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1.
Mol Brain ; 17(1): 16, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38475840

RESUMO

Neuroligin (NLGN) 3 is a postsynaptic cell adhesion protein organizing synapse formation through two different types of transsynaptic interactions, canonical interaction with neurexins (NRXNs) and a recently identified noncanonical interaction with protein tyrosine phosphatase (PTP) δ. Although, NLGN3 gene is known as a risk gene for neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID), the pathogenic contribution of the canonical NLGN3-NRXN and noncanonical NLGN3-PTPδ pathways to these disorders remains elusive. In this study, we utilized Nlgn3 mutant mice selectively lacking the interaction with either NRXNs or PTPδ and investigated their social and memory performance. Neither Nlgn3 mutants showed any social cognitive deficiency in the social novelty recognition test. However, the Nlgn3 mutant mice lacking the PTPδ pathway exhibited significant decline in the social conditioned place preference (sCPP) at the juvenile stage, suggesting the involvement of the NLGN3-PTPδ pathway in the regulation of social motivation and reward. In terms of learning and memory, disrupting the canonical NRXN pathway attenuated contextual fear conditioning while disrupting the noncanonical NLGN3-PTPδ pathway enhanced it. Furthermore, disruption of the NLGN3-PTPδ pathway negatively affected the remote spatial reference memory in the Barnes maze test. These findings highlight the differential contributions of the canonical NLGN3-NRXN and noncanonical NLGN3-PTPδ synaptogenic pathways to the regulation of higher order brain functions associated with ASD and ID.


Assuntos
Transtorno do Espectro Autista , Moléculas de Adesão Celular Neuronais , Deficiência Intelectual , Proteínas de Membrana , Proteínas do Tecido Nervoso , Animais , Camundongos , Transtorno do Espectro Autista/genética , Moléculas de Adesão Celular , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Cognição , Aprendizagem em Labirinto , Mudança Social , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo
2.
Int J Mol Sci ; 25(5)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38473788

RESUMO

Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide, with high morbidity and mortality rates. The evidence for the tumor-supporting capacities of cancer-associated fibroblasts (CAFs) that modulate cancer cell proliferation, invasion, metastasis, and tumor immunity, including in CRC, has been attracting attention. The present study examined the expression status of CD70 and POSTN in CRC and analyzed their association with clinicopathological features and clinical outcomes. In the present study, in total 15% (40/269) and 44% (119/269) of cases exhibited CD70 and POSTN expression on CAFs, respectively. Co-expression of CD70 and POSTN was detected in 8% (21/269) of patients. Fluorescent immunohistochemistry identified the co-expression of CD70 and POSTN with FAP and PDPN, respectively. ACTA2 was not co-expressed with CD70 or POSTN in CRC CAFs. CRC with CD70+/POSTN+ status in CAFs was significantly associated with distant organ metastasis (p = 0.0020) or incomplete resection status (p = 0.0011). CD70+/POSTN+ status tended to associate with advanced pT stage (p = 0.032) or peritoneal metastasis (p = 0.0059). Multivariate Cox hazards regression analysis identified CD70+/POSTN+ status in CAFs [hazard ratio (HR) = 3.78] as a potential independent risk factor. In vitro experiments revealed the activated phenotypes of colonic fibroblasts induced by CD70 and POSTN, while migration and invasion assays identified enhanced migration and invasion of CRC cells co-cultured with CD70- and POSTN-expressing colonic fibroblasts. On the basis of our observations, CD70 and POSTN immunohistochemistry can be used in the prognostication of CRC patients. CRC CAFs may be a promising target in the treatment of CRC patients.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias Colorretais , Humanos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos/metabolismo , Imuno-Histoquímica , Proliferação de Células , Neoplasias Colorretais/patologia , Moléculas de Adesão Celular/metabolismo , Ligante CD27/metabolismo
3.
Sheng Li Xue Bao ; 76(1): 1-11, 2024 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-38444127

RESUMO

Perineuronal nets (PNNs) are specialized extracellular matrix (ECM) structures present in the central nervous system (CNS) and have been identified as significant regulators of developmental plasticity in the developing cortex. PNNs are particularly enriched in the cortex surrounding parvalbumin-expressing (PV+) cells. A growing body of evidence suggests that the abnormalities in PV+ neurons and PNNs are associated with various neurological disorders, including schizophrenia, which is a neurodevelopmental defect disease. The N-methyl-D-aspartate receptor (NMDAR) selective antagonist is frequently employed to establish animal models of schizophrenia in laboratory settings. The crucial involvement of GluN2B-containing NMDARs in the development of CNS has been extensively established. However, the role of GluN2B in the pathophysiology of schizophrenia has yet to be thoroughly investigated. The present study inhibited GluN2B function through intraperitoneal infusion of the GluN2B selective antagonist ifenprodil into juvenile mice aged 3-4 weeks, followed by the administration of social stress when these mice reached 9 weeks of age. Then, immunofluorescence staining was employed to examine the changes in the PNNs and PV+ cells, an acoustic startle and prepulse inhibition test was used to detect activities of the PV+ cells, and Western blot was used to quantify the protein expression levels of GluN2A and GluN2B in the prefrontal cortex (PFC). The study revealed that in the PFC of mice subjected to GluN2B antagonist treatment in early life and social stress in adulthood, there was an increase in the number of PV+ cells wrapped by PNNs, and a decrease in the activation of PV+ cells during the prepulse inhibition test, which is an indicator of sensory gating functions, as well as changes in the protein expression levels of GluN2A and GluN2B, which resulted in an increase in the ratio of GluN2A to GluN2B. These aberrations in the mice are comparable to those observed in animal models and patients with schizophrenia. The findings suggest that even a transient hypofunction of GluN2B in early life poses a significant risk for the emergence of schizophrenia symptoms in adulthood.


Assuntos
Receptores de N-Metil-D-Aspartato , Estresse Psicológico , Animais , Humanos , Camundongos , Moléculas de Adesão Celular , Sistema Nervoso Central , Córtex Cerebral , Matriz Extracelular , Proteínas Nucleares
5.
Front Cell Infect Microbiol ; 14: 1324441, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38505290

RESUMO

Integrins are heterodimers composed of non-covalently associated alpha and beta subunits that mediate the dynamic linkage between extracellular adhesion molecules and the intracellular actin cytoskeleton. Integrins are present in various tissues and organs and are involved in different physiological and pathological molecular responses in vivo. Wound healing is an important process in the recovery from traumatic diseases and consists of three overlapping phases: inflammation, proliferation, and remodeling. Integrin regulation acts throughout the wound healing process to promote wound healing. Prolonged inflammation may lead to failure of wound healing, such as wound chronicity. One of the main causes of chronic wound formation is bacterial colonization of the wound. In this review, we review the role of integrins in the regulation of wound healing processes such as angiogenesis and re-epithelialization, as well as the role of integrins in mediating bacterial infections during wound chronicity, and the challenges and prospects of integrins as therapeutic targets for infected wound healing.


Assuntos
Integrinas , Cicatrização , Humanos , Cicatrização/fisiologia , Moléculas de Adesão Celular , Morfogênese , Inflamação/patologia , Pele/patologia
6.
Elife ; 132024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38450720

RESUMO

Synapse is the fundamental structure for neurons to transmit information between cells. The proper synapse formation is crucial for developing neural circuits and cognitive functions of the brain. The aberrant synapse formation has been proved to cause many neurological disorders, including autism spectrum disorders and intellectual disability. Synaptic cell adhesion molecules (CAMs) are thought to play a major role in achieving mechanistic cell-cell recognition and initiating synapse formation via trans-synaptic interactions. Due to the diversity of synapses in different brain areas, circuits and neurons, although many synaptic CAMs, such as Neurexins (NRXNs), Neuroligins (NLGNs), Synaptic cell adhesion molecules (SynCAMs), Leucine-rich-repeat transmembrane neuronal proteins (LRRTMs), and SLIT and NTRK-like protein (SLITRKs) have been identified as synaptogenic molecules, how these molecules determine specific synapse formation and whether other molecules driving synapse formation remain undiscovered are unclear. Here, to provide a tool for synapse labeling and synaptic CAMs screening by artificial synapse formation (ASF) assay, we generated synaptotagmin-1-tdTomato (Syt1-tdTomato) transgenic mice by inserting the tdTomato-fused synaptotagmin-1 coding sequence into the genome of C57BL/6J mice. In the brain of Syt1-tdTomato transgenic mice, the tdTomato-fused synaptotagmin-1 (SYT1-tdTomato) signals were widely observed in different areas and overlapped with synapsin-1, a widely-used synaptic marker. In the olfactory bulb, the SYT1-tdTomato signals are highly enriched in the glomerulus. In the cultured hippocampal neurons, the SYT1-tdTomato signals showed colocalization with several synaptic markers. Compared to the wild-type (WT) mouse neurons, cultured hippocampal neurons from Syt1-tdTomato transgenic mice presented normal synaptic neurotransmission. In ASF assays, neurons from Syt1-tdTomato transgenic mice could form synaptic connections with HEK293T cells expressing NLGN2, LRRTM2, and SLITRK2 without immunostaining. Therefore, our work suggested that the Syt1-tdTomato transgenic mice with the ability to label synapses by tdTomato, and it will be a convenient tool for screening synaptogenic molecules.


Assuntos
Moléculas de Adesão Celular , Sinapses , Humanos , Camundongos , Animais , Camundongos Transgênicos , Células HEK293 , Camundongos Endogâmicos C57BL , Moléculas de Adesão Celular/metabolismo , Sinapses/fisiologia , Sinaptotagminas/metabolismo , Moléculas de Adesão de Célula Nervosa/metabolismo
7.
J Am Heart Assoc ; 13(6): e031283, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38456416

RESUMO

BACKGROUND: Dilated cardiomyopathy (DCM) is the leading cause of heart failure with a poor prognosis. Recent studies suggest that endothelial to mesenchymal transition (EndMT) may be involved in the pathogenesis and cardiac remodeling during DCM development. EDIL3 (epidermal growth factor-like repeats and discoidin I-like domains 3) is an extracellular matrix glycoprotein that has been reported to promote EndMT in various diseases. However, the roles of EDIL3 in DCM still remain unclear. METHODS AND RESULTS: A mouse model of DCM and human umbilical vein endothelial cells were used to explore the roles and mechanisms of EDIL3 in DCM. The results indicated that EndMT and EDIL3 were activated in DCM mice. EDIL3 deficiency attenuated cardiac dysfunction and remodeling in DCM mice. EDIL3 knockdown alleviated EndMT by inhibiting USP10 (ubiquitin specific peptidase 10) dependent Smad4 deubiquitination in vivo and in vitro. Recombinant human EDIL3 promoted EndMT via reinforcing deubiquitination of Smad4 in human umbilical vein endothelial cells treated with IL-1ß (interleukin 1ß) and TGF-ß (transforming growth factor beta). Inhibiting USP10 abolished EndMT exacerbated by EDIL3. In addition, recombinant EDIL3 also aggravates doxorubicin-induced EndMT by promoting Smad4 deubiquitination in HUVECs. CONCLUSIONS: Taken together, these results indicate that EDIL3 deficiency attenuated EndMT by inhibiting USP10 dependent Smad4 deubiquitination in DCM mice.


Assuntos
Cardiomiopatia Dilatada , Animais , Humanos , Camundongos , Proteínas de Ligação ao Cálcio/metabolismo , Cardiomiopatia Dilatada/metabolismo , Moléculas de Adesão Celular/metabolismo , Discoidinas , Fator de Crescimento Epidérmico , Transição Epitelial-Mesenquimal , Células Endoteliais da Veia Umbilical Humana/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Ubiquitina Tiolesterase , Proteases Específicas de Ubiquitina/metabolismo
8.
J Gen Virol ; 105(3)2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38471041

RESUMO

Many viruses downregulate their cognate receptors, facilitating virus replication and pathogenesis via processes that are not yet fully understood. In the case of herpes simplex virus 1 (HSV1), the receptor binding protein glycoprotein D (gD) has been implicated in downregulation of its receptor nectin1, but current understanding of the process is limited. Some studies suggest that gD on the incoming virion is sufficient to achieve nectin1 downregulation, but the virus-encoded E3 ubiquitin ligase ICP0 has also been implicated. Here we have used the physiologically relevant nTERT human keratinocyte cell type - which we have previously shown to express readily detectable levels of endogenous nectin1 - to conduct a detailed investigation of nectin1 expression during HSV1 infection. In these cells, nectin1, but not nectin2 or the transferrin receptor, disappeared from the cell surface in a process that required virus protein synthesis rather than incoming virus, but did not involve virus-induced host shutoff. Furthermore, gD was not only required but was sufficient for nectin1 depletion, indicating that no other virus proteins are essential. NK cells were shown to be activated in the presence of keratinocytes, a process that was greatly inhibited in cells infected with wild-type virus. However, degranulation of NK cells was also inhibited in ΔgD-infected cells, indicating that blocking of NK cell activation was independent of gD downregulation of nectin1. By contrast, a superinfection time-course revealed that the ability of HSV1 infection to block subsequent infection of a GFP-expressing HSV1 was dependent on gD and occurred in line with the timing of nectin1 downregulation. Thus, the role of gD-dependent nectin1 impairment during HSV infection is important for virus infection, but not immune evasion, which is achieved by other mechanisms.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Superinfecção , Humanos , Moléculas de Adesão Celular/metabolismo , Linhagem Celular , Regulação para Baixo , Herpesvirus Humano 1/fisiologia , Queratinócitos , Receptores Virais/metabolismo , Proteínas do Envelope Viral/genética
9.
Clin Transl Med ; 14(3): e1630, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38509842

RESUMO

BACKGROUND AND AIMS: Liver regeneration retardation post partial hepatectomy (PH) is a common clinical problem after liver transplantation. Identification of key regulators in liver regeneration post PH may be beneficial for clinically improving the prognosis of patients after liver transplantation. This study aimed to clarify the function of junctional protein-associated with coronary artery disease (JCAD) in liver regeneration post PH and to reveal the underlying mechanisms. METHODS: JCAD knockout (JCAD-KO), liver-specific JCAD-KO (Jcad△Hep) mice and their control group were subjected to 70% PH. RNA sequencing was conducted to unravel the related signalling pathways. Primary hepatocytes from KO mice were treated with epidermal growth factor (EGF) to evaluate DNA replication. Fluorescent ubiquitination-based cell cycle indicator (FUCCI) live-imaging system was used to visualise the phases of cell cycle. RESULTS: Both global and liver-specific JCAD deficiency postponed liver regeneration after PH as indicated by reduced gene expression of cell cycle transition and DNA replication. Prolonged retention in G1 phase and failure to transition over the cell cycle checkpoint in JCAD-KO cell line was indicated by a FUCCI live-imaging system as well as pharmacologic blockage. JCAD replenishment by adenovirus reversed the impaired DNA synthesis in JCAD-KO primary hepatocyte in exposure to EGF, which was abrogated by a Yes-associated protein (YAP) inhibitor, verteporfin. Mechanistically, JCAD competed with large tumour suppressor 2 (LATS2) for WWC1 interaction, leading to LATS2 inhibition and thereafter YAP activation, and enhanced expression of cell cycle-associated genes. CONCLUSION: JCAD deficiency led to delayed regeneration after PH as a result of blockage in cell cycle progression through the Hippo-YAP signalling pathway. These findings uncovered novel functions of JCAD and suggested a potential strategy for improving graft growth and function post liver transplantation. KEY POINTS: JCAD deficiency leads to an impaired liver growth after PH due to cell division blockage. JCAD competes with LATS2 for WWC1 interaction, resulting in LATS2 inhibition, YAP activation and enhanced expression of cell cycle-associated genes. Delineation of JCADHippoYAP signalling pathway would facilitate to improve prognosis of acute liver failure and graft growth in living-donor liver transplantation.


Assuntos
Moléculas de Adesão Celular , Regeneração Hepática , Transplante de Fígado , Animais , Humanos , Camundongos , Fator de Crescimento Epidérmico/genética , Fator de Crescimento Epidérmico/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/metabolismo , Regeneração Hepática/genética , Doadores Vivos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Moléculas de Adesão Celular/metabolismo
10.
BMC Cancer ; 24(1): 367, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38515057

RESUMO

BACKGROUND: Cell adhesion molecule 3 (CADM3), a transmembrane glycoprotein on cell membranes, plays a role in the way of ligand and receptor interaction. However, there are few studies on CADM3 in tumors, and how it works in breast cancer (BC) remains unclear. METHODS: The Cancer Genome Atlas (TCGA) database and clinical samples were used to analyze CADM3 expression and its correlation with clinicopathological factors and prognosis. Its correlation with immune infiltration was analyzed by TCGA. The effects of CADM3 on proliferation and migration were investigated by cell clonal formation, CCK-8, cell scratch and transwell assay. Protein interaction network was prepared and the function prediction of related genes was conducted. The correlation between CADM3 and MAPK pathway was further explored by western blot experiment. RESULTS: The expression of CADM3 in BC tissues were significantly lower than that in adjacent normal tissues. High level of CADM3 was related to better prognosis of BC patients. CADM3 was an independent prognostic factor for BC. Expression of CADM3 was significantly associated with the status of ER and PR, age and PAM50 subtypes. CADM3 positively related to many immune infiltrating cells. Overexpression of CADM3 can notably reduce cell proliferation and migration. CADM3 was related to MAPK pathway and the phosphorylation of ERK1/2 and JNK1 was inhibited in BC cells with high CADM3. CONCLUSIONS: Our research reveals the clinical significance of CADM3 in BC and indicates the critical roles of CADM3 in immune infiltration and MAPK pathway.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Relevância Clínica , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Prognóstico , Imunoglobulinas/genética , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo
11.
Tokai J Exp Clin Med ; 49(1): 1-8, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38509005

RESUMO

In epithelial tissues, intercellular adhesion structures are formed between adjacent cells via intercellular adhesion factors, such as zonula occludens (ZO-1), to maintain the structure and function of tissues and organs, thereby contributing to homeostasis. Epithelial cells are polarized into apical and basal regions by tight junctions (TJs), a type of intercellular adhesion structure, and thus, their intracellular organelles are asymmetrically distributed. Normal epithelial cells maintain their cellular function by controlling cytoskeletal reorganization, motility, and division by maintaining asymmetry in their intracellular organelles. Among the features common to many cancer tissues are abnormalities in cell polarity and intercellular adhesion. Lung adenocarcinoma consists of a mixture of five different histologic types that can be distinguished in the same section: lepidic, papillary, acinar, micropapillary, and solid patterns. Therefore, it is often difficult to accurately assess histological images because the staining differs according to the histological types. In the present study, we evaluated ZO-1 staining based on histological features observed in a single section and examined its relationship to clinicopathological features. In non-tumor areas, ZO-1 was expressed on the plasma membrane and in the cytoplasm of normal alveolar epithelial cells. However, in tumor areas, ZO-1 staining was mainly localized in the cytoplasm and on the plasma membrane only in a few cells. ZO-1-negative cases tended to have poorer prognoses in all histological types, with a poorer prognosis in the solid pattern. These results suggest that ZO-1 expression in solid-pattern lung adenocarcinoma may be a useful prognostic marker.


Assuntos
Adenocarcinoma de Pulmão , Moléculas de Adesão Celular , Humanos , Prognóstico , Proteína da Zônula de Oclusão-1 , Células Epiteliais
12.
Immunol Invest ; 53(1): 40-69, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38509665

RESUMO

The remarkable diversity of lymphocytes, essential components of the immune system, serves as an ingenious mechanism for maximizing the efficient utilization of limited host defense resources. While cell adhesion molecules, notably in gut-tropic T cells, play a central role in this mechanism, the counterbalancing molecular details have remained elusive. Conversely, we've uncovered the molecular pathways enabling extracellular vesicles secreted by lymphocytes to reach the gut's mucosal tissues, facilitating immunological regulation. This discovery sheds light on immune fine-tuning, offering insights into immune regulation mechanisms.


Assuntos
Exossomos , Vesículas Extracelulares , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Linfócitos , Linfócitos T , Moléculas de Adesão Celular/metabolismo
13.
Exp Dermatol ; 33(3): e15049, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38509717

RESUMO

Extramammary Paget disease (EMPD) is a rare skin cancer mainly found in areas rich in apocrine sweat glands. Since the effective treatments for advanced and/or metastasized EMPD are limited, there is an urgent need to develop novel therapeutic approaches. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed in cancers and considered to be a promising therapeutic target. NECTIN4 is also expressed in EMPD, but its role and the efficacy of NECTIN4-targeted therapy in EMPD remain unclear. This study investigated the potential of NECTIN4 as a novel therapeutic target for EMPD. NECTIN4 expression was immunohistochemically analysed in EMPD patients' primary (118 samples) and metastatic (21 samples) lesions. Using an EMPD cell line, KS-EMPD-1, the effects of NECTIN4 inhibition on cell proliferation and migration were investigated. NECTIN4 was expressed in primary and metastatic EMPD lesions, and the H-score of NECTIN4 staining was significantly higher in metastatic lesions than in primary ones. Knockdown of NECTIN4 significantly inhibited cell proliferation and affected cell migration. The cytotoxic effects of NECTIN4-targeted antibody-drug conjugate (ADC) were further evaluated, revealing a significant decrease in EMPD cell viability. In conclusion, NECTIN4 is a potential therapeutic target and NECTIN4-targeted ADC is promising as a therapeutic option for EMPD.


Assuntos
Neoplasias , Doença de Paget Extramamária , Humanos , Doença de Paget Extramamária/tratamento farmacológico , Doença de Paget Extramamária/patologia , Epiderme/metabolismo , Moléculas de Adesão Celular
14.
Proc Natl Acad Sci U S A ; 121(13): e2319055121, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38502695

RESUMO

Elevated cancer metabolism releases lactic acid and CO2 into the under-perfused tumor microenvironment, resulting in extracellular acidosis. The surviving cancer cells must adapt to this selection pressure; thus, targeting tumor acidosis is a rational therapeutic strategy to manage tumor growth. However, none of the major approved treatments are based explicitly on disrupting acid handling, signaling, or adaptations, possibly because the distinction between acid-sensitive and acid-resistant phenotypes is not clear. Here, we report pH-related phenotypes of sixty-eight colorectal cancer (CRC) cell lines by measuring i) extracellular acidification as a readout of acid production by fermentative metabolism and ii) growth of cell biomass over a range of extracellular pH (pHe) levels as a measure of the acid sensitivity of proliferation. Based on these measurements, CRC cell lines were grouped along two dimensions as "acid-sensitive"/"acid-resistant" versus "low metabolic acid production"/"high metabolic acid production." Strikingly, acid resistance was associated with the expression of CEACAM6 and CEACAM5 genes coding for two related cell-adhesion molecules, and among pH-regulating genes, of CA12. CEACAM5/6 protein levels were strongly induced by acidity, with a further induction under hypoxia in a subset of CRC lines. Lack of CEACAM6 (but not of CEACAM5) reduced cell growth and their ability to differentiate. Finally, CEACAM6 levels were strongly increased in human colorectal cancers from stage II and III patients, compared to matched samples from adjacent normal tissues. Thus, CEACAM6 is a marker of acid-resistant clones in colorectal cancer and a potential motif for targeting therapies to acidic regions within the tumors.


Assuntos
Acidose , Neoplasias Colorretais , Humanos , Linhagem Celular Tumoral , Transdução de Sinais , Proteínas Ligadas por GPI/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Fenótipo , Acidose/metabolismo , Microambiente Tumoral , Antígenos CD/genética , Moléculas de Adesão Celular/genética , Antígeno Carcinoembrionário/genética
15.
Nat Commun ; 15(1): 2192, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38467634

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all cancers. To improve PDAC therapy, we establish screening systems based on organoid and co-culture technologies and find a payload of antibody-drug conjugate (ADC), a bromodomain and extra-terminal (BET) protein degrader named EBET. We select CEACAM6/CD66c as an ADC target and developed an antibody, #84.7, with minimal reactivity to CEACAM6-expressing normal cells. EBET-conjugated #84.7 (84-EBET) has lethal effects on various PDAC organoids and bystander efficacy on CEACAM6-negative PDAC cells and cancer-associated fibroblasts. In mouse studies, a single injection of 84-EBET induces marked tumor regression in various PDAC-patient-derived xenografts, with a decrease in the inflammatory phenotype of stromal cells and without significant body weight loss. Combination with standard chemotherapy or PD-1 antibody induces more profound and sustained regression without toxicity enhancement. Our preclinical evidence demonstrates potential efficacy by delivering BET protein degrader to PDAC and its microenvironment via CEACAM6-targeted ADC.


Assuntos
Carcinoma Ductal Pancreático , Imunoconjugados , Neoplasias Pancreáticas , Humanos , Camundongos , Animais , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/genética , Linhagem Celular Tumoral , Microambiente Tumoral , Antígenos CD , Moléculas de Adesão Celular , Proteínas Ligadas por GPI
16.
Front Immunol ; 15: 1352583, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38455043

RESUMO

Objective: The relationships between circulating inflammatory proteins and COVID-19 have been observed in previous cohorts. However, it is not unclear which circulating inflammatory proteins may boost the risk of or protect against COVID-19. Methods: We performed Mendelian randomization (MR) analysis using GWAS summary result of 91 circulating inflammation-related proteins (N = 14,824) to assess their causal impact on severe COVID-19. The COVID-19 phenotypes encompassed both hospitalized (N = 2,095,324) and critical COVID-19 (N = 1,086,211). Moreover, sensitivity analyses were conducted to evaluate the robustness and reliability. Results: We found that seven circulating inflammatory proteins confer positive causal effects on severe COVID-19. Among them, serum levels of IL-10RB, FGF-19, and CCL-2 positively contributed to both hospitalized and critical COVID-19 conditions (OR: 1.10~1.16), while the other 4 proteins conferred risk on critical COVID-19 only (OR: 1.07~1.16), including EIF4EBP1, IL-7, NTF3, and LIF. Meanwhile, five proteins exert protective effects against hospitalization and progression to critical COVID-19 (OR: 0.85~0.95), including CXCL11, CDCP1, CCL4/MIP, IFNG, and LIFR. Sensitivity analyses did not support the presence of heterogeneity in the majority of MR analyses. Conclusions: Our study revealed risk and protective inflammatory proteins for severe COVID-19, which may have vital implications for the treatment of the disease.


Assuntos
COVID-19 , Humanos , Reprodutibilidade dos Testes , Hospitalização , Inflamação , Análise da Randomização Mendeliana , Antígenos de Neoplasias , Moléculas de Adesão Celular
18.
ACS Nano ; 18(8): 6612-6622, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38359901

RESUMO

To perform multiplex profiling of single cells and eliminate the risk of potential sample loss caused by centrifugation, we developed a microfluidic flow cytometry and mass spectrometry system (µCytoMS) to evaluate the drug uptake and induced protein expression at the single cell level. It involves a microfluidic chip for the alignment and purification of single cells followed by detection with laser-induced fluorescence (LIF) and inductively coupled plasma mass spectrometry (ICP-MS). Biofunctionalized nanoprobes (BioNPs), conjugating ∼3000 6-FAM-Sgc8 aptamers on a single gold nanoparticle (AuNP) (Kd = 0.23 nM), were engineered to selectively bind with protein tyrosine kinase 7 (PTK7) on target cells. PTK7 expression induced by oxaliplatin (OXA) uptake was assayed with LIF, while ICP-MS measurement of 195Pt revealed OXA uptake of the drug in individual cells, which provided further in-depth information about the drug in relation to PTK7 expression. At an ultralow flow of ∼0.043 dyn/cm2 (20 µL/min), the chip facilitates the extremely fast focusing of BioNPs labeled single cells without the need for centrifugal purification. It ensures multiplex profiling of single cells at a throughput speed of 500 cells/min as compared to 40 cells/min in previous studies. Using a machine learning algorithm to initially profile drug uptake and marker expression in tumor cell lines, µCytoMS was able to perform in situ profiling of the PTK7 response to the OXA at single-cell resolution for tests done on clinical samples from 10 breast cancer patients. It offers great potential for multiplex single-cell phenotypic analysis and clinical diagnosis.


Assuntos
Nanopartículas Metálicas , Microfluídica , Humanos , Citometria de Fluxo , Ouro , Biomarcadores , Espectrometria de Massas/métodos , Moléculas de Adesão Celular , Receptores Proteína Tirosina Quinases
19.
Int J Mol Sci ; 25(4)2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38396964

RESUMO

TFF3 is a typical secretory poplypeptide of mucous epithelia belonging to the trefoil factor family (TFF) of lectins. In the intestine, respiratory tract, and saliva, TFF3 mainly exists as a high-molecular-mass complex with IgG Fc binding protein (FCGBP), which is indicative of a role in mucosal innate immunity. For the first time, we identified different forms of TFF3 in the endocervix, i.e., monomeric and homodimeric TFF3, as well as a high-molecular-mass TFF3-FCGBP complex; the latter also exists in a hardly soluble form. Immunohistochemistry co-localized TFF3 and FCGBP. Expression analyses of endocervical and post-menopausal vaginal specimens revealed a lack of mucin and TFF3 transcripts in the vaginal specimens. In contrast, genes encoding other typical components of the innate immune defense were expressed in both the endocervix and vagina. Of note, FCGBP is possibly fucosylated. Endocervical specimens from transgender individuals after hormonal therapy showed diminished expression, particularly of FCGBP. Furthermore, mucus swabs from the endocervix and vagina were analyzed concerning TFF3, FCGBP, and lysozyme. It was the aim of this study to illuminate several aspects of the cervico-vaginal innate immune barrier, which is clinically relevant as bacterial and viral infections are also linked to infertility, pre-term birth and cervical cancer.


Assuntos
Colo do Útero , Mucinas , Vagina , Feminino , Humanos , Proteínas de Transporte , Moléculas de Adesão Celular/metabolismo , Colo do Útero/imunologia , Imunidade Inata , Imunoglobulina G/metabolismo , Mucinas/metabolismo , Fator Trefoil-2/metabolismo , Fator Trefoil-3/genética , Fator Trefoil-3/metabolismo , Vagina/imunologia
20.
Genes (Basel) ; 15(2)2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38397233

RESUMO

The primary goal of this investigation was to identify mRNA targets affected by dysregulated miRNAs in RIF. This was accomplished by comprehensively analyzing mRNA and miRNA expression profiles in two groups: female subjects with normal reproductive function (control, n = 5) and female subjects experiencing recurrent implantation failure (RIF, n = 5). We conducted transcriptome sequencing and small RNA sequencing on endometrial tissue samples from these cohorts. Subsequently, we validated a selection of intriguing findings using real-time PCR with samples from the same cohort. In total, our analysis revealed that 929 mRNAs exhibited differential expression patterns between the control and RIF patient groups. Notably, our investigation confirmed the significant involvement of dysregulated genes in the context of RIF. Furthermore, we uncovered promising correlation patterns within these mRNA/miRNA pairs. Functional categorization of these miRNA/mRNA pairs highlighted that the differentially expressed genes were predominantly associated with processes such as angiogenesis and cell adhesion. We identified new target genes that are regulated by miR-665, including Blood Vessel Epicardial Substance (BVES) and Adenosylhomocysteinase like 2 (AHCYL2). Our findings suggest that abnormal regulation of genes involved in angiogenesis and cell adhesion, including BVES and AHCYL2, contributes to the endometrial dysfunction observed in women with recurrent implantation failure (RIF) compared to healthy women.


Assuntos
Implantação do Embrião , MicroRNAs , Feminino , Humanos , Adesão Celular , Moléculas de Adesão Celular/metabolismo , Implantação do Embrião/genética , Endométrio/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Musculares/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
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