RESUMEN
Hematological malignancies refer to a heterogeneous group of neoplastic conditions of lymphoid and hematopoietic tissues classified in leukemias, Hodgkin and non-Hodgkin lymphomas and multiple myeloma, according to their presumed cell of origin, genetic abnormalities, and clinical features. Metabolic adaptation and immune escape, which influence various cellular functions, including the proliferation and survival of hematological malignant tumor cells, are major aspects of these malignancies that lead to therapeutic drug resistance. Targeting specific metabolic pathways is emerging as a novel therapeutic strategy in hematopoietic neoplasms, particularly in acute myeloid leukemia and multiple myeloma. In this context, CD147, also known as extracellular matrix metalloproteinase inducer (EMMPRIN) or Basigin, is one target candidate involved in reprograming metabolism in different cancer cells, including hematological malignant tumor cells. CD147 overexpression significantly contributes to the metabolic transformation of these cancer cells, by mediating signaling pathway, growth, metastasis and metabolic reprogramming, through its interaction, direct or not, with various membrane proteins related to metabolic regulation, including monocarboxylate transporters, integrins, P-glycoprotein, and glucose transporter 1. This review explores the metabolic functions of CD147 and its impact on the tumor microenvironment, influencing the progression and neoplastic transformation of leukemias, myeloma, and lymphomas. Furthermore, we highlight new opportunities for the development of targeted therapies against CD147, potentially improving the treatment of hematologic malignancies.
Asunto(s)
Basigina , Neoplasias Hematológicas , Microambiente Tumoral , Humanos , Basigina/metabolismo , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/patología , Animales , Transducción de SeñalRESUMEN
Psoriasis is a chronic, proliferative, and inflammatory skin disease closely associated with inflammatory cytokine production. Cyclophilin A (CypA) is an important proinflammatory factor; however, its role in psoriasis remains unclear. The present data indicate that CypA levels are increased in the lesion skin and serum of patients with psoriasis, which is positively correlated with the psoriasis area severity index. Furthermore, extracellular CypA (eCypA) triggered psoriasis-like inflammatory responses in keratinocytes. Moreover, anti-CypA mAb significantly reduced pathological injury, keratinocyte proliferation, cytokine expression in imiquimod-induced mice. Notably, the therapeutic effect of anti-CypA mAb was better than that of the clinically used anti-IL-17A mAb and methotrexate. Mechanistically, eCypA binds to ACE2 and CD147 and is blocked by anti-CypA mAb. eCypA not only induces the dimerization and phosphorylation of ACE2 to trigger the JAK1/STAT3 signaling pathway for cytokine expression but also interacts with CD147 to promote PI3K/AKT/mTOR signaling-mediated keratinocyte proliferation. These findings demonstrate that the binding of eCypA to ACE2 and CD147 cooperatively triggers psoriasis-like inflammation and anti-CypA mAb is a promising candidate for the treatment of psoriasis.
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Enzima Convertidora de Angiotensina 2 , Basigina , Ciclofilina A , Queratinocitos , Unión Proteica , Psoriasis , Transducción de Señal , Basigina/metabolismo , Basigina/inmunología , Ciclofilina A/metabolismo , Humanos , Animales , Psoriasis/metabolismo , Psoriasis/inmunología , Ratones , Queratinocitos/metabolismo , Queratinocitos/inmunología , Enzima Convertidora de Angiotensina 2/metabolismo , Inflamación/metabolismo , Inflamación/inmunología , Modelos Animales de Enfermedad , Masculino , Femenino , Proliferación Celular , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Citocinas/metabolismoRESUMEN
Fusobacterium nucleatum can bind to host cells and potentiate intestinal tumorigenesis. Here we used a genome-wide screen to identify an adhesin, RadD, which facilitates the attachment of F. nucleatum to colorectal cancer (CRC) cells in vitro. RadD directly binds to CD147, a receptor overexpressed on CRC cell surfaces, which initiated a PI3K-AKT-NF-κB-MMP9 cascade, subsequently enhancing tumorigenesis in mice. Clinical specimen analysis showed that elevated radD gene levels in CRC tissues correlated positively with activated oncogenic signalling and poor patient outcomes. Finally, blockade of the interaction between RadD and CD147 in mice effectively impaired F. nucleatum attachment and attenuated F. nucleatum-induced oncogenic response. Together, our study provides insights into an oncogenic mechanism driven by F. nucleatum RadD and suggests that the RadD-CD147 interaction could be a potential therapeutic target for CRC.
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Adhesinas Bacterianas , Adhesión Bacteriana , Basigina , Carcinogénesis , Neoplasias Colorrectales , Fusobacterium nucleatum , Fusobacterium nucleatum/patogenicidad , Fusobacterium nucleatum/genética , Fusobacterium nucleatum/fisiología , Neoplasias Colorrectales/microbiología , Neoplasias Colorrectales/patología , Animales , Humanos , Ratones , Basigina/metabolismo , Basigina/genética , Adhesinas Bacterianas/metabolismo , Adhesinas Bacterianas/genética , Carcinogénesis/genética , Línea Celular Tumoral , Infecciones por Fusobacterium/microbiología , Infecciones por Fusobacterium/complicaciones , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Transducción de Señal , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , FemeninoRESUMEN
Olfactory perception is an important physiological function for human well-being and health. Loss of olfaction, or anosmia, caused by viral infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has received considerable attention, especially in persistent cases that take a long time to recover. This review discusses the integration of different components of the olfactory epithelium to serve as a structural and functional unit and explores how they are affected during viral infections, leading to the development of olfactory dysfunction. The review mainly focused on the role of receptors mediating the disruption of olfactory signal transduction pathways such as angiotensin converting enzyme 2 (ACE2), transmembrane protease serine type 2 (TMPRSS2), neuropilin 1 (NRP1), basigin (CD147), olfactory, transient receptor potential vanilloid 1 (TRPV1), purinergic, and interferon gamma receptors. Furthermore, the compromised function of the epithelial sodium channel (ENaC) induced by SARS-CoV-2 infection and its contribution to olfactory dysfunction are also discussed. Collectively, this review provides fundamental information about the many types of receptors that may modulate olfaction and participate in olfactory dysfunction. It will help to understand the underlying pathophysiology of virus-induced anosmia, which may help in finding and designing effective therapies targeting molecules involved in viral invasion and olfaction. To the best of our knowledge, this is the only review that covered all the receptors potentially involved in, or mediating, the disruption of olfactory signal transduction pathways during COVID-19 infection. This wide and complex spectrum of receptors that mediates the pathophysiology of olfactory dysfunction reflects the many ways in which anosmia can be therapeutically managed.
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Anosmia , COVID-19 , SARS-CoV-2 , Humanos , COVID-19/metabolismo , COVID-19/complicaciones , COVID-19/fisiopatología , COVID-19/virología , Anosmia/fisiopatología , Anosmia/etiología , Anosmia/metabolismo , Enzima Convertidora de Angiotensina 2/metabolismo , Mucosa Olfatoria/metabolismo , Mucosa Olfatoria/virología , Transducción de Señal , Serina Endopeptidasas/metabolismo , Neuropilina-1/metabolismo , Basigina/metabolismo , Canales Catiónicos TRPV/metabolismoRESUMEN
Chimeric antigen receptor (CAR) T cell therapy has shown promising results in hematologic malignancies, but its effectiveness in solid cancers remains challenging. Macrophages are immune cells residing within the tumor microenvironment. They can phagocytose tumor cells. Recently, CAR macrophages (CAR-M) have been a promising candidate for treating solid cancers. One of the common cancer antigens overexpressed in various types of cancer is CD147. CAR-T and NK cells targeting CD147 antigen have shown significant efficacy against hepatocellular carcinoma. Nevertheless, CAR-M targeting the CD147 molecule has not been investigated. In this study, we generated CAR targeting the CD147 molecule using the THP-1 monocytic cell line (CD147 CAR-M). The CD147 CAR-M exhibited typical macrophage characteristics, including phagocytosis of zymosan bioparticles and polarization ability toward M1 and M2 phenotypes. Furthermore, the CD147 CAR-M demonstrated enhanced anti-tumor activity against K562 and MDA-MB-231 cells without exhibiting off-target cytotoxicity against normal cells. Our research provides valuable insights into the potential of CD147 CAR-M as a promising platform for cancer immunotherapy, with applications in both hematologic malignancies and solid cancers.
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Basigina , Inmunoterapia Adoptiva , Macrófagos , Fagocitosis , Receptores Quiméricos de Antígenos , Humanos , Fagocitosis/inmunología , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Inmunoterapia Adoptiva/métodos , Basigina/inmunología , Basigina/metabolismo , Neoplasias/inmunología , Neoplasias/terapia , Ratones , Animales , Línea Celular Tumoral , Microambiente Tumoral/inmunologíaRESUMEN
Low-coverage whole genome sequencing was performed for tissue samples from thyroid patients who received surgery treatment from 2015 to 2021. The potential biological significance of CD147 protein in thyroid cancer was explored through correlation analysis of CD147 protein expression level and clinical features of thyroid cancer patients. Low coverage whole genome sequencing was performed on the extracted DNA samples. The copy number analysis software was used to analyze the sequencing data, calculate the copy number of CD147 gene, further verify the expression of CD147 gene, and analyze its association with clinical features. The relationship between CIN and high risk was evaluated in the internal cohort. The association of CIN with the disease-free survival was validated in the cohort from The Cancer Genome Atlas Program. Thyroglobulin plays a key role in regulating thyroid function and maintaining normal metabolic rate. By sequencing tissue samples from this study, we can gain a deeper understanding of the association between cin and thyroid disease. The percentage of high risk patients in the multiple CIN group (77.8 %) was significantly higher than that in the 22q negative group (31.3 %), BRAF V600E group (22.2 %) and all negative group (25.0 %; p = 0.043).
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Basigina , Inestabilidad Cromosómica , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/metabolismo , Basigina/genética , Basigina/metabolismo , Masculino , Femenino , Pronóstico , Persona de Mediana Edad , Regulación Neoplásica de la Expresión Génica , Adulto , Biomarcadores de Tumor/genética , Secuenciación Completa del GenomaRESUMEN
T lymphocytes play a primary role in the adaptive antiviral immunity. Both lymphocytosis and lymphopenia were found to be associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While lymphocytosis indicates an active anti-viral response, lymphopenia is a sign of poor prognosis. T-cells, in essence, rarely express ACE2 receptors, making the cause of cell depletion enigmatic. Moreover, emerging strains posed an immunological challenge, potentially alarming for the next pandemic. Herein, we review how possible indirect and direct key mechanisms could contribute to SARS-CoV-2-associated-lymphopenia. The fundamental mechanism is the inflammatory cytokine storm elicited by viral infection, which alters the host cell metabolism into a more acidic state. This "hyperlactic acidemia" together with the cytokine storm suppresses T-cell proliferation and triggers intrinsic/extrinsic apoptosis. SARS-CoV-2 infection also results in a shift from steady-state hematopoiesis to stress hematopoiesis. Even with low ACE2 expression, the presence of cholesterol-rich lipid rafts on activated T-cells may enhance viral entry and syncytia formation. Finally, direct viral infection of lymphocytes may indicate the participation of other receptors or auxiliary proteins on T-cells, that can work alone or in concert with other mechanisms. Therefore, we address the role of CD147-a novel route-for SARS-CoV-2 and its new variants. CD147 is not only expressed on T-cells, but it also interacts with other co-partners to orchestrate various biological processes. Given these features, CD147 is an appealing candidate for viral pathogenicity. Understanding the molecular and cellular mechanisms behind SARS-CoV-2-associated-lymphopenia will aid in the discovery of potential therapeutic targets to improve the resilience of our immune system against this rapidly evolving virus.
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Basigina , COVID-19 , Linfopenia , SARS-CoV-2 , Humanos , Linfopenia/inmunología , Linfopenia/virología , COVID-19/inmunología , COVID-19/virología , COVID-19/patología , SARS-CoV-2/metabolismo , Basigina/metabolismo , Enzima Convertidora de Angiotensina 2/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/virología , Síndrome de Liberación de Citoquinas/inmunología , AnimalesRESUMEN
With the advent of promising lung cancer immunotherapies targeting proteins at the cell surface of RAS-driven human cancers, the mass spectrometry (MS)-based surfaceomics remains a feasible strategy for therapeutic target discovery. This chapter describes a protocol for discovery of druggable protein targets at the surface of RAS-driven human cancer cells. This method relies on bottom-up MS-based quantitative surfaceomics that employs in parallel, targeted hydrazide-based cell-surface glycoproteomics and global shotgun membrane proteomics to enable unbiased quantitative profiling of thousands of cell surface membrane proteins. A large-scale molecular map of the KRASG12V surface was attained, resulting in confident detection and quantitation of more than 500 cell surface membrane proteins that were found to be unique or upregulated at the surface of cells harboring the KRASG12V mutant. A multistep bioinformatic progression revealed a subset of unique and/or significantly upregulated proteins as priority drug targets selected for orthogonal cross-validation using immunofluorescence, structured illumination microscopy, and western blotting. Among cross-validated targets, CUB domain containing protein 1 (CDCP1) and basigin (BSG-CD147) were selected as leading targets due to their involvement in cell adhesion and migration, consistent with the KRASG12V malignant phenotype as revealed by scanning electron microscopy and phenotypic cancer cell assays. Follow-up studies confirmed CDCP1 as an actionable therapeutic target, resulting in development of recombinant antibodies capable of killing KRAS-transformed cancer cells in preclinical setting. The present MS-based surfaceomics workflow represents a powerful drug target discovery platform that enables development of innovative immunotherapeutics (e.g., antibody drug conjugate against CDCP1) for attacking oncogenic RAS-driven cancers at the cell surface.
Asunto(s)
Proteómica , Humanos , Proteómica/métodos , Línea Celular Tumoral , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Basigina/metabolismo , Basigina/genética , Moléculas de Adhesión Celular/metabolismo , Moléculas de Adhesión Celular/genética , Antígenos CD/metabolismo , Antígenos CD/genética , Membrana Celular/metabolismo , Descubrimiento de Drogas/métodos , Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antígenos de Neoplasias/metabolismo , Antígenos de Neoplasias/genética , Espectrometría de Masas/métodos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Proteínas ras/metabolismo , Proteínas ras/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Antineoplásicos/farmacologíaRESUMEN
Angiogenesis is critical for rheumatoid arthritis (RA) progression. The effects of tofacitinib, a JAK-STAT inhibitor used for RA treatment, on angiogenesis in RA are unclear. We, therefore, evaluated the levels of angiogenic factors in two systems of a human co-culture of fibroblast (HT1080) and monocytic (U937) cell lines treated with tofacitinib and in serum samples from RA patients before and after six months of tofacitinib treatment. Tofacitinib reduced CD147 levels, matrix metalloproteinase-9 (MMP-9) activity, and angiogenic potential but increased endostatin levels and secreted proteasome 20S activity. In vitro, tofacitinib did not change CD147 mRNA but increased miR-146a-5p expression and reduced STAT3 phosphorylation. We recently showed that CD147 regulates the ability of MMP-9 and secreted proteasome 20S to cleave collagen XVIIIA into endostatin. We show here that tofacitinib-enhanced endostatin levels are mediated by CD147, as CD147-siRNA or an anti-CD147 antibody blocked proteasome 20S activity. The correlation between CD147 and different disease severity scores supported this role. Lastly, tofacitinib reduced endostatin' s degradation by inhibiting cathepsin S activity and recombinant cathepsin S reversed this in both systems. Thus, tofacitinib inhibits angiogenesis by reducing pro-angiogenic factors and enhancing the anti-angiogenic factor endostatin in a dual effect mediated partly through CD147 and partly through cathepsin S.
Asunto(s)
Artritis Reumatoide , Basigina , Catepsinas , Endostatinas , Piperidinas , Pirimidinas , Humanos , Basigina/metabolismo , Basigina/genética , Piperidinas/farmacología , Endostatinas/metabolismo , Endostatinas/farmacología , Pirimidinas/farmacología , Catepsinas/metabolismo , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Factor de Transcripción STAT3/metabolismo , Neovascularización Patológica/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Inhibidores de la Angiogénesis/farmacología , Femenino , Persona de Mediana Edad , Masculino , Pirroles/farmacología , Línea CelularRESUMEN
BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis, and the outcomes of common therapy were not favorable. METHODS: The samples of 84 patients with TNBC and 40 patients with breast fibroadenoma were collected in the pathology department specimen library of our hospital. The prognosis of patients was obtained through outpatient follow-up information, telephone and WeChat contacts, and medical records. The mRNA expression was analyzed using bioinformation and quantitative real-time polymerase chain reaction (qPCR). The protein expression was determined by hematoxylin-eosin staining and immunohistochemical staining. The results of survival analysis were visualized using Kaplan-Meier curves. RESULTS: The immunohistochemical staining showed that hypoxia-inducible factor-1alpha (HIF-1α) was mainly distributed in the nucleus and cytoplasm, while CD147 is mainly distributed in cell membrane and cytoplasm. The qPCR results exhibited that the expression level of HIF-1α and CD147 in TNBC tissue was significantly higher than that in breast fibroadenoma tissue. The expression of HIF-1α was related to the histological grade and lymph node metastasis in TNBC, and the expression of CD147 was related to Ki-67, histological grade and lymph node metastasis. There was a positive relationship between the expression of CD147 and HIF-1α. The upregulated expression of CD147 was closely related to the poor prognosis of OS in TNBC. CONCLUSION: CD147 could be a biomarker for the prognosis of TNBC and closely related to the expression of HIF-1α.
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Basigina , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/mortalidad , Neoplasias de la Mama Triple Negativas/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Femenino , Persona de Mediana Edad , Basigina/metabolismo , Basigina/genética , Adulto , Pronóstico , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Metástasis Linfática , Fibroadenoma/patología , Fibroadenoma/genética , Fibroadenoma/metabolismo , Estimación de Kaplan-Meier , Inmunohistoquímica , AncianoRESUMEN
Immunosuppression is a major hallmark of tumor progression in non-small cell lung cancer (NSCLC). Cluster of differentiation 147 (CD147), an important pro-tumorigenic factor, is closely linked to NSCLC immunosuppression. However, the role of CD147 di-methylation in the immunosuppressive tumor microenvironment (TME) remains unclear. Here, di-methylation of CD147 at Lys148 (CD147-K148me2) is identified as a common post-translational modification (PTM) in NSCLC that is significantly associated with unsatisfying survival outcomes among NSCLC sufferers, especially those in the advanced stages of the disease. The methyltransferase NSD2 catalyzes CD147 to generate CD147-K148me2. Further analysis demonstrates that CD147-K148me2 reestablishes the immunosuppressive TME and promotes NSCLC progression. Mechanistically, this modification promotes the interaction between cyclophilin A (CyPA) and CD147, and in turn, increases CCL5 gene transcription by activating p38-ZBTB32 signaling, leading to increased NSCLC cell-derived CCL5 secretion. Subsequently, CD147-K148me2-mediated CCL5 upregulation facilitates M2-like tumor-associated macrophage (TAM) infiltration in NSCLC tissues via CCL5/CCR5 axis-dependent intercellular crosstalk between tumor cells and macrophages, which is inhibited by blocking CD147-K148me2 with the targeted antibody 12C8. Overall, this study reveals the role of CD147-K148me2-driven intercellular crosstalk in the development of NSCLC immunosuppression, and provides a potential interventional strategy for PTM-targeted NSCLC therapy.
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Basigina , Carcinoma de Pulmón de Células no Pequeñas , Quimiocina CCL5 , Neoplasias Pulmonares , Receptores CCR5 , Microambiente Tumoral , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Basigina/metabolismo , Basigina/genética , Ratones , Animales , Receptores CCR5/metabolismo , Receptores CCR5/genética , Quimiocina CCL5/metabolismo , Quimiocina CCL5/genética , Microambiente Tumoral/inmunología , Macrófagos/metabolismo , Macrófagos/inmunología , Línea Celular Tumoral , Terapia de Inmunosupresión , Modelos Animales de Enfermedad , Transducción de SeñalRESUMEN
Male cases diagnosed COVID-19 with more complications and higher mortality compared with females, and the overall consequences of male sex hormones and semen parameters deterioration were observed in COVID-19 patients, whereas the involvement and mechanism for spermatogenic cell remains unclear. The study was aimed to investigate the infection mode of S protein (D614G) pseudovirus (pseu-S-D614G) to spermatogenic cells, as well as the influence on cell growth. Both mouse spermatogonia (GC-1 cell, immortalized spermatogonia) and spermatocyte (GC-2 cell, immortalized spermatocytes) were used to detect the infection of pseu-S-D614G of SARS-CoV-2, and further explored the effect of SARS-CoV-2-spike protein (S-protein) and SARS-CoV-2-spike protein (omicron) (O-protein) on GC-1 cell apoptosis and proliferation. The data showed that the pseu-S-D614G invaded into GC-1 cells through either human ACE2 (hACE2) or human CD147 (hCD147), whereas GC-2 cells were insensitive to viral infection. In addition, the apoptosis and proliferation suppression inflicted by S-protein and O-protein on GC-1 cells was through Bax-Caspase3 signaling rather than arresting cell cycle progression. These findings suggest that CD147, apart from ACE2, may be a potential receptor for SARS-CoV-2 infection in testicular tissues, and that the apoptotic effect was induced in spermatogonia cells by S-protein or O-protein, eventually resulted in the damage to male fertility.
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Enzima Convertidora de Angiotensina 2 , Apoptosis , Basigina , COVID-19 , SARS-CoV-2 , Espermatogonias , Glicoproteína de la Espiga del Coronavirus , Animales , Humanos , Masculino , Ratones , Enzima Convertidora de Angiotensina 2/metabolismo , Apoptosis/fisiología , Basigina/metabolismo , Línea Celular , Proliferación Celular , COVID-19/metabolismo , Espermatocitos/metabolismo , Espermatocitos/virología , Espermatogonias/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismoRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in December 2019 and rapidly became a pandemic as coronavirus disease 2019 (COVID-19). Apart from other organs, presence of specific receptor angiotensin-converting enzyme (ACE2) and corresponding proteases such as transmembrane serine protease 2, basigin and cysteine protease cathepsin L make follicular somatic cells as well as oocyte as potential targets for SARS-CoV-2 infection. The SARS-CoV-2 causes inflammation and hypoxia that generate reactive oxygen species (ROS) in critically ill patients. In addition, a large number of casualties and insecurity of life due to repeated waves of SARS-CoV-2 infection generate psychological stress and cortisol resulting in the further generation of ROS. The excess levels of ROS under physiological range cause meiotic instability, while high levels result in oxidative stress that trigger various death pathways and affect number as well as quality of follicular oocytes. Although, emerging evidence suggests that the SARS-CoV-2 utilises cellular machinery of ovarian follicular cells, generates ROS and impairs quality of follicular oocytes, the underlying mechanism of viral entry into host cell and its negative impact on the follicular oocyte remains poorly understood. Therefore, this review summarises emerging evidence on the presence of cellular machinery for SARS-CoV-2 in ovarian follicles and the potential negative impact of viral infection on the follicular oocytes that affect ovarian functions in critically ill and stressed women.
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Enzima Convertidora de Angiotensina 2 , COVID-19 , Oocitos , SARS-CoV-2 , Humanos , COVID-19/virología , SARS-CoV-2/fisiología , Femenino , Oocitos/virología , Enzima Convertidora de Angiotensina 2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Internalización del Virus , Catepsina L/metabolismo , Basigina/metabolismo , Folículo Ovárico/virología , Folículo Ovárico/metabolismo , Estrés Oxidativo , Serina Endopeptidasas/metabolismoRESUMEN
Desmoplasia is a common feature of aggressive cancers, driven by a complex interplay of protein production and degradation. Basigin is a type 1 integral membrane receptor secreted in exosomes or released by ectodomain shedding from the cell surface. Given that soluble basigin is increased in the circulation of patients with a poor cancer prognosis, we explored the putative role of the ADAM12-generated basigin ectodomain in cancer progression. We show that recombinant basigin ectodomain binds ß1 integrin and stimulates gelatin degradation and the migration of cancer cells in a matrix metalloproteinase (MMP)- and ß1-integrin-dependent manner. Subsequent in vitro and in vivo experiments demonstrated the altered expression of extracellular matrix proteins, including fibronectin and collagen type 5. Thus, we found increased deposits of collagen type 5 in the stroma of nude mice tumors of the human tumor cell line MCF7 expressing ADAM12-mimicking the desmoplastic response seen in human cancer. Our findings indicate a feedback loop between ADAM12 expression, basigin shedding, TGFß signaling, and extracellular matrix (ECM) remodeling, which could be a mechanism by which ADAM12-generated basigin ectodomain contributes to the regulation of desmoplasia, a key feature in human cancer progression.
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Proteína ADAM12 , Basigina , Proteínas de la Matriz Extracelular , Animales , Femenino , Humanos , Ratones , Proteína ADAM12/metabolismo , Proteína ADAM12/genética , Basigina/metabolismo , Basigina/genética , Línea Celular Tumoral , Movimiento Celular , Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica , Células MCF-7 , Ratones Desnudos , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/genética , Unión Proteica , Dominios Proteicos , Integrina beta1/metabolismoRESUMEN
Acute myeloid leukemia (AML) is an aggressive blood cancer. With low survival rates, new drug targets are needed to improve treatment regimens and patient outcomes. Pseudolaric acid B (PAB) is a plant-derived bioactive compound predicted to interact with cluster of differentiation 147 (CD147/BSG). CD147 is a transmembrane glycoprotein overexpressed in various malignancies with suggested roles in regulating cancer cell survival, proliferation, invasion, and apoptosis. However, the detailed function of PAB in AML remains unknown. In this study, AML cell lines and patient-derived cells were used to show that PAB selectively targeted AML (IC50: 1.59 ± 0.47 µM). Moreover, proliferation assays, flow cytometry, and immunoblotting confirmed that PAB targeting of CD147 resulted in AML cell apoptosis. Indeed, the genetic silencing of CD147 significantly suppressed AML cell growth and attenuated PAB activity. Overall, PAB imparts anti-AML activity through transmembrane glycoprotein CD147.
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Apoptosis , Basigina , Proliferación Celular , Diterpenos , Leucemia Mieloide Aguda , Humanos , Basigina/metabolismo , Basigina/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Diterpenos/farmacología , Supervivencia Celular/efectos de los fármacosRESUMEN
CD147 is upregulated in cancers, including aggressive T-ALL. Traditional treatments for T-ALL often entail severe side effects and the risk of relapse, highlighting the need for more efficacious therapies. ADCP contributes to the antitumor response by enhancing the ability of phagocytic cells to engulf cancer cells upon antibody binding. We aimed to engineer CD147KO THP-1 cells and evaluated their differentiation properties compared to the wild type. A humanized anti-CD147 antibody, HuM6-1B9, was also constructed for investing the phagocytic function of CD147KO THP-1 cells mediated by HuM6-1B9 in the phagocytosis of Jurkat T cells. The CD147KO THP-1 was generated by CRISPR/Cas9 and maintained polarization profiles. HuM6-1B9 was produced in CHO-K1 cells and effectively bound to CD147 with high binding affinity (KD: 2.05 ± 0.30 × 10-9 M). Additionally, HuM6-1B9 enhanced the phagocytosis of Jurkat T cells by CD147KO THP-1-derived LPS-activated macrophages (M-LPS), without self-ADCP. The formation of THP-1-derived mMDSC was limited in CD147KO THP-1 cells, highlighting the significant impact of CD147 deletion. Maintaining expression markers and phagocytic function in CD147KO THP-1 macrophages supports future engineering and the application of induced pluripotent stem cell-derived macrophages. The combination of HuM6-1B9 and CD147KO monocyte-derived macrophages holds promise as an alternative strategy for T-ALL.
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Basigina , Diferenciación Celular , Fagocitosis , Humanos , Células Jurkat , Basigina/metabolismo , Basigina/genética , Células THP-1 , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/inmunología , Anticuerpos Monoclonales Humanizados/farmacología , Animales , Células CHO , Cricetulus , Monocitos/metabolismo , Monocitos/inmunología , Macrófagos/metabolismo , Macrófagos/inmunología , Sistemas CRISPR-CasRESUMEN
CD147 is a T cell activation-associated molecule which is closely involved in the formation of the immune synapse (IS). However, the precise role of CD147 in T cell activation and IS formation remains unclear. In the present study, we demonstrated that CD147 translocated to the IS upon T cell activation and was primarily distributed in the peripheral super molecular cluster (p-SMAC). The knock down of CD147 expression in T cells, but not in B cells, impaired IS formation. CD147 participated in IS formation between T cells and different types of antigen-presenting cells (APCs), including macrophages and dendritic cells. Ligation of CD147 with its monoclonal antibody (mAb) HAb18 effectively inhibited T cell activation and IL-2 secretion. CD98, a critical molecule interacting with CD147, was distributed in IS in a CD147-dependent way. Phosphorylation levels of T cell receptor (TCR) related molecules, like ZAP-70, ERK, and cJun, were down-regulated by CD147 ligation, which is crucial for the interaction of CD147 and TCR signaling transduction. CD147 is indispensable for the formation of immune synapses and plays an important role in the regulation of its function.
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Basigina , Sinapsis Inmunológicas , Activación de Linfocitos , Linfocitos T , Basigina/metabolismo , Basigina/inmunología , Sinapsis Inmunológicas/metabolismo , Sinapsis Inmunológicas/inmunología , Activación de Linfocitos/inmunología , Humanos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Fosforilación , Anticuerpos Monoclonales/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Linfocitos B/inmunología , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Interleucina-2/metabolismo , Interleucina-2/inmunología , Animales , Células JurkatRESUMEN
A hallmark of Alzheimer's disease (AD) is amyloid-ß (Aß) plaque deposition in the brain, causing deficits in cognitive function. Amyloid-beta oligomers (AßOs), the soluble precursor peptides producing Aß plaques, also produce neurotoxicity and microgliosis together with glycolytic reprogramming. Recently, monocarboxylate transporter 1 (MCT1), a key glycolysis regulator, and its ancillary protein, CD147, are found to play an important role in the secretion of exosomes, 30-200 nm vesicles in size, which are considered as toxic molecule carriers in AD. However, the effect of low-concentration AßOs (1 nM) on microglia MCT1 and CD147 expression as well as 1 nM AßOs-treated microglia-derived exosomes on neuronal toxicity remain largely elusive. In this study, 1 nM AßOs induce significant axonopathy and microgliosis. Furthermore, 1 nM AßOs-treated neurons- or microglia-derived exosomes produce axonopathy through their autologous or heterologous uptake by neurons, supporting the role of exosomes as neurotoxicity mediators in AD. Interestingly, MCT1 and CD147 are enhanced in microglia by treatment with 1 nM AßOs or exosomes from 1 nM AßOs-treated- microglia or neurons, suggesting the implication of AßOs-induced enhanced MCT1 and CD147 in microglia with AD neuropathogenesis, which is consistent with the in-silico analysis of the single cell RNA sequencing data from microglia in mouse models of AD and AD patients.
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Péptidos beta-Amiloides , Exosomas , Microglía , Neuronas , Exosomas/metabolismo , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/toxicidad , Microglía/metabolismo , Microglía/patología , Microglía/efectos de los fármacos , Animales , Neuronas/metabolismo , Neuronas/patología , Neuronas/efectos de los fármacos , Ratones , Basigina/metabolismo , Basigina/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Células Cultivadas , Simportadores/metabolismo , Simportadores/genética , Ratones Endogámicos C57BL , HumanosRESUMEN
Background: In vitro studies often use two-dimensional (2D) monolayers, but 3D cell organization, such as in spheroids, better mimics the complexity of solid tumors. To metastasize, cancer cells undergo the process of epithelial-to-mesenchymal transition (EMT) to become more invasive and pro-angiogenic, with expression of both epithelial and mesenchymal markers. Aims: We asked whether EMMPRIN/CD147 contributes to the formation of the 3D spheroid structure, and whether spheroids, which are often used to study proliferation and drug resistance, could better model the EMT process and the metastatic properties of cells, and improve our understanding of the role of EMMPRIN in them. Methods: We used the parental mouse CT26 colon carcinoma (CT26-WT) cells, and infected them with a lentivirus vector to knock down EMMPRIN expression (CT26-KD cells), or with an empty lentivirus vector (CT26-NC) that served as a negative control. In some cases, we repeated the experiments with the 4T1 or LLC cell lines. We compared the magnitude of change between CT26-KD and CT26-WT/NC cells in different metastatic properties in cells seeded as monolayers or as spheroids formed by the scaffold-free liquid overlay method. Results: We show that reduced EMMPRIN expression changed the morphology of cells and their spatial organization in both 2D and 3D models. The 3D models more clearly demonstrated how reduced EMMPRIN expression inhibited proliferation and the angiogenic potential, while it enhanced drug resistance, invasiveness, and EMT status, and moreover it enhanced cell dormancy and prevented CT26-KD cells from forming metastatic-like lesions when seeded on basement membrane extract (BME). Most interestingly, this approach enabled us to identify that EMMPRIN and miR-146a-5p form a negative feedback loop, thus identifying a key mechanism for EMMPRIN activities. These results underline EMMPRIN role as a gatekeeper that prevents dormancy, and suggest that EMMPRIN links EMT characteristics to the process of spheroid formation. Conclusions: Thus, 3D models can help identify mechanisms by which EMMPRIN facilitates tumor and metastasis progression, which might render EMMPRIN as a promising target for anti-metastatic tumor therapy.
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Basigina , Neoplasias del Colon , Transición Epitelial-Mesenquimal , Esferoides Celulares , Basigina/metabolismo , Basigina/genética , Esferoides Celulares/metabolismo , Animales , Neoplasias del Colon/patología , Neoplasias del Colon/metabolismo , Ratones , Línea Celular Tumoral , Metástasis de la NeoplasiaRESUMEN
Chemotherapy remains the first-line treatment for advanced esophageal cancer. However, durable benefits are achieved by only a limited subset of individuals due to the elusive chemoresistance. Here, we utilize patient-derived xenografts (PDXs) from esophageal squamous-cell carcinoma to investigate chemoresistance mechanisms in preclinical settings. We observe that activated cancer-associated fibroblasts (CAFs) are enriched in the tumor microenvironment of PDXs resistant to chemotherapy. Mechanistically, we reveal that cancer-cell-derived S100A8 triggers the intracellular RhoA-ROCK-MLC2-MRTF-A pathway by binding to the CD147 receptor of CAFs, inducing CAF polarization and leading to chemoresistance. Therapeutically, we demonstrate that blocking the S100A8-CD147 pathway can improve chemotherapy efficiency. Prognostically, we found the S100A8 levels in peripheral blood can serve as an indicator of chemotherapy responsiveness. Collectively, our study offers a comprehensive understanding of the molecular mechanisms underlying chemoresistance in esophageal cancer and highlights the potential value of S100A8 in the clinical management of esophageal cancer.