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1.
Fish Shellfish Immunol ; 150: 109648, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38777253

RESUMEN

Laminin receptor (LR), which mediating cell adhesion to the extracellular matrix, plays a crucial role in cell signaling and regulatory functions. In the present study, a laminin receptor gene (SpLR) was cloned and characterized from the mud crab (Scylla paramamosain). The full length of SpLR contained an open reading frame (ORF) of 960 bp encoding 319 amino acids, a 5' untranslated region (UTR) of 66 bp and a 3' UTR of 49 bp. The predicted protein comprised two Ribosomal-S2 domains and a 40S-SA-C domain. The mRNA of SpLR was highly expressed in the gill, followed by the hepatopancreas. The expression of SpLR was up-regulated after mud crab dicistrovirus-1(MCDV-1) infection. Knocking down SpLR in vivo by RNA interference significantly down-regulated the expression of the immune genes SpJAK, SpSTAT, SpToll1, SpALF1 and SpALF5. This study shown that the expression level of SpToll1 and SpCAM in SpLR-interfered group significantly increased after MCDV-1 infection. Moreover, silencing of SpLR in vivo decreased the MCDV-1 replication and increased the survival rate of mud crabs after MCDV-1 infection. These findings collectively suggest a pivotal role for SpLR in the mud crab's response to MCDV-1 infection. By influencing the expression of critical innate immune factors and impacting viral replication dynamics, SpLR emerges as a key player in the intricate host-pathogen interaction, providing valuable insights into the molecular mechanisms underlying MCDV-1 pathogenesis in mud crabs.


Asunto(s)
Secuencia de Aminoácidos , Proteínas de Artrópodos , Braquiuros , Regulación de la Expresión Génica , Inmunidad Innata , Filogenia , Receptores de Laminina , Alineación de Secuencia , Animales , Braquiuros/genética , Braquiuros/inmunología , Receptores de Laminina/genética , Receptores de Laminina/inmunología , Proteínas de Artrópodos/genética , Proteínas de Artrópodos/inmunología , Proteínas de Artrópodos/química , Inmunidad Innata/genética , Regulación de la Expresión Génica/inmunología , Alineación de Secuencia/veterinaria , Perfilación de la Expresión Génica/veterinaria , Secuencia de Bases
2.
Mol Immunol ; 139: 65-75, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34454186

RESUMEN

After decades of cancer vaccine efforts, there is an imperious necessity for novel ideas that may result in better tumor control in patients. We have proposed the use of a novel Variable Epitope Library (VEL) vaccine strategy, which incorporates an unprecedented number of mutated epitopes to target antigenic variability and break tolerance against tumor-associated antigens. Here, we used an oncofetal antigen/immature laminin receptor protein-derived sequence to generate 9-mer and 43-mer VEL immunogens. 4T1 tumor-bearing mice developed epitope-specific CD8+IFN-γ+ and CD4+IFN-γ+ T cell responses after treatment. Tumor and lung analysis demonstrated that VELs could increase the number of tumor-infiltrating lymphocytes with diverse effector functions while reducing the number of immunosuppressive myeloid-derived suppressor and regulatory T cells. Most importantly, VEL immunogens inhibited tumor growth and metastasis after a single dose. The results presented here are consistent with our previous studies and provide evidence for VEL immunogens' feasibility as promising cancer immunotherapy.


Asunto(s)
Antígenos de Neoplasias/inmunología , Neoplasias de la Mama , Vacunas contra el Cáncer/inmunología , Epítopos de Linfocito T/inmunología , Receptores de Laminina/inmunología , Animales , Vacunas contra el Cáncer/farmacología , Modelos Animales de Enfermedad , Mapeo Epitopo/métodos , Femenino , Ratones , Ratones Endogámicos BALB C
3.
Mol Nutr Food Res ; 64(7): e1901036, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31978263

RESUMEN

SCOPE: Epigallocatechin gallate (EGCG), an active polyphenol in green tea, exhibits various physiological effects, including activation of low-density lipoprotein receptors (LDLR). The previous studies have suggested that EGCG activates LDLR via extracellular signal-regulated kinase (ERK) pathway in HepG2 cells. However, the detailed molecular mechanism remains unclear. Recently, 67 kDa laminin receptor (67LR) is identified as a receptor for EGCG. Therefore, this study aims to determine whether 67LR is involved in the mechanism of LDLR activation by EGCG. METHODS AND RESULTS: EGCG induces upregulation of LDLR when 67LR is knocked down in HepG2 cells. Similar effect is observed after the cells are treated with 67LR monoclonal antibody. The loss of antiallergic effect following 67LR siRNA knockdown and 67LR antibody treatment confirms the results since the antiallergic effect of EGCG is known to be mediated by 67LR. CONCLUSION: EGCG activates LDLR expression via 67LR-independent pathway in HepG2 cells.


Asunto(s)
Catequina/análogos & derivados , Receptores de LDL/metabolismo , Receptores de Laminina/metabolismo , Proteínas Ribosómicas/metabolismo , Anticuerpos/farmacología , Catequina/farmacología , Colesterol/metabolismo , Técnicas de Silenciamiento del Gen , Células Hep G2 , Humanos , Cadenas Ligeras de Miosina/metabolismo , Fosforilación/efectos de los fármacos , Receptores de LDL/genética , Receptores de Laminina/genética , Receptores de Laminina/inmunología , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/inmunología , Regulación hacia Arriba/efectos de los fármacos
4.
Front Immunol ; 11: 585399, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33603733

RESUMEN

Streptococcus suis serotype 2 (SS2), an important zoonotic pathogen that causes septicemia, arthritis, and irreversible meningitis in pigs and humans, can be transmitted to humans from pigs. S. suis causes huge economic losses to the swine industry and poses a serious threat to public health. Previously, we found that the brain tissues of mice with SS2-induced meningitis showed disrupted structural integrity and significantly enhanced polymorphonuclear neutrophil (PMN) infiltration. We showed that the brain tissues of SS2-infected mice had increased ribosomal protein SA (RPSA)-positive PMN counts. However, the inflammatory responses of RPSA+ PMNs to SS2 and their effects on the blood-brain barrier (BBB) remain unclear. Therefore, in studying the pathogenesis of SS2-induced meningitis, it is essential that we explore the functions of RPSA+ PMNs and their effects on the BBB. Herein, using flow cytometry and immunofluorescence microscopy analyses, we found that RPSA expression enhances PMN-induced phagocytosis and PMN-induced formation of neutrophil extracellular traps (NETs), which facilitate further elimination of bacteria. PMN surface expression of RPSA also alleviates local inflammation and tissue injuries by inhibiting secretion of the pro-inflammatory cytokines, TNF-α and IL-6. Moreover, the single-cell BBB model showed that RPSA disrupts BBB integrity by downregulating expression of tight junction-associated membrane proteins on PMNs. Taken together, our data suggest that PMN-surface expression of RPSA is a double-edged sword. RPSA+ PMN owns a stronger ability of bacterial cleaning and weakens inflammatory cytokines release which are useful to anti-infection, but does hurt BBB. Partly, RPSA+ PMN may be extremely useful to control the infection as a therapeutic cellular population, following novel insights into the special PMN population.


Asunto(s)
Trampas Extracelulares/inmunología , Meningitis Neumocócica/inmunología , Neutrófilos/inmunología , Fagocitosis/inmunología , Receptores de Laminina/inmunología , Proteínas Ribosómicas/inmunología , Animales , Barrera Hematoencefálica/inmunología , Barrera Hematoencefálica/patología , Citocinas/inmunología , Meningitis Neumocócica/patología , Ratones , Ratones Endogámicos C57BL , Neutrófilos/metabolismo , Receptores de Laminina/metabolismo , Proteínas Ribosómicas/metabolismo , Streptococcus suis/inmunología
5.
Nature ; 560(7716): 55-60, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30022166

RESUMEN

Acute lymphoblastic leukaemia (ALL) has a marked propensity to metastasize to the central nervous system (CNS). In contrast to brain metastases from solid tumours, metastases of ALL seldom involve the parenchyma but are isolated to the leptomeninges, which is an infrequent site for carcinomatous invasion. Although metastasis to the CNS occurs across all subtypes of ALL, a unifying mechanism for invasion has not yet been determined. Here we show that ALL cells in the circulation are unable to breach the blood-brain barrier in mice; instead, they migrate into the CNS along vessels that pass directly between vertebral or calvarial bone marrow and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin, which is known to coordinate pathfinding of neuronal progenitor cells in the CNS. The laminin receptor α6 integrin is expressed in most cases of ALL. We found that α6 integrin-laminin interactions mediated the migration of ALL cells towards the cerebrospinal fluid in vitro. Mice with ALL xenografts were treated with either a PI3Kδ inhibitor, which decreased α6 integrin expression on ALL cells, or specific α6 integrin-neutralizing antibodies and showed significant reductions in ALL transit along bridging vessels, blast counts in the cerebrospinal fluid and CNS disease symptoms despite minimally decreased bone marrow disease burden. Our data suggest that α6 integrin expression, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS.


Asunto(s)
Sistema Nervioso Central/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Animales , Anticuerpos Neutralizantes/inmunología , Membrana Basal/metabolismo , Barrera Hematoencefálica/metabolismo , Médula Ósea , Movimiento Celular , Sistema Nervioso Central/irrigación sanguínea , Sistema Nervioso Central/metabolismo , Líquido Cefalorraquídeo/metabolismo , Circulación Cerebrovascular , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Progresión de la Enfermedad , Femenino , Xenoinjertos/inmunología , Xenoinjertos/patología , Integrina alfa6/inmunología , Integrina alfa6/metabolismo , Laminina/metabolismo , Masculino , Ratones , Ratones SCID , Trasplante de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimología , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Receptores de Laminina/antagonistas & inhibidores , Receptores de Laminina/inmunología , Receptores de Laminina/metabolismo , Cráneo , Espacio Subaracnoideo
6.
Cell Physiol Biochem ; 46(5): 2072-2081, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29723847

RESUMEN

BACKGROUND/AIMS: Inflammatory bowel disease (IBD) is a condition that involves chronic inflammation in all or part of the digestive tract. Often painful and debilitating, IBD can lead to life-threatening complications and increase the risk for colon cancer. In this study, we investigated the epigallocatechin-3-gallate (EGCG) mediated anti-inflammation response in lipopolysaccharide (LPS)-stimulated human colorectal cells through the negative regulator of Toll-like receptor (TLR) signaling. METHODS: human intestinal epithelial cells (HT-29) were used in all experiments. Cell cytotoxicity and nitric oxide (NO) were evaluated by WST-1 and the Griess reagent. Western blot analysis and ELISA were used to determine inflammatory mediators and 67-kDa laminin receptor (67LR)-mediated Tollip signaling pathways. RESULTS: Treatment of EGCG and LPS did not affect the cytotoxicity in HT-29 cells. LPS treatment dose-dependently increased the pro-inflammatory cytokine, such as interleukin (IL)-8, whereas EGCG significantly reduced the LPS-stimulated IL-8 production. Additionally, EGCG treatment markedly increased the Toll-interacting protein (Tollip) expression, which negatively regulates the TLR signaling in a dose and time-dependent manner. In particular, in the result from an RNA interference-mediated assay, our finding showed that silencing of Tollip resulted in abrogation of the inhibitory action of EGCG on LPS-induced production of pro-inflammatory mediators (inducible nitric oxide synthase-mediated NO/COX2, and IL-8) and activation of MAPKs and NF-κB signaling pathways. Interestingly, we also found that Tollip expression induced by EGCG could be modulated through 67LR expressed on the surface of HT-29 cells. CONCLUSIONS: Our novel finding indicates that 67LR and Tollip signaling activated by EGCG treatment is essential for inhibition of inflammation in human intestinal epithelial cells.


Asunto(s)
Antiinflamatorios/farmacología , Catequina/análogos & derivados , Mucosa Intestinal/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/inmunología , Lipopolisacáridos/inmunología , Receptores de Laminina/inmunología , Transducción de Señal/efectos de los fármacos , Catequina/farmacología , Células HT29 , Humanos , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología
7.
Exp Cell Res ; 351(2): 135-141, 2017 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-28118986

RESUMEN

The 37kDa/67kDa laminin receptor (LRP/LR) is a non-integrin laminin receptor which is overexpressed in tumorigenic cells and supports progression of cancer via promoting metastasis, angiogenesis and telomerase activity and impediment of apoptosis. The present study investigates the role of LRP/LR on the metastatic potential of early (A375) and late (A375SM) stage malignant melanoma cells. Flow cytometry revealed that both early and late stage malignant melanoma cells display high levels of LRP/LR on their cell surface. Flow cytometry and western blot analysis showed that late stage malignant melanoma cells display significantly higher total and cell surface LRP/LR levels in comparison to early stage malignant melanoma cells and the poorly invasive breast cancer (MCF-7) control cell line. Targeting LRP/LR using the LRP/LR specific antibody IgG1-iS18 resulted in a significant reduction of the adhesive potential to laminin-1 and the invasive potential through the 'ECM-simulating' Matrigel™ of both early and late stage malignant melanoma cells. Furthermore, Pearson's correlation coefficient confirmed that increased LRP levels correlate with the increased invasive and adhesive potential in early and late stage melanoma cells. Thus, blocking LRP/LR using the IgG1-iS18 antibody may therefore be a promising therapeutic strategy for early and late stage malignant melanoma treatment.


Asunto(s)
Anticuerpos Antineoplásicos/farmacología , Anticuerpos Neutralizantes/farmacología , Regulación Neoplásica de la Expresión Génica , Inmunoglobulina G/farmacología , Melanoma/inmunología , Receptores de Laminina/antagonistas & inhibidores , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Colágeno/química , Combinación de Medicamentos , Femenino , Citometría de Flujo , Humanos , Laminina/química , Células MCF-7 , Melanoma/genética , Melanoma/patología , Estadificación de Neoplasias , Proteoglicanos/química , Receptores de Laminina/genética , Receptores de Laminina/inmunología , Transducción de Señal , Células Tumorales Cultivadas
8.
BMC Cancer ; 16(1): 917, 2016 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-27884119

RESUMEN

BACKGROUND: Cancer has become a global burden due to its high incidence and mortality rates, with an estimated 14.1 million cancer cases reported worldwide in 2012 particularly as a result of metastasis. Metastasis involves two crucial steps: adhesion and invasion, and the non-integrin receptor; the 37-kDa/67-kDa laminin receptor precursor/ high affinity laminin receptor (LRP/LR) has been shown to be overexpressed on the surface of tumorigenic cells, thus being implicated in the enhancement of these two crucial steps. The current study investigated the role of LRP/LR on the aggressiveness of pancreatic cancer (AsPC-1) and neuroblastoma (IMR-32) cells with respect to their adhesive and invasive potential. METHODS: AsPC-1 and IMR-32 cells were utilized as the experimental cell lines for the study. Cell surface LRP/LR levels were visualised and quantified on the experimental and control (MCF-7) cell lines via confocal microscopy and flow cytometry, respectively. Total LRP/LR levels in the cell lines were assessed by Western blotting and the adhesive and invasive potential of the above-mentioned cell lines was determined before and after supplementation with the anti-LRP/LR specific antibody IgG1-iS18. Statistical significance of the data was confirmed via the use of the two-tailed student's t-test and Pearson's correlation coefficient. RESULTS: Flow cytometry revealed that AsPC-1 and IMR-32 cells displayed significantly higher cell surface LRP/LR levels in comparison to the MCF-7 control cell line. However, Western blotting and subsequent densitometric analysis revealed that all three tumorigenic cell lines displayed no significant difference in total LRP/LR levels. The treatment of AsPC-1 and IMR-32 cells with IgG1-iS18 caused a significant reduction in the adhesive and invasive potential of the cells to laminin-1 and through the ECM-like Matrigel™, respectively. Pearson's correlation coefficients indicated a high correlation, thus suggesting a directly proportional relationship between cell surface LRP/LR levels and the adhesive and invasive potential of AsPC-1 and IMR-32 cells. CONCLUSION: These findings suggest that through the interference of the LRP/LR-laminin-1 interaction, the anti-LRP/LR specific antibody IgG1-iS18 may act as an alternative therapeutic tool for the treatment of metastatic pancreatic cancer and neuroblastoma.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Adhesión Celular/efectos de los fármacos , Inmunoglobulina G/inmunología , Neuroblastoma/prevención & control , Neoplasias Pancreáticas/prevención & control , Receptores de Laminina/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Western Blotting , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Invasividad Neoplásica , Neuroblastoma/metabolismo , Neuroblastoma/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Laminina/inmunología , Receptores de Laminina/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas
9.
J Alzheimers Dis ; 49(3): 645-57, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26484914

RESUMEN

The neuronal perturbations in Alzheimer's disease are attributed to the formation of extracellular amyloid-ß (Aß) neuritic plaques, composed predominantly of the neurotoxic Aß42 isoform. Although the plaques have demonstrated a role in synaptic dysfunction, neuronal cytotoxicity has been attributed to soluble Aß42 oligomers. The 37kDa/67kDa laminin receptor has been implicated in Aß42 shedding and Aß42-induced neuronal cytotoxicity, as well as internalization of this neurotoxic peptide. As the cellular prion protein binds to both LRP/LR and Aß42, the mechanism underlying this cytotoxicity may be indirectly due to the PrPc-Aß42 interaction with LRP/LR. The effects of this interaction were investigated by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assays. PrPc overexpression significantly enhanced Aß42 cytotoxicity in vitro, while PrP-/-  cells were more resistant to the cytotoxic effects of Aß42 and exhibited significantly less cell death than PrPc expressing N2a cells. Although anti-LRP/LR specific antibody IgG1-iS18 significantly enhanced cell viability in both pSFV1-huPrP1-253 transfected and non-transfected cells treated with exogenous Aß42, it failed to have any cell rescuing effect in PrP-/-  HpL3-4 cells. These results suggest that LRP/LR plays a significant role in Aß42-PrPc mediated cytotoxicity and that anti-LRP/LR specific antibodies may serve as potential therapeutic tools for Alzheimer's disease.


Asunto(s)
Péptidos beta-Amiloides/toxicidad , Anticuerpos/farmacología , Fragmentos de Péptidos/toxicidad , Priones/metabolismo , Receptores de Laminina/inmunología , Péptidos beta-Amiloides/metabolismo , Animales , Línea Celular Transformada , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Citometría de Flujo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Humanos , Ratones , Fragmentos de Péptidos/metabolismo , Priones/genética , Proteínas Ribosómicas , Transfección
10.
Cancer Biol Ther ; 16(5): 724-32, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25799942

RESUMEN

The oncofetal antigen - immature laminin receptor protein (OFA/iLRP) has been linked to metastatic tumor spread for several years. The present study, in which 2 highly-specific, high-affinity OFA/iLRP-reactive mouse monoclonal antibodies were examined for ability to suppress tumor cell growth and metastatic spread in the A20 B-cell leukemia model and the B16 melanoma model, provides the first direct evidence that targeting OFA/iLRP with exogenous antibodies can have therapeutic benefit. While the antibodies were modestly effective at preventing tumor growth at the primary injection site, both antibodies strongly suppressed end-organ tumor formation following intravenous tumor cell injection. Capacity of anti-OFA/iLRP antibodies to suppress tumor spread through the blood in the leukemia model suggests their use as a therapy for individuals with leukemic disease (either for patients in remission or even as part of an induction therapy). The results also suggest use against metastatic spread with solid tumors.


Asunto(s)
Antígenos de Neoplasias/inmunología , Melanoma Experimental/inmunología , Receptores de Laminina/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Antígenos de Neoplasias/genética , Modelos Animales de Enfermedad , Melanoma Experimental/genética , Ratones , Receptores de Laminina/genética
11.
J Agric Food Chem ; 63(10): 2811-9, 2015 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-25732404

RESUMEN

Obesity-related insulin resistance is associated with chronic systemic low-grade inflammation, and toll-like receptor 4 (TLR4) regulates inflammation. We investigated the pathways involved in epigallocatechin gallate (EGCG) modulation of insulin and TLR4 signaling in adipocytes. Inflammation was induced in adipocytes by lipopolysaccharide (LPS). An antibody against the 67 kDa laminin receptor (67LR, to which EGCG exclusively binds) was used to examine the effect of EGCG on TLR4 signaling, and a TLR4/MD-2 antibody was used to inhibit TLR4 activity and to determine the insulin sensitivity of differentiated 3T3-L1 adipocytes. We found that EGCG dose-dependently inhibited LPS stimulation of adipocyte inflammation by reducing inflammatory mediator and cytokine levels (IKKß, p-NF-κB, TNF-α, and IL-6). Pretreatment with the 67LR antibody prevented EGCG inhibition of inflammatory cytokines, decreased glucose transporter isoform 4 (GLUT4) expression, and inhibited insulin-stimulated glucose uptake. TLR4 inhibition attenuated inflammatory cytokine levels and increased glucose uptake by reversing GLUT4 levels. These data suggest that EGCG suppresses TLR4 signaling in LPS-stimulated adipocytes via 67LR and attenuates insulin-stimulated glucose uptake associated with decreased GLUT4 expression.


Asunto(s)
Adipocitos/efectos de los fármacos , Antiinflamatorios/farmacología , Catequina/análogos & derivados , Lipopolisacáridos/inmunología , Receptores de Laminina/inmunología , Receptor Toll-Like 4/inmunología , Células 3T3-L1 , Adipocitos/inmunología , Animales , Catequina/farmacología , Interleucina-6/inmunología , Ratones , FN-kappa B/inmunología , Receptores de Laminina/genética , Receptor Toll-Like 4/genética , Factor de Necrosis Tumoral alfa/inmunología
12.
Cell Mol Biol Lett ; 19(3): 393-406, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25082063

RESUMEN

The 37-kDa immature laminin receptor protein (iLRP) is a speciesconserved, universal immunogenic protein that is expressed in all thus-far examined embryonic and early fetal cells of inbred and outbred rodents. It has also been identified in human concepti. It is altered through normal maturation processes to become a non-immunogenic 67-kDa dimeric mature laminin receptor protein (mLRP) in mid-to late gestation in the mammalian fetus. This antigen ceases to be expressed as an active autoimmunogen in the full-term fetus and in the normal differentiating tissues and organs of the neonate or adult organism, apparently due to dimerization, but it is re-expressed as an immunogenic monomer in tumor cells. In this review, we highlight the known mechanisms of immune responses with particular emphasis on the possible role of the 37-kDa oncofetal antigen/immature laminin receptor (OFA/iLRP) in both pregnancy and cancer.


Asunto(s)
Neoplasias/inmunología , Receptores de Laminina/inmunología , Proteínas Ribosómicas/inmunología , Adulto , Animales , Femenino , Humanos , Ratones , Modelos Inmunológicos , Neoplasias/metabolismo , Embarazo , Receptores de Laminina/metabolismo , Proteínas Ribosómicas/metabolismo
13.
PLoS One ; 9(5): e96268, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24798101

RESUMEN

Two key events, namely adhesion and invasion, are pivotal to the occurrence of metastasis. Importantly, the 37 kDa/67 kDa laminin receptor (LRP/LR) has been implicated in enhancing these two events thus facilitating cancer progression. In the current study, the role of LRP/LR in the adhesion and invasion of liver cancer (HUH-7) and leukaemia (K562) cells was investigated. Flow cytometry revealed that the HUH-7 cells displayed significantly higher cell surface LRP/LR levels compared to the poorly-invasive breast cancer (MCF-7) control cells, whilst the K562 cells displayed significantly lower cell surface LRP/LR levels in comparison to the MCF-7 control cells. However, Western blotting and densitometric analysis revealed that all three tumorigenic cell lines did not differ significantly with regards to total LRP/LR levels. Furthermore, treatment of liver cancer cells with anti-LRP/LR specific antibody IgG1-iS18 (0.2 mg/ml) significantly reduced the adhesive potential of cells to laminin-1 and the invasive potential of cells through the ECM-like Matrigel, whilst leukaemia cells showed no significant differences in both instances. Additionally, Pearson's correlation coefficients suggested direct proportionality between cell surface LRP/LR levels and the adhesive and invasive potential of liver cancer and leukaemia cells. These findings suggest the potential use of anti-LRP/LR specific antibody IgG1-iS18 as an alternative therapeutic tool for metastatic liver cancer through impediment of the LRP/LR- laminin-1 interaction.


Asunto(s)
Anticuerpos Antiidiotipos/farmacología , Adhesión Celular , Leucemia/patología , Neoplasias Hepáticas/patología , Invasividad Neoplásica , Receptores de Laminina/fisiología , Anticuerpos Antiidiotipos/uso terapéutico , Línea Celular Tumoral , Citometría de Flujo , Humanos , Inmunoglobulina G/inmunología , Laminina/metabolismo , Leucemia/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Células MCF-7 , Receptores de Laminina/genética , Receptores de Laminina/inmunología
14.
PLoS One ; 8(6): e66297, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23823499

RESUMEN

Adhesion and invasion have been identified as the two key components of metastasis. The 37 kDa/67 kDa laminin receptor (LRP/LR) is thought to enhance these two processes thus endorsing the progression of cancer. Here we report on LRP/LR and the metastatic potential of MDA-MB 231 breast and WHCO1 oesophageal cancer cells. Western blot analysis revealed a significant increase in total laminin receptor precursor (LRP) levels of breast and oesophageal cancer cells in comparison to non-invasive MCF-7 breast cancer cells, whereas LRP/LR cell surface levels in both cell lines were not significantly different to those of MCF-7 cells as analysed by flow cytometry. Incubation of breast and oesophageal cancer cells with the anti-LRP/LR specific antibody, IgG1-iS18, resulted in significant reduction in the adhesive potential of WHCO1 and MDA-MB 231 cells by 92% and 16%, respectively. Moreover, invasion was significantly impeded by 98% and 25% for WHCO1 and MDA-MB 231 cells, respectively. Pearson's correlation coefficients proved a positive correlation between total LRP/LR levels and invasive potential as well as between the adhesive and invasive potential of breast and oesophageal cancer cells. Our findings suggest that through interference of the LRP/LR-laminin-1 interaction, anti-LRP/LR specific antibody IgG1-iS18 may act as a possible alternative therapeutic tool for metastatic breast and oesophageal cancer treatment.


Asunto(s)
Anticuerpos/inmunología , Neoplasias de la Mama/patología , Adhesión Celular/inmunología , Neoplasias Esofágicas/patología , Inmunoglobulina G/inmunología , Invasividad Neoplásica/inmunología , Receptores de Laminina/inmunología , Línea Celular Tumoral , Femenino , Humanos , Masculino
15.
J Mol Biol ; 419(1-2): 102-9, 2012 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-22391421

RESUMEN

The 37-kDa/67-kDa laminin receptor [laminin receptor precursor/high-affinity laminin receptor (LRP/LR)] is thought to play a major role in invasion and adhesion, key components of metastatic cancer. Lung cancer, cervical cancer, colon cancer and prostate cancer are among the top 10 cancer types worldwide. Here, we report that LRP/LR levels on the surface of lung cancer cells, cervical cancer cells, colon cancer cells and prostate cancer cells are significantly increased compared to non-tumorigenic fibroblasts. Adhesion of lung cancer cells, cervical cancer cells, colon cancer cells and prostate cancer cells to laminin-1 is significantly reduced, employing the anti-LRP/LR-specific antibody IgG1-iS18. Invasion of these cell lines into the Matrigel™ matrix was significantly impeded with IgG1-iS18. The Pearson's correlation coefficient proves a correlation between LRP/LR cell-surface levels and invasion potential, as well as adhesion and invasion, respectively. Our findings suggest that IgG1-iS18 antibody might act as alternative therapeutic tool for treatment of various metastatic cancer types.


Asunto(s)
Anticuerpos Antiidiotipos/inmunología , Adhesión Celular/inmunología , Inmunoglobulina G/inmunología , Neoplasias/inmunología , Neoplasias/patología , Receptores de Laminina/inmunología , Animales , Especificidad de Anticuerpos , Línea Celular , Línea Celular Tumoral , Femenino , Fibroblastos/inmunología , Fibroblastos/metabolismo , Células HeLa , Humanos , Masculino , Ratones , Células 3T3 NIH , Invasividad Neoplásica , Neoplasias/terapia , Receptores de Superficie Celular/inmunología , Receptores de Superficie Celular/metabolismo , Receptores de Laminina/metabolismo
16.
Aging Cell ; 10(5): 798-806, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21615674

RESUMEN

Cellular senescence is an age-associated phenomenon that promotes tumor invasiveness owing to the secretion of proinflammatory cytokines, proteases, and growth factors. Herein we demonstrate that cellular senescence also potentially increases susceptibility to bacterial pneumonia caused by Streptococcus pneumoniae (the pneumococcus), the leading cause of infectious death in the elderly. Aged mice had increased lung inflammation as determined by cytokine analysis and histopathology of lung sections. Immunoblotting for p16, pRb, and mH2A showed that elderly humans and aged mice had increased levels of these senescence markers in their lungs vs. young controls. Keratin 10 (K10), laminin receptor (LR), and platelet-activating factor receptor (PAFr), host proteins known to be co-opted for bacterial adhesion, were also increased. Aged mice were found to be highly susceptible to pneumococcal challenge in a PsrP, the pneumococcal adhesin that binds K10, dependent manner. In vitro senescent A549 lung epithelial cells had elevated K10 and LR protein levels and were up to 5-fold more permissive for bacterial adhesion. Additionally, exposure of normal cells to conditioned media from senescent cells doubled PAFr levels and pneumococcal adherence. Genotoxic stress induced by bleomycin and oxidative stress enhanced susceptibility of young mice to pneumonia and was positively correlated with enhanced p16, inflammation, and LR levels. These findings suggest that cellular senescence facilitates bacterial adhesion to cells in the lungs and provides an additional molecular mechanism for the increased incidence of community-acquired pneumonia in the elderly. This study is the first to suggest a second negative consequence for the senescence-associated secretory phenotype.


Asunto(s)
Senescencia Celular , Susceptibilidad a Enfermedades , Pulmón/microbiología , Neumonía Neumocócica/microbiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Envejecimiento/inmunología , Envejecimiento/patología , Animales , Adhesión Bacteriana , Biomarcadores , Bleomicina/administración & dosificación , Bleomicina/farmacología , Línea Celular Tumoral , Citocinas/análisis , Citocinas/inmunología , Femenino , Humanos , Immunoblotting , Inmunohistoquímica , Inflamación/inmunología , Inflamación/patología , Estimación de Kaplan-Meier , Queratina-10/inmunología , Queratina-10/metabolismo , Pulmón/inmunología , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Estrés Oxidativo , Neumonía Neumocócica/inmunología , Neumonía Neumocócica/patología , Receptores de Laminina/inmunología , Receptores de Laminina/metabolismo , Streptococcus pneumoniae/inmunología , Streptococcus pneumoniae/patogenicidad
17.
Immunology ; 129(2): 248-56, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19824923

RESUMEN

We previously showed alterations in the thymus during experimental infection with Plasmodium berghei. Such alterations comprised histological changes, with loss of cortical-medullary limits, and the intrathymic presence of parasites. As the combination of chemokines, adhesion molecules and extracellular matrix (ECM) is critical to appropriate thymocyte development, we analysed the thymic expression of ECM ligands and receptors, as well as chemokines and their respective receptors during the experimental P. berghei infection. Increased expression of ECM components was observed in thymi from infected mice. In contrast, down-regulated surface expression of fibronectin and laminin receptors was observed in thymocytes from these animals. Moreover, in thymi from infected mice there was increased CXCL12 and CXCR4, and a decreased expression of CCL25 and CCR9. An altered thymocyte migration towards ECM elements and chemokines was seen when the thymi from infected mice were analysed. Evaluation of ex vivo migration patterns of CD4/CD8-defined thymocyte subpopulations revealed that double-negative (DN), and CD4(+) and CD8(+) single-positive (SP) cells from P. berghei-infected mice have higher migratory responses compared with controls. Interestingly, increased numbers of DN and SP subpopulations were found in the spleens of infected mice. Overall, we show that the thymic atrophy observed in P. berghei-infected mice is accompanied by thymic microenvironmental changes that comprise altered expression of thymocyte migration-related molecules of the ECM and chemokine protein families, which in turn can alter the thymocyte migration pattern. These thymic disturbances may have consequences for the control of the immune response against this protozoan.


Asunto(s)
Movimiento Celular/inmunología , Malaria/inmunología , Plasmodium berghei/inmunología , Células Precursoras de Linfocitos T/metabolismo , Timo/metabolismo , Animales , Antígenos CD4/biosíntesis , Antígenos CD8/biosíntesis , Células Cultivadas , Quimiocinas/biosíntesis , Quimiocinas/genética , Quimiocinas/inmunología , Regulación de la Expresión Génica , Malaria/parasitología , Malaria/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Animales , Plasmodium berghei/patogenicidad , Células Precursoras de Linfocitos T/inmunología , Células Precursoras de Linfocitos T/parasitología , Células Precursoras de Linfocitos T/patología , Receptores de Citoadhesina/biosíntesis , Receptores de Citoadhesina/genética , Receptores de Citoadhesina/inmunología , Receptores de Fibronectina/biosíntesis , Receptores de Fibronectina/genética , Receptores de Fibronectina/inmunología , Receptores de Laminina/biosíntesis , Receptores de Laminina/genética , Receptores de Laminina/inmunología , Timo/inmunología , Timo/parasitología , Timo/patología
18.
Biomaterials ; 30(17): 3091-9, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19268360

RESUMEN

We describe here for the first time an efficient high yield production method for clinical grade recombinant human Oncofetal Antigen/immature laminin receptor protein (OFA/iLRP). We also demonstrate significant antitumor activity for this protein when administered in liposomal delivery form in a murine model of syngeneic fibrosarcoma. OFA/iLRP is a therapeutically very promising universal tumor antigen that is expressed in all mammalian solid tumors tested so far. We have cloned the human OFA/iLRP cDNA in a bacterial expression plasmid which incorporates a 6x HIS-tag. Large scale cultures of the plasmid transformed Escherichia coli were performed and the crude HIS-tagged OFA/iLRP was isolated as inclusion bodies and solubilized in guanidine chloride. The protein was then purified by successive passage through three column chromatography steps of immobilized metal affinity, anion exchange, and gel filtration. The resulting protein was 94% pure and practically devoid of endotoxin and host cell protein. The purified OFA/iLRP was tested in mice for safety and efficacy in tumor rejection with satisfactory results. This protein will be used for loading onto autologous dendritic cells in an FDA approved phase I/II human cancer vaccine trial in OFA/iLRP-positive breast cancer patients.


Asunto(s)
Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Fibrosarcoma/inmunología , Receptores de Laminina/inmunología , Proteínas Ribosómicas/inmunología , Secuencia de Aminoácidos , Animales , Antígenos de Neoplasias/química , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/aislamiento & purificación , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/metabolismo , Línea Celular Tumoral/inmunología , Ensayos Clínicos como Asunto , Clonación Molecular , Modelos Animales de Enfermedad , Escherichia coli/genética , Femenino , Fibrosarcoma/metabolismo , Guanidina/farmacología , Histidina/química , Humanos , Cuerpos de Inclusión/inmunología , Cuerpos de Inclusión/metabolismo , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Peso Molecular , Plásmidos/genética , Control de Calidad , Receptores de Laminina/química , Receptores de Laminina/genética , Receptores de Laminina/aislamiento & purificación , Proteínas Recombinantes/química , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/aislamiento & purificación , Proteínas Ribosómicas/química , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/aislamiento & purificación , Solubilidad , Transformación Bacteriana , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Am J Physiol Cell Physiol ; 297(1): C121-32, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19176763

RESUMEN

Insulin and (-)-epigallocatechin gallate (EGCG) have been reported to regulate fat cell mitogenesis and adipogenesis, respectively. This study investigated the pathways involved in EGCG modulation of insulin-stimulated mitogenesis in 3T3-L1 preadipocytes. EGCG inhibited insulin stimulation of preadipocyte proliferation in a dose- and time-dependent manner. EGCG also suppressed insulin-stimulated phosphorylation of the insulin receptor-beta, insulin receptor (IR) substrates 1 and 2 (IRS1 and IRS2), and mitogen-activated protein kinase pathway proteins, RAF1, MEK1/2, and ERK1/2, but not JNK. Furthermore, EGCG inhibited the association of IR with the IRS1 and IRS2 proteins, but not with the IRS4 protein. These data suggest that EGCG selectively affects particular types of IRS and MAPK family members. Generally, EGCG was more effective than epicatechin, epicatechin gallate, and epigallocatechin in modulating insulin-stimulated mitogenic signaling. We identified the EGCG receptor [also known as the 67-kDa laminin receptor (67LR)] in fat cells and found that its expression was sensitive to growth phase, tissue type, and differentiation state. Pretreatment of preadipocytes with 67LR antiserum prevented the effects of EGCG on insulin-stimulated phosphorylation of IRS2, RAF1, and ERK1/2 and insulin-stimulated preadipocyte proliferation (cell number and bromodeoxyuridine incorporation). Moreover, EGCG tended to increase insulin-stimulated associations between the 67LR and IR, IRS1, IRS2, and IRS4 proteins. These data suggest that EGCG mediates anti-insulin signaling in preadipocyte mitogenesis via the 67LR pathway.


Asunto(s)
Adipocitos/efectos de los fármacos , Fármacos Antiobesidad/farmacología , Camellia sinensis , Catequina/análogos & derivados , Proliferación Celular/efectos de los fármacos , Insulina/metabolismo , Receptores de Laminina/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Células 3T3-L1 , Adipocitos/metabolismo , Animales , Fármacos Antiobesidad/aislamiento & purificación , Camellia sinensis/química , Catequina/aislamiento & purificación , Catequina/farmacología , Relación Dosis-Respuesta a Droga , Sueros Inmunes , Proteínas Sustrato del Receptor de Insulina/metabolismo , MAP Quinasa Quinasa 1/metabolismo , MAP Quinasa Quinasa 2/metabolismo , Ratones , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-raf/metabolismo , Receptores de Laminina/inmunología , Receptores de Laminina/metabolismo , Factores de Tiempo
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