Cell and Bioscience最新文献

{"title":"CXCL11 reprograms M2-biased macrophage polarization to alleviate pulmonary fibrosis in mice.","authors":"Ji-Young Kim, Dong-Wook Cho, Jung-Yun Choi, Suji Jeong, Minje Kang, Woo Jin Kim, In-Sun Hong, Haengseok Song, Heesoon Chang, Se-Ran Yang, Seung-Joon Lee, Mira Park, Seok-Ho Hong","doi":"10.1186/s13578-024-01320-7","DOIUrl":"10.1186/s13578-024-01320-7","url":null,"abstract":"<p><strong>Background: </strong>In understanding the pathophysiology of pulmonary fibrosis (PF), macrophage plasticity has been implicated with a crucial role in the fibrogenic process. Growing evidence indicates that accumulation of M2 macrophages correlates with the progression of PF, suggesting that targeted modulation of molecules that influence M2 macrophage polarization could be a promising therapeutic approach for PF. Here, we demonstrated a decisive role of C-X-C motif chemokine ligand 11 (CXCL11) in driving M1 macrophage polarization to alleviate PF in the bleomycin-induced murine model.</p><p><strong>Results: </strong>We intravenously administered secretome derived from naïve (M0) and polarized macrophages (M1 and M2) into PF mice and found that lung fibrosis was effectively reversed in only the M1-treated group, with modulation of the M1/M2 ratio toward the ratio of the control group. These findings suggest that the factors secreted from M1 macrophages contribute to alleviating PF by targeting macrophages and reshaping the immunofibrotic environment in a paracrine manner. Secretome analysis of macrophages identified CXCL11 as an M1-specific chemokine, and administration of recombinant CXCL11 effectively improved fibrosis with the reduction of M2 macrophages in vivo. Furthermore, a mechanistic in vitro study revealed that CXCL11 reprogrammed macrophages from M2 to M1 through the activation of pERK, pAKT, and p65 signaling.</p><p><strong>Conclusions: </strong>Collectively, we demonstrate an unprecedented role for M1 macrophage-derived CXCL11 as an inducer of M1 macrophage polarization to revert the fibrogenic process in mice with PF, which may provide a clinically meaningful benefit.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"140"},"PeriodicalIF":6.1,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stearoyl-CoA desaturase in CD4⁺ T cells suppresses tumor growth through activation of the CXCR3/CXCL11 axis in CD8⁺ T cells.","authors":"Sung-Hyun Hwang, Yeseul Yang, Jae-Ha Jung, Jin Won Kim, Yongbaek Kim","doi":"10.1186/s13578-024-01308-3","DOIUrl":"10.1186/s13578-024-01308-3","url":null,"abstract":"<p><strong>Background: </strong>Within the tumor microenvironment, altered lipid metabolism promotes cancer cell malignancy by activating oncogenic cascades; however, impact of lipid metabolism in CD4⁺ tumor-infiltrating lymphocytes (TILs) remains poorly understood. Here, we elucidated that role of stearoyl-CoA desaturase (SCD) increased by treatment with cancer-associated fibroblast (CAF) supernatant in CD4⁺ T cells on their subset differentiation and activity of CD8⁺ T cells.</p><p><strong>Results: </strong>In our study, we observed that CD4⁺ TILs had higher lipid droplet content than CD4⁺ splenic T cells. In tumor tissue, CAF-derived supernatant provided fatty acids to CD4⁺ TILs, which increased the expression of SCD and oleic acid (OA) content. Increased SCD expression by OA treatment enhanced the levels of Th1 cell markers TBX21, interleukin-2, and interferon-γ. However, SCD inhibition upregulated the expression of regulatory T (Treg) cell markers, FOXP3 and transforming growth factor-β. Comparative fatty acid analysis of genetically engineered Jurkat cells revealed that OA level was significantly higher in SCD-overexpressing cells. Overexpression of SCD increased expression of Th1 cell markers, while treatment with OA enhanced the transcriptional level of TBX21 in Jurkat cells. In contrast, palmitic acid which is higher in SCD-KO cells than other subclones enhanced the expression of Treg cell markers through upregulation of mitochondrial superoxide. Furthermore, SCD increased the secretion of the C-X-C motif chemokine ligand 11 (CXCL11) from CD4⁺ T cells. The binding of CXCL11 to CXCR3 on CD8⁺ T cells augmented their cytotoxic activity. In a mouse tumor model, the suppressive effect of CD8⁺ T cells on tumor growth was dependent on CXCR3 expression.</p><p><strong>Conclusion: </strong>These findings illustrate that SCD not only orchestrates the differentiation of T helper cells, but also promotes the antitumor activity of CD8⁺ T cells, suggesting its function in adverse tumor microenvironments.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"137"},"PeriodicalIF":6.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel function for α-synuclein as a regulator of NCK2 in olfactory bulb: implications for its role in olfaction.","authors":"Jing Ren, Chao Wu, Mengxia Zeng, Mingqin Qu, Ge Gao, Ning Chen, Jingjing Yue, Yuwen Jiang, Tongfei Zhao, Na Xiang, Fangang Meng, Ling-Ling Lu","doi":"10.1186/s13578-024-01313-6","DOIUrl":"10.1186/s13578-024-01313-6","url":null,"abstract":"<p><p>To investigate physiological function of α-synuclein is important for understanding its pathophysiological mechanism in synucleinopathies including Parkinson's disease. Employing knockout mice, we found that Snac/α-synuclein deletion induced aberrant projection of olfactory sensory neurons and hyposmia. We identified 9 axon guidance associated differentially expressed proteins using iTRAQ based Liquid Chromatograph Mass Spectrometer. NCK2 is most significantly down-regulated protein among them. We further found that either α-synuclein deletion or NCK2 deficiency induced Eph A4 inactivation. Re-expressing Snac/α-synuclein in its knockout neurons reversed the down-regulation of NCK2, as well as the inactivation of EphA4. Overexpression of Snac/α-synuclein in α-synuclein deleted mice reversed the down-regulation of NCK2 and pEphA4, and improved the olfactory impairment of mice. Correlation analysis showed that there is a significant correlation between the protein level of α-synuclein, NCK2, and pEphA4, respectively. Nonetheless, immunoprecipitation analysis showed that NCK2 was associated with both EphA4 and Rho A, suggesting that NCK2 as a scaffolding protein to modulate Eph A4/Rho A pathway. Moreover, Rho A activity was significantly lower in α-synuclein deficient mice. Thus, α-synuclein regulates olfactory neurons projection through NCK2 dependent EphA4/Rho A pathway. Malfunction of α-synuclein because of deletion may cause aberrant olfactory neurons projection. This extended our knowledge of α-synuclein functions, which may explain why olfaction is usually impaired in some synucleinopathies.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"139"},"PeriodicalIF":6.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ancestral retrovirus envelope protein ERVWE1 upregulates circ_0001810, a potential biomarker for schizophrenia, and induces neuronal mitochondrial dysfunction via activating AK2.","authors":"Wenshi Li, Xing Xue, Xuhang Li, Xiulin Wu, Ping Zhou, Yaru Xia, Jiahang Zhang, Mengqi Zhang, Fan Zhu","doi":"10.1186/s13578-024-01318-1","DOIUrl":"10.1186/s13578-024-01318-1","url":null,"abstract":"<p><strong>Background: </strong>Increasingly studies highlight the crucial role of the ancestral retrovirus envelope protein ERVWE1 in the pathogenic mechanisms of schizophrenia, a severe psychiatric disorder affecting approximately 1% of the global population. Recent studies also underscore the significance of circular RNAs (circRNAs), crucial for neurogenesis and synaptogenesis, in maintaining neuronal functions. However, the precise relationship between ERVWE1 and circRNAs in the etiology of schizophrenia remains elusive.</p><p><strong>Results: </strong>This study observed elevated levels of hsa_circ_0001810 (circ_0001810) in the blood samples of schizophrenia patients, displaying a significant positive correlation with ERVWE1 expression. Interestingly, in vivo studies demonstrated that ERVWE1 upregulated circ_0001810 in neuronal cells. Circ_0001810, acting as a competing endogenous RNA (ceRNA), bound to miR-1197 and facilitated the release of adenylate kinase 2 (AK2). The bioinformatics analysis of the schizophrenia datasets revealed increased levels of AK2 and enrichment of mitochondrial dynamics. Notably, miR-1197 was reduced in schizophrenia patients, while AK2 levels were increased. Additionally, AK2 showed positive correlations with ERVWE1 and circ_0001810. Further studies demonstrated that AK2 led to mitochondrial dysfunction, characterized by loss of intracellular ATP, mitochondrial depolarization, and disruption of mitochondrial dynamics. Our comprehensive investigation suggested that ERVWE1 influenced ATP levels, promoted mitochondrial depolarization, and disrupted mitochondrial dynamics through the circ_0001810/AK2 pathway.</p><p><strong>Conclusions: </strong>Circ_0001810 and AK2 were increased in schizophrenia and positively correlated with ERVWE1. Importantly, ERVWE1 triggered mitochondrial dysfunction through circ_0001810/miR-1197/AK2 pathway. Recent focus on the impact of mitochondrial dynamics on schizophrenia development had led to our discovery of a novel mechanism by which ERVWE1 contributed to the etiology of schizophrenia, particularly through mitochondrial dynamics. Moreover, these findings collectively proposed that circ_0001810 might serve as a potential blood-based biomarker for schizophrenia. Consistent with our previous theories, ERVWE1 is increasingly recognized as a promising therapeutic target for schizophrenia.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"138"},"PeriodicalIF":6.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potassium channels in depression: emerging roles and potential targets.","authors":"Jiahao Zhang, Yao Zhu, Meng Zhang, Jinglan Yan, Yuanjia Zheng, Lin Yao, Ziwei Li, Zihan Shao, Yongjun Chen","doi":"10.1186/s13578-024-01319-0","DOIUrl":"10.1186/s13578-024-01319-0","url":null,"abstract":"<p><p>Potassium ion channels play a fundamental role in regulating cell membrane repolarization, modulating the frequency and shape of action potentials, and maintaining the resting membrane potential. A growing number of studies have indicated that dysfunction in potassium channels associates with the pathogenesis and treatment of depression. However, the involvement of potassium channels in the onset and treatment of depression has not been thoroughly summarized. In this review, we performed a comprehensive analysis of the association between multiple potassium channels and their roles in depression, and compiles the SNP loci of potassium channels associated with depression, as well as antidepressant drugs that target these channels. We discussed the pivotal role of potassium channels in the treatment of depression, provide valuable insights into new therapeutic targets for antidepressant treatment and critical clues to future drug discovery.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"136"},"PeriodicalIF":6.1,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knockdown of hepatic mitochondrial calcium uniporter mitigates MASH and fibrosis in mice.","authors":"Shuyu Li, Fangyuan Chen, Min Liu, Yajun Zhang, Jingjing Xu, Xi Li, Zhiyin Shang, Shaoping Huang, Shu Song, Chuantao Tu","doi":"10.1186/s13578-024-01315-4","DOIUrl":"10.1186/s13578-024-01315-4","url":null,"abstract":"<p><strong>Background: </strong>Mitochondrial calcium uniporter (MCU) plays pleiotropic roles in cellular physiology and pathology that contributes to a variety of diseases, but the role and potential mechanism of MCU in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH) remain poorly understood.</p><p><strong>Methods and results: </strong>Here, hepatic knockdown of MCU in C57BL/6J mice was achieved by tail vein injection of AAV8-mediated the CRISPR/Cas9. Mice were fed a Choline-deficient, L-amino acid-defined high-fat diet (CDAHFD) for 8 weeks to induce MASH and fibrosis. We find that expression of MCU enhanced in MASH livers of humans and mice. MCU knockdown robustly limits lipid droplet accumulation, steatosis, inflammation, and hepatocyte apoptotic death during MASH development both in vivo in mice and in vitro in cellular models. MCU-deficient mice strikingly mitigate MASH-related fibrosis. Moreover, the protective effects of MCU knockdown against MASH progression are accompanied by a reduced level of mitochondrial calcium, limiting hepatic oxidative stress, and attenuating mitochondrial dysfunction. Mechanically, RNA sequencing analysis and protein immunoblotting indicate that knockdown MCU inhibited the Hippo/YAP pathway activation and restored the AMP-activated protein kinase (AMPK) activity during MASH development both in vitro and in vivo.</p><p><strong>Conclusions: </strong>MCU is up-regulated in MASH livers in humans and mice; and hepatic MCU knockdown protects against diet-induced MASH and fibrosis in mice. Thus, targeting MCU may represent a novel therapeutic strategy for MASH and fibrosis.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"135"},"PeriodicalIF":6.1,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Musashi-2 in cancer-associated fibroblasts promotes non-small cell lung cancer metastasis through paracrine IL-6-driven epithelial-mesenchymal transition.","authors":"Parinya Samart, Gayathri Heenatigala Palliyage, Surapol Issaragrisil, Sudjit Luanpitpong, Yon Rojanasakul","doi":"10.1186/s13578-023-01158-5","DOIUrl":"10.1186/s13578-023-01158-5","url":null,"abstract":"<p><strong>Background: </strong>Lung cancer, the most common cause of cancer-related mortality worldwide, is predominantly associated with advanced/metastatic disease. The interaction between tumor cells and cancer-associated fibroblasts (CAFs) in tumor microenvironment is known to be essential for regulating tumor progression and metastasis, but the underlying mechanisms, particularly the role of RNA-binding protein Musashi-2 (MSI2) in CAFs in promoting non-small cell lung cancer (NSCLC) invasiveness and metastatic spread, remain obscure.</p><p><strong>Methods: </strong>Genomic and proteomic database analyses were performed to evaluate the potential clinical significance of MSI2 in NSCLC tumor and stromal clinical specimens. Molecular approaches were used to modify MSI2 in CAFs and determine its functional role in NSCLC cell motility in vitro using 2D and 3D models, and in metastasis in a xenograft mouse model using live-cell imaging.</p><p><strong>Results: </strong>MSI2, both gene and protein, is upregulated in NSCLC tissues and is associated with poor prognosis and high metastatic risk in patients. Interestingly, MSI2 is also upregulated in NSCLC stroma and activated fibroblasts, including CAFs. Depletion of MSI2 in CAFs by CRISPR-Cas9 strongly inhibits NSCLC cell migration and invasion in vitro, and attenuates local and distant metastatic spread of NSCLC cells in vivo. The crosstalk between CAFs and NSCLC cells occurs via paracrine signaling, which is regulated by MSI2 in CAFs via IL-6. The secreted IL-6 promotes epithelial-mesenchymal transition in NSCLC cells, which drives metastasis.</p><p><strong>Conclusion: </strong>Our findings reveal for the first time that MSI2 in CAFs is important in CAF-mediated NSCLC cell invasiveness and metastasis via IL-6 paracrine signaling. Therefore, targeting the MSI2/IL-6 axis in CAFs could be effective in combating NSCLC metastasis.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"13 1","pages":"205"},"PeriodicalIF":7.5,"publicationDate":"2023-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10631049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71523148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Causal relationship between gut microbiota and myasthenia gravis: a bidirectional mendelian randomization study.","authors":"Tengfei Su, Xiang Yin, Jiaxin Ren, Yue Lang, Weiguanliu Zhang, Li Cui","doi":"10.1186/s13578-023-01163-8","DOIUrl":"10.1186/s13578-023-01163-8","url":null,"abstract":"<p><strong>Background: </strong>Observational studies have demonstrated an association between gut microbiota and myasthenia gravis; however, the causal relationship between the two still lacks clarity. Our goals are to ascertain the existence of a bidirectional causal relationship between gut microbiota composition and myasthenia gravis, and to investigate how gut microbiota plays a role in reducing the risk of myasthenia gravis.</p><p><strong>Methods: </strong>We acquired gut microbiota data at the phylum, class, order, family, and genus levels from the MiBioGen consortium (N = 18,340) and myasthenia gravis data from the FinnGen Research Project (426 cases and 373,848 controls). In the two-sample Mendelian randomization analysis, we assessed the causal relationship between the gut microbiota and myasthenia gravis. We also conducted bidirectional MR analysis to determine the direction of causality. The inverse variance weighted, mendelian randomization-Egger, weighted median, simple mode, and weighted mode were used to test the causal relationship between the gut microbiota and severe myasthenia gravis. We used MR-Egger intercept and Cochran's Q test to assess for pleiotropy and heterogeneity, respectively. Furthermore, we utilized the MR-PRESSO method to evaluate horizontal pleiotropy and detect outliers.</p><p><strong>Results: </strong>In the forward analysis, the inverse-variance weighted method revealed that there is a positive correlation between the genus Lachnoclostridium (OR = 2.431,95%CI 1.047-5.647, p = 0.039) and the risk of myasthenia gravis. Additionally, the family Clostridiaceae1 (OR = 0.424,95%CI 0.202-0.889, p = 0.023), family Defluviitaleaceae (OR = 0.537,95%CI  0.290-0.995, p = 0.048), family Enterobacteriaceae (OR = 0.341,95%CI  0.135-0.865, p = 0.023), and an unknown genus (OR = 0.407,95%CI  0.209-0.793, p = 0.008) all demonstrated negative correlation with the risk of developing myasthenia gravis. Futhermore, reversed Mendelian randomization analysis proved a negative correlation between the risk of myasthenia gravis and genus Barnesiella (OR = 0.945,95%CI  0.906-0.985, p = 0.008).</p><p><strong>Conclusion: </strong>Our research yielded evidence of a causality connection in both directions between gut microbiota and myasthenia gravis. We identified specific types of microbes associated with myasthenia gravis, which offers a fresh window into the pathogenesis of this disease and the possibility of developing treatment strategies. Nonetheless, more studies, both basic and clinical, are necessary to elucidate the precise role and therapeutic potential of the gut microbiota in the pathogenesis of myasthenia gravis.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"13 1","pages":"204"},"PeriodicalIF":7.5,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10629094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71487926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SHMT2 regulates esophageal cancer cell progression and immune Escape by mediating m6A modification of c-myc.","authors":"Zhe Qiao, Yu Li, Yao Cheng, Shaomin Li, Shiyuan Liu","doi":"10.1186/s13578-023-01148-7","DOIUrl":"10.1186/s13578-023-01148-7","url":null,"abstract":"<p><strong>Background: </strong>In recent years, the role of altered cellular metabolism in tumor progression has attracted widespread attention. Related metabolic enzymes have also been considered as potential cancer therapeutic targets. Serine hydroxymethyltransferase 2 (SHMT2) has been reported to be upregulated in several cancers and associated with poor prognosis. However, there are few studies of SHMT2 in esophageal cancer (EC), and the related functions and mechanisms also need to be further explored.</p><p><strong>Methods: </strong>In this study, we first analyzed SHMT2 expression in EC by online database and clinical samples. Then, the biological functions of SHMT2 in EC were investigated by cell and animal experiments. The intracellular m6A methylation modification levels were also evaluated by MeRIP. Linked genes and mechanisms of SHMT2 were analyzed by bioinformatics and rescue experiments.</p><p><strong>Results: </strong>We found that SHMT2 expression was abnormally upregulated in EC and associated with poor prognosis. Functionally, SHMT2 silencing suppressed c-myc expression in an m6A-dependent manner, thereby blocking the proliferation, migration, invasion and immune escape abilities of EC cells. Mechanistically, SHMT2 encouraged the accumulation of methyl donor SAM through a one-carbon metabolic network, thereby regulating the m6A modification and stability of c-myc mRNA in a METTL3/FTO/ALKBH5/IGF2BP2-dependent way. In vivo animal experiments also demonstrated that SHMT2 mediated MYC expression by m6A-methylation modification, thus boosting EC tumorigenesis.</p><p><strong>Conclusion: </strong>In conclusion, our data illustrated that SHMT2 regulated malignant progression and immune escape of EC cell through c-myc m6A modification. These revealed mechanisms related to SHMT2 in EC and maybe offer promise for the development of new therapeutic approaches.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"13 1","pages":"203"},"PeriodicalIF":7.5,"publicationDate":"2023-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10629073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71487930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL3-mediated m6A methylation regulates ovarian cancer progression by recruiting myeloid-derived suppressor cells.","authors":"Jinyong Wang, Dakai Ling, Lulin Shi, Huayun Li, Minhua Peng, Huihong Wen, Tao Liu, Ruifang Liang, Yongjian Lin, Laiyou Wei, Guangzhi Zhang, Shanze Chen","doi":"10.1186/s13578-023-01149-6","DOIUrl":"10.1186/s13578-023-01149-6","url":null,"abstract":"<p><strong>Background: </strong>Ovarian cancer (OC) typically develops an immunosuppressive microenvironment by funtional changes of host immune cells. Dysregulated m6A level is associated with cancer progression via the intrinsic oncogenic pathways. However, the role of m6A in regulating host immune cell function during anti-tumor immunity needs comprehensive analysis. This study aimed to investigate the role of METTL3, a catalytic subunit of the methyltransferase complex, in regulating host immune cell response against OC.</p><p><strong>Methods: </strong>In this study, myeloid-specific Mettl3 gene knockout (Mettl3-cKO) mice were bred using the Cre-LoxP system. Intraperitoneally injection of ID8 cells was used as a syngeneic OC model. Furthermore, the compositions of immune cell populations were analyzed by flow cytometry and single-cell sequencing. Moreover, chemokines and cytokines secretion were assessed using ELISA. Lastly, the role of METTL3 in regulating IL-1β secretion and inflammasome activation in bone marrow-derived macrophages cocultured with ID8 cells was specified by ELISA and immunoblotting.</p><p><strong>Results: </strong>It was revealed that OC cell growth was enhanced in Mettl3-cKO mice. Furthermore, a shift of decreased M1 to increased M2 macrophage polarization was observed during OC progression. Moreover, Mettl3 depletion in myeloid lineage cells increased secretion of CCL2 and CXCL2 in peritoneal lavage fluild. Interestingly, Mettl3 deficiency enhanced IL-1β secretion induced by viable ID8 cells independent of inflammasome activation and cell death. Therefore, OC cells in tumor-bearing mice trigger a slight inflammatory response with a low-to-moderate secretion of pro-inflammatory cytokines and chemokines.</p><p><strong>Conclusion: </strong>This study provides new insights into METTL3-mediated m6A methylation, which regulates host immune response against OC.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"13 1","pages":"202"},"PeriodicalIF":7.5,"publicationDate":"2023-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10629157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71487927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}