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1.
Autophagy ; 20(2): 295-310, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-37712615

RESUMEN

ABBREVIATIONS: AO: acridine orange; ATM: ATM serine/threonine kinase; CHEK1: checkpoint kinase 1; CHEK2: checkpoint kinase 2; CI: combination index; DMSO: dimethyl sulfoxide; DSBs: double-strand breaks; GBM: glioblastoma; HR: homologous recombination; H2AX: H2A.X variant histone; IHC: immunohistochemistry; LAPTM4B: lysosomal protein transmembrane 4 beta; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PARP: poly(ADP-ribose) polymerase; RAD51: RAD51 recombinase; SQSTM1: sequestosome 1; SSBs: single-strand breaks; RNF168: ring finger protein 168; XPO1: exportin 1.


Asunto(s)
Glioblastoma , Piperazinas , Humanos , Proteína Sequestosoma-1/metabolismo , Autofagia , Ftalazinas/farmacología , Proteínas/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Oncogénicas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
2.
Stem Cell Res Ther ; 14(1): 334, 2023 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-37981679

RESUMEN

BACKGROUND: Mesenchymal stem cells (MSCs) are adult stem cells with self-renewal and multi-directional differentiation potential and possess the functions of immunomodulation, regulation of cell growth, and repair of damage. Over recent years, MSCs have been found to regulate the secretion of inflammatory factors and to exert regulatory effects on various lymphocytes in inflammatory states, and on the subsequent repair of tissue damage caused by inflammation. In the present study, we analyzed the effects of tissue inflammation on the characteristics of MSCs. METHODS: Human fat derived from the infrapatellar fat pad (IPFP) of knees with differing degrees of inflammation was extracted from specimens derived from total knee arthroplasties. HE and immunohistochemical staining was performed to directly observe the evidence and degree of inflammation in human infrapatellar fat pad tissue in order to classify MSCs cells, by their origin, into highly inflamed and lowly inflamed groups, and to study the effect of tissue inflammation on cell acquisition rates via cellular counting data. Flow cytometry assays were performed to investigate the effect of tissue inflammation on MSC surface marker expression. Trilineage differentiation, including osteogenesis, adipogenesis, and chondrogenesis, was performed to assess the effect of tissue inflammation on the ability of MSCs to undergo directed differentiation. The effect of tissue inflammation on the ability of MSCs to proliferate was investigated via clone formation studies. RNA-sequencing was performed to evaluate the transcriptomes of MSCs derived from different areas of inflammation. The effect of tissue inflammation on tissue repair capacity and safety of MSCs was investigated via a murine model of acute liver injury. RESULTS: The results of cell count data indicate that a high degree of tissue inflammation significantly decreases the acquisition rate of MSCs, and the proportion of CD34+ and CD146+ cells. The results of our trilineage differentiation assay show that a higher degree of inflammation decreases osteogenic differentiation and enhances adipogenic and chondrogenic differentiation of MSCs. However, these differences were not statistically significant. Clone formation assays indicate that the degree of tissue inflammation at the MSC source does not significantly affect the proliferative capacity of MSCs. The transcriptomes of MSCs remain relatively stable in fat pad tissues derived from both highly and lowly inflamed samples. The results of acute liver injury investigations in mice indicate that MSCs of high and low inflammatory tissue origin have no significant difference in their tissue repair capability. CONCLUSIONS: High tissue inflammation at the source of MSCs reduces the acquisition rate of MSCs and the percentage of CD34+ and CD146+ cells acquisition. However, source tissue inflammation may not significantly affect trilineage differentiation potential and proliferative capacity of MSCs. Also, MSCs obtained from differing source degrees of inflammation retain stable and similar transcriptomic profile and are both safe and efficacious for tissue repair/regeneration without detectable differences.


Asunto(s)
Células Madre Mesenquimatosas , Osteogénesis , Adulto , Humanos , Animales , Ratones , Osteogénesis/fisiología , Antígeno CD146/metabolismo , Modelos Animales de Enfermedad , Células Madre Mesenquimatosas/metabolismo , Diferenciación Celular , Tejido Adiposo , Inflamación/metabolismo , Hígado , Condrogénesis , Células Cultivadas
3.
MedComm (2020) ; 4(4): e318, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37361896

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-caused coronavirus disease 2019 (COVID-19) is a global crisis with no satisfactory therapies. Vitamin D3 (VD3) is considered a potential candidate for COVID-19 treatment; however, little information is available regarding the exact effects of VD3 on SARS-CoV-2 infection and the underlying mechanism. Herein, we confirmed that VD3 reduced SARS-CoV-2 nucleocapsid (N) protein-caused hyperinflammation in human bronchial epithelial (HBE) cells. Meanwhile, VD3 inhibited the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation in N protein-overexpressed HBE (HBE-N) cells. Notably, the inhibitors of caspase-1, NLRP3, and NLRP3 or caspase-1 small interference RNA (siRNA) enhanced VD3-induced NLRP3 inflammasome inactivation, with subsequent suppression of interleukin-6 (IL6) and IL1ß release in HBE-N cells, which were abolished by the NLRP3 agonist. Moreover, VD3 increased NLRP3 ubiquitination (Ub-NLRP3) expression and the binding of the VDR with NLRP3, with decreased BRCA1/BRCA2-containing complex subunit 3 (BRCC3) expression and NLRP3-BRCC3 association. VD3-induced Ub-NLRP3 expression, NLRP3 inflammasome inactivation, and hyperinflammation inhibition were improved by the BRCC3 inhibitor or BRCC3 siRNA, which were attenuated by the vitamin D receptor (VDR) antagonist or VDR siRNA in HBE-N cells. Finally, the results of the in vivo study in AAV-Lung-enhanced green fluorescent protein-N-infected lungs were consistent with the findings of the in vitro experiment. In conclusion, VD3 attenuated N protein-caused hyperinflammation by inactivating the NLRP3 inflammasome partially through the VDR-BRCC3 signaling pathway.

4.
Cancer Cell ; 41(4): 693-710.e8, 2023 04 10.
Artículo en Inglés | MEDLINE | ID: mdl-36963400

RESUMEN

Malignant gliomas are largely refractory to immune checkpoint blockade (ICB) therapy. To explore the underlying immune regulators, we examine the microenvironment in glioma and find that tumor-infiltrating T cells are mainly confined to the perivascular cuffs and express high levels of CCR5, CXCR3, and programmed cell death protein 1 (PD-1). Combined analysis of T cell clustering with T cell receptor (TCR) clone expansion shows that potential tumor-killing T cells are mainly categorized into pre-exhausted/exhausted and effector CD8+ T subsets, as well as cytotoxic CD4+ T subsets. Notably, a distinct subpopulation of CD4+ T cells exhibits innate-like features with preferential interleukin-8 (IL-8) expression. With IL-8-humanized mouse strain, we demonstrate that IL-8-producing CD4+ T, myeloid, and tumor cells orchestrate myeloid-derived suppressor cell infiltration and angiogenesis, which results in enhanced tumor growth but reduced ICB efficacy. Antibody-mediated IL-8 blockade or the inhibition of its receptor, CXCR1/2, unleashes anti-PD-1-mediated antitumor immunity. Our findings thus highlight IL-8 as a combinational immunotherapy target for glioma.


Asunto(s)
Glioma , Inhibidores de Puntos de Control Inmunológico , Interleucina-8 , Animales , Ratones , Linfocitos T CD8-positivos , Línea Celular Tumoral , Glioma/tratamiento farmacológico , Glioma/patología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia/métodos , Interleucina-8/metabolismo , Linfocitos T , Microambiente Tumoral
5.
Adv Sci (Weinh) ; 9(27): e2105938, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35882624

RESUMEN

Autophagy is a highly conserved process that is vital for tumor progression and treatment response. Although autophagy is proposed to maintain the stemness phenotype in adult diffuse glioma, the molecular basis of the link between autophagy and stemness is poorly understood, which makes it impossible to effectively screen for the population that will benefit from autophagy-targeted treatment. Here, ATG9B as essential for self-renewal capacity and tumor-propagation potential is identified. Notably, ASCL2 transcriptionally regulates the expression of ATG9B to maintain stemness properties. The ASCL2-ATG9B axis is an independent prognostic biomarker and indicator of autophagic activity. Furthermore, the highly effective blood-brain barrier (BBB)-permeable autophagy inhibitor ROC-325, which can significantly inhibit the progression of ASCL2-ATG9B axisHigh gliomas as a single agent is investigated. These data demonstrate that a new ASCL2-ATG9B signaling axis is crucial for maintaining the stemness phenotype and tumor progression, revealing a potential autophagy inhibition strategy for adult diffuse gliomas.


Asunto(s)
Autofagia , Glioma , Autofagia/genética , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Biomarcadores , Glioma/genética , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Fenotipo
6.
Lab Invest ; 102(12): 1304-1313, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35882906

RESUMEN

Glioma progression is accompanied with increased tumor tissue stiffness, yet the underlying mechanisms are unclear. Herein, we employed atomic force microscopy analysis to show that tissue stiffness was higher in isocitrate dehydrogenase (IDH)-wild type gliomas than IDH-mutant gliomas. Bioinformatic analyses revealed that tissue inhibitor of metalloproteinase-1 (TIMP1) was one of the preferentially upregulated genes in IDH-wild type gliomas as compared to IDH-mutant gliomas, and its higher expression indicated worse prognosis of glioma patients. TIMP1 intensity determined by immunofluorescence staining on glioma tissues positively correlated with glioma tissue stiffness. Mechanistically, TIMP1 expression was positively correlated with the gene expression of two predominant extracellular matrix components, tenascin C and fibronectin, both of which were also highly expressed in IDH-wild type gliomas. By introducing IDH1-R132H-containing vectors into human IDH1-wild type glioma cells to obtain an IDH1-mutant cell line, we found that IDH1 mutation increased the TIMP1 promoter methylation through methylation-specific PCR. More importantly, IDH1-R132H mutation decreased both the expression of TIMP1, fibronectin, tenascin C, and the tumor tissue stiffness in IDH1-mutant glioma xenografts in contrast to IDH1-wild type counterparts. Moreover, TIMP1 knockdown in IDH-wild type glioma cells inhibited the expression of tenascin C and fibronectin, and decreased tissue stiffness in intracranial glioma xenografts. Conclusively, we revealed an IDH mutation status-mediated mechanism in regulating glioma tissue stiffness through modulating TIMP1 and downstream extracellular matrix components.


Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Fibronectinas/genética , Neoplasias Encefálicas/metabolismo , Tenascina/genética , Inhibidor Tisular de Metaloproteinasa-1/genética , Glioma/metabolismo , Mutación , Matriz Extracelular/metabolismo
7.
Cancer Commun (Lond) ; 42(9): 868-886, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35848447

RESUMEN

BACKGROUND: Elucidation of the post-transcriptional modification has led to novel strategies to treat intractable tumors, especially glioblastoma (GBM). The ubiquitin-proteasome system (UPS) mediates a reversible, stringent and stepwise post-translational modification which is closely associated with malignant processes of GBM. To this end, developing novel therapeutic approaches to target the UPS may contribute to the treatment of this disease. This study aimed to screen the vital and aberrantly regulated component of the UPS in GBM. Based on the molecular identification, functional characterization, and mechanism investigation, we sought to elaborate a novel therapeutic strategy to target this vital factor to combat GBM. METHODS: We combined glioma datasets and human patient samples to screen and identify aberrantly regulated E3 ubiquitin ligase. Multidimensional database analysis and molecular and functional experiments in vivo and in vitro were used to evaluate the roles of HECT, UBA and WWE domain-containing E3 ubiquitin ligase 1 (HUWE1) in GBM. dCas9 synergistic activation mediator system and recombinant adeno-associated virus (rAAV) were used to endogenously overexpress full-length HUWE1 in vitro and in glioma orthotopic xenografts. RESULTS: Low expression of HUWE1 was closely associated with worse prognosis of GBM patients. The ubiquitination and subsequent degradation of N-Myc mediated by HUWE1, leading to the inactivation of downstream Delta-like 1 (DLL1)-NOTCH1 signaling pathways, inhibited the proliferation, invasion, and migration of GBM cells in vitro and in vivo. A rAAV dual-vector system for packaging and delivery of dCas9-VP64 was used to augment endogenous HUWE1 expression in vivo and showed an antitumor activity in glioma orthotopic xenografts. CONCLUSIONS: The E3 ubiquitin ligase HUWE1 acts through the N-Myc-DLL1-NOTCH1 signaling axis to suppress GBM progression. Antitumor activity of rAAV dual-vector delivering dCas9-HUWE1 system uncovers a promising therapeutic strategy for GBM.


Asunto(s)
Glioblastoma , Proteínas Supresoras de Tumor , Ubiquitina-Proteína Ligasas , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Glioblastoma/genética , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteína Proto-Oncogénica N-Myc/genética , Proteína Proto-Oncogénica N-Myc/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Transducción de Señal , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación
8.
Clin Exp Metastasis ; 39(4): 691-710, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35661947

RESUMEN

Plexin-domain containing 2 (PLXDC2) has been reported as an oncoprotein in several human malignancies. However, its expression and roles in gastric cancer remain largely unclear. In this study, we found that PLXDC2 was highly expressed in gastric cancer tissues, and the expression levels were positively correlated with clinicopathological features, but negatively with the patients' outcome. Cox regression analysis identified PLXDC2 as an independent prognostic indicator for the patients. Knockdown of PLXDC2 markedly suppressed the in vitro invasion and in vivo metastasis of gastric cancer cells, while overexpression of PLXDC2 resulted in opposite effects. Mechanistically, PLXDC2 enhanced the level of phosphorylated Cortactin (p-Cortactin) by physically interacting with protein tyrosine phosphatase 1B (PTP1B), an important dephosphorylase, to prevent its dephosphorylating of p-Cortactin, thereby promoting the formation of invadopodia. Collectively, our results indicate that PLXDC2 contributes to the invasion and metastasis of gastric cancer by inhibiting PTP1B to facilitate the invadopodium formation, and may serve as a potential prognostic biomarker and a therapeutic target for this disease.


Asunto(s)
Podosomas , Neoplasias Gástricas , Línea Celular Tumoral , Cortactina/genética , Cortactina/metabolismo , Humanos , Invasividad Neoplásica , Monoéster Fosfórico Hidrolasas/metabolismo , Podosomas/metabolismo , Podosomas/patología , Receptores de Superficie Celular , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología
9.
Signal Transduct Target Ther ; 7(1): 72, 2022 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-35273141

RESUMEN

Medulloblastoma (MB) is one of the most common childhood malignant brain tumors (WHO grade IV), traditionally divided into WNT, SHH, Group 3, and Group 4 subgroups based on the transcription profiles, somatic DNA alterations, and clinical outcomes. Unlike WNT and SHH subgroup MBs, Group 3 and Group 4 MBs have similar transcriptomes and lack clearly specific drivers and targeted therapeutic options. The recently revised WHO Classification of CNS Tumors has assigned Group 3 and 4 to a provisional non-WNT/SHH entity. In the present study, we demonstrate that Kir2.1, an inwardly-rectifying potassium channel, is highly expressed in non-WNT/SHH MBs, which promotes tumor cell invasion and metastasis by recruiting Adam10 to enhance S2 cleavage of Notch2 thereby activating the Notch2 signaling pathway. Disruption of the Notch2 pathway markedly inhibited the growth and metastasis of Kir2.1-overexpressing MB cell-derived xenograft tumors in mice. Moreover, Kir2.1high/nuclear N2ICDhigh MBs are associated with the significantly shorter lifespan of the patients. Thus, Kir2.1high/nuclear N2ICDhigh can be used as a biomarker to define a novel subtype of non-WNT/SHH MBs. Our findings are important for the modification of treatment regimens and the development of novel-targeted therapies for non-WNT/SHH MBs.


Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Animales , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/metabolismo , Neoplasias Cerebelosas/patología , Niño , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/genética , Meduloblastoma/metabolismo , Meduloblastoma/patología , Ratones , Mutación , Canales de Potasio de Rectificación Interna , Transducción de Señal
10.
Signal Transduct Target Ther ; 7(1): 33, 2022 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-35105853

RESUMEN

Platelet-derived growth subunit A (PDGFA) plays critical roles in development of glioblastoma (GBM) with substantial evidence from TCGA database analyses and in vivo mouse models. So far, only platelet-derived growth receptor α (PDGFRA) has been identified as receptor for PDGFA. However, PDGFA and PDGFRA are categorized into different molecular subtypes of GBM in TCGA_GBM database. Our data herein further showed that activity or expression deficiency of PDGFRA did not effectively block PDGFA activity. Therefore, PDGFRA might be not necessary for PDGFA function.To profile proteins involved in PDGFA function, we performed co-immunoprecipitation (Co-IP) and Mass Spectrum (MS) and delineated the network of PDGFA-associated proteins for the first time. Unexpectedly, the data showed that EPHA2 could be temporally activated by PDGFA even without activation of PDGFRA and AKT. Furthermore, MS, Co-IP, in vitro binding thermodynamics, and proximity ligation assay consistently proved the interaction of EPHA2 and PDGFA. In addition, we observed that high expression of EPHA2 leaded to upregulation of PDGF signaling targets in TCGA_GBM database and clinical GBM samples. Co-upregulation of PDGFRA and EPHA2 leaded to worse patient prognosis and poorer therapeutic effects than other contexts, which might arise from expression elevation of genes related with malignant molecular subtypes and invasive growth. Due to PDGFA-induced EPHA2 activation, blocking PDGFRA by inhibitor could not effectively suppress proliferation of GBM cells, but simultaneous inhibition of both EPHA2 and PDGFRA showed synergetic inhibitory effects on GBM cells in vitro and in vivo. Taken together, our study provided new insights on PDGFA function and revealed EPHA2 as a potential receptor of PDGFA. EPHA2 might contribute to PDGFA signaling transduction in combination with PDGFRA and mediate the resistance of GBM cells to PDGFRA inhibitor. Therefore, combination of inhibitors targeting PDGFRA and EHA2 represented a promising therapeutic strategy for GBM treatment.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Glioblastoma/metabolismo , Proteínas de Neoplasias/metabolismo , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptor EphA2/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Glioblastoma/diagnóstico , Glioblastoma/genética , Humanos , Proteínas de Neoplasias/genética , Factor de Crecimiento Derivado de Plaquetas/genética , Pronóstico , Receptor EphA2/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética
11.
Front Endocrinol (Lausanne) ; 12: 712513, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34566889

RESUMEN

The improvement in the quality of life is accompanied by an accelerated pace of living and increased work-related pressures. Recent decades has seen an increase in the proportion of obese patients, as well as an increase in the prevalence of breast cancer. More and more evidences prove that obesity may be one of a prognostic impact factor in patients with breast cancer. Obesity presents unique diagnostic and therapeutic challenges in the population of breast cancer patients. Therefore, it is essential to have a better understanding of the relationship between obesity and breast cancer. This study aims to construct a prognostic risk prediction model combining obesity and breast cancer. In this study, we obtained a breast cancer sample dataset from the GEO database containing obesity data [determined by the body mass index (BMI)]. A total of 1174 genes that were differentially expressed between breast cancer samples of patients with and without obesity were screened by the rank-sum test. After weighted gene co-expression network analysis (WGCNA), 791 related genes were further screened. Relying on single-factor COX regression analysis to screen the candidate genes to 30, these 30 genes and another set of TCGA data were intersected to obtain 24 common genes. Finally, lasso regression analysis was performed on 24 genes, and a breast cancer prognostic risk prediction model containing 6 related genes was obtained. The model was also found to be related to the infiltration of immune cells. This study provides a new and accurate prognostic model for predicting the survival of breast cancer patients with obesity.


Asunto(s)
Neoplasias de la Mama/genética , Obesidad/genética , Pronóstico , Transcriptoma , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/inmunología , Femenino , Expresión Génica , Humanos , Inmunidad Celular , Obesidad/epidemiología , Obesidad/inmunología , Modelos de Riesgos Proporcionales , Riesgo , Tasa de Supervivencia
12.
J Pathol ; 255(4): 374-386, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34370292

RESUMEN

Calcyphosine (CAPS) was initially identified from the canine thyroid. It also exists in many types of tumor, but its expression and function in glioma remain unknown. Here we explored the clinical significance and the functional mechanisms of CAPS in glioma. We found that CAPS was highly expressed in glioma and high expression of CAPS was correlated with poor survival, in glioma patients and public databases. Cox regression analysis showed that CAPS was an independent prognostic factor for glioma patients. Knockdown of CAPS suppressed the proliferation, whereas overexpression of CAPS promoted the proliferation of glioma both in vitro and in vivo. CAPS regulated the G2/M phase transition of the cell cycle, but had no obvious effect on apoptosis. CAPS affected PLK1 phosphorylation through interaction with MYPT1. CAPS knockdown decreased p-MYPT1 at S507 and p-PLK1 at S210. Expression of MYPT1 S507 phosphomimic rescued PLK1 phosphorylation and the phenotype caused by CAPS knockdown. The PLK1 inhibitor volasertib enhanced the therapeutic effect of temozolomide in glioma. Our data suggest that CAPS promotes the proliferation of glioma by regulating the cell cycle and the PLK1 inhibitor volasertib might be a chemosensitizer of glioma. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.


Asunto(s)
Neoplasias Encefálicas/patología , Proteínas de Unión al Calcio/metabolismo , Glioma/patología , Adulto , Anciano , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Neoplasias Encefálicas/metabolismo , Ciclo Celular/efectos de los fármacos , Ciclo Celular/fisiología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Femenino , Glioma/metabolismo , Humanos , Masculino , Ratones , Persona de Mediana Edad , Pteridinas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Cell Res ; 31(8): 836-846, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34135479

RESUMEN

Severe COVID-19 disease caused by SARS-CoV-2 is frequently accompanied by dysfunction of the lungs and extrapulmonary organs. However, the organotropism of SARS-CoV-2 and the port of virus entry for systemic dissemination remain largely unknown. We profiled 26 COVID-19 autopsy cases from four cohorts in Wuhan, China, and determined the systemic distribution of SARS-CoV-2. SARS-CoV-2 was detected in the lungs and multiple extrapulmonary organs of critically ill COVID-19 patients up to 67 days after symptom onset. Based on organotropism and pathological features of the patients, COVID-19 was divided into viral intrapulmonary and systemic subtypes. In patients with systemic viral distribution, SARS-CoV-2 was detected in monocytes, macrophages, and vascular endothelia at blood-air barrier, blood-testis barrier, and filtration barrier. Critically ill patients with long disease duration showed decreased pulmonary cell proliferation, reduced viral RNA, and marked fibrosis in the lungs. Permanent SARS-CoV-2 presence and tissue injuries in the lungs and extrapulmonary organs suggest direct viral invasion as a mechanism of pathogenicity in critically ill patients. SARS-CoV-2 may hijack monocytes, macrophages, and vascular endothelia at physiological barriers as the ports of entry for systemic dissemination. Our study thus delineates systemic pathological features of SARS-CoV-2 infection, which sheds light on the development of novel COVID-19 treatment.


Asunto(s)
COVID-19/patología , Pulmón/virología , SARS-CoV-2/aislamiento & purificación , Anciano , Anciano de 80 o más Años , Autopsia , COVID-19/virología , China , Estudios de Cohortes , Enfermedad Crítica , Femenino , Fibrosis , Hospitalización , Humanos , Riñón/patología , Riñón/virología , Leucocitos Mononucleares/patología , Leucocitos Mononucleares/virología , Pulmón/patología , Masculino , Persona de Mediana Edad , ARN Viral/metabolismo , SARS-CoV-2/genética , Bazo/patología , Bazo/virología , Tráquea/patología , Tráquea/virología
14.
Am J Cancer Res ; 11(4): 1572-1585, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33948374

RESUMEN

Chemotherapy resistance after curative surgery is a major contributor to the mortality of colorectal cancer (CRC). Detailed mechanism studies of specific molecular alterations are critical to improving the available therapies for long-term disease administration. We explored the functional role of LINC01347 in chemotherapy resistance of CRC. Elevated LINC01347 expression was correlated with CRC disease progression during chemotherapy treatment. However, the functional role of LINC01347 and mechanism remained undefined. In this study, we demonstrated that elevated LINC01347 expression was correlated with late clinical stage and poor prognosis in CRC tumor tissues with TCGA data. Exogenous LINC01347 expression promoted cell proliferation and 5-FU resistance of CRC cells, while LINC01347 knockdown attenuated cell growth and 5-FU resistance in vitro and in vivo. Molecular analysis indicated that LINC01347 participated in the transcriptional regulation of LOXL2 by sponging miR-328-5p. LOXL2 knockdown impaired the LINC01347 overexpression induced 5-FU resistance in CRC cells. The clinical analysis supported miR-328-5p/LOXL2 as a candidate biomarker for chemotherapy resistance of CRC patients. Our study provided a molecular basis for the development of 5-FU based chemotherapy resistance in CRC by LINC01347/miR-328/LOXL2 axis. We identified LINC01347 as a prognostic biomarker and potential therapeutic target against 5-FU based chemotherapy resistance of CRC.

15.
Am J Transl Res ; 13(3): 1365-1376, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33841662

RESUMEN

Long noncoding RNAs (lncRNAs) play crucial roles in the acquired resistance to EGFR-directed therapies in lung cancer. LncRNA OSER1-AS1 has been reported to promote tumorigenesis of hepatocellular carcinoma. However, its functions and underlying molecular mechanisms remain unclear in the acquired gefitinib-resistance of lung cancer. Our study revealed that increased expression of OSER1-AS1 was correlated with gefitinib resistance in lung adenocarcinoma. Higher OSER1-AS1 expression predicted disease progression of lung adenocarcinoma patients. The in vitro assays indicated OSER1-AS1 contributed to gefitinib resistance of lung adenocarcinoma cells via inhibiting cell apoptosis and cell cycle arrest. In vivo experiments showed that the knockdown of OSER1-AS1 restored the sensitivity of lung cancer cells to gefitinib. Further studies showed that OSER1-AS1 functioned as a molecular sponge of miR-612. OSER1-AS1 down-regulated miR-612 to increase FOXM1 expression, suggesting that miR-612/FOXM1 axis was regulated by OSER1-AS1, which was partially responsible for gefitinib resistance of lung adenocarcinoma. In conclusion, OSER1-AS1 promoted gefitinib resistance of lung adenocarcinoma through the miR-612/FOXM1 axis.

16.
Front Mol Biosci ; 8: 619110, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33644115

RESUMEN

Breast cancer is one of the most common cancers. Although the present molecular classification improves the treatment effect and prognosis of breast cancer, the heterogeneity of the molecular subtype remains very complex, and the applicability and effectiveness of treatment methods are still limited leading to poorer patient prognosis than expected. Further identification of more refined molecular typing based on gene expression profile will yield better understanding of the heterogeneity, improving treatment effects and prolonging prognosis of patients. Here, we downloaded the mRNA expression profiles and corresponding clinical data of patients with breast cancer from public databases and performed typical molecular typing using PAM50 (Prediction Analysis of Microarray 50) method. Comparative analyses were performed to screen the common and specific differentially expressed genes (DEGs) between cancer and corresponding para-cancerous tissues in each breast cancer subtype. The GO and KEGG analyses of the DEGs were performed to enrich the common and specific functional progress and signaling pathway involved in breast cancer subtypes. A total of 38 key common and specific DEGs were identified and selected based on the validated results, GO/KEGG enrichments, and the priority of expression, including four common DEGs and 34 specific DEGs in different subtypes. The prognostic value of these key common and specific DEGs was further analyzed to obtain useful potential markers in clinic. Finally, the potential roles and the specific prognostic values of the common and specific DEGs were speculated and summarized in total breast cancer and different subtype breast cancer based on the results of these analyses. The findings of our study provide the basis of more refined molecular typing of breast cancer, potential new therapeutic targets and prognostic markers for different breast cancer subtypes.

17.
Front Biosci (Landmark Ed) ; 26(3): 552-565, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33049683

RESUMEN

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with poor progrnosis and a high recurrence rate after surgery. To this end, we examined the role of Nanog that is highly expressed in this tumor. NANOG is a transcription factor involved in the pluripotency of embryonic stem cells (ESCs) and the induction of malignancy in cancer stem-like cells (CSCs). Bioinformatic analysis revealed that NANOG may be associated with the development of stem-like traits in GBM. Forced expression of NANOG markedly increased the expression of cancer stem cell markers and promoted the sphere formation and migration of GBM cells. Nanog enhanced the expression of SHH which is required for the maintenance of the positive feedback loop of Hedgehog signaling pathway. Treatment of GBM cells with SANT-1 and GANT61 significantly reduced the tumor progression. These data support a view that reduction of Nanog might have therapeutic benefits in GBM.


Asunto(s)
Neoplasias Encefálicas/patología , Glioblastoma/patología , Proteína Homeótica Nanog/fisiología , Células Madre Neoplásicas/patología , Humanos , Proteína Homeótica Nanog/metabolismo , Transducción de Señal
18.
Am J Cancer Res ; 10(3): 939-952, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32266101

RESUMEN

Chemotherapy resistance is a major challenge for breast cancer treatment. It is necessary to elucidate the mechanisms of anthracycline resistance to develop new chemosensitizers for breast cancer. In this study, we explored the effects of ligustrazine (TMP) on reverting anthracycline resistance of breast cancer cells, as well as its related mechanisms. Clinical significance of fibrinogen gamma chain (FGG) expression was also analyzed in breast cancer tissues. We provided evidence that breast tumor cell derived FGG participated in anthracycline chemoresistance of breast cancer. Further, TMP reverted epirubicin resistance by inhibiting JAK2/STAT3 signaling and decreasing FGG expression. Meanwhile, the elimination of cancer stem cell was observed in TMP treated chemoresistant breast cancer cells. Clinical analysis demonstrated that patients with FGG expressing breast cancer showed a dramatically low response to anthracycline-based chemotherapy and poor survival. Our data collectively indicated that FGG was an independent detrimental factor for anthracycline based chemotherapy for breast cancer patients. TMP was a novel chemosensitizer for FGG-induced anthracycline chemoresistance in breast cancer treatment.

19.
Lab Invest ; 100(6): 812-823, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31949244

RESUMEN

Glioblastoma multiforme (GBM) is characterized by highly invasive growth, which leads to extensive infiltration and makes complete tumor excision difficult. Since cytoskeleton proteins are related to leading processes and cell motility, and through analysis of public GBM databases, we determined that an actin-interacting protein, zyxin (ZYX), may involved in GBM invasion. Our own glioma cohort as well as the cancer genome atlas (TCGA), Rembrandt, and Gravendeel databases consistently showed that increased ZYX expression was related to tumor progression and poor prognosis of glioma patients. In vitro and in vivo experiments further confirmed the oncogenic roles of ZYX and demonstrated the role of ZYX in GBM invasive growth. Moreover, RNA-seq and mass-spectrum data from GBM cells with or without ZYX revealed that stathmin 1 (STMN1) was a potential target of ZYX. Subsequently, we found that both mRNA and protein levels of STMN1 were positively regulated by ZYX. Functionally, STMN1 not only promoted invasion of GBM cells but also rescued the invasion repression caused by ZYX loss. Taken together, our results indicate that high ZYX expression was associated with worse prognosis and highlighted that the ZYX-STMN1 axis might be a potential therapeutic target for GBM.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Invasividad Neoplásica/patología , Zixina , Animales , Biomarcadores de Tumor , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidad , Línea Celular Tumoral , Movimiento Celular/genética , Técnicas de Silenciamiento del Gen , Glioblastoma/diagnóstico , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/mortalidad , Humanos , Ratones , Ratones Endogámicos NOD , Pronóstico , Estatmina/análisis , Estatmina/genética , Estatmina/metabolismo , Zixina/análisis , Zixina/genética , Zixina/metabolismo
20.
Stem Cell Res Ther ; 10(1): 330, 2019 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-31747975

RESUMEN

BACKGROUND: The existing cell surface markers used for sorting glioma stem cells (GSCs) have obvious limitations, such as vulnerability to the enzymatic digestion and time-consuming labeling procedure. Reduced nicotinamide adenine dinucleotide (NADH) as a cellular metabolite with property of autofluorescence has the potential to be used as a new biomarker for sorting GSCs. METHODS: A method for sorting GSCs was established according to the properties of the autofluorescence of NADH. Then, the NADHhigh and NADHlow subpopulations were sorted. The stem-like properties of the subpopulations were evaluated by qRT-PCR, western blot analyses, limiting dilution assay, cell viability assay, bioluminescence imaging, and immunofluorescence analysis in vitro and in vivo. The relationship between CD133+/CD15+ cells and NADHhigh subpopulation was also assessed. RESULTS: NADHhigh cells expressed higher stem-related genes, formed more tumor spheres, and harbored stronger pluripotency in vitro and higher tumorigenicity in vivo, compared to NADHlow subpopulation. NADHhigh glioma cells had the similar stemness with CD133+ or CD15+ GSCs, but the three subpopulations less overlaid each other. Also, NADHhigh glioma cells were more invasive and more resistant to chemotherapeutic drug temozolomide (TMZ) than NADHlow cells. In addition, the autofluorescence of NADH might be an appropriate marker to sort cancer stem cells (CSCs) in other cancer types, such as breast and colon cancer. CONCLUSION: Our findings demonstrate that intracellular autofluorescence of NADH is a non-labeling, sensitive maker for isolating GSCs, even for other CSCs.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/patología , Citometría de Flujo , Glioma/patología , NAD/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Animales , Antígenos CD/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Femenino , Fluorescencia , Glioma/tratamiento farmacológico , Humanos , Ratones Endogámicos NOD , Ratones SCID , Invasividad Neoplásica , Células Madre Neoplásicas/efectos de los fármacos , Temozolomida/farmacología , Temozolomida/uso terapéutico
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