In order to explore whether αCGRP (Calca) deficiency aggravates pulmonary fibrosis (PF). Clinical data from patients with PF (n = 52) were retrospectively analyzed. Lung tissue from a bleomycin (BLM)-induced rat model was compared with that of Calca-knockout (KO) and wild type (WT) using immunohistochemistry, RNA-seq, and UPLC-MS/MS metabolomic analyses. The results showed that decreased αCGRP expression and activation of the type 2 immune response were detected in patients with PF. In BLM-induced and Calca-KO rats, αCGRP deficiency potentiated apoptosis of AECs and induced M2 macrophages. RNA-seq identified enrichment of pathways involved in nuclear translocation and immune system disorders in Calca-KO rats compared to WT. Mass spectrometry of lung tissue from Calca-KO rats showed abnormal lipid metabolism, including increased levels of LTB4, PDX, 1-HETE. PPAR pathway signaling was significantly induced in both transcriptomic and metabolomic datasets in Calca-KO rats, and immunofluorescence analysis confirmed that the nuclear translocation of PPARγ in BLM-treated and Calca-KO rats was synchronized with STAT6 localization in the cytoplasmic and nuclear fractions. In conclusion, αCGRP is protective against PF, and αCGRP deficiency promotes M2 polarization of macrophages, probably by activating the PPARγ pathway, which leads to activation of the type 2 immune response and accelerates PF development.
{"title":"αCGRP deficiency aggravates pulmonary fibrosis by activating the PPARγ signaling pathway","authors":"Xiaoting Lv, Qingquan Chen, Zewei Zhang, Kaili Du, Yaping Huang, Xingzhe Li, Yiming Zeng","doi":"10.1038/s41435-023-00206-x","DOIUrl":"10.1038/s41435-023-00206-x","url":null,"abstract":"In order to explore whether αCGRP (Calca) deficiency aggravates pulmonary fibrosis (PF). Clinical data from patients with PF (n = 52) were retrospectively analyzed. Lung tissue from a bleomycin (BLM)-induced rat model was compared with that of Calca-knockout (KO) and wild type (WT) using immunohistochemistry, RNA-seq, and UPLC-MS/MS metabolomic analyses. The results showed that decreased αCGRP expression and activation of the type 2 immune response were detected in patients with PF. In BLM-induced and Calca-KO rats, αCGRP deficiency potentiated apoptosis of AECs and induced M2 macrophages. RNA-seq identified enrichment of pathways involved in nuclear translocation and immune system disorders in Calca-KO rats compared to WT. Mass spectrometry of lung tissue from Calca-KO rats showed abnormal lipid metabolism, including increased levels of LTB4, PDX, 1-HETE. PPAR pathway signaling was significantly induced in both transcriptomic and metabolomic datasets in Calca-KO rats, and immunofluorescence analysis confirmed that the nuclear translocation of PPARγ in BLM-treated and Calca-KO rats was synchronized with STAT6 localization in the cytoplasmic and nuclear fractions. In conclusion, αCGRP is protective against PF, and αCGRP deficiency promotes M2 polarization of macrophages, probably by activating the PPARγ pathway, which leads to activation of the type 2 immune response and accelerates PF development.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10266974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9665715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-05-16DOI: 10.1038/s41435-023-00207-w
Elisabeth M. Simonin, Bettina Wagner
IgE-binding monocytes are a rare peripheral immune cell type involved in the allergic response through binding of IgE on their surface. IgE-binding monocytes are present in both healthy and allergic individuals. We performed RNA sequencing to ask how the function of IgE-binding monocytes differs in the context of allergy. Using a large animal model of allergy, equine Culicoides hypersensitivity, we compared the transcriptome of IgE-binding monocytes in allergic and non-allergic horses at two seasonal timepoints: (i) when allergic animals were clinical healthy, in the winter “Remission Phase”, and (ii) during chronic disease, in the summer “Clinical Phase”. Most transcriptional differences between allergic and non-allergic horses occurred only during the “Remission Phase”, suggesting principal differences in monocyte function even in the absence of allergen exposure. F13A1, a subunit of fibrinoligase, was significantly upregulated at both timepoints in allergic horses. This suggested a role for increased fibrin deposition in the coagulation cascade to promote allergic inflammation. IgE-binding monocytes also downregulated CCR10 expression in allergic horses during the “Clinical Phase”, suggesting a defect in maintenance of skin homeostasis, which further promotes allergic inflammation. Together, this transcriptional analysis provides valuable clues into the mechanisms used by IgE-binding monocytes in allergic individuals.
{"title":"IgE-binding monocytes upregulate the coagulation cascade in allergic horses","authors":"Elisabeth M. Simonin, Bettina Wagner","doi":"10.1038/s41435-023-00207-w","DOIUrl":"10.1038/s41435-023-00207-w","url":null,"abstract":"IgE-binding monocytes are a rare peripheral immune cell type involved in the allergic response through binding of IgE on their surface. IgE-binding monocytes are present in both healthy and allergic individuals. We performed RNA sequencing to ask how the function of IgE-binding monocytes differs in the context of allergy. Using a large animal model of allergy, equine Culicoides hypersensitivity, we compared the transcriptome of IgE-binding monocytes in allergic and non-allergic horses at two seasonal timepoints: (i) when allergic animals were clinical healthy, in the winter “Remission Phase”, and (ii) during chronic disease, in the summer “Clinical Phase”. Most transcriptional differences between allergic and non-allergic horses occurred only during the “Remission Phase”, suggesting principal differences in monocyte function even in the absence of allergen exposure. F13A1, a subunit of fibrinoligase, was significantly upregulated at both timepoints in allergic horses. This suggested a role for increased fibrin deposition in the coagulation cascade to promote allergic inflammation. IgE-binding monocytes also downregulated CCR10 expression in allergic horses during the “Clinical Phase”, suggesting a defect in maintenance of skin homeostasis, which further promotes allergic inflammation. Together, this transcriptional analysis provides valuable clues into the mechanisms used by IgE-binding monocytes in allergic individuals.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10266973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10069547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-05-08DOI: 10.1038/s41435-023-00205-y
Aliya Rehati, Buzukela Abuduaini, Zhao Liang, Dong Chen, Fangping He
Heat shock protein family A (Hsp70) member 5 (HSPA5) is an endoplasmic reticulum chaperone, which regulates cell metabolism, particularly lipid metabolism. While HSPA5’s role in regulating cell function is well described, HSPA5 binding to RNA and its biological function in nonalcoholic fatty liver disease (NAFLD) is still lacking. In the present study, the ability of HSPA5 to modulate alternative splicing (AS) of cellular genes was assessed using Real-Time PCR on 89 NAFLD-associated genes. RNA immunoprecipitation coupled to RNA sequencing (RIP-Seq) assays were also performed to identify cellular mRNAs bound by HSPA5. We obtained the HSPA5-bound RNA profile in HeLa cells and peak calling analysis revealed that HSPA5 binds to coding genes and lncRNAs. Moreover, RIP-Seq assays demonstrated that HSPA5 immunoprecipitates specific cellular mRNAs such as EGFR, NEAT1, LRP1 and TGFß1, which are important in the pathology of NAFLD. Finally, HSPA5 binding sites may be associated with splicing sites. We used the HOMER algorithm to search for motifs enriched in coding sequence (CDs) peaks, which identified over-representation of the AGAG motif in both sets of immunoprecipitated peaks. HSPA5 regulated genes at the 5′UTR alternative splicing and introns and in an AG-rich sequence-dependent manner. We propose that the HSPA5-AGAG interaction might play an important role in regulating alternative splicing of NAFLD-related genes. This report is the first to demonstrate that HSPA5 regulated pre-RNA alternative splicing, stability, or translation and affected target protein(s) via binding to lncRNA and mRNA linked to NAFLD.
{"title":"Identification of heat shock protein family A member 5 (HSPA5) targets involved in nonalcoholic fatty liver disease","authors":"Aliya Rehati, Buzukela Abuduaini, Zhao Liang, Dong Chen, Fangping He","doi":"10.1038/s41435-023-00205-y","DOIUrl":"10.1038/s41435-023-00205-y","url":null,"abstract":"Heat shock protein family A (Hsp70) member 5 (HSPA5) is an endoplasmic reticulum chaperone, which regulates cell metabolism, particularly lipid metabolism. While HSPA5’s role in regulating cell function is well described, HSPA5 binding to RNA and its biological function in nonalcoholic fatty liver disease (NAFLD) is still lacking. In the present study, the ability of HSPA5 to modulate alternative splicing (AS) of cellular genes was assessed using Real-Time PCR on 89 NAFLD-associated genes. RNA immunoprecipitation coupled to RNA sequencing (RIP-Seq) assays were also performed to identify cellular mRNAs bound by HSPA5. We obtained the HSPA5-bound RNA profile in HeLa cells and peak calling analysis revealed that HSPA5 binds to coding genes and lncRNAs. Moreover, RIP-Seq assays demonstrated that HSPA5 immunoprecipitates specific cellular mRNAs such as EGFR, NEAT1, LRP1 and TGFß1, which are important in the pathology of NAFLD. Finally, HSPA5 binding sites may be associated with splicing sites. We used the HOMER algorithm to search for motifs enriched in coding sequence (CDs) peaks, which identified over-representation of the AGAG motif in both sets of immunoprecipitated peaks. HSPA5 regulated genes at the 5′UTR alternative splicing and introns and in an AG-rich sequence-dependent manner. We propose that the HSPA5-AGAG interaction might play an important role in regulating alternative splicing of NAFLD-related genes. This report is the first to demonstrate that HSPA5 regulated pre-RNA alternative splicing, stability, or translation and affected target protein(s) via binding to lncRNA and mRNA linked to NAFLD.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10266971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10116533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-05-03DOI: 10.1038/s41435-023-00203-0
Jörg Hänze, Johannes Schulte-Herbrüggen, Rainer Hofmann, Axel Hegele
Exploring the regulation of co-inhibitory (PD-1, PD-L1, CTLA-4) and co-stimulatory (CD28) genes by chemotherapeutic drugs is important for combined immune checkpoint blockade (ICB) therapy. ICB interferes with T-cell receptor and major histocompatibility complex (MHC) signaling by antibody drugs directed against the co-inhibitors. Here, we analyzed urothelial (T24) cell line with respect to cytokine signaling by interferon γ (IFNG) and the leukemia lymphocyte (Jurkat) cell line with respect to T-cell activation as mimicked by phorbolester and calcium ionophore (pma/iono). Alongside, we considered possible intervention with the chemotherapeutics gemcitabine, cisplatin and vinflunine. Noteworthy, cisplatin significantly induced PD-L1-mRNA in naïve and IFNG treated cells whereas gemcitabine and vinflunine had no effect on PD-L1-mRNA. At the protein level, PD-L1 showed typical induction in IFNG treated cells. In Jurkat cells, cisplatin significantly induced PD-1-mRNA and PD-L1-mRNA. Pma/iono administration did not alter PD-1-mRNA and PD-L1-mRNA but significantly increased CTLA-4-mRNA and CD28-mRNA levels where vinflunine suppressed the CD28-mRNA induction. In sum, we demonstrated that certain cytostatic drugs being relevant for the therapy of urothelial cancer, affect co-inhibitory and co-stimulatory modulators of immune signaling with potential impact for perspective combined ICB therapy of patients.
{"title":"Modulation of immune checkpoint regulators in interferon γ induced urothelial carcinoma and activated T-lymphocyte cells by cytostatics","authors":"Jörg Hänze, Johannes Schulte-Herbrüggen, Rainer Hofmann, Axel Hegele","doi":"10.1038/s41435-023-00203-0","DOIUrl":"10.1038/s41435-023-00203-0","url":null,"abstract":"Exploring the regulation of co-inhibitory (PD-1, PD-L1, CTLA-4) and co-stimulatory (CD28) genes by chemotherapeutic drugs is important for combined immune checkpoint blockade (ICB) therapy. ICB interferes with T-cell receptor and major histocompatibility complex (MHC) signaling by antibody drugs directed against the co-inhibitors. Here, we analyzed urothelial (T24) cell line with respect to cytokine signaling by interferon γ (IFNG) and the leukemia lymphocyte (Jurkat) cell line with respect to T-cell activation as mimicked by phorbolester and calcium ionophore (pma/iono). Alongside, we considered possible intervention with the chemotherapeutics gemcitabine, cisplatin and vinflunine. Noteworthy, cisplatin significantly induced PD-L1-mRNA in naïve and IFNG treated cells whereas gemcitabine and vinflunine had no effect on PD-L1-mRNA. At the protein level, PD-L1 showed typical induction in IFNG treated cells. In Jurkat cells, cisplatin significantly induced PD-1-mRNA and PD-L1-mRNA. Pma/iono administration did not alter PD-1-mRNA and PD-L1-mRNA but significantly increased CTLA-4-mRNA and CD28-mRNA levels where vinflunine suppressed the CD28-mRNA induction. In sum, we demonstrated that certain cytostatic drugs being relevant for the therapy of urothelial cancer, affect co-inhibitory and co-stimulatory modulators of immune signaling with potential impact for perspective combined ICB therapy of patients.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10266969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9754320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-04-22DOI: 10.1038/s41435-023-00204-z
Catherine M. Stein
Resistance to M. tuberculosis, often referred to as “RSTR” in the literature, is being increasingly studied because of its potential relevance as a clinical outcome in vaccine studies. This review starts by addressing the importance of epidemiological characterization of this phenotype, and ongoing challenges in that characterization. Then, this review summarizes the extant genetic and genomic studies of this phenotype, including heritability studies, candidate gene studies, and genome-wide association studies, as well as whole transcriptome studies. Findings from recent studies that used longitudinal characterization of the RSTR phenotype are compared to those using a cross-sectional definition, and the challenges of using tuberculin skin test and interferon-gamma release assay are discussed. Finally, future directions are proposed. Since this is a rapidly evolving area of public health significance, this review will help frame future research questions and study designs.
{"title":"Genetic epidemiology of resistance to M. tuberculosis Infection: importance of study design and recent findings","authors":"Catherine M. Stein","doi":"10.1038/s41435-023-00204-z","DOIUrl":"10.1038/s41435-023-00204-z","url":null,"abstract":"Resistance to M. tuberculosis, often referred to as “RSTR” in the literature, is being increasingly studied because of its potential relevance as a clinical outcome in vaccine studies. This review starts by addressing the importance of epidemiological characterization of this phenotype, and ongoing challenges in that characterization. Then, this review summarizes the extant genetic and genomic studies of this phenotype, including heritability studies, candidate gene studies, and genome-wide association studies, as well as whole transcriptome studies. Findings from recent studies that used longitudinal characterization of the RSTR phenotype are compared to those using a cross-sectional definition, and the challenges of using tuberculin skin test and interferon-gamma release assay are discussed. Finally, future directions are proposed. Since this is a rapidly evolving area of public health significance, this review will help frame future research questions and study designs.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10121418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9658150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-04-12DOI: 10.1038/s41435-023-00200-3
Mervat Naguib, Shereen El Sawy, Laila Rashed, Maha AlHelf, Marwa Abdelgwad
The main aim of this study was to assess the expression level of circulating long non-coding RNA maternally expressed gene 3 (lncRNA-MEG3), microRNA (miR-125a-5P), the chemokine C-X-C motif ligand13 (CXCL13), and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) in immune thrombocytopenia (ITP) cases and to study its relation to the disease severity and treatment response. This case-control study included 45 patients newly diagnosed as ITP and 45 healthy subjects. We assessed complete blood count, antinuclear antibodies, hepatitis B and C virus serology, lncRNA-MEG3, miR-125a-5P, and CXCL13 expression in serum by real-time PCR and NF-kb protein by ELISA. In ITP patients compared to control, lncRNA-MEG3 was significantly increased, and miRNA-125a-5P was decreased, and this was associated with higher CXCL13 and NF-kB levels (P < 0.001, for all).There was a significant negative correlation between platelet count and lncRNA-MEG3, CXCL13, and NF-kb, while a positive correlation with miR-125a-5p in ITP patients. Patients who responded to steroids had significantly higher miR-125a-5p (P = 0.016) and significantly lower lncRNA-MEG3 (P < 0.001), CXCL13 (P = 0.005), and NF-kb (p = 0.002). Based on the ROC curves, lncRNA-MEG3 displayed the highest area under the curve (AUC) in the identification of organ bleeding (AUC = 0.805), the response to steroids (AUC = 0.853), and the need for splenectomy (AUC = 0.75).
{"title":"Long non-coding RNA maternally expressed gene 3, miR-125a-5p, CXCL13, and NF-kB in patients with immune thrombocytopenia","authors":"Mervat Naguib, Shereen El Sawy, Laila Rashed, Maha AlHelf, Marwa Abdelgwad","doi":"10.1038/s41435-023-00200-3","DOIUrl":"10.1038/s41435-023-00200-3","url":null,"abstract":"The main aim of this study was to assess the expression level of circulating long non-coding RNA maternally expressed gene 3 (lncRNA-MEG3), microRNA (miR-125a-5P), the chemokine C-X-C motif ligand13 (CXCL13), and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) in immune thrombocytopenia (ITP) cases and to study its relation to the disease severity and treatment response. This case-control study included 45 patients newly diagnosed as ITP and 45 healthy subjects. We assessed complete blood count, antinuclear antibodies, hepatitis B and C virus serology, lncRNA-MEG3, miR-125a-5P, and CXCL13 expression in serum by real-time PCR and NF-kb protein by ELISA. In ITP patients compared to control, lncRNA-MEG3 was significantly increased, and miRNA-125a-5P was decreased, and this was associated with higher CXCL13 and NF-kB levels (P < 0.001, for all).There was a significant negative correlation between platelet count and lncRNA-MEG3, CXCL13, and NF-kb, while a positive correlation with miR-125a-5p in ITP patients. Patients who responded to steroids had significantly higher miR-125a-5p (P = 0.016) and significantly lower lncRNA-MEG3 (P < 0.001), CXCL13 (P = 0.005), and NF-kb (p = 0.002). Based on the ROC curves, lncRNA-MEG3 displayed the highest area under the curve (AUC) in the identification of organ bleeding (AUC = 0.805), the response to steroids (AUC = 0.853), and the need for splenectomy (AUC = 0.75).","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10110462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9483579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-03-08DOI: 10.1038/s41435-023-00202-1
Gong Zhang, Ruyi Huang, Hui Zhao, Yuke Xia, Hui Huang, Mengjia Qian, Yuehe Fu, Yiyao Cui
Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive disease with poor prognosis. Acetylation modifications affect a great number of biological processes of malignant tumors. The current study aims at revealing the role of acetylation-related mechanism in TNBC progression. Methyltransferase like-3 (METTL3) was found to be downregulated in TNBC cells via quantitative polymerase chain reaction (qPCR) and western blot analyses. Co-Immunoprecipitation (Co-IP) and GST pulldown assays revealed the interaction between acetyl-CoA acetyltransferase 1 (ACAT1) and METTL3. Through further immunoprecipitation (IP) assay, we determined that ACAT1 stabilizes METTL3 protein via inhibiting the degradation of ubiquitin-proteasome. Functionally, ACAT1 inhibits TNBC cell migration and invasion. Moreover, nuclear receptor subfamily 2 group F member 6 (NR2F6) regulates ACAT1 expression at transcriptional level. Finally, we demonstrated that NR2F6/ACAT/METTL3 axis suppresses the migration and invasion of TNBC cells via METTL3. In conclusion, NR2F6 transcriptionally activates ACAT1 and promotes the suppressive effects of ACAT1-mediated METTL3 acetylation on TNBC cell migration and invasion.
{"title":"ACAT1-mediated METTL3 acetylation inhibits cell migration and invasion in triple negative breast cancer","authors":"Gong Zhang, Ruyi Huang, Hui Zhao, Yuke Xia, Hui Huang, Mengjia Qian, Yuehe Fu, Yiyao Cui","doi":"10.1038/s41435-023-00202-1","DOIUrl":"10.1038/s41435-023-00202-1","url":null,"abstract":"Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive disease with poor prognosis. Acetylation modifications affect a great number of biological processes of malignant tumors. The current study aims at revealing the role of acetylation-related mechanism in TNBC progression. Methyltransferase like-3 (METTL3) was found to be downregulated in TNBC cells via quantitative polymerase chain reaction (qPCR) and western blot analyses. Co-Immunoprecipitation (Co-IP) and GST pulldown assays revealed the interaction between acetyl-CoA acetyltransferase 1 (ACAT1) and METTL3. Through further immunoprecipitation (IP) assay, we determined that ACAT1 stabilizes METTL3 protein via inhibiting the degradation of ubiquitin-proteasome. Functionally, ACAT1 inhibits TNBC cell migration and invasion. Moreover, nuclear receptor subfamily 2 group F member 6 (NR2F6) regulates ACAT1 expression at transcriptional level. Finally, we demonstrated that NR2F6/ACAT/METTL3 axis suppresses the migration and invasion of TNBC cells via METTL3. In conclusion, NR2F6 transcriptionally activates ACAT1 and promotes the suppressive effects of ACAT1-mediated METTL3 acetylation on TNBC cell migration and invasion.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9347242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-02-18DOI: 10.1038/s41435-023-00201-2
Michael J. Diaz, Dorottya B. Kacsoh, Dhruv N. Patel, Michelle Yeagley, Monica Hsiang, George Blanck
While for certain cancers, such as cervical cancer, the link to viral infections is very strong and very clear, other cancers represent a history of links to viral infections that are either co-morbidities or drive the cancer in ways that are not yet fully understood, for example the “hit and run” possibility. To further understand the connection of viral infections and the progress of breast cancer, we identified the chemical features of known anti-viral, T-cell receptor alpha chain (TRA) complementarity determining region-3 (CDR3) amino acid sequences among the CDR3s of breast cancer patient TRA recombinations and assessed the association of those features with patient outcomes. The application of this novel paradigm indicated consistent associations of tumor-derived, anti-CMV CDR3 chemical sequence motifs with better breast cancer patient outcomes but did not indicate an opportunity to establish risk stratifications for other cancer types. Interestingly, breast cancer samples with no detectable TRA recombinations represented a better outcome than samples with the non-anti-CMV CDR3s, further adding to a rapidly developing series of results allowing a distinction between positive and possibly harmful cancer immune responses.
某些癌症（如宫颈癌）与病毒感染之间的联系非常密切和明确，而其他癌症则与病毒感染之间存在联系，这些联系要么是并发症，要么是以尚未完全明了的方式驱动癌症，例如 "打了就跑 "的可能性。为了进一步了解病毒感染与乳腺癌进展之间的联系，我们在乳腺癌患者 TRA 重组的 CDR3 中确定了已知抗病毒 T 细胞受体α链（TRA）互补决定区-3（CDR3）氨基酸序列的化学特征，并评估了这些特征与患者预后之间的关联。这种新范式的应用表明，肿瘤衍生的抗CMV CDR3化学序列基序与乳腺癌患者更好的预后有一致的关联，但并不表明有机会为其他癌症类型建立风险分层。有趣的是，未检测到 TRA 重组的乳腺癌样本比未检测到抗 CMV CDR3 的样本预后更好，这进一步丰富了快速发展的一系列结果，从而区分了积极的和可能有害的癌症免疫反应。
{"title":"Tumor resident, TRA anti-viral CDR3 chemical sequence motifs are associated with a better breast cancer outcome","authors":"Michael J. Diaz, Dorottya B. Kacsoh, Dhruv N. Patel, Michelle Yeagley, Monica Hsiang, George Blanck","doi":"10.1038/s41435-023-00201-2","DOIUrl":"10.1038/s41435-023-00201-2","url":null,"abstract":"While for certain cancers, such as cervical cancer, the link to viral infections is very strong and very clear, other cancers represent a history of links to viral infections that are either co-morbidities or drive the cancer in ways that are not yet fully understood, for example the “hit and run” possibility. To further understand the connection of viral infections and the progress of breast cancer, we identified the chemical features of known anti-viral, T-cell receptor alpha chain (TRA) complementarity determining region-3 (CDR3) amino acid sequences among the CDR3s of breast cancer patient TRA recombinations and assessed the association of those features with patient outcomes. The application of this novel paradigm indicated consistent associations of tumor-derived, anti-CMV CDR3 chemical sequence motifs with better breast cancer patient outcomes but did not indicate an opportunity to establish risk stratifications for other cancer types. Interestingly, breast cancer samples with no detectable TRA recombinations represented a better outcome than samples with the non-anti-CMV CDR3s, further adding to a rapidly developing series of results allowing a distinction between positive and possibly harmful cancer immune responses.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9346730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aging is a complex process that significantly impacts the immune system. The aging-related decline of the immune system, termed immunosenescence, can lead to disease development, including cancer. The perturbation of immunosenescence genes may characterize the associations between cancer and aging. However, the systematical characterization of immunosenescence genes in pan-cancer remains largely unexplored. In this study, we comprehensively investigated the expression of immunosenescence genes and their roles in 26 types of cancer. We developed an integrated computational pipeline to identify and characterize immunosenescence genes in cancer based on the expression profiles of immune genes and clinical information of patients. We identified 2218 immunosenescence genes that were significantly dysregulated in a wide variety of cancers. These immunosenescence genes were divided into six categories based on their relationships with aging. Besides, we assessed the importance of immunosenescence genes in clinical prognosis and identified 1327 genes serving as prognostic markers in cancers. BTN3A1, BTN3A2, CTSD, CYTIP, HIF1AN, and RASGRP1 were associated with ICB immunotherapy response and served as prognostic factors after ICB immunotherapy in melanoma. Collectively, our results furthered the understanding of the relationship between immunosenescence and cancer and provided insights into immunotherapy for patients.
{"title":"Pan-cancer transcriptomic analysis identified six classes of immunosenescence genes revealed molecular links between aging, immune system and cancer","authors":"Xinyue Wang, Shuang Guo, Hanxiao Zhou, Yue Sun, Jing Gan, Yakun Zhang, Wen Zheng, Caiyu Zhang, Peng Wang, Hui Zhi, Yue Gao, Xiaofeng Chen, Shangwei Ning","doi":"10.1038/s41435-023-00197-9","DOIUrl":"10.1038/s41435-023-00197-9","url":null,"abstract":"Aging is a complex process that significantly impacts the immune system. The aging-related decline of the immune system, termed immunosenescence, can lead to disease development, including cancer. The perturbation of immunosenescence genes may characterize the associations between cancer and aging. However, the systematical characterization of immunosenescence genes in pan-cancer remains largely unexplored. In this study, we comprehensively investigated the expression of immunosenescence genes and their roles in 26 types of cancer. We developed an integrated computational pipeline to identify and characterize immunosenescence genes in cancer based on the expression profiles of immune genes and clinical information of patients. We identified 2218 immunosenescence genes that were significantly dysregulated in a wide variety of cancers. These immunosenescence genes were divided into six categories based on their relationships with aging. Besides, we assessed the importance of immunosenescence genes in clinical prognosis and identified 1327 genes serving as prognostic markers in cancers. BTN3A1, BTN3A2, CTSD, CYTIP, HIF1AN, and RASGRP1 were associated with ICB immunotherapy response and served as prognostic factors after ICB immunotherapy in melanoma. Collectively, our results furthered the understanding of the relationship between immunosenescence and cancer and provided insights into immunotherapy for patients.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9340055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-02-15DOI: 10.1038/s41435-023-00199-7
Stephane Tereza Queiroz de Andrade, Tamíris Isabela Guidugli, Andrea Borrego, Bridilla Luiza Colhado Rodrigues, Natália Coelho Couto de Azevedo Fernandes, Juliana Mariotti Guerra, Jean Gabriel de Sousa, Nancy Starobinas, José Ricardo Jensen, Wafa Hanna Koury Cabrera, Marcelo De Franco, Olga Martinez Ibañez, Solange Massa, Orlando Garcia Ribeiro
Ulcerative Colitis (UC) is an inflammatory disease characterized by colonic mucosal lesions associated with an increased risk of carcinogenesis. UC pathogenesis involves environmental and genetic factors. Genetic studies have indicated the association of gene variants coding for the divalent metal ion transporter SLC11A1 protein (formerly NRAMP1) with UC susceptibility in several animal species. Two mouse lines were genetically selected for high (AIRmax) or low (AIRmin) acute inflammatory responses (AIR). AIRmax is susceptible, and AIRmin is resistant to DSS-induced colitis and colon carcinogenesis. Furthermore, AIRmin mice present polymorphism of the Slc11a1 gene. Here we investigated the possible modulating effect of the Slc11a1 R and S variants in DSS-induced colitis by using AIRmin mice homozygous for Slc11a1 R (AIRminRR) or S (AIRminSS) alleles. We evaluated UC by the disease activity index (DAI), considering weight loss, diarrhea, blood in the anus or feces, cytokines, histopathology, and cell populations in the distal colon epithelium. AIRminSS mice have become susceptible to DSS effects, with higher DAI, IL6, G-CSF, and MCP-1 production and morphological and colon histopathological alterations than AIRminRR mice. The results point to a role of the Slc11a1 S allele in DSS colitis induction in the genetic background of AIRmin mice.
{"title":"Slc11a1 gene polymorphism influences dextran sulfate sodium (DSS)-induced colitis in a murine model of acute inflammation","authors":"Stephane Tereza Queiroz de Andrade, Tamíris Isabela Guidugli, Andrea Borrego, Bridilla Luiza Colhado Rodrigues, Natália Coelho Couto de Azevedo Fernandes, Juliana Mariotti Guerra, Jean Gabriel de Sousa, Nancy Starobinas, José Ricardo Jensen, Wafa Hanna Koury Cabrera, Marcelo De Franco, Olga Martinez Ibañez, Solange Massa, Orlando Garcia Ribeiro","doi":"10.1038/s41435-023-00199-7","DOIUrl":"10.1038/s41435-023-00199-7","url":null,"abstract":"Ulcerative Colitis (UC) is an inflammatory disease characterized by colonic mucosal lesions associated with an increased risk of carcinogenesis. UC pathogenesis involves environmental and genetic factors. Genetic studies have indicated the association of gene variants coding for the divalent metal ion transporter SLC11A1 protein (formerly NRAMP1) with UC susceptibility in several animal species. Two mouse lines were genetically selected for high (AIRmax) or low (AIRmin) acute inflammatory responses (AIR). AIRmax is susceptible, and AIRmin is resistant to DSS-induced colitis and colon carcinogenesis. Furthermore, AIRmin mice present polymorphism of the Slc11a1 gene. Here we investigated the possible modulating effect of the Slc11a1 R and S variants in DSS-induced colitis by using AIRmin mice homozygous for Slc11a1 R (AIRminRR) or S (AIRminSS) alleles. We evaluated UC by the disease activity index (DAI), considering weight loss, diarrhea, blood in the anus or feces, cytokines, histopathology, and cell populations in the distal colon epithelium. AIRminSS mice have become susceptible to DSS effects, with higher DAI, IL6, G-CSF, and MCP-1 production and morphological and colon histopathological alterations than AIRminRR mice. The results point to a role of the Slc11a1 S allele in DSS colitis induction in the genetic background of AIRmin mice.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10110460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9716907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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