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1.
Int J Mol Sci ; 23(21)2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36361869

RESUMO

Genetic and epigenetic changes might facilitate the acquisition of stem cell-like phenotypes of tumors, resulting in worse patients outcome. Although the role of chromobox (CBX) domain proteins, a family of epigenetic factors that recognize specific histone marks, in the pathogenesis of several tumor types is well documented, little is known about their association with cancer stemness. Here, we have characterized the relationship between the CBX family members' expression and cancer stemness in liver, lung, pancreatic, and uterine tumors using publicly available TCGA and GEO databases and harnessing several bioinformatic tools (i.e., Oncomine, GEPIA2, TISIDB, GSCA, UALCAN, R2 platform, Enrichr, GSEA). We demonstrated that significant upregulation of CBX3 and downregulation of CBX7 are consistently associated with enriched cancer stem-cell-like phenotype across distinct tumor types. High CBX3 expression is observed in higher-grade tumors that exhibit stem cell-like traits, and CBX3-associated gene expression profiles are robustly enriched with stemness markers and targets for c-Myc transcription factor regardless of the tumor type. Similar to high-stemness tumors, CBX3-overexpressing cancers manifest a higher mutation load. On the other hand, higher-grade tumors are characterized by the significant downregulation of CBX7, and CBX7-associated gene expression profiles are significantly depleted with stem cell markers. In contrast to high-stemness tumors, cancer with CBX7 upregulation exhibit a lower mutation burden. Our results clearly demonstrate yet unrecognized association of high CBX3 and low CBX7 expression with cancer stem cell-like phenotype of solid tumors.


Assuntos
Neoplasias , Transcriptoma , Humanos , Neoplasias/genética , Epigênese Genética , Células-Tronco Neoplásicas/metabolismo , Família , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Proteínas Cromossômicas não Histona/metabolismo
2.
Int J Mol Sci ; 23(21)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36362068

RESUMO

Differentiated thyroid carcinomas (DTCs), which have papillary and follicular types, are common endocrine malignancies worldwide. Cancer stem cells (CSCs) are a particular type of cancer cells within bulk tumors involved in cancer initiation, drug resistance, and metastasis. Cells with high intracellular aldehyde hydrogenase (ALDH) activity are a population of CSCs in DTCs. Disulfiram (DSF), an ALDH inhibitor used for the treatment of alcoholism, reportedly targets CSCs in various cancers when combined with copper. This study reported for the first time that DSF/copper can inhibit the proliferation of papillary and follicular DTC lines. DSF/copper suppressed thyrosphere formation, indicating the inhibition of CSC activity. Molecular mechanisms of DSF/copper involved downregulating the expression of B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and cell cycle-related proteins, including cyclin B2, cyclin-dependent kinase (CDK) 2, and CDK4, in a dose-dependent manner. BMI1 overexpression diminished the inhibitory effect of DSF/copper in the thyrosphere formation of DTC cells. BMI1 knockdown by RNA interference in DTC cells also suppressed the self-renewal capability. DSF/copper could inhibit the nuclear localization and transcriptional activity of c-Myc and the binding of E2F1 to the BMI1 promoter. Overexpression of c-Myc or E2F1 further abolished the inhibitory effect of DSF/copper on BMI1 expression, suggesting that the suppression of c-Myc and E2F1 by DSF/copper was involved in the downregulation of BMI1 expression. In conclusion, DSF/copper targets CSCs in DTCs by inhibiting c-Myc- or E2F1-mediated BMI1 expression. Therefore, DSF is a potential therapeutic agent for future therapy in DTCs.


Assuntos
Cobre , Dissulfiram , Células-Tronco Neoplásicas , Neoplasias da Glândula Tireoide , Humanos , Aldeído Desidrogenase/metabolismo , Linhagem Celular Tumoral , Cobre/química , Cobre/farmacologia , Dissulfiram/farmacologia , Dissulfiram/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Complexo Repressor Polycomb 1/antagonistas & inibidores , Complexo Repressor Polycomb 1/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/metabolismo
3.
Front Immunol ; 13: 848759, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36311769

RESUMO

Introduction: In sarcoidosis, peripheral lymphopenia and anergy have been associated with increased inflammation and maladaptive immune activity, likely promoting development of chronic and progressive disease. However, the molecular mechanisms that lead to reduced lymphocyte proportions, particularly CD4+ T-cells, have not been fully elucidated. We posit that paradoxical peripheral lymphopenia is characterized by a dysregulated transcriptomic network associated with cell function and fate that results from altered transcription factor targeting activity. Methods: Messenger RNA-sequencing (mRNA-seq) was performed on peripheral blood mononuclear cells (PBMCs) from ACCESS study subjects with sarcoidosis and matched controls and findings validated on a sarcoidosis case-control cohort and a sarcoidosis case series. Preserved PBMC transcriptomic networks between case-control cohorts were assessed to establish cellular associations with gene modules and define regulatory targeting involved in sarcoidosis immune dysregulation utilizing weighted gene co-expression network analysis and differential transcription factor involvement analysis. Network centrality measures identified master transcriptional regulators of subnetworks related to cell proliferation and death. Predictive models of differential PBMC proportions constructed from ACCESS target gene expression corroborated the relationship between aberrant transcription factor regulatory activity and imputed and clinical PBMC populations in the validation cohorts. Results: We identified two unique and preserved gene modules significantly associated with sarcoidosis immune dysregulation. Strikingly, increased expression of a monocyte-driven, and not a lymphocyte-driven, gene module related to innate immunity and cell death was the best predictor of peripheral CD4+ T-cell proportions. Within the gene network of this monocyte-driven module, TLE3 and CBX8 were determined to be master regulators of the cell death subnetwork. A core gene signature of differentially over-expressed target genes of TLE3 and CBX8 involved in cellular communication and immune response regulation accurately predicted imputed and clinical monocyte expansion and CD4+ T-cell depletion. Conclusions: Altered transcriptional regulation associated with aberrant gene expression of a monocyte-driven transcriptional network likely influences lymphocyte function and survival. Although further investigation is warranted, this indicates that crosstalk between hyperactive monocytes and lymphocytes may instigate peripheral lymphopenia and underlie sarcoidosis immune dysregulation and pathogenesis. Future therapies selectively targeting master regulators, or their targets, may mitigate dysregulated immune processes in sarcoidosis and disease progression.


Assuntos
Linfopenia , Sarcoidose , Humanos , Leucócitos Mononucleares , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Imunidade Inata , Linfopenia/metabolismo , Complexo Repressor Polycomb 1/metabolismo
4.
Genes Dev ; 36(15-16): 871-873, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-36207141

RESUMO

Bmi1 is essential for normal and leukemic hematopoiesis, but its target genes in hematopoietic stem cells (HSCs) are incompletely understood. In this issue of Genes & Development, Burgess et al. (pp. 887-900) demonstrate a novel role of Bmi1 in regulating ribosome biogenesis and protein synthesis. Bmi1-deficient HSCs exhibited reduced transplantability, with the up-regulation of ARX and genes involved in ribosome biogenesis. However, depletion of ARX or its known targets, p16 Ink4a /p19 Arf , only partially rescues Bmi1 loss-induced hematopoietic defects. They further demonstrate an increased protein synthesis rate and resultant proteostatic stress in Bmi1 -/- HSCs, indicating a novel mechanism by which Bmi1 controls HSC maintenance.


Assuntos
Complexo Repressor Polycomb 1 , Proteínas Proto-Oncogênicas , Inibidor p16 de Quinase Dependente de Ciclina/genética , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Proteínas Proto-Oncogênicas/metabolismo
5.
Dokl Biochem Biophys ; 506(1): 210-214, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36303054

RESUMO

Polycomb group (PcG) repressors and Trithorax group (TrxG) activators of transcription are essential for the proper development and maintenance of gene expression profiles in multicellular organisms. In Drosophila, PcG/TrxG proteins interact with DNA elements called PRE (Polycomb response elements). We have previously shown that the repressive activity of inactive PRE in transgenes can be induced by architectural protein-binding sites. It was shown that the induction of repression is associated with the recruitment of PcG/TrxG proteins, including the DNA-binding factors Pho and Combgap. In the present study, we tested the association of the two other PRE DNA-binding factors, GAF and Psq, with bxdPRE in the presence and absence of sites for architectural proteins. As a result, it was shown that both factors can be efficiently recruited to the bxdPRE only in the presence of adjacent binding sites for architectural proteins Su(Hw), CTCF, or Pita.


Assuntos
Cromatina , Proteínas de Drosophila , Animais , Cromatina/genética , Cromatina/metabolismo , Ligação Proteica , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Proteínas do Grupo Polycomb/genética , Sítios de Ligação , Drosophila/genética , DNA , Drosophila melanogaster/genética
6.
Arch Biochem Biophys ; 730: 109425, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36198346

RESUMO

Radiotherapy acts by damaging DNA and hindering cancer cell proliferation. H2AX is phosphorylated to produce γH2AX that accumulates in a response to DNA double-strand breaks. Non-coding RNA can influence DNA damage response and enhance DNA repair, which show potential for cancer treatment. The study aimed to observe the influence of SPI1 on the radiosensitivity of lung squamous cell carcinoma (LUSC) and to investigate the mechanisms. SPI1, TPX2, and RNF2 were overexpressed in LUSC tissues and radioresistant cells comspared with adjacent tissues and parental cells, respectively. The binding between SPI1 and TPX2 or RNF2 promoter was investigated using ChIP-qPCR and dual-luciferase assays. SPI1 bound to TPX2 and RNF2 promoters and activated their transcription. SPI1 downregulation increased the radiosensitivity of LUSC cells, which was compromised by TPX2 or RNF2 overexpression. Meanwhile, SPI1 downregulation elevated the protein expression of γH2AX at the late stage of DNA damage response and suppressed DNA damage repair in LUSC cells, which were compromised by TPX2 or RNF2. These results indicate that SPI1 silencing potentiates radiosensitivity in LUSC cells by downregulating the transcription of TPX2 and RNF2, which provides a potential target for the radiotherapy in LUSC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Ativação Transcricional , Carcinoma Pulmonar de Células não Pequenas/genética , Tolerância a Radiação/genética , Carcinoma de Células Escamosas/patologia , Proliferação de Células/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/patologia , RNA não Traduzido , Pulmão/metabolismo , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo
7.
Int J Mol Sci ; 23(19)2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36233063

RESUMO

Ring1 and YY1 Binding Protein (RYBP) is a member of the non-canonical polycomb repressive complex 1 (PRC1), and like other PRC1 members, it is best described as a transcriptional regulator. Previously, we showed that RYBP, along with other PRC1 members, is also involved in the DNA damage response. RYBP inhibits recruitment of breast cancer gene 1(BRCA1) complex to DNA damage sites through its binding to K63-linked ubiquitin chains. In addition, ataxia telangiectasia mutated (ATM) kinase serves as an important sensor kinase in early stages of DNA damage response. Here, we report that overexpression of RYBP results in inhibition in both ATM activity and recruitment to DNA damage sites. Cells expressing RYBP show less phosphorylation of the ATM substrate, Chk2, after DNA damage. Due to its ability to inhibit ATM activity, we find that RYBP sensitizes cancer cells to poly-ADP-ribose polymerase (PARP) inhibitors. Although we find a synergistic effect between PARP inhibitor and ATM inhibitor in cancer cells, this synergy is lost in cells expressing RYBP. We also show that overexpression of RYBP hinders cancer cell migration through, at least in part, ATM inhibition. We provide new mechanism(s) by which RYBP expression may sensitize cancer cells to DNA damaging agents and inhibits cancer metastasis.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia , Neoplasias , Inibidores de Poli(ADP-Ribose) Polimerases , Proteínas Repressoras , Adenosina Difosfato Ribose , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Transporte , Proteínas de Ciclo Celular/metabolismo , Dano ao DNA , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Complexo Repressor Polycomb 1/metabolismo , Proteínas Repressoras/metabolismo , Ubiquitinas/metabolismo
8.
Genes Dev ; 36(15-16): 887-900, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-36167470

RESUMO

The polycomb complex component Bmi1 promotes the maintenance of stem cells in multiple postnatal tissues, partly by negatively regulating the expression of p16Ink4a and p19Arf, tumor suppressors associated with cellular senescence. However, deficiency for p16Ink4a and p19Arf only partially rescues the function of Bmi1-deficient stem cells. We conditionally deleted Bmi1 from adult hematopoietic cells and found that this slowly depleted hematopoietic stem cells (HSCs). Rather than inducing senescence, Bmi1 deficiency increased HSC division. The increased cell division was caused partly by increased Aristaless-related homeobox (ARX) transcription factor expression, which also increased ribosomal RNA expression. However, ARX deficiency did not rescue HSC depletion. Bmi1 deficiency also increased protein synthesis, protein aggregation, and protein ubiquitylation independent of its effects on cell division and p16Ink4a, p19Arf, and ARX expression. Bmi1 thus promotes HSC quiescence by negatively regulating ARX expression and promotes proteostasis by suppressing protein synthesis. This highlights a new connection between the regulation of stem cell maintenance and proteostasis.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina , Proteostase , Inibidor p16 de Quinase Dependente de Ciclina/genética , Células-Tronco Hematopoéticas , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Agregados Proteicos , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Ribossômico/metabolismo
9.
Commun Biol ; 5(1): 1039, 2022 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-36180527

RESUMO

SARS-CoV-2 infection causes COVID-19, a severe acute respiratory disease associated with cardiovascular complications including long-term outcomes. The presence of virus in cardiac tissue of patients with COVID-19 suggests this is a direct, rather than secondary, effect of infection. Here, by expressing individual SARS-CoV-2 proteins in the Drosophila heart, we demonstrate interaction of virus Nsp6 with host proteins of the MGA/MAX complex (MGA, PCGF6 and TFDP1). Complementing transcriptomic data from the fly heart reveal that this interaction blocks the antagonistic MGA/MAX complex, which shifts the balance towards MYC/MAX and activates glycolysis-with similar findings in mouse cardiomyocytes. Further, the Nsp6-induced glycolysis disrupts cardiac mitochondrial function, known to increase reactive oxygen species (ROS) in heart failure; this could explain COVID-19-associated cardiac pathology. Inhibiting the glycolysis pathway by 2-deoxy-D-glucose (2DG) treatment attenuates the Nsp6-induced cardiac phenotype in flies and mice. These findings point to glycolysis as a potential pharmacological target for treating COVID-19-associated heart failure.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , COVID-19 , Proteínas de Drosophila/metabolismo , Insuficiência Cardíaca , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Desoxiglucose/metabolismo , Drosophila/metabolismo , Glicólise , Insuficiência Cardíaca/metabolismo , Camundongos , Miócitos Cardíacos/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , SARS-CoV-2
10.
Front Immunol ; 13: 980911, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36081495

RESUMO

Acute myelocytic leukemia (AML) is a malignancy of the stem cell precursors of the myeloid lineage. CD4+ and CD8+ T cells play pivotal roles in influencing AML progression but are functionally suppressed in the bone marrow microenvironment. We aimed to find hub genes related to T cell exhaustion and suppression, thereby providing evidence for immunotherapy. In this study, gene transcriptome expression data from TCGA and TARGET databases were utilized to find key genes. Firstly, CIBERSORT immune cell infiltration algorithm and WGCNA method were used to identify CD4+ and CD8+ T cells-related genes. Univariate and multivariate cox regression analyses were then introduced to construct the overall survival prognosis model and included hub genes. The ESTIMATE and ssGSEA scoring methods were used to analyze the correlation between the hub genes and immune activity. Single-cell transcriptome analysis was applied to detect the immune cells expressing hub genes, hence, to detect exact mechanisms. Consequently, FLT3LG and IFITM3P6 were determined to be positively correlated with patients' overall survival and microenvironment immune activity. Further study suggested FLT3-FLT3LG and IFITM3P6-miR-6748-3p-CBX7 signaling axes were involved in CD4+ and CD8+ T cells activation. This may be one of the mechanisms of T cells suppression in AML.


Assuntos
Medula Óssea , Linfócitos T CD8-Positivos , Fatores de Crescimento de Células Hematopoéticas , Leucemia Mieloide Aguda , Proteínas de Membrana , Proteínas de Ligação a RNA , Medula Óssea/metabolismo , Células da Medula Óssea/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Prognóstico , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Microambiente Tumoral
11.
Dev Growth Differ ; 64(7): 409-416, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36053973

RESUMO

The stimulated by retinoic acid gene 8 (STRA8)/MEIOSIN complex and polycomb repressive complex (PRC) 1.6, a PRC1 subtype, are believed to be positive and negative regulators of meiotic onset, respectively. During meiotic initiation, the transcription repressive activity of PRC1.6 must be attenuated so that meiosis-related genes can be effectively activated by the STRA8/MEIOSIN complex. However, the molecular mechanisms that control the impairment of PRC1.6 function remain unclear. We recently demonstrated that the Mga gene, which encodes a scaffolding component of PRC1.6, produces variant mRNA by alternative splicing specifically during meiosis. Furthermore, the anomalous MGA protein encoded by the variant mRNA bears an intrinsic ability to function as a dominant negative regulator against the construction of PRC1.6 and is therefore assumed to be, at least in part, involved in impairment of the complex. Therefore, to unequivocally evaluate the physiological significance of Mga variant mRNA production in gametogenesis, we examined the consequences of a genetic manipulation that renders mice unable to produce Mga variant mRNA. Our data revealed that mutant mice were equivalent to wild-type mice in terms of viability and fertility. Our detailed examination of spermatogenesis also revealed that this genetic alteration is not associated with any apparent abnormalities in testis size, spermatogenic cycle, timing of meiotic onset, or marker gene expression of spermatogonia and spermatocytes. Taken together, these data indicate that the production of germ cell-specific Mga variant mRNA is dispensable not only for viability but also for gametogenesis.


Assuntos
Processamento Alternativo , Células Germinativas , Processamento Alternativo/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fertilidade , Células Germinativas/metabolismo , Masculino , Meiose/genética , Camundongos , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espermatogênese/genética , Tretinoína/metabolismo
12.
Aging (Albany NY) ; 14(15): 6227-6254, 2022 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-35969177

RESUMO

BACKGROUND: Chromobox (CBX) proteins are important Polycomb family proteins in the development of gastric cancer. Nonetheless, the relationship between CBXs and gastric cancer microenvironment remains unclear. METHODS: Multiple databases were used for the analysis of CBXs expression and clinical value in gastric cancer patients. A Cox regression analysis was used to evaluate the prognostic importance of CBXs. Thereafter, regression analysis of LASSO Cox was used to construct the prognostic model. Spearman's correlation between risk score and immune infiltration was analyzed using the McP-counter algorithm. A predicted nomogram was developed to predict the overall survival of gastric cancer patients after 1, 2, and 3 years. RESULTS: In contrast with normal tissues, mRNA and protein expression levels of CBX2/3 were significantly high in gastric cancer tissues, whereas those of CBX6/7 were low. CBXs significantly correlated with immune subtypes and molecular subtypes. A prognostic gene model based on five CBX genes (CBX1, CBX2, CBX3, CBX7, and CBX8) predicted the overall survival of gastric cancer patients. A significant correlation was noted between the risk score of the CBXs-related prognostic gene model and immune-cell infiltration. Low risk patients could achieve a better response to immune checkpoint inhibitors. A predictive nomogram constructed using the above five CBX genes revealed that overall survival rates over 1, 2, and 3 years could be reasonably predicted. Therefore, the roles of CBXs were associated with chromatin modifications and histone methylation, etc. Conclusion: In summary, we identified a prognostic CBXs model comprising five genes (CBX1, CBX2, CBX3, CBX7, and CBX8) for gastric cancer patients through bioinformatics analysis.


Assuntos
Complexo Repressor Polycomb 1 , Neoplasias Gástricas , Proteínas Cromossômicas não Histona , Humanos , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Proteínas do Grupo Polycomb/genética , Prognóstico , RNA Mensageiro/metabolismo , Neoplasias Gástricas/genética , Microambiente Tumoral/genética
13.
Inflamm Res ; 71(10-11): 1283-1303, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35933565

RESUMO

BACKGROUND: Pulmonary fibrosis (PF) is a chronic, progressive interstitial lung disease with unknown etiology, associated with increasing morbidity and pessimistic prognosis. Pulmonary fibroblasts (PFbs) are the key effector cells of PF, in which abnormal activation and proliferation is an important pathogenesis of PF. Ring finger protein 2 (RNF2), is identified as the catalytic subunit of poly-comb repressive complex 1, which is closely related to occurrence and development of lung cancer, but its function in PF has not been revealed. In this paper, we sought to identify the regulatory role of RNF2 in lung fibrogenesis and its underlying mechanisms. METHODS: The expression of RNF2 in lung fibrosis tissue (human and Bleomycin-induced mouse) and cell model (TGF-ß1-induced HFL1 cells) was examined by immunoblotting analysis and immunofluorescence. Western blot, qRT-PCR were performed to evaluate the expression of pro-fibrogenic cytokines (including α-SMA, ECM and MMPs/ TIMPs) induced by TGF-ß1 in HFL1 cells. Cell proliferation, cycle progression and apoptosis were examined by fow cytometric. Molecular interactions were tested by Co-IP assays. RESULTS: RNF2 expression was elevated in PF tissues compared to normal adjacent tissues and in PFbs (HFL1) induced by TGF-ß1. Furthermore, knockdown of RNF2 could evidently inhibit the abnormal expression of pro-fibrogenic cytokines (including α-SMA, ECM and MMPs/TIMPs) induced by TGF-ß1 in HFL1 cells. Functionally, RNF2 silencing could significantly suppress TGF-ß1-induced anomalous proliferation, cell cycle progression, apoptosis and autophagy in HFL1 cells. Mechanistically, RNF2 deficiency could effectively inhibit the abnormal activation of mTOR signaling pathway in TGF-ß1-induced HFL1 cells, and mTOR pathway had feedback regulation on the expression of RNF2. Further studies RNF2 could regulate the phosphorylation level of RB1 through interacting with p16 to destroy the binding of p16 and CDK4 competitively. Simultaneously, overexpression of RNF2 could show the opposite results. CONCLUSIONS: These results indicated that RNF2 is a potent pro-fibrogenic molecule for PFbs activation and proliferation through mTOR and p16-CDK4-Rb signaling pathways, and RNF2 inhibition will be a potential therapeutic avenue for treating PF.


Assuntos
Fibrose Pulmonar , Fator de Crescimento Transformador beta1 , Camundongos , Humanos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Transdução de Sinais , Pulmão/patologia , Bleomicina/efeitos adversos , Bleomicina/metabolismo , Serina-Treonina Quinases TOR , Fibroblastos/metabolismo , Proliferação de Células , Complexo Repressor Polycomb 1/metabolismo , Complexo Repressor Polycomb 1/farmacologia , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/farmacologia , Ubiquitina-Proteína Ligases
14.
Nat Commun ; 13(1): 4601, 2022 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-35933409

RESUMO

Polycomb group (PcG) proteins are known to repress developmental genes during embryonic development and tissue homeostasis. Here, we report that PCGF6 controls neuroectoderm specification of human pluripotent stem cells (PSCs) by activating SOX2 gene. Human PSCs with PCGF6 depletion display impaired neuroectoderm differentiation coupled with increased mesendoderm outcomes. Transcriptome analysis reveals that de-repression of the WNT/ß-catenin signaling pathway is responsible for the differentiation of PSC toward the mesendodermal lineage. Interestingly, PCGF6 and MYC directly interact and co-occupy a distal regulatory element of SOX2 to activate SOX2 expression, which likely accounts for the regulation in neuroectoderm differentiation. Supporting this notion, genomic deletion of the SOX2-regulatory element phenocopies the impaired neuroectoderm differentiation, while overexpressing SOX2 rescues the neuroectoderm phenotype caused by PCGF6-depletion. Together, our study reveals that PCGF6 can function as lineage switcher between mesendoderm and neuroectoderm in human PSCs by both suppression and activation mechanisms.


Assuntos
Placa Neural , Células-Tronco Pluripotentes , Complexo Repressor Polycomb 1/metabolismo , Fatores de Transcrição SOXB1 , Diferenciação Celular , Humanos , Proteínas do Grupo Polycomb/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo
15.
Nat Commun ; 13(1): 4510, 2022 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-35948547

RESUMO

The ovarian reserve defines the female reproductive lifespan, which in humans spans decades due to robust maintenance of meiotic arrest in oocytes residing in primordial follicles. Epigenetic reprogramming, including DNA demethylation, accompanies meiotic entry, but the chromatin changes that underpin the generation and preservation of ovarian reserves are poorly defined. We report that the Polycomb Repressive Complex 1 (PRC1) establishes repressive chromatin states in perinatal mouse oocytes that directly suppress the gene expression program of meiotic prophase-I and thereby enable the transition to dictyate arrest. PRC1 dysfuction causes depletion of the ovarian reserve and leads to premature ovarian failure. Our study demonstrates a fundamental role for PRC1-mediated gene silencing in female reproductive lifespan, and reveals a critical window of epigenetic programming required to establish ovarian reserve.


Assuntos
Reserva Ovariana , Complexo Repressor Polycomb 1 , Animais , Proteínas de Ciclo Celular/metabolismo , Cromatina/genética , Feminino , Inativação Gênica , Humanos , Meiose/genética , Camundongos , Reserva Ovariana/genética , Complexo Repressor Polycomb 1/metabolismo
16.
Cell Mol Life Sci ; 79(9): 469, 2022 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-35932322

RESUMO

BACKGROUND: Cholangiocarcinoma (CCA) is a class of malignant tumors originating from bile duct epithelial cells. Due to difficult early diagnosis and limited treatment, the prognosis of CCA is extremely poor. BMI1 is dysregulated in many human malignancies. However, the prognostic significance and oncogenic role of BMI1 in cholangiocarcinoma (CCA) are not well elucidated. METHODS: In the present study, we investigated its clinical importance and the potential mechanisms in the progression of CCA. We detected BMI1 expression in a large CCA cohort. We demonstrated that BMI1 was substantially upregulated in CCA tissues and was identified as an independent prognostic biomarker of CCA. Moreover, overexpression of BMI1 promoted CCA proliferation, migration, and invasion. And BMI1 knockdown could inhibit proliferation and metastases of CCA in vitro and in vitro/vivo validation. Interestingly, we found that CCA-derived exosomes contain BMI1 proteins, which can transfer BMI1 between CCA cells. The unique BMI1-containing exosomes promote CCA proliferation and metastasis through autocrine/paracrine mechanisms. In addition, we demonstrated that BMI1 inhibits CD8+T cell-recruiting chemokines by promoting repressive H2A ubiquitination in CCA cells. CONCLUSIONS: BMI1 is an unfavorable prognostic biomarker of CCA. Our data depict a novel function of BMI1 in CCA tumorigenesis and metastasis mediated by exosomes. Besides, BMI1 inhibition may augment immune checkpoint blockade to inhibit tumor progression by activating cell-intrinsic immunity of CCA.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Exossomos , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Biomarcadores , Carcinogênese , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Exossomos/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo
17.
Cell Mol Life Sci ; 79(8): 443, 2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35867177

RESUMO

MiR-181 expression levels increased in hepatocellular carcinoma (HCC) compared to non-cancerous tissues. MiR-181 has been widely reported as a possible driver of tumourigenesis but also acts as a tumour suppressor. In addition, the miR-181 family regulates the development and function of immune and vascular cells, which play vital roles in the progression of tumours. More complicatedly, many genes have been identified as miR-181 targets to mediate the effects of miR-181. However, the role of miR-181 in the development of primary tumours remains largely unexplored. We aimed to examine the function of miR-181 and its vital mediators in the progression of diethylnitrosamine-induced primary liver cancers in mice. The size of liver tumours was significantly reduced by 90% in global (GKO) or liver-specific (LKO) 181ab1 knockout mice but not in hematopoietic and endothelial lineage-specific knockout mice, compared to WT mice. In addition, the number of tumours was significantly reduced by 50% in GKO mice. Whole-genome RNA-seq analysis and immunohistochemistry showed that epithelial-mesenchymal transition was partially reversed in GKO tumours compared to WT tumours. The expression of CBX7, a confirmed miR-181 target, was up-regulated in GKO compared to WT tumours. Stable CBX7 expression was achieved with an AAV/Transposase Hybrid-Vector System and up-regulated CBX7 expression inhibited liver tumour progression in WT mice. Hepatic CBX7 deletion restored the progression of LKO liver tumours. MiR-181a expression was the lowest and CBX7 expression the highest in iClust2 and 3 subclasses of human HCC compared to iClust1. Gene expression profiles of GKO tumours overlapped with low-proliferative peri-portal-type HCCs. Liver-specific loss of miR-181ab1 inhibited primary liver tumour progression via up-regulating CBX7 expression, but tumour induction requires both hepatic and non-hepatic miR-181. Also, miR-181ab1-deficient liver tumours may resemble low-proliferative periportal-type human HCC. miR-181 was increased with liver tumour growth. More miR-181, darker colour and higher shape. CBX7 was very low in pericentral hepatocytes, increased in early liver tumours, but reduced in advanced liver tumours. Its levels were maintained in miR-181 KO liver tumours. In tumours (T), brown (darker is more) represents miR-181, the blue circle (thicker is more) represents CBX7.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Regulação para Cima/genética
18.
Comput Math Methods Med ; 2022: 1372879, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35813444

RESUMO

Background: Chromobox protein homolog 8 (CBX8), a transcriptional repressor, participates in many biological processes in various carcinomas. Cell differentiation, aging, and cell cycle progression are examples of such processes. It is critical to investigate CBX8 expression and its relationship with clinicopathological characteristics in liver hepatocellular carcinoma (LIHC), kidney renal clear cell carcinoma (KIRC), and ovarian cancer (OV) to investigate CBX8's potential diagnostic and prognostic values. Methods: TCGA and CPTAC databases were used to compare the data between cancer and matched normal tissues on RNA and protein expression profiles and their relevant clinical information to determine the relationship between CBX8 and clinicopathological features. Kaplan-Meier analyses were used to assess CBX8 relationship's with disease-free survival (DFS), relapse-free survival (RFS), and overall survival (OS). The multivariate Cox regression analysis was used to identify independent risk factors which affect prognosis. DNA methylation and genetic changes and their impact on prognoses were evaluated by cBioPortal and MethSurv websites. Spearman's correlation was used to determine the relationship of CBX8 expression with somatic mutation. Tumor immune estimation resource (TIMER) was adopted to investigate the relationship between CBX8 and immune cell infiltration (ICI). CBX8-relevant genes and proteins are analyzed by EnhancedVolcano and STRING databases. The gene set enrichment analysis (GSEA) was performed to investigate the potential functions of CBX8. Results: CBX8 RNA and protein overexpression were confirmed in LIHC, KIRC, and OV (p < 0.05). High CBX8 was significantly related to the clinical features and poor prognoses. The CBX8 genetic alteration rate was 3%. DNA methylation was also associated with prognoses. CBX8 closely interacted with ICI, TMB, MSI, purity, and ploidy. GO analyses revealed that CBX8-associated genes were enriched in biological processes, cell cycle regulation, and molecular functions. KEGG analyses exhibited that CBX8 was gathered in signaling pathway regulation. GSEA revealed that cell cycle, DNA replication, and Wnt signaling pathways were differentially enriched in the high CBX8 expression group. Conclusions: CBX8 could be a potential diagnostic and prognostic biomarker for LIHC, KIRC, and OV cancers.


Assuntos
Carcinoma Hepatocelular , Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Hepáticas , Neoplasias Ovarianas , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Mineração de Dados , Feminino , Humanos , Rim , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Prognóstico , RNA
19.
Cell Mol Gastroenterol Hepatol ; 14(5): 1146-1165, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35863742

RESUMO

BACKGROUND & AIMS: Accumulating evidence strongly suggests that hyperglycemia promotes the progression of pancreatic cancer (PC). Approximately 80% of patients with PC are intolerant to hyperglycemic conditions. In this study, we define the role of Bmi1, a stemness-related oncogene, in controlling the Warburg effect, and immune suppression under hyperglycemia conditions. METHODS: The diabetes mellitus model was established by intraperitoneal injection of streptozotocin. The role of the hyperglycemia-Bmi1-HK2 axis in glycolysis-related immunosuppression was examined in both orthotopic and xenograft in vivo models. Evaluation of immune infiltrates was carried out by flow cytometry. Human PC cell lines, SW1990, BxPC-3, and CFPAC-1, were used for mechanistic in vitro studies. RESULTS: Through bioinformatics analysis, we found that hyperglycemia was strongly related to aerobic glycolysis, immunosuppression, and cancer cell stemness. High glucose condition in the tumor microenvironment promotes immune suppression by upregulating glycolysis in PC cells, which can be rescued via knockdown Bmi1 expression or after 2-deoxy-D-glucose treatment. Through gain-/loss-of-function assessments, we found that Bmi1 upregulated the expression of UPF1, which enhanced the stability of HK2 mRNA and thereby increased the expression of HK2. The role of the hyperglycemia-Bmi-HK2 pathway in the inhibition of antitumor immunity was further verified via the immune-competent and immunodeficient mice model. We also demonstrated that hyperglycemia promotes the expression of Bmi1 by elevating the intracellular acetyl-CoA levels and histone H4 acetylation levels. CONCLUSIONS: Our results suggest that the previously unreported Bmi1-UPF1-HK2 pathway contributes to PC progression and immunosuppression, which may bring in new targets for developing effective therapies to treat patients with PC.


Assuntos
Hiperglicemia , Neoplasias Pancreáticas , Humanos , Camundongos , Animais , Estreptozocina , Acetilcoenzima A/metabolismo , Histonas/metabolismo , Neoplasias Pancreáticas/genética , Glicólise/genética , RNA Mensageiro/genética , Glucose , Camundongos Nus , Terapia de Imunossupressão , Desoxiglucose , Microambiente Tumoral , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo
20.
Int J Mol Sci ; 23(15)2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35897796

RESUMO

B-cell-specific Moloney murine leukemia virus integration region 1 (Bmi-1, also known as RNF51 or PCGF4) is one of the important members of the PcG gene family, and is involved in regulating cell proliferation, differentiation and senescence, and maintaining the self-renewal of stem cells. Many studies in recent years have emphasized the role of Bmi-1 in the occurrence and development of tumors. In fact, Bmi-1 has multiple functions in cancer biology and is closely related to many classical molecules, including Akt, c-MYC, Pten, etc. This review summarizes the regulatory mechanisms of Bmi-1 in multiple pathways, and the interaction of Bmi-1 with noncoding RNAs. In particular, we focus on the pathological processes of Bmi-1 in cancer, and explore the clinical relevance of Bmi-1 in cancer biomarkers and prognosis, as well as its implications for chemoresistance and radioresistance. In conclusion, we summarize the role of Bmi-1 in tumor progression, reveal the pathophysiological process and molecular mechanism of Bmi-1 in tumors, and provide useful information for tumor diagnosis, treatment, and prognosis.


Assuntos
Neoplasias , Complexo Repressor Polycomb 1 , Animais , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Resistência a Medicamentos , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Neoplasias/etiologia , Neoplasias/genética , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo
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