Pub Date : 2025-05-20DOI: 10.1016/j.biocel.2025.106805
Jiaxin Zhao , Jianli Ke , Xiaochao Cao , Jie Li , Mingzhen Gu , Xiaoling Zhou , Yinglu Yan , Jiyuan Ke
Chemotherapy is a primary therapeutic option in cancer treatment, but often associated with unwanted side effects and drug resistance. Claudin-3 (CLDN3) and claudin-4 (CLDN4) are essential components of tight junctions, frequently overexpressed in ovarian cancer, serve as potential therapeutic targets. In this study, we utilized flow cytometry, qPCR, Western blot, and animal experiments to investigate the regulation of CLDN3 and CLDN4 by chemotherapy drug, gemcitabine, in the ovarian cancer cell line A2780. We reported that gemcitabine can induce expression of CLDN3 and CLDN4 in ovarian cancer cells. Mechanistically, we showed that gemcitabine induces expression of CLDN3 and CLDN4 through p38 MAP kinase mediated transcriptional regulation. Overexpression of CLDN3 or CLDN4 functionally protected A2780 ovarian cancer from gemcitabine induced cell killing. It appears that gemcitabine induced expression of CLDN3/4 is a chemoresistance mechanism for cancer cells. Gemcitabine-induced upregulation of CLDN3/4 suggests that ovarian cancer cells may be more effectively targeted using claudin-3/4-specific antibodies or antibody-drug conjugates (ADCs) in combination with chemotherapy, which could have clinical implications for ovarian cancer treatment in the future.
{"title":"p38 MAPK–mediated upregulation of claudin-3 and claudin-4 by gemcitabine contributes to chemoresistance in ovarian cancer","authors":"Jiaxin Zhao , Jianli Ke , Xiaochao Cao , Jie Li , Mingzhen Gu , Xiaoling Zhou , Yinglu Yan , Jiyuan Ke","doi":"10.1016/j.biocel.2025.106805","DOIUrl":"10.1016/j.biocel.2025.106805","url":null,"abstract":"<div><div>Chemotherapy is a primary therapeutic option in cancer treatment, but often associated with unwanted side effects and drug resistance. Claudin-3 (CLDN3) and claudin-4 (CLDN4) are essential components of tight junctions, frequently overexpressed in ovarian cancer, serve as potential therapeutic targets. In this study, we utilized flow cytometry, qPCR, Western blot, and animal experiments to investigate the regulation of CLDN3 and CLDN4 by chemotherapy drug, gemcitabine, in the ovarian cancer cell line A2780. We reported that gemcitabine can induce expression of CLDN3 and CLDN4 in ovarian cancer cells. Mechanistically, we showed that gemcitabine induces expression of CLDN3 and CLDN4 through p38 MAP kinase mediated transcriptional regulation. Overexpression of CLDN3 or CLDN4 functionally protected A2780 ovarian cancer from gemcitabine induced cell killing. It appears that gemcitabine induced expression of CLDN3/4 is a chemoresistance mechanism for cancer cells. Gemcitabine-induced upregulation of CLDN3/4 suggests that ovarian cancer cells may be more effectively targeted using claudin-3/4-specific antibodies or antibody-drug conjugates (ADCs) in combination with chemotherapy, which could have clinical implications for ovarian cancer treatment in the future.</div></div>","PeriodicalId":50335,"journal":{"name":"International Journal of Biochemistry & Cell Biology","volume":"185 ","pages":"Article 106805"},"PeriodicalIF":3.4,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144116978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-19DOI: 10.1016/j.biocel.2025.106790
Sai Wu , Vincent Rossi , Christopher A. Jackson , Isabella Lonardo , Joseph A. Ricottone , Joan M. Hevel , Michael C. Yu
In eukaryotes, protein arginine methylation is a prevalent post-translational modification found in a multitude of proteins responsible for key biological processes, ranging from transcription to signaling. One model suggests that phosphorylation of serine 9 (S9) in the Saccharomyces cerevisiae major protein arginine methyltransferase Hmt1 is critical for its oligomerization and activity. In this study, we used classic biochemical approaches to demonstrate that neither the S9 phosphomimetic nor the non-phosphorylatable substitution mutants of Hmt1 affect its oligomerization. These mutants remain active in vivo, retaining their ability to methylate the SR-/hnRNP-like protein Npl3 and displaying a monomethylarginine and asymmetric dimethylarginine banding profile similar to that of the wild-type. In cells lacking Dbf2, the proposed kinase responsible for phosphorylating Hmt1 at S9, Npl3 remains methylated. Additionally, monomethylarginine and asymmetric dimethylarginine banding profiles in cells lacking Dbf2 mostly resemble those observed in the wild-type rather than in hmt1Δ cells. Synchronized yeast cells expressing either S9 substitution exhibit entry into the M phase of the cell cycle at a rate similar to that of both wild-type and hmt1Δ cells. Our results suggest that the C-terminal epitope tagging of Hmt1 is responsible for the previously observed loss of enzymatic activities, rather than the S9 phosphorylation status of Hmt1. Finally, we demonstrate that S9 phosphorylation plays a role in maintaining Hmt1 protein levels in vivo. Overall, our finding demonstrates a novel role for Hmt1 S9 phosphorylation in tuning its in vivo protein levels.
{"title":"Serine phosphorylation of protein arginine methyltransferase Hmt1 is critical for controlling its protein levels","authors":"Sai Wu , Vincent Rossi , Christopher A. Jackson , Isabella Lonardo , Joseph A. Ricottone , Joan M. Hevel , Michael C. Yu","doi":"10.1016/j.biocel.2025.106790","DOIUrl":"10.1016/j.biocel.2025.106790","url":null,"abstract":"<div><div>In eukaryotes, protein arginine methylation is a prevalent post-translational modification found in a multitude of proteins responsible for key biological processes, ranging from transcription to signaling. One model suggests that phosphorylation of serine 9 (S9) in the <em>Saccharomyces cerevisiae</em> major protein arginine methyltransferase Hmt1 is critical for its oligomerization and activity. In this study, we used classic biochemical approaches to demonstrate that neither the S9 phosphomimetic nor the non-phosphorylatable substitution mutants of Hmt1 affect its oligomerization. These mutants remain active <em>in vivo,</em> retaining their ability to methylate the SR-/hnRNP-like protein Npl3 and displaying a monomethylarginine and asymmetric dimethylarginine banding profile similar to that of the wild-type. In cells lacking Dbf2, the proposed kinase responsible for phosphorylating Hmt1 at S9, Npl3 remains methylated. Additionally, monomethylarginine and asymmetric dimethylarginine banding profiles in cells lacking Dbf2 mostly resemble those observed in the wild-type rather than in <em>hmt1Δ</em> cells. Synchronized yeast cells expressing either S9 substitution exhibit entry into the M phase of the cell cycle at a rate similar to that of both wild-type and <em>hmt1Δ</em> cells. Our results suggest that the C-terminal epitope tagging of Hmt1 is responsible for the previously observed loss of enzymatic activities, rather than the S9 phosphorylation status of Hmt1. Finally, we demonstrate that S9 phosphorylation plays a role in maintaining Hmt1 protein levels <em>in vivo</em>. Overall, our finding demonstrates a novel role for Hmt1 S9 phosphorylation in tuning its <em>in vivo</em> protein levels.</div></div>","PeriodicalId":50335,"journal":{"name":"International Journal of Biochemistry & Cell Biology","volume":"185 ","pages":"Article 106790"},"PeriodicalIF":3.4,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144121277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-19DOI: 10.1016/j.biocel.2025.106798
Hanfei Wang , Li Hou , Xintong Chen , Linling Gui , Weiwei Jiang , Weibing Tang
Background
The intestinal barrier has an important role in maintaining homeostasis. The aim of this study was to determine the protective effect of Clostridium butyricum (CBM) on small intestinal barrier damage in mice and the role of farnesoid X receptor (FXR) in regulating the intestinal barrier by C. butyricum.
Methods and results
A model of small intestinal injury induced by dextran sulfate sodium (DSS) was constructed to detect repair of intestinal barrier damage after feeding with C. butyricum. In the DSS model group, expression of the tight junction protein (TJP) was significantly decreased and expression of inflammatory factors was significantly increased. TJP expression was significantly increased and inflammatory factor expression was significantly decreased after C. butyricum feeding, which indicated that intestinal barrier function was repaired. In addition, inhibition of FXR expression as well as the downstream signaling pathways were demonstrated in the DSS model group. FXR and its downstream signaling pathways were significantly upregulated after feeding with C. butyricum. Then, intestinal barrier function was evaluated by constructing an intestinal-specific FXR knockout (KO) DSS model in mice. Suppression of TJP and upregulated expression of inflammatory factors were detected in the KO DSS group but there was no significant difference in the expression of TJP and inflammatory factors after C. butyricum feeding. Furthermore, there was no significant difference in FXR downstream signaling pathway expression after C. butyricum feeding compared to the KO DSS group. C. butyricum supernatants (CSs) upregulated the FXR signaling pathways in vitro. CSs did not activate the FXR signaling pathway when FXR was suppressed.
Conclusions
C. butyricum supplementation effectively ameliorated DSS-induced intestinal barrier disruption. C. butyricum may have a protective effect on the small intestine through the FXR signaling pathway.
背景：肠道屏障在维持体内平衡中起着重要作用。本研究旨在探讨丁酸梭菌（Clostridium butyricum， CBM）对小鼠小肠屏障损伤的保护作用及法内脂X受体（farnesoid X receptor， FXR）在丁酸梭菌调节小肠屏障中的作用。方法与结果：建立硫酸葡聚糖钠（DSS）致小肠损伤模型，观察丁酸梭菌饲喂后小肠屏障损伤的修复情况。DSS模型组大鼠紧密连接蛋白（TJP）表达明显降低，炎性因子表达明显升高。饲喂丁酸梭菌后，TJP表达显著升高，炎症因子表达显著降低，表明肠道屏障功能得到修复。此外，在DSS模型组中，FXR的表达以及下游信号通路均受到抑制。饲喂丁酸梭菌后，FXR及其下游信号通路显著上调。然后，通过构建小鼠肠道特异性FXR敲除（KO） DSS模型来评估肠道屏障功能。KO DSS组TJP表达受到抑制，炎症因子表达上调，但饲喂丁酸梭菌后TJP和炎症因子表达无显著差异。此外，与KO DSS组相比，丁酸梭菌饲喂后FXR下游信号通路的表达无显著差异。C. butyricum上清液（CSs）上调FXR信号通路。当FXR被抑制时，CSs不激活FXR信号通路。结论：补充丁酸梭菌可有效改善dss引起的肠屏障破坏。丁酸梭菌可能通过FXR信号通路对小肠产生保护作用。
{"title":"Clostridium butyricum protects the ileal barrier in mice by regulating the farnesoid X receptor signaling pathway","authors":"Hanfei Wang , Li Hou , Xintong Chen , Linling Gui , Weiwei Jiang , Weibing Tang","doi":"10.1016/j.biocel.2025.106798","DOIUrl":"10.1016/j.biocel.2025.106798","url":null,"abstract":"<div><h3>Background</h3><div>The intestinal barrier has an important role in maintaining homeostasis. The aim of this study was to determine the protective effect of <em>Clostridium butyricum</em> (CBM) on small intestinal barrier damage in mice and the role of farnesoid X receptor (FXR) in regulating the intestinal barrier by <em>C. butyricum</em>.</div></div><div><h3>Methods and results</h3><div>A model of small intestinal injury induced by dextran sulfate sodium (DSS) was constructed to detect repair of intestinal barrier damage after feeding with <em>C. butyricum</em>. In the DSS model group, expression of the tight junction protein (TJP) was significantly decreased and expression of inflammatory factors was significantly increased. TJP expression was significantly increased and inflammatory factor expression was significantly decreased after <em>C. butyricum</em> feeding, which indicated that intestinal barrier function was repaired. In addition, inhibition of FXR expression as well as the downstream signaling pathways were demonstrated in the DSS model group. FXR and its downstream signaling pathways were significantly upregulated after feeding with <em>C. butyricum</em>. Then, intestinal barrier function was evaluated by constructing an intestinal-specific FXR knockout (KO) DSS model in mice. Suppression of TJP and upregulated expression of inflammatory factors were detected in the KO DSS group but there was no significant difference in the expression of TJP and inflammatory factors after <em>C. butyricum</em> feeding. Furthermore, there was no significant difference in FXR downstream signaling pathway expression after <em>C. butyricum</em> feeding compared to the KO DSS group. <em>C. butyricum</em> supernatants (CSs) upregulated the FXR signaling pathways <em>in vitro</em>. CSs did not activate the FXR signaling pathway when FXR was suppressed.</div></div><div><h3>Conclusions</h3><div><em>C. butyricum</em> supplementation effectively ameliorated DSS-induced intestinal barrier disruption. <em>C. butyricum</em> may have a protective effect on the small intestine through the FXR signaling pathway.</div></div>","PeriodicalId":50335,"journal":{"name":"International Journal of Biochemistry & Cell Biology","volume":"185 ","pages":"Article 106798"},"PeriodicalIF":3.4,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144121274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-19DOI: 10.1016/j.biocel.2025.106804
Qiu-ai Shu , Xin-di Huang , Jian Wu , Xi-ru Liang , Ya-lan Wang , Jin-min Yu , Zi-wei Wang , Na Liu , Jin-hai Wang , Ning Xie
The prognosis of pancreatic adenocarcinoma remains dismal up to now, partly owing to a lack of clinically feasible therapeutic targets. ARHGAP11A, a member of Rho GTPase-activating proteins family, has been reported as a prognostic biomarker and oncogene for multiple cancers. However, the specific effects of ARHGAP11A in pancreatic adenocarcinoma remain obscure. In this study, we explored and validated the oncogenic role of ARHGAP11A in pancreatic adenocarcinoma via thorough bioinformatics analyses of public databases and our own RNA-seq data, and in vitro experiments. We found that ARHGAP11A was significantly upregulated in pancreatic adenocarcinoma and correlated with poor clinical outcomes of pancreatic adenocarcinoma patients. Functional enrichment analyses revealed that ARHGAP11A-related genes were enriched in pathways of cell cycle and cell apoptosis. Further molecular functional experiments on ARHGAP11A knockdown pancreatic adenocarcinoma cell lines demonstrated that ARHGAP11A knockdown significantly inhibited cell proliferation, promoted cell cycle arrest in the G1/S stage, and induced cell apoptosis. In comparison, overexpression of ARHGAP11A could remarkably promote the proliferation, cell cycle progression, and apoptosis resistance of pancreatic adenocarcinoma cells. In conclusion, our study demonstrates that ARHGAP11A plays an oncogenic role in pancreatic adenocarcinoma, thus providing a novel therapeutic target and prognostic biomarker for patients with pancreatic adenocarcinoma.
{"title":"ARHGAP11A is a potential prognostic biomarker and therapeutic target for pancreatic adenocarcinoma","authors":"Qiu-ai Shu , Xin-di Huang , Jian Wu , Xi-ru Liang , Ya-lan Wang , Jin-min Yu , Zi-wei Wang , Na Liu , Jin-hai Wang , Ning Xie","doi":"10.1016/j.biocel.2025.106804","DOIUrl":"10.1016/j.biocel.2025.106804","url":null,"abstract":"<div><div>The prognosis of pancreatic adenocarcinoma remains dismal up to now, partly owing to a lack of clinically feasible therapeutic targets. ARHGAP11A, a member of Rho GTPase-activating proteins family, has been reported as a prognostic biomarker and oncogene for multiple cancers. However, the specific effects of ARHGAP11A in pancreatic adenocarcinoma remain obscure. In this study, we explored and validated the oncogenic role of ARHGAP11A in pancreatic adenocarcinoma via thorough bioinformatics analyses of public databases and our own RNA-seq data, and <em>in vitro</em> experiments. We found that ARHGAP11A was significantly upregulated in pancreatic adenocarcinoma and correlated with poor clinical outcomes of pancreatic adenocarcinoma patients. Functional enrichment analyses revealed that ARHGAP11A-related genes were enriched in pathways of cell cycle and cell apoptosis. Further molecular functional experiments on ARHGAP11A knockdown pancreatic adenocarcinoma cell lines demonstrated that ARHGAP11A knockdown significantly inhibited cell proliferation, promoted cell cycle arrest in the G1/S stage, and induced cell apoptosis. In comparison, overexpression of ARHGAP11A could remarkably promote the proliferation, cell cycle progression, and apoptosis resistance of pancreatic adenocarcinoma cells. In conclusion, our study demonstrates that ARHGAP11A plays an oncogenic role in pancreatic adenocarcinoma, thus providing a novel therapeutic target and prognostic biomarker for patients with pancreatic adenocarcinoma.</div></div>","PeriodicalId":50335,"journal":{"name":"International Journal of Biochemistry & Cell Biology","volume":"185 ","pages":"Article 106804"},"PeriodicalIF":3.4,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144107719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-16DOI: 10.1016/j.biocel.2025.106803
Jie Zhang , Min Zhao , Haolan Zhang, Chenjie Ma, Chunyan Ma, Le Li
The dysregulation of the urea cycle resulting in an excessive buildup of ammonia is identified as a pivotal mechanism driving tumor progression. In particular, argininosuccinate lyase (ASL) is crucial for cancer cell proliferation, cleaves argininosuccinic acid to produce arginine and fumarate in the urea cycle. However, the mechanisms controlling ASL expression in cancer cells remain unclear. Herein, we found that TAp73, a transcription factor within the p53 family, regulates the urea cycle pathway in tumor cells with mutant or null p53. Deletion of TAp73 led to increased accumulation of ammonia and changes in urea cycle metabolites. Subsequent experimentation involving the suppression of TAp73 substantiated its pronounced capability in impeding tumor proliferation and tumorigenicity in both in vitro and in vivo settings. Chromatin immunoprecipitation revealed that TAp73 could bind to specific sequences in the ASL promoter, thus promoting ASL expression, increasing intracellular arginine, and reducing ammonia levels. This investigation undertook a clinical scrutiny of TAp73 expression levels in tumor patients' transcriptomes, revealing an inverse relationship between TAp73 expression and patient survival. These results suggested that TAp73 led to abnormalities in the urea cycle by enhancing ASL expression and will be an important factor in promoting tumor proliferation and a potential target for tumor drugs.
{"title":"Critical role of argininosuccinate lyase in TAp73-mediated proliferating tumor cells","authors":"Jie Zhang , Min Zhao , Haolan Zhang, Chenjie Ma, Chunyan Ma, Le Li","doi":"10.1016/j.biocel.2025.106803","DOIUrl":"10.1016/j.biocel.2025.106803","url":null,"abstract":"<div><div>The dysregulation of the urea cycle resulting in an excessive buildup of ammonia is identified as a pivotal mechanism driving tumor progression. In particular, argininosuccinate lyase (ASL) is crucial for cancer cell proliferation, cleaves argininosuccinic acid to produce arginine and fumarate in the urea cycle. However, the mechanisms controlling ASL expression in cancer cells remain unclear. Herein, we found that TAp73, a transcription factor within the p53 family, regulates the urea cycle pathway in tumor cells with mutant or null p53. Deletion of TAp73 led to increased accumulation of ammonia and changes in urea cycle metabolites. Subsequent experimentation involving the suppression of TAp73 substantiated its pronounced capability in impeding tumor proliferation and tumorigenicity in both in vitro and in vivo settings. Chromatin immunoprecipitation revealed that TAp73 could bind to specific sequences in the <em>ASL</em> promoter, thus promoting ASL expression, increasing intracellular arginine, and reducing ammonia levels. This investigation undertook a clinical scrutiny of TAp73 expression levels in tumor patients' transcriptomes, revealing an inverse relationship between TAp73 expression and patient survival. These results suggested that TAp73 led to abnormalities in the urea cycle by enhancing ASL expression and will be an important factor in promoting tumor proliferation and a potential target for tumor drugs.</div></div>","PeriodicalId":50335,"journal":{"name":"International Journal of Biochemistry & Cell Biology","volume":"185 ","pages":"Article 106803"},"PeriodicalIF":3.4,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144095529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Soft tissue sarcoma is a highly malignant tumor with extensive heterogeneity across multiple omics. However, a comprehensive multi-omics subtyping system has not yet been established.
Methods
We integrated sarcoma multi-omics data, including clinical information, transcriptome expression profiles, DNA methylation, and somatic mutations. Using ten advanced clustering algorithms, we identified robust subtypes and validated the reproducibility of our analysis in two independent external datasets. We also identified subtype-specific treatment strategies and analyzed the differences in microenvironments between subtypes using single-cell data.
Results
Based on multi-omics subtyping, we identified two novel sarcoma molecular subtypes, named sarcoma multi-omics subtype 1 (SAMS1) and SAMS2. SAMS2 exhibited a poorer prognosis, with significantly activated Myc, glycolysis, and Wnt beta-catenin signaling pathways. SAMS2 was characterized by a lower abundance of immune cell infiltration and anti-tumor immunity deficiency, which owned a lower response rate to immunotherapy but was sensitive to certain targeted drugs, including pazopanib, axitinib, thapsigargin, and elesclomol. MK886 and NU1025 were identified as effective therapeutic targets for the SAMS2. In SAMS2-like tumor epithelial cells, HOXB13/COL16A1 and BASP1 regulated epithelial-mesenchymal transition. We found that WNT7B was highly expressed in STS and was associated with poor patient prognosis, suggesting its potential as a novel therapeutic target for STS patients.
Conclusion
The STS molecular subtyping system based on multi-omics data effectively distinguishes patients with poor prognosis. The subtyping results are robust and reliable, providing new insights for the precise diagnosis and treatment of these patients.
{"title":"Deciphering the molecular heterogeneity of soft tissue sarcoma by integrating multiomics and single cell sequence","authors":"Haixiang Zhang , Peng Luo , Hao Jiang , Aimin Jiang , Wei Wei , Chunbiao Wu","doi":"10.1016/j.biocel.2025.106801","DOIUrl":"10.1016/j.biocel.2025.106801","url":null,"abstract":"<div><h3>Background</h3><div>Soft tissue sarcoma is a highly malignant tumor with extensive heterogeneity across multiple omics. However, a comprehensive multi-omics subtyping system has not yet been established.</div></div><div><h3>Methods</h3><div>We integrated sarcoma multi-omics data, including clinical information, transcriptome expression profiles, DNA methylation, and somatic mutations. Using ten advanced clustering algorithms, we identified robust subtypes and validated the reproducibility of our analysis in two independent external datasets. We also identified subtype-specific treatment strategies and analyzed the differences in microenvironments between subtypes using single-cell data.</div></div><div><h3>Results</h3><div>Based on multi-omics subtyping, we identified two novel sarcoma molecular subtypes, named sarcoma multi-omics subtype 1 (SAMS1) and SAMS2. SAMS2 exhibited a poorer prognosis, with significantly activated Myc, glycolysis, and Wnt beta-catenin signaling pathways. SAMS2 was characterized by a lower abundance of immune cell infiltration and anti-tumor immunity deficiency, which owned a lower response rate to immunotherapy but was sensitive to certain targeted drugs, including pazopanib, axitinib, thapsigargin, and elesclomol. MK886 and NU1025 were identified as effective therapeutic targets for the SAMS2. In SAMS2-like tumor epithelial cells, <em>HOXB13</em>/<em>COL16A1</em> and <em>BASP1</em> regulated epithelial-mesenchymal transition. We found that <em>WNT7B</em> was highly expressed in STS and was associated with poor patient prognosis, suggesting its potential as a novel therapeutic target for STS patients.</div></div><div><h3>Conclusion</h3><div>The STS molecular subtyping system based on multi-omics data effectively distinguishes patients with poor prognosis. The subtyping results are robust and reliable, providing new insights for the precise diagnosis and treatment of these patients.</div></div>","PeriodicalId":50335,"journal":{"name":"International Journal of Biochemistry & Cell Biology","volume":"185 ","pages":"Article 106801"},"PeriodicalIF":3.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-15DOI: 10.1016/j.biocel.2025.106802
Shinese Ashokcoomar , Tarien J. Naidoo , Bridgette M. Cumming , Zainab Baig , Barry Truebody , Jared S. Mackenzie , Adrie J.C. Steyn , Manormoney Pillay
The development of improved anti-tuberculosis (TB) strategies to address drug-resistance and ineffectual TB treatment regimens should focus on interrupting the initial host-pathogen interaction. This study aimed to elucidate the effect of surface-located adhesin, Mycobacterium tuberculosis (Mtb) curli pili (MTP), on the bioenergetic and metabolomic profiles of THP-1 macrophages during initial stages of infection. Differentiated THP-1 macrophages were infected with wildtype (WT), ∆mtp, or mtp-complemented strains of Mtb. Bioenergetic profiles and metabolic flux were determined and statistical analysis highlighted differences/similarities amongst the THP-1 macrophage groups. The ∆mtp infected THP-1 macrophages mimicked the higher oxygen consumption rate (OCR) for basal respiration, ATP production, maximal respiration and spare respiratory capacity of the uninfected THP-1 macrophages, relative to the WT and mtp-complement infected THP-1 macrophages. The ∆mtp infected THP-1 macrophages displayed the highest compensatory glycolytic rate. Mtb infection caused the redirection of carbon from the tricarboxylic acid cycle to glycolysis, in addition to an increased flux through the pentose phosphate pathway. However, in the ∆mtp infected THP-1 macrophages, the total metabolite abundance was lower, similar to the uninfected THP-1 macrophages. Data indicates that the absence of MTP facilitates prompt clearance of the intracellular pathogen before it establishes a successful infection. This implies that the presence of MTP facilitates the survival of the pathogen during the early stages until infection is established. These findings support the growing evidence that the MTP adhesin is an important virulence factor and interruption of the interaction between pathogen and host, will facilitate swift clearance of the infection by the host.
{"title":"Mycobacterium tuberculosis curli pili reduces oxygen consumption rate of THP-1 macrophages during early infection","authors":"Shinese Ashokcoomar , Tarien J. Naidoo , Bridgette M. Cumming , Zainab Baig , Barry Truebody , Jared S. Mackenzie , Adrie J.C. Steyn , Manormoney Pillay","doi":"10.1016/j.biocel.2025.106802","DOIUrl":"10.1016/j.biocel.2025.106802","url":null,"abstract":"<div><div>The development of improved anti-tuberculosis (TB) strategies to address drug-resistance and ineffectual TB treatment regimens should focus on interrupting the initial host-pathogen interaction. This study aimed to elucidate the effect of surface-located adhesin, <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>) curli pili (MTP), on the bioenergetic and metabolomic profiles of THP-1 macrophages during initial stages of infection. Differentiated THP-1 macrophages were infected with wildtype (WT), ∆<em>mtp</em>, or <em>mtp</em>-complemented strains of <em>Mtb</em>. Bioenergetic profiles and metabolic flux were determined and statistical analysis highlighted differences/similarities amongst the THP-1 macrophage groups. The ∆<em>mtp</em> infected THP-1 macrophages mimicked the higher oxygen consumption rate (OCR) for basal respiration, ATP production, maximal respiration and spare respiratory capacity of the uninfected THP-1 macrophages, relative to the WT and <em>mtp</em>-complement infected THP-1 macrophages. The ∆<em>mtp</em> infected THP-1 macrophages displayed the highest compensatory glycolytic rate. <em>Mtb</em> infection caused the redirection of carbon from the tricarboxylic acid cycle to glycolysis, in addition to an increased flux through the pentose phosphate pathway. However, in the ∆<em>mtp</em> infected THP-1 macrophages, the total metabolite abundance was lower, similar to the uninfected THP-1 macrophages. Data indicates that the absence of MTP facilitates prompt clearance of the intracellular pathogen before it establishes a successful infection. This implies that the presence of MTP facilitates the survival of the pathogen during the early stages until infection is established. These findings support the growing evidence that the MTP adhesin is an important virulence factor and interruption of the interaction between pathogen and host, will facilitate swift clearance of the infection by the host.</div></div>","PeriodicalId":50335,"journal":{"name":"International Journal of Biochemistry & Cell Biology","volume":"185 ","pages":"Article 106802"},"PeriodicalIF":3.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144070670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-10DOI: 10.1016/j.biocel.2025.106797
Yufeng Zhang , Yanfang Liu , Han Wan , Huiling Deng , Pengfei Xu , Lu Cao , Xiru Yang , Hui Li
It is unclear whether high mobility group protein B1 (HMGB1) is associated with the malignant characterization of hand, foot, and mouth disease (HFMD), and whether it plays a key regulatory role in the process of enterovirus 71 (EV71)-induced brain damage. Firstly, we analyzed the correlation between clinical information and HMGB1 concentrations in patients with mild and severe HFMD. Immunofluorescence was used to determine the expression level of HMGB1 in astrocytes. The levels of cellular inflammatory factors (IL-1β, IL-4, IL-6, TNF-α and TGF-β1), chemokines (CCL2, CXCL10 and CXCL12) and adhesion factors (integrin β, P-gp, VCAM-1 and ICAM-1) were detected by ELISA kits. Western blot was used to measure the levels of blood-brain barrier (BBB) stability related factors (retinoic acid (RA), ANG1, ApoE and IGF-1) in astrocytes and BBB structure related proteins (occluding, claudin, PTCH-1 and ZO-1) in endothelial cells. Clinical studies found that the expression of HMGB1 was closely related to the HFMD severity. Knockdown of HMGB1 alleviated EV71-induced neuron damage and inhibited cellular inflammation and apoptosis. Importantly, silencing HMGB1 depressed excessive proliferation and the inflammation response of astrocytes caused by EV71 infection. Furthermore, knockdown of HMGB1 enhanced BBB stability by improving astrocyte adhesion and endothelial tight junctions. Mechanistically, HMGB1 regulated the stability of BBB by regulating sHh signaling and secretion in astrocytes. In conclusion, the level of HMGB1 is closely related to the clinical symptoms of patients with HFMD, and inhibiting the expression of HMGB1 promotes BBB stability by promoting sHh signaling in astrocytes.
{"title":"Silencing HMGB1 secretion inhibited EV71-induced blood-brain barrier dysfunction and neural inflammation by depressing astrocyte activation via sHh signal blockage","authors":"Yufeng Zhang , Yanfang Liu , Han Wan , Huiling Deng , Pengfei Xu , Lu Cao , Xiru Yang , Hui Li","doi":"10.1016/j.biocel.2025.106797","DOIUrl":"10.1016/j.biocel.2025.106797","url":null,"abstract":"<div><div>It is unclear whether high mobility group protein B1 (HMGB1) is associated with the malignant characterization of hand, foot, and mouth disease (HFMD), and whether it plays a key regulatory role in the process of enterovirus 71 (EV71)-induced brain damage. Firstly, we analyzed the correlation between clinical information and HMGB1 concentrations in patients with mild and severe HFMD. Immunofluorescence was used to determine the expression level of HMGB1 in astrocytes. The levels of cellular inflammatory factors (IL-1β, IL-4, IL-6, TNF-α and TGF-β1), chemokines (CCL2, CXCL10 and CXCL12) and adhesion factors (integrin β, P-gp, VCAM-1 and ICAM-1) were detected by ELISA kits. Western blot was used to measure the levels of blood-brain barrier (BBB) stability related factors (retinoic acid (RA), ANG1, ApoE and IGF-1) in astrocytes and BBB structure related proteins (occluding, claudin, PTCH-1 and ZO-1) in endothelial cells. Clinical studies found that the expression of HMGB1 was closely related to the HFMD severity. Knockdown of HMGB1 alleviated EV71-induced neuron damage and inhibited cellular inflammation and apoptosis. Importantly, silencing HMGB1 depressed excessive proliferation and the inflammation response of astrocytes caused by EV71 infection. Furthermore, knockdown of HMGB1 enhanced BBB stability by improving astrocyte adhesion and endothelial tight junctions. Mechanistically, HMGB1 regulated the stability of BBB by regulating sHh signaling and secretion in astrocytes. In conclusion, the level of HMGB1 is closely related to the clinical symptoms of patients with HFMD, and inhibiting the expression of HMGB1 promotes BBB stability by promoting sHh signaling in astrocytes.</div></div>","PeriodicalId":50335,"journal":{"name":"International Journal of Biochemistry & Cell Biology","volume":"185 ","pages":"Article 106797"},"PeriodicalIF":3.4,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144046249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-07DOI: 10.1016/j.biocel.2025.106789
Xiaona Fan , Hongsheng Xue , Ziwei Liu , Ying Zhou , Xuying Huang , Xiaomei Dong , Qianqian Sun , Jiannan Yao , Jian Liu
The development of acquired paclitaxel resistance poses a significant challenge in managing lung cancer clinically. Understanding the mechanism and developing effective strategies to counter paclitaxel resistance are highly desired. To explore the potential mechanisms of acquired paclitaxel resistance, we established a series of lung cancer cell lines exhibiting different levels of resistance to paclitaxel. Transcriptomic RNA-sequencing revealed a progressive decrease in alpha-2-macroglobulin (A2M) levels as paclitaxel resistance advanced in NCI-H446 cells. This was accompanied by the upregulation of known paclitaxel resistance inducers ABCB1, TMEM243, and ID1. A2M loss was further validated in paclitaxel-resistant A549 and HCC827 lung cancer cells. TCGA and CPTAC analyses demonstrated that A2M is downregulated in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), inversely correlating with tumor progression. Restoring A2M expression inhibited proliferation and invasion in paclitaxel-resistant lung cancer cells, suggesting its tumor-suppressing role in lung cancer. Notably, restoring A2M re-suppressed the expression of the paclitaxel resistance mediators (ABCB1, TMEM243 and ID1) in the drug-resistant cells, and re-sensitized them to paclitaxel. In summary, our data indicate that A2M is progressively lost during the development of paclitaxel resistance in lung cancer, and restoring A2M may help overcome this resistance. Thus, A2M deficiency may serve as both a predictor and a therapeutic target for paclitaxel resistance in lung cancer.
{"title":"Restoration of A2M reduces drug resistance and malignancy in paclitaxel-resistant lung cancer cells","authors":"Xiaona Fan , Hongsheng Xue , Ziwei Liu , Ying Zhou , Xuying Huang , Xiaomei Dong , Qianqian Sun , Jiannan Yao , Jian Liu","doi":"10.1016/j.biocel.2025.106789","DOIUrl":"10.1016/j.biocel.2025.106789","url":null,"abstract":"<div><div>The development of acquired paclitaxel resistance poses a significant challenge in managing lung cancer clinically. Understanding the mechanism and developing effective strategies to counter paclitaxel resistance are highly desired. To explore the potential mechanisms of acquired paclitaxel resistance, we established a series of lung cancer cell lines exhibiting different levels of resistance to paclitaxel. Transcriptomic RNA-sequencing revealed a progressive decrease in alpha-2-macroglobulin (A2M) levels as paclitaxel resistance advanced in NCI-H446 cells. This was accompanied by the upregulation of known paclitaxel resistance inducers ABCB1, TMEM243, and ID1. A2M loss was further validated in paclitaxel-resistant A549 and HCC827 lung cancer cells. TCGA and CPTAC analyses demonstrated that A2M is downregulated in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), inversely correlating with tumor progression. Restoring A2M expression inhibited proliferation and invasion in paclitaxel-resistant lung cancer cells, suggesting its tumor-suppressing role in lung cancer. Notably, restoring A2M re-suppressed the expression of the paclitaxel resistance mediators (ABCB1, TMEM243 and ID1) in the drug-resistant cells, and re-sensitized them to paclitaxel. In summary, our data indicate that A2M is progressively lost during the development of paclitaxel resistance in lung cancer, and restoring A2M may help overcome this resistance. Thus, A2M deficiency may serve as both a predictor and a therapeutic target for paclitaxel resistance in lung cancer.</div></div>","PeriodicalId":50335,"journal":{"name":"International Journal of Biochemistry & Cell Biology","volume":"185 ","pages":"Article 106789"},"PeriodicalIF":3.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143929467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-02DOI: 10.1016/j.biocel.2025.106788
YingYing Pei , Chunlin Li , Bin Zhang , Qi Zheng , Shengnan Chen , Ji Li
Nasopharyngeal carcinoma (NPC) is an aggressive and highly metastatic malignancy, presenting significant challenges for early diagnosis and treatment. Asparaginase-like protein 1 (ASRGL1) is an important enzyme involved in amino acid metabolism, and previous studies have linked it to the progression of various tumors. However, the specific role of ASRGL1 in NPC remains unclear. This study analyzed multiple publicly available datasets related to NPC. We conducted single-cell RNA sequencing (scRNA-seq) analysis on the GSE150430 dataset to identify different cell subpopulations and examine ASRGL1 expression and its functional implications. The expression of ASRGL1 and its correlation with EMT were validated using transcriptomic data. The expression of ASRGL1 in C666–1 cells was interfered with by siRNA, cell proliferation and invasion were detected by CCK8, EdU, plate cloning, Transwell and scratch method, and EMT was evaluated by detecting the expression of E-cadherin and N-cadherin. Amino acid metabolomics and GC-MS headspace metabolomics were used to analyze the effects of ASRGL1 knockdown on the metabolic pattern of NPC cells. This study found that ASRGL1 was mainly expressed in fibroblasts, epithelial cells and myeloid cells in nasopharyngeal carcinoma (NPC). The ASRGL1-cell gene was significantly enriched in the epithelial-mesenchymal transition pathway. Knocking down ASRGL1 can further inhibit the proliferation, invasion and EMT of C666–1 cells. At the same time, the utilization of various amino acids was significantly reduced, and further GC-MS metabolomics analysis showed that the cell metabolism was unbalanced. This study elucidates the expression characteristics and potential functional roles of asparaginase-like protein 1 (ASRGL1) in nasopharyngeal carcinoma (NPC), providing new insights into its potential as a diagnostic marker and therapeutic target.
{"title":"Single-cell transcriptomics and metabolomics reveal the potential role of ASRGL1 in metabolic reprogramming and invasion of nasopharyngeal carcinoma cells","authors":"YingYing Pei , Chunlin Li , Bin Zhang , Qi Zheng , Shengnan Chen , Ji Li","doi":"10.1016/j.biocel.2025.106788","DOIUrl":"10.1016/j.biocel.2025.106788","url":null,"abstract":"<div><div>Nasopharyngeal carcinoma (NPC) is an aggressive and highly metastatic malignancy, presenting significant challenges for early diagnosis and treatment. Asparaginase-like protein 1 (ASRGL1) is an important enzyme involved in amino acid metabolism, and previous studies have linked it to the progression of various tumors. However, the specific role of ASRGL1 in NPC remains unclear. This study analyzed multiple publicly available datasets related to NPC. We conducted single-cell RNA sequencing (scRNA-seq) analysis on the GSE150430 dataset to identify different cell subpopulations and examine ASRGL1 expression and its functional implications. The expression of ASRGL1 and its correlation with EMT were validated using transcriptomic data. The expression of ASRGL1 in C666–1 cells was interfered with by siRNA, cell proliferation and invasion were detected by CCK8, EdU, plate cloning, Transwell and scratch method, and EMT was evaluated by detecting the expression of E-cadherin and N-cadherin. Amino acid metabolomics and GC-MS headspace metabolomics were used to analyze the effects of ASRGL1 knockdown on the metabolic pattern of NPC cells. This study found that ASRGL1 was mainly expressed in fibroblasts, epithelial cells and myeloid cells in nasopharyngeal carcinoma (NPC). The ASRGL1-cell gene was significantly enriched in the epithelial-mesenchymal transition pathway. Knocking down ASRGL1 can further inhibit the proliferation, invasion and EMT of C666–1 cells. At the same time, the utilization of various amino acids was significantly reduced, and further GC-MS metabolomics analysis showed that the cell metabolism was unbalanced. This study elucidates the expression characteristics and potential functional roles of asparaginase-like protein 1 (ASRGL1) in nasopharyngeal carcinoma (NPC), providing new insights into its potential as a diagnostic marker and therapeutic target.</div></div>","PeriodicalId":50335,"journal":{"name":"International Journal of Biochemistry & Cell Biology","volume":"185 ","pages":"Article 106788"},"PeriodicalIF":3.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143922373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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