters or human ACE2 transgenic mice, B38-CAP significantly improves lung edema and pathologies of lung injury. These results provide the first in vivo evidence that increasing ACE2-like enzymatic activity is a potential therapeutic strategy to alleviate lung pathologies in COVID-19 patients.


Asunto(s)
Enzima Convertidora de Angiotensina 2/metabolismo , Tratamiento Farmacológico de COVID-19 , COVID-19/prevención & control , Lesión Pulmonar/prevención & control , SARS-CoV-2/efectos de los fármacos , Internalización del Virus/efectos de los fármacos , Lesión Pulmonar Aguda , Angiotensina II , Animales , COVID-19/patología , Carboxipeptidasas , Chlorocebus aethiops , Cricetinae , Modelos Animales de Enfermedad , Femenino , Humanos , Pulmón/patología , Masculino , Ratones , Ratones Transgénicos , Edema Pulmonar/patología , Edema Pulmonar/prevención & control , Glicoproteína de la Espiga del Coronavirus/efectos de los fármacos , Células Vero
6.
J Mol Cell Cardiol ; 133: 26-35, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31128166

RESUMEN

We have previously reported that promoter polymorphism of myocardin-related transcription factor A (MRTF-A) is associated with coronary atherosclerosis. However, the contribution of MRTF-A to the development of atherosclerosis remains unknown. Macrophages are known to be important mediators of atherosclerosis. It has been demonstrated that local proliferation and survival of macrophages are atherogenic. In this study, we found that MRTF-A was highly expressed in lesional macrophages in human carotid atherosclerotic plaque. We then investigated the role of macrophagic MRTF-A in the pathogenesis of atherosclerosis. ApoE null MRTF-A transgenic mice (ApoE-/-/MRTF-Atg/+), in which human MRTF-A was specifically overexpressed in monocytes/macrophages, were established and fed with normal diet to examine the progression of atherosclerosis. We found that ApoE-/-/MRTF-Atg/+ aggravated atherosclerosis and lesional macrophages were more prominently accumulated in the aortic sinus of ApoE-/-/MRTF-Atg/+ than in that of ApoE-/- littermates. We also found that MRTF-A promoted proliferation and mitigated apoptosis of macrophages both in vitro and in vivo, and down regulated the expression of cyclin-dependent kinase inhibitors. From these findings, we conclude that MRTF-A modulates functional properties of pro-atherogenic macrophages. Our study may play a valuable role in understanding the pathological role of macrophagic MRTF-A in the progression of atherosclerosis.


Asunto(s)
Aterosclerosis/etiología , Aterosclerosis/metabolismo , Susceptibilidad a Enfermedades , Macrófagos/metabolismo , Transactivadores/genética , Animales , Apoptosis/genética , Aterosclerosis/patología , Biomarcadores , Proliferación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Expresión Génica , Humanos , Inmunohistoquímica , Macrófagos/inmunología , Ratones , Ratones Noqueados , Ratones Transgénicos , Transducción de Señal , Transactivadores/metabolismo
7.
Front Microbiol ; 9: 2006, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30210477

RESUMEN

Growth retardation of calves is defined as a symptom of impaired growth and development, probably due to growth hormone disorder as well as natural and environmental factors in livestock. The growth-promoting effects of probiotics were determined in 50 growth-retarded growth calves. They were supplied with Bacillus amyloliquefaciens C-1 (Ba, 4 × 1010CFU/d, n = 16), B. subtilis (Bs, 4 × 1010CFU/d, n = 18), and negative control (NC, n = 16) for 30 days. Pre- and post-intervention, the growth performance (weight gain rate, feed intake and feed conversion rate) was analyzed, the serum GH, IGH-1 and immunoglobulin levels were assayed, and the fecal microbiota was detected. Calves in Ba and Bs groups demonstrated increased body weight gain, feed intake and GH/IGF-1 levels, as well as a more efficient feed conversion rate, compared with NC group (P < 0.05). Additionally, the abundances of bacteria contributing to the production of energy and SCFAs (short chain fatty acids), including Proteobacteria, Rhodospirillaceae, Campylobacterales, and Butyricimonas were increased compared with NC group (P < 0.05, FDR < 0.1); and the suspected pathogens, which included Anaeroplasma and Acholeplasma were decreased (P < 0.05, FDR < 0.1) in both the Bs and Ba groups. Akkermansia, which is involved in the intestinal mucosal immune response, was increased in Bs group after intervention (P < 0.05, FDR < 0.1), but exhibited no obvious difference in Ba group. The increased bacterial genera in Ba group were Sphaerochaeta and Treponema (P < 0.05, FDR < 0.1). These results indicate that the probiotics B. amyloliquefaciens and B. subtilis exhibited similar therapeutic potential in terms of growth performance by regulating hormones, and improving the intestinal and rumen development in growth-retarded animals.

8.
Sci Rep ; 7(1): 13650, 2017 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-29057966

RESUMEN

Mice deficient in the megakaryoblastic leukaemia 1 (Mkl1) gene experience less severe dextran sulphate sodium (DSS)-induced colitis, implying that Mkl1 plays a pathological role in inflammatory bowel disease (IBD). However, the contribution of Mkl1 to the development of colitis remains to be elucidated. The expression of Mkl1 is higher in the colonic lamina propria macrophages (LPMac) of DSS-treated mice than in those of control mice. Therefore, we established a transgenic mouse line that overexpresses human MKL1 (MKL1-Tg) specifically in cells of the monocyte/macrophage lineage, in order to investigate the potential role of macrophage MKL1 in the pathogenesis of colitis. MKL1-Tg mice displayed spontaneous colon shortening and rectal prolapse. Flow cytometric and quantitative RT-PCR analyses revealed that, in MKL1-Tg mice compared to littermate controls, the population of LPMac was decreased and had an altered inflammatory phenotype indicative of impaired anti-inflammatory properties, whereas bone marrow-derived macrophages from MKL1-Tg mice skewed towards M1 polarisation. In addition, MKL1-Tg mice had higher susceptibility to DSS-induced colitis than their littermate controls. These observations indicated that MKL1 crucially contributes to the development of colitis via the regulation of the function of macrophages, suggesting that it may be a potential therapeutic target for the prevention of IBD.


Asunto(s)
Colitis/metabolismo , Macrófagos/metabolismo , Transactivadores/metabolismo , Animales , Polaridad Celular , Colitis/patología , Colon/metabolismo , Colon/patología , Sulfato de Dextran , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/metabolismo , Femenino , Expresión Génica , Humanos , Inflamación/metabolismo , Inflamación/patología , Macrófagos/patología , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Prolapso Rectal/metabolismo , Prolapso Rectal/patología , Transactivadores/genética
9.
Int J Clin Exp Med ; 8(8): 13628-33, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26550305

RESUMEN

Hepatocellular carcinoma (HCC) is one of the most common lethal malignancies in the world, and the current knowledge on the molecular and genetic basis of HCC is still limited. Previous study has shown miR-149 plays a tumor suppressive role in HCC, here we aimed to investigate the association between rs71428439 polymorphism, which located in the pre-miR-149, and the risk of HCC in a Chinese Han population. A total of 177 HCC patients and 103 healthy controls were genotyped, by a multivariate logistic regression, we found that individuals with GG genotype have significantly higher risk of HCC (adjusted OR=3.397, 95% CI=1.565-7.375, P=0.002) compared with those with AA genotype, similar results were also observed in recessive model (adjusted OR=2.563, 95% CI=1.300-5.054, P=0.007) and dominant model (adjusted OR=2.074, 95% CI=1.147-3.752, P=0.016). We further observed that tumor tissues in patients with GG genotype expressed lower level of miR-149 compared with those with AA or AG genotype, and consequently, AKT1, a pre-validated miR-149 target in vitro, was found to have higher expression level in tumors with GG genotype. In summary, our data indicated that rs71428439 may be a genetic risk factor of HCC in the Chinese Han population, and its mechanism possibly involves downregulated miR-149 expression and upregulated AKT1 expression.

10.
Proc Natl Acad Sci U S A ; 110(51): 20699-704, 2013 Dec 17.
Artículo en Inglés | MEDLINE | ID: mdl-24302768

RESUMEN

High-mobility group box 1 (HMGB1) is a DNA-binding protein abundantly expressed in the nucleus that has gained much attention for its regulation of immunity and inflammation. Despite this, whether and how HMGB1 contributes to protective and/or pathological responses in vivo is unclear. In this study, we constructed Hmgb1-floxed (Hmgb1(f)(/f)) mice to achieve the conditional inactivation of the gene in a cell- and tissue-specific manner by crossing these mice with an appropriate Cre recombinase transgenic strain. Interestingly, although mice with HMGB1 ablation in myeloid cells apparently develop normally, they are more sensitive to endotoxin shock compared with control mice, which is accompanied by massive macrophage cell death. Furthermore, these mice also show an increased sensitivity to Listeria monocytogenes infection. We also provide evidence that the loss of HMGB1 in macrophages results in the suppression of autophagy, which is commonly induced by lipopolysaccharide stimulation or L. monocytogenes infection. Thus, intracellular HMGB1 contributes to the protection of mice from endotoxemia and bacterial infection by mediating autophagy in macrophages. These newly generated HMGB1 conditional knockout mice will serve a useful tool with which to study further the in vivo role of this protein in various pathological conditions.


Asunto(s)
Endotoxemia/inmunología , Proteína HMGB1/inmunología , Inmunidad Innata , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Macrófagos/inmunología , Animales , Autofagia/genética , Autofagia/inmunología , Línea Celular , Endotoxemia/genética , Endotoxemia/metabolismo , Endotoxemia/patología , Eliminación de Gen , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Listeriosis/genética , Listeriosis/metabolismo , Listeriosis/patología , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Transgénicos
11.
J Autoimmun ; 47: 25-33, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23953137

RESUMEN

HLA locus contains immune-related genes and genetically regulates immune responses against both foreign- and self-antigens in humans. Inhibitor of κB-like protein (IκBL), encoded by HLA-linked NFKBIL1, is a protein of unknown function, while genetic variations in NFKBIL1 are known to associate with the susceptibility to inflammatory and/or autoimmune diseases. In this study, we found that IκBL suppressed exon exclusion in alternative splicing of human immune-related genes such as CD45. Yeast-two-hybrid screening and immunoprecipitation assay revealed molecular association of IκBL with CLK1, a serine/threonine and tyrosine kinase, which plays a role in the alternative splicing. Unexpectedly, we found that the regulation of alternative splicing in CD45 by IκBL was independent from the kinase activity of CLK1. On the other hand, it was demonstrated that an SR protein, ASF/SF2, bound both IκBL and CLK1 at the RNA-recognition motifs of ASF/SF2, implying a competition of IκBL and CLK1 on SR protein. In addition, IκBL was found to regulate the CLK1-dependent synthesis of M2 RNA, a splice variant of influenza A virus M gene. These observations suggest a functional involvement of IκBL in the regulation of alternative splicing in both human and viral genes, which is a novel link of HLA locus to the regulation of immunity and infection in humans.


Asunto(s)
Empalme Alternativo , Antígenos HLA/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Virus de la Influenza A/genética , Antígenos Comunes de Leucocito/genética , Proteínas de la Matriz Viral/genética , Proteínas Adaptadoras Transductoras de Señales , Animales , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Células COS , Chlorocebus aethiops , Células HEK293 , Células HeLa , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Inflamación/genética , Inflamación/inmunología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/inmunología , Estructura Terciaria de Proteína , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/inmunología , Interferencia de ARN , ARN Interferente Pequeño , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Factores de Empalme Serina-Arginina
12.
Hypertens Res ; 33(8): 831-5, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20505677

RESUMEN

Macrophages have critical roles in the pathogenesis of atherosclerosis by activating the innate immune system and producing inflammatory cytokines. Accumulating evidence indicates that angiotensin type 1 receptor (AT1R) blockers exert anti-inflammatory effects in inflammatory diseases including atherosclerosis. In this study, we investigated the effect of losartan, an AT1R blocker, on the proinflammatory gene expression induced by bacterial lipopolysaccharide (LPS) in a well-defined in vitro human THP-1 macrophage system. We found that losartan significantly attenuated the LPS-induced expression of proinflammatory genes TNF-alpha, IL-8 and COX-2. However, exogenous angiotensin II (AngII) had no effect on LPS-induced inflammatory signaling despite the expression of AT1R. In addition, losartan did not block LPS-induced IkappaB phosphorylation, which is downstream of Toll-like receptor activation. Peroxisome proliferator-activated receptor-gamma (PPARgamma) antagonists, GW9662 and T0070907, reversed the inhibitory effects of losartan on LPS-induced TNF-alpha and IL-8 expression in THP-1 macrophages. These observations suggest that losartan inhibits LPS-induced proinflammatory gene expression in macrophages by activating the PPARgamma pathway rather than by the competitive inhibition of AT1R binding to AngII.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Losartán/farmacología , Macrófagos/efectos de los fármacos , PPAR gamma/metabolismo , Transducción de Señal/efectos de los fármacos , Angiotensina II/farmacología , Angiotensinógeno/genética , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/inmunología , Aterosclerosis/patología , Línea Celular , Expresión Génica/efectos de los fármacos , Expresión Génica/inmunología , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/inmunología , Hipertensión/patología , Proteínas I-kappa B/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Lipopolisacáridos/farmacología , Macrófagos/citología , Macrófagos/metabolismo , Monocitos/citología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Fosforilación/efectos de los fármacos , Receptor de Angiotensina Tipo 1/genética , Renina/genética , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/inmunología , Transducción de Señal/inmunología
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