Pub Date : 2024-09-06DOI: 10.1186/s13062-024-00519-5
Xiao-Mei Liu, Zi-Hao Wang, Qian-Xue Wei, Yang Song, Xiao-Xin Ma
Choriocarcinoma is a malignant cancer that belongs to gestational trophoblastic neoplasia (GTN). Herein, serum metabolomic analysis was performed on 29 GTN patients and 30 healthy individuals to characterize the metabolic variations during GTN progression. Ultimately 24 differential metabolites (DMs) were identified, of which, Equol was down-regulated in GTN patients, whose VIP score is the 3rd highest among the 24 DMs. As an intestinal metabolite of daidzein, the anticancer potential of Equol has been demonstrated in multiple cancers, but not choriocarcinoma. Hence, human choriocarcinoma cell lines JEG-3 and Bewo were used and JEG-3-derived subcutaneous xenograft models were developed to assess the effect of Equol on choriocarcinoma. The results suggested that Equol treatment effectively suppressed choriocarcinoma cell proliferation, induced cell apoptosis, and reduced tumorigenesis. Label-free quantitative proteomics showed that 136 proteins were significantly affected by Equol and 20 proteins were enriched in Gene Ontology terms linked to protein degradation. Tripartite motif containing 21 (TRIM21), a E3 ubiquitin ligase, was up-regulated by Equol. Equol-induced effects on choriocarcinoma cells could be reversed by TRIM21 inhibition. Annexin A2 (ANXA2) interacted with TRIM21 and its ubiquitination was modulated by TRIM21. We found that TRIM21 was responsible for proteasome-mediated degradation of ANXA2 induced by Equol, and the inhibitory effects of Equol on the malignant behaviors of choriocarcinoma cells were realized by TRIM21-mediated down-regulation of ANXA2. Moreover, β-catenin activation was inhibited by Equol, which also depended on TRIM21-mediated down-regulation of ANXA2. Taken together, Equol may be a novel candidate for the treatment for choriocarcinoma.
{"title":"Equol exerts anti-tumor effects on choriocarcinoma cells by promoting TRIM21-mediated ubiquitination of ANXA2.","authors":"Xiao-Mei Liu, Zi-Hao Wang, Qian-Xue Wei, Yang Song, Xiao-Xin Ma","doi":"10.1186/s13062-024-00519-5","DOIUrl":"10.1186/s13062-024-00519-5","url":null,"abstract":"<p><p>Choriocarcinoma is a malignant cancer that belongs to gestational trophoblastic neoplasia (GTN). Herein, serum metabolomic analysis was performed on 29 GTN patients and 30 healthy individuals to characterize the metabolic variations during GTN progression. Ultimately 24 differential metabolites (DMs) were identified, of which, Equol was down-regulated in GTN patients, whose VIP score is the 3rd highest among the 24 DMs. As an intestinal metabolite of daidzein, the anticancer potential of Equol has been demonstrated in multiple cancers, but not choriocarcinoma. Hence, human choriocarcinoma cell lines JEG-3 and Bewo were used and JEG-3-derived subcutaneous xenograft models were developed to assess the effect of Equol on choriocarcinoma. The results suggested that Equol treatment effectively suppressed choriocarcinoma cell proliferation, induced cell apoptosis, and reduced tumorigenesis. Label-free quantitative proteomics showed that 136 proteins were significantly affected by Equol and 20 proteins were enriched in Gene Ontology terms linked to protein degradation. Tripartite motif containing 21 (TRIM21), a E3 ubiquitin ligase, was up-regulated by Equol. Equol-induced effects on choriocarcinoma cells could be reversed by TRIM21 inhibition. Annexin A2 (ANXA2) interacted with TRIM21 and its ubiquitination was modulated by TRIM21. We found that TRIM21 was responsible for proteasome-mediated degradation of ANXA2 induced by Equol, and the inhibitory effects of Equol on the malignant behaviors of choriocarcinoma cells were realized by TRIM21-mediated down-regulation of ANXA2. Moreover, β-catenin activation was inhibited by Equol, which also depended on TRIM21-mediated down-regulation of ANXA2. Taken together, Equol may be a novel candidate for the treatment for choriocarcinoma.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"78"},"PeriodicalIF":5.7,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145136","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}
Pub Date : 2024-09-05DOI: 10.1186/s13062-024-00524-8
Yuanwen Peng, Jun Liu, Lili Sun, Qiuying Zheng, Can Cao, Wenyong Ding, Shufeng Yang, Li Ma, Wenli Zhang
Background: GALNTs (UDP-GalNAc; polypeptide N-acetylgalactosaminyltransferases) initiate mucin-type O-GalNAc glycosylation by adding N-GalNAc to protein serine/threonine residues. Abnormalities in O-GalNAc glycosylation are involved in various disorders such as Parkinson's disease (PD), a neurodegenerative disorder. GALNT9 is potentially downregulated in PD patients.
Methods: To determine whether GALNT9 enrichment ameliorates cytotoxicity related to PD-like variations, a pcDNA3.1-GALNT9 plasmid was constructed and transfected into SH-SY5Y cells to establish a GALNT9-overexpressing cell model.
Results: Downregulation of GALNT9 and O-GalNAc glycosylation was confirmed in our animal and cellular models of PD-like variations. GALNT9 supplementation greatly attenuated cytotoxicity induced by MPP+ (1-Methyl-4-phenylpyridinium iodide) since it led to increased levels of tyrosine hydroxylase and dopamine, reduced rates of apoptosis, and significantly ameliorated MPP+-induced mitochondrial dysfunction by alleviating abnormal levels of mitochondrial membrane potential and reactive oxygen species. A long-lasting mPTP (mitochondrial permeability transition pores) opening and calcium efflux resulted in significantly lower activity in the cytochrome C-associated apoptotic pathway and mitophagy process, signifying that GALNT9 supplementation maintained neuronal cell health under MPP+ exposure. Additionally, it was found that glycans linked to proteins influenced the formation of protein aggregates containing α-synuclein, and GALNT9 supplement dramatically reduced such insoluble protein aggregations under MPP+ treatment. Glial GALNT9 predominantly appears under pathological conditions like PD-like variations.
Conclusions: GALNT9 enrichment improved cell survival, and glial GALNT9 potentially represents a pathogenic index for PD patients. This study provides insights into the development of therapeutic strategies for the treatment of PD.
{"title":"GALNT9 enrichment attenuates MPP<sup>+</sup>-induced cytotoxicity by ameliorating protein aggregations containing α-synuclein and mitochondrial dysfunction.","authors":"Yuanwen Peng, Jun Liu, Lili Sun, Qiuying Zheng, Can Cao, Wenyong Ding, Shufeng Yang, Li Ma, Wenli Zhang","doi":"10.1186/s13062-024-00524-8","DOIUrl":"10.1186/s13062-024-00524-8","url":null,"abstract":"<p><strong>Background: </strong>GALNTs (UDP-GalNAc; polypeptide N-acetylgalactosaminyltransferases) initiate mucin-type O-GalNAc glycosylation by adding N-GalNAc to protein serine/threonine residues. Abnormalities in O-GalNAc glycosylation are involved in various disorders such as Parkinson's disease (PD), a neurodegenerative disorder. GALNT9 is potentially downregulated in PD patients.</p><p><strong>Methods: </strong>To determine whether GALNT9 enrichment ameliorates cytotoxicity related to PD-like variations, a pcDNA3.1-GALNT9 plasmid was constructed and transfected into SH-SY5Y cells to establish a GALNT9-overexpressing cell model.</p><p><strong>Results: </strong>Downregulation of GALNT9 and O-GalNAc glycosylation was confirmed in our animal and cellular models of PD-like variations. GALNT9 supplementation greatly attenuated cytotoxicity induced by MPP<sup>+</sup> (1-Methyl-4-phenylpyridinium iodide) since it led to increased levels of tyrosine hydroxylase and dopamine, reduced rates of apoptosis, and significantly ameliorated MPP<sup>+</sup>-induced mitochondrial dysfunction by alleviating abnormal levels of mitochondrial membrane potential and reactive oxygen species. A long-lasting mPTP (mitochondrial permeability transition pores) opening and calcium efflux resulted in significantly lower activity in the cytochrome C-associated apoptotic pathway and mitophagy process, signifying that GALNT9 supplementation maintained neuronal cell health under MPP<sup>+</sup> exposure. Additionally, it was found that glycans linked to proteins influenced the formation of protein aggregates containing α-synuclein, and GALNT9 supplement dramatically reduced such insoluble protein aggregations under MPP<sup>+</sup> treatment. Glial GALNT9 predominantly appears under pathological conditions like PD-like variations.</p><p><strong>Conclusions: </strong>GALNT9 enrichment improved cell survival, and glial GALNT9 potentially represents a pathogenic index for PD patients. This study provides insights into the development of therapeutic strategies for the treatment of PD.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"77"},"PeriodicalIF":5.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139269","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}
Pub Date : 2024-09-05DOI: 10.1186/s13062-024-00522-w
Dong Guo, Yang Dong, Hongbin Li, Hongwei Li, Bo Yang
Moyamoya disease, characterized by basal cerebral artery obstruction, was studied for differential protein expression to elucidate its pathogenesis. Proteomic analysis of cerebrospinal fluid from 10 patients, categorized by postoperative angiography into good and poor prognosis groups, revealed 46 differentially expressed proteins. Notably, cadherin 18 (CDH18) was the most significantly upregulated in the good prognosis group. In addition, the expression of cadherin 18 (CDH18) and phenotypic transformation-related proteins were measured by qRT-PCR and western blot. The effects of CDH18 in vascular smooth muscle cells were detected by CCK-8, EdU, transwell and wound healing assays. The overexpression of CDH18 in vascular smooth muscle cells (VSMCs) was found to inhibit proliferation, migration, and phenotypic transformation. These findings suggest CDH18 as a potential therapeutic target in moyamoya disease.
研究人员对以大脑基底动脉阻塞为特征的莫亚莫亚病进行了蛋白质差异表达研究,以阐明其发病机制。根据术后血管造影术将 10 名患者分为预后良好组和预后不良组,对这些患者的脑脊液进行的蛋白质组学分析发现了 46 种不同表达的蛋白质。值得注意的是,在预后良好组中,粘连蛋白 18(CDH18)的上调最为显著。此外,还通过 qRT-PCR 和 Western blot 检测了粘连蛋白 18(CDH18)和表型转化相关蛋白的表达。CDH18对血管平滑肌细胞的影响通过CCK-8、EdU、transwell和伤口愈合实验进行了检测。在血管平滑肌细胞(VSMCs)中过表达 CDH18 可抑制其增殖、迁移和表型转化。这些发现表明 CDH18 是治疗 moyamoya 病的潜在靶点。
{"title":"Proteomics and digital subtraction angiography approaches reveal CDH18 as a potential target for therapy of moyamoya disease.","authors":"Dong Guo, Yang Dong, Hongbin Li, Hongwei Li, Bo Yang","doi":"10.1186/s13062-024-00522-w","DOIUrl":"10.1186/s13062-024-00522-w","url":null,"abstract":"<p><p>Moyamoya disease, characterized by basal cerebral artery obstruction, was studied for differential protein expression to elucidate its pathogenesis. Proteomic analysis of cerebrospinal fluid from 10 patients, categorized by postoperative angiography into good and poor prognosis groups, revealed 46 differentially expressed proteins. Notably, cadherin 18 (CDH18) was the most significantly upregulated in the good prognosis group. In addition, the expression of cadherin 18 (CDH18) and phenotypic transformation-related proteins were measured by qRT-PCR and western blot. The effects of CDH18 in vascular smooth muscle cells were detected by CCK-8, EdU, transwell and wound healing assays. The overexpression of CDH18 in vascular smooth muscle cells (VSMCs) was found to inhibit proliferation, migration, and phenotypic transformation. These findings suggest CDH18 as a potential therapeutic target in moyamoya disease.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"76"},"PeriodicalIF":5.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139270","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}
Pub Date : 2024-08-29DOI: 10.1186/s13062-024-00509-7
Xu Wang, Tianjiao Sun, Jiapeng Fan, Xueliang Zuo, Jiading Mao
Gastrin is a gastrointestinal peptide hormone that plays an important role in the progression of colorectal cancer (CRC). However, the molecular mechanism remains unclear. In this study, we identified gastrin-related circRNAs via high-throughput sequencing and selected circRNA_0017065 as the research focus. We further studied its specific role and molecular mechanism in the progression of CRC. Knockdown and overexpression of circRNA_0017065 were performed, and the biological function of circRNA_0017065 in CRC progression was studied via in vitro and in vivo functional experiments. The potential downstream target genes were subsequently identified via screening of databases and gene chip data. The expression of circRNA_0017065 in tumour tissues was significantly upregulated compared with that in adjacent normal tissues. In vitro and in vivo functional experiments revealed that the proliferation and migration of CRC cells were significantly suppressed after circRNA_0017065 knockdown, while apoptosis was promoted. After overexpression of circRNA_0017065, the proliferation and migration of CRC cells were significantly promoted, while apoptosis was inhibited. Mechanistic studies revealed that circRNA_0017065 can act as a sponge for miR-3174 and promote CRC progression via the miR-3174/RBFOX2 axis. In general, gastrin-related circRNA_0017065 plays a key role in the occurrence and development of CRC and is expected to be a potential molecular target for the treatment of CRC metastasis.
{"title":"Gastrin-related circRNA_0017065 promotes the proliferation and metastasis of colorectal cancer through the miR-3174/RBFOX2 axis.","authors":"Xu Wang, Tianjiao Sun, Jiapeng Fan, Xueliang Zuo, Jiading Mao","doi":"10.1186/s13062-024-00509-7","DOIUrl":"10.1186/s13062-024-00509-7","url":null,"abstract":"<p><p>Gastrin is a gastrointestinal peptide hormone that plays an important role in the progression of colorectal cancer (CRC). However, the molecular mechanism remains unclear. In this study, we identified gastrin-related circRNAs via high-throughput sequencing and selected circRNA_0017065 as the research focus. We further studied its specific role and molecular mechanism in the progression of CRC. Knockdown and overexpression of circRNA_0017065 were performed, and the biological function of circRNA_0017065 in CRC progression was studied via in vitro and in vivo functional experiments. The potential downstream target genes were subsequently identified via screening of databases and gene chip data. The expression of circRNA_0017065 in tumour tissues was significantly upregulated compared with that in adjacent normal tissues. In vitro and in vivo functional experiments revealed that the proliferation and migration of CRC cells were significantly suppressed after circRNA_0017065 knockdown, while apoptosis was promoted. After overexpression of circRNA_0017065, the proliferation and migration of CRC cells were significantly promoted, while apoptosis was inhibited. Mechanistic studies revealed that circRNA_0017065 can act as a sponge for miR-3174 and promote CRC progression via the miR-3174/RBFOX2 axis. In general, gastrin-related circRNA_0017065 plays a key role in the occurrence and development of CRC and is expected to be a potential molecular target for the treatment of CRC metastasis.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"75"},"PeriodicalIF":5.7,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11360539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142092294","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}
Background: Excavation of key molecules can help identify therapeutic targets and improve the prognosis of pancreatic cancer. This study evaluated the roles of SUMO3 in cell viability, glycolysis, gemcitabine (GEM) sensitivity, and the antitumor activity of butyric acid (BA) in pancreatic cancer.
Methods: The mRNA and protein levels of SUMO3 were detected by qRT-PCR, Western blot, and immunohistochemical assay. SUMO3 was silenced or overexpressed in pancreatic cancer cells with or without Wnt/β-catenin pathway inhibitor, glycolysis inhibitor, GEM, or BA treatment. Cell viability was measured using the Cell Counting Kit-8 assay. Glycolysis was measured by determining the extracellular acidification rate, ATP level, and lactate content. Apoptosis was measured by flow cytometry, and TUNEL staining was used to examine in vitro and in vivo sensitivity to GEM chemotherapy. Luciferase reporter and chromatin immunoprecipitation assays were conducted to detect the binding of the SUMO3 promoter and NF-κB p65.
Results: SUMO3 was increased and associated with poor survival in pancreatic cancer. SUMO3 knockdown decreased cell viability and glycolysis in vitro and inhibited tumor growth in vivo. SUMO3 overexpression increased cell viability and glycolysis in vitro through the β-catenin pathway. SUMO3 knockdown increased GEM sensitivity, whereas SUMO3 overexpression decreased GEM sensitivity and inhibited the antitumor activity of BA. BA promoted histone acetylation and p-IκBα expression to inhibit NF-κB p65-mediated SUMO3 transcription.
Conclusion: SUMO3 acted as an active molecule in cell survival and growth by enhancing glycolysis in response to either GEM or BA. The mechanism was related to the constitutive IκBα/NF-κB/SUMO3/β-catenin signaling pathway.
{"title":"SUMO3 inhibition by butyric acid suppresses cell viability and glycolysis and promotes gemcitabine antitumor activity in pancreatic cancer.","authors":"Liming Zhu, Gang Chen, Changjing Huang, Huifeng Gao, Yilin Wang, Yehua Shen","doi":"10.1186/s13062-024-00513-x","DOIUrl":"10.1186/s13062-024-00513-x","url":null,"abstract":"<p><strong>Background: </strong>Excavation of key molecules can help identify therapeutic targets and improve the prognosis of pancreatic cancer. This study evaluated the roles of SUMO3 in cell viability, glycolysis, gemcitabine (GEM) sensitivity, and the antitumor activity of butyric acid (BA) in pancreatic cancer.</p><p><strong>Methods: </strong>The mRNA and protein levels of SUMO3 were detected by qRT-PCR, Western blot, and immunohistochemical assay. SUMO3 was silenced or overexpressed in pancreatic cancer cells with or without Wnt/β-catenin pathway inhibitor, glycolysis inhibitor, GEM, or BA treatment. Cell viability was measured using the Cell Counting Kit-8 assay. Glycolysis was measured by determining the extracellular acidification rate, ATP level, and lactate content. Apoptosis was measured by flow cytometry, and TUNEL staining was used to examine in vitro and in vivo sensitivity to GEM chemotherapy. Luciferase reporter and chromatin immunoprecipitation assays were conducted to detect the binding of the SUMO3 promoter and NF-κB p65.</p><p><strong>Results: </strong>SUMO3 was increased and associated with poor survival in pancreatic cancer. SUMO3 knockdown decreased cell viability and glycolysis in vitro and inhibited tumor growth in vivo. SUMO3 overexpression increased cell viability and glycolysis in vitro through the β-catenin pathway. SUMO3 knockdown increased GEM sensitivity, whereas SUMO3 overexpression decreased GEM sensitivity and inhibited the antitumor activity of BA. BA promoted histone acetylation and p-IκBα expression to inhibit NF-κB p65-mediated SUMO3 transcription.</p><p><strong>Conclusion: </strong>SUMO3 acted as an active molecule in cell survival and growth by enhancing glycolysis in response to either GEM or BA. The mechanism was related to the constitutive IκBα/NF-κB/SUMO3/β-catenin signaling pathway.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"74"},"PeriodicalIF":5.7,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11345958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055002","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}
Hematopoietic stem cells (HSCs) exhibit significant functional and metabolic alterations within the lung cancer microenvironment, contributing to tumor progression and immune evasion by increasing differentiation into myeloid-derived suppressor cells (MDSCs). Our aim is to analyze the metabolic transition of HSCs from glycolysis to oxidative phosphorylation (OXPHOS) in lung cancer and determine its effects on HSC functionality. Using a murine Lewis Lung Carcinoma lung cancer model, we conducted metabolic profiling of long-term and short-term HSCs, as well as multipotent progenitors, comparing their metabolic states in normal and cancer conditions. We measured glucose uptake using 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) and assessed levels of lactate, acetyl-coenzyme A, and ATP. Mitochondrial functionality was evaluated through flow cytometry, alongside the impact of the glucose metabolism inhibitor 2-DG on HSC differentiation and mitochondrial activity. HSCs under lung cancer conditions showed increased glucose uptake and lactate production, with an associated rise in OXPHOS activity, marking a metabolic shift. Treatment with 2-DG led to decreased T-HSCs and MDSCs and an increased red blood cell count, highlighting its potential to influence metabolic and differentiation pathways in HSCs. This study provides novel insights into the metabolic reprogramming of HSCs in lung cancer, emphasizing the critical shift from glycolysis to OXPHOS and its implications for the therapeutic targeting of cancer-related metabolic pathways.
造血干细胞(HSCs)在肺癌微环境中表现出显著的功能和代谢改变,通过增加分化成髓源性抑制细胞(MDSCs)来促进肿瘤进展和免疫逃避。我们的目的是分析肺癌中造血干细胞从糖酵解到氧化磷酸化(OXPHOS)的代谢转变,并确定其对造血干细胞功能的影响。我们利用小鼠路易斯肺癌肺癌模型,对长期和短期造血干细胞以及多能祖细胞进行了代谢分析,比较了它们在正常和癌症条件下的代谢状态。我们使用 2-[N-(7-硝基苯并-2-氧杂-1,3-二唑-4-基)氨基]-2-脱氧葡萄糖(2-NBDG)测量葡萄糖摄取量,并评估乳酸、乙酰辅酶 A 和 ATP 的水平。线粒体功能通过流式细胞术进行评估,同时还评估了葡萄糖代谢抑制剂2-DG对造血干细胞分化和线粒体活性的影响。肺癌条件下的造血干细胞显示出葡萄糖摄取和乳酸生成的增加,与之相关的是OXPHOS活性的上升,这标志着新陈代谢的转变。用2-DG处理后,T-造血干细胞和MDSCs减少,红细胞数量增加,这突显了2-DG影响造血干细胞代谢和分化途径的潜力。这项研究为肺癌造血干细胞的代谢重编程提供了新的见解,强调了从糖酵解到OXPHOS的关键转变及其对癌症相关代谢途径靶向治疗的影响。
{"title":"Reprogramming hematopoietic stem cell metabolism in lung cancer: glycolysis, oxidative phosphorylation, and the role of 2-DG.","authors":"Ziqi Guo, Yaping Liu, Xin Li, Yuying Huang, Zuping Zhou, Cheng Yang","doi":"10.1186/s13062-024-00514-w","DOIUrl":"10.1186/s13062-024-00514-w","url":null,"abstract":"<p><p>Hematopoietic stem cells (HSCs) exhibit significant functional and metabolic alterations within the lung cancer microenvironment, contributing to tumor progression and immune evasion by increasing differentiation into myeloid-derived suppressor cells (MDSCs). Our aim is to analyze the metabolic transition of HSCs from glycolysis to oxidative phosphorylation (OXPHOS) in lung cancer and determine its effects on HSC functionality. Using a murine Lewis Lung Carcinoma lung cancer model, we conducted metabolic profiling of long-term and short-term HSCs, as well as multipotent progenitors, comparing their metabolic states in normal and cancer conditions. We measured glucose uptake using 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) and assessed levels of lactate, acetyl-coenzyme A, and ATP. Mitochondrial functionality was evaluated through flow cytometry, alongside the impact of the glucose metabolism inhibitor 2-DG on HSC differentiation and mitochondrial activity. HSCs under lung cancer conditions showed increased glucose uptake and lactate production, with an associated rise in OXPHOS activity, marking a metabolic shift. Treatment with 2-DG led to decreased T-HSCs and MDSCs and an increased red blood cell count, highlighting its potential to influence metabolic and differentiation pathways in HSCs. This study provides novel insights into the metabolic reprogramming of HSCs in lung cancer, emphasizing the critical shift from glycolysis to OXPHOS and its implications for the therapeutic targeting of cancer-related metabolic pathways.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"73"},"PeriodicalIF":5.7,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11344923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054926","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}
Pub Date : 2024-08-22DOI: 10.1186/s13062-024-00517-7
Kangjie Xu, Dongling Li, Kangkang Ji, Yanhua Zhang, Minglei Zhang, Hai Zhou, Xuefeng Hou, Jian Jiang, Zihang Zhang, Hua Dai, Hang Sun
Background: Kidney renal clear cell carcinoma (KIRC) represents a significant proportion of renal cell carcinomas and is characterized by high aggressiveness and poor prognosis despite advancements in immunotherapy. Disulfidptosis, a novel cell death pathway, has emerged as a critical mechanism in various cellular processes, including cancer. This study leverages machine learning to identify disulfidptosis-related long noncoding RNAs (DRlncRNAs) as potential prognostic biomarkers in KIRC, offering new insights into tumor pathogenesis and treatment avenues.
Results: Our analysis of data from The Cancer Genome Atlas (TCGA) led to the identification of 431 DRlncRNAs correlated with disulfidptosis-related genes. Five key DRlncRNAs (SPINT1-AS1, AL161782.1, OVCH1-AS1, AC131009.3, and AC108673.3) were used to develop a prognostic model that effectively distinguished between low- and high-risk patients with significant differences in overall survival and progression-free survival. The low-risk group had a favorable prognosis associated with a protective immune microenvironment and a better response to targeted drugs. Conversely, the high-risk group displayed aggressive tumor features and poor immunotherapy outcomes. Validation through qRT‒PCR confirmed the differential expression of these DRlncRNAs in KIRC cells compared to normal kidney cells, underscoring their potential functional significance in tumor biology.
Conclusions: This study established a robust link between disulfidptosis-related lncRNAs and patient prognosis in KIRC, underscoring their potential as prognostic biomarkers and therapeutic targets. The differential expression of these lncRNAs in tumor versus normal tissue further highlights their relevance in KIRC pathogenesis. The predictive model not only enhances our understanding of KIRC biology but also provides a novel stratification tool for precision medicine approaches, improving treatment personalization and outcomes in KIRC patients.
{"title":"Disulfidptosis-associated LncRNA signature predicts prognosis and immune response in kidney renal clear cell carcinoma.","authors":"Kangjie Xu, Dongling Li, Kangkang Ji, Yanhua Zhang, Minglei Zhang, Hai Zhou, Xuefeng Hou, Jian Jiang, Zihang Zhang, Hua Dai, Hang Sun","doi":"10.1186/s13062-024-00517-7","DOIUrl":"10.1186/s13062-024-00517-7","url":null,"abstract":"<p><strong>Background: </strong>Kidney renal clear cell carcinoma (KIRC) represents a significant proportion of renal cell carcinomas and is characterized by high aggressiveness and poor prognosis despite advancements in immunotherapy. Disulfidptosis, a novel cell death pathway, has emerged as a critical mechanism in various cellular processes, including cancer. This study leverages machine learning to identify disulfidptosis-related long noncoding RNAs (DRlncRNAs) as potential prognostic biomarkers in KIRC, offering new insights into tumor pathogenesis and treatment avenues.</p><p><strong>Results: </strong>Our analysis of data from The Cancer Genome Atlas (TCGA) led to the identification of 431 DRlncRNAs correlated with disulfidptosis-related genes. Five key DRlncRNAs (SPINT1-AS1, AL161782.1, OVCH1-AS1, AC131009.3, and AC108673.3) were used to develop a prognostic model that effectively distinguished between low- and high-risk patients with significant differences in overall survival and progression-free survival. The low-risk group had a favorable prognosis associated with a protective immune microenvironment and a better response to targeted drugs. Conversely, the high-risk group displayed aggressive tumor features and poor immunotherapy outcomes. Validation through qRT‒PCR confirmed the differential expression of these DRlncRNAs in KIRC cells compared to normal kidney cells, underscoring their potential functional significance in tumor biology.</p><p><strong>Conclusions: </strong>This study established a robust link between disulfidptosis-related lncRNAs and patient prognosis in KIRC, underscoring their potential as prognostic biomarkers and therapeutic targets. The differential expression of these lncRNAs in tumor versus normal tissue further highlights their relevance in KIRC pathogenesis. The predictive model not only enhances our understanding of KIRC biology but also provides a novel stratification tool for precision medicine approaches, improving treatment personalization and outcomes in KIRC patients.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"71"},"PeriodicalIF":5.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035291","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}
Background: TSPAN7 is an important factor in tumor progression. However, the precise function of TSPAN7 and its role in pan-cancer are not clear.
Methods: Based on Xinhua cohort incorporating 370 patients with kidney neoplasm, we conducted differential expression analysis by immunohistochemistry between tumor and normal tissues, and explored correlations of TSPAN7 with patients' survival. Subsequently, we conducted a pan-cancer study, and successively employed differential expression analysis, competing endogenous RNA (ceRNA) analysis, protein-protein interaction (PPI) analysis, correlation analysis of TSPAN7 with clinical characteristics, tumor purity, tumor genomics, tumor immunity, and drug sensitivity. Last but not least, gene set enrichment analysis was applied to identify enriched pathways of TSPAN7.
Results: In Xinhua cohort, TSPAN7 expression was significantly up-regulated (P-value = 0.0019) in tumor tissues of kidney neoplasm patients. High TSPAN7 expression was associated with decreases in overall survival (OS) (P-value = 0.009) and progression-free survival (P-value = 0.009), and it was further revealed as an independent risk factor for OS (P-value = 0.0326, HR = 5.66, 95%CI = 1.155-27.8). In pan-cancer analysis, TSPAN7 expression was down-regulated in most tumors, and it was associated with patients' survival, tumor purity, tumor genomics, tumor immunity, and drug sensitivity. The ceRNA network and PPI network of TSPAN7 were also constructed. Last but not least, the top five enriched pathways of TSPAN7 in various tumors were identified.
Conclusion: TSPAN7 served as a promising biomarker of various tumors, especially kidney neoplasms, and it was closely associated with tumor purity, tumor genomics, tumor immunology, and drug sensitivity in pan-cancer level.
{"title":"Unveiling the unique role of TSPAN7 across tumors: a pan-cancer study incorporating retrospective clinical research and bioinformatic analysis.","authors":"Bingnan Lu, Yifan Liu, Yuntao Yao, Dawei Zhu, Xiangmin Zhang, Keqin Dong, Xiao Xu, Donghao Lv, Zihui Zhao, Haoyu Zhang, Xinyue Yang, Wenjia Fu, Runzhi Huang, Jianwei Cao, Jian Chu, Xiuwu Pan, Xingang Cui","doi":"10.1186/s13062-024-00516-8","DOIUrl":"10.1186/s13062-024-00516-8","url":null,"abstract":"<p><strong>Background: </strong>TSPAN7 is an important factor in tumor progression. However, the precise function of TSPAN7 and its role in pan-cancer are not clear.</p><p><strong>Methods: </strong>Based on Xinhua cohort incorporating 370 patients with kidney neoplasm, we conducted differential expression analysis by immunohistochemistry between tumor and normal tissues, and explored correlations of TSPAN7 with patients' survival. Subsequently, we conducted a pan-cancer study, and successively employed differential expression analysis, competing endogenous RNA (ceRNA) analysis, protein-protein interaction (PPI) analysis, correlation analysis of TSPAN7 with clinical characteristics, tumor purity, tumor genomics, tumor immunity, and drug sensitivity. Last but not least, gene set enrichment analysis was applied to identify enriched pathways of TSPAN7.</p><p><strong>Results: </strong>In Xinhua cohort, TSPAN7 expression was significantly up-regulated (P-value = 0.0019) in tumor tissues of kidney neoplasm patients. High TSPAN7 expression was associated with decreases in overall survival (OS) (P-value = 0.009) and progression-free survival (P-value = 0.009), and it was further revealed as an independent risk factor for OS (P-value = 0.0326, HR = 5.66, 95%CI = 1.155-27.8). In pan-cancer analysis, TSPAN7 expression was down-regulated in most tumors, and it was associated with patients' survival, tumor purity, tumor genomics, tumor immunity, and drug sensitivity. The ceRNA network and PPI network of TSPAN7 were also constructed. Last but not least, the top five enriched pathways of TSPAN7 in various tumors were identified.</p><p><strong>Conclusion: </strong>TSPAN7 served as a promising biomarker of various tumors, especially kidney neoplasms, and it was closely associated with tumor purity, tumor genomics, tumor immunology, and drug sensitivity in pan-cancer level.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"72"},"PeriodicalIF":5.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035292","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}
A substantive body of evidence has demonstrated the significant roles of circular RNA (circRNA) in cancer. However, the contribution of dysregulated circRNAs to ovarian cancer (OC) remains elusive. We aim to elucidate the critical roles and mechanisms of hsa_circ_0020093, which was demonstrated to be downregulated in OC tissues in our previous study. In this study, we confirmed the decreased expression of hsa_circ_0020093 in OC tissues and cell lines and demonstrated the negative correlation between its expression and FIGO stage, abdominal implantation and CA125 level of OC patients. Through gain and loss of function studies, we confirmed the inhibitory role of hsa_circ_0020093 in ovarian tumor growth in vitro and in vivo. Mechanistically, based on the peri-nuclear accumulation of hsa_circ_0020093, we discovered the interaction between hsa_circ_0020093 and the mitochondrial protein LRPPRC by RNA pull-down, mass spectrometry, RNA Binding Protein Immunoprecipitation. As a result, qRT-PCR and transmission electron microscopy results showed that the mitochondria mRNA expression and mitochondria abundance were decreased upon hsa_circ_0020093-overexpression. Meanwhile, we also unearthed the hsa_circ_0020093/miR-107/LATS2 axis in OC according to RNA-sequencing, RIP and luciferase reporter assay data. Furthermore, LRPPRC and LATS2 are both reported as the upstream regulators of YAP, our study also studied the crosstalk between hsa_circ_0020093, LRPPRC and miR-107/LATS2, and unearthed the up-regulation of phosphorylated YAP in hsa_circ_0020093-overexpressing OC cells and xenograft tumors. Collectively, our study indicated the novel mechanism of hsa_circ_0020093 in suppressing OC progression through both hsa_circ_0020093/LRPPRC and hsa_circ_0020093/miR-107/LATS2 axes, providing a potential therapeutic target for OC patients.
{"title":"hsa_circ_0020093 suppresses ovarian cancer progression by modulating LRPPRC activity and miR-107/LATS2 signaling.","authors":"Yu Sun, Xiyi Chen, Yaqian Shi, Fang Teng, Chencheng Dai, Lili Ge, Juan Xu, Xuemei Jia","doi":"10.1186/s13062-024-00520-y","DOIUrl":"10.1186/s13062-024-00520-y","url":null,"abstract":"<p><p>A substantive body of evidence has demonstrated the significant roles of circular RNA (circRNA) in cancer. However, the contribution of dysregulated circRNAs to ovarian cancer (OC) remains elusive. We aim to elucidate the critical roles and mechanisms of hsa_circ_0020093, which was demonstrated to be downregulated in OC tissues in our previous study. In this study, we confirmed the decreased expression of hsa_circ_0020093 in OC tissues and cell lines and demonstrated the negative correlation between its expression and FIGO stage, abdominal implantation and CA125 level of OC patients. Through gain and loss of function studies, we confirmed the inhibitory role of hsa_circ_0020093 in ovarian tumor growth in vitro and in vivo. Mechanistically, based on the peri-nuclear accumulation of hsa_circ_0020093, we discovered the interaction between hsa_circ_0020093 and the mitochondrial protein LRPPRC by RNA pull-down, mass spectrometry, RNA Binding Protein Immunoprecipitation. As a result, qRT-PCR and transmission electron microscopy results showed that the mitochondria mRNA expression and mitochondria abundance were decreased upon hsa_circ_0020093-overexpression. Meanwhile, we also unearthed the hsa_circ_0020093/miR-107/LATS2 axis in OC according to RNA-sequencing, RIP and luciferase reporter assay data. Furthermore, LRPPRC and LATS2 are both reported as the upstream regulators of YAP, our study also studied the crosstalk between hsa_circ_0020093, LRPPRC and miR-107/LATS2, and unearthed the up-regulation of phosphorylated YAP in hsa_circ_0020093-overexpressing OC cells and xenograft tumors. Collectively, our study indicated the novel mechanism of hsa_circ_0020093 in suppressing OC progression through both hsa_circ_0020093/LRPPRC and hsa_circ_0020093/miR-107/LATS2 axes, providing a potential therapeutic target for OC patients.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"69"},"PeriodicalIF":5.7,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11337591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008333","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}
Pub Date : 2024-08-21DOI: 10.1186/s13062-024-00508-8
Mina Ohadi, Masoud Arabfard, Safoura Khamse, Samira Alizadeh, Sara Vafadar, Hadi Bayat, Nahid Tajeddin, Ali M A Maddi, Ahmad Delbari, Hamid R Khorram Khorshid
Background: The recombination landscape and subsequent natural selection have vast consequences forevolution and speciation. However, most of the crossover and recombination hotspots are yet to be discovered. We previously reported the relevance of C and G trinucleotide two-repeat units (CG-TTUs) in crossovers and recombination.
Methods: On a genome-wide scale, here we mapped all combinations of A and T trinucleotide two-repeat units (AT-TTUs) in human, consisting of AATAAT, ATAATA, ATTATT, TTATTA, TATTAT, and TAATAA. We also compared a number of the colonies formed by the AT-TTUs (distance between consecutive AT-TTUs < 500 bp) in several other primates and mouse.
Results: We found that the majority of the AT-TTUs (> 96%) resided in approximately 1.4 million colonies, spread throughout the human genome. In comparison to the CG-TTU colonies, the AT-TTU colonies were significantly more abundant and larger in size. Pure units and overlapping units of the pure units were readily detectable in the same colonies, signifying that the units were the sites of unequal crossover. We discovered dynamic sharedness of several of the colonies across the primate species studied, which mainly reached maximum complexity and size in human.
Conclusions: We report novel crossover and recombination hotspots of the finest molecular resolution, massively spread and shared across the genomes of human and several other primates. With respect to crossovers and recombination, these genomes are far more dynamic than previously envisioned.
背景:重组景观和随后的自然选择对生物进化和物种繁衍具有重大影响。然而,大多数交叉和重组热点尚未被发现。我们以前曾报道过 C 和 G 三核苷酸双重复单位(CG-TTUs)在交叉和重组中的相关性:在全基因组范围内,我们绘制了人类中 A 和 T 三核苷酸双重复单位(AT-TTU)的所有组合,包括 AATAAT、ATAATA、ATTATT、TTATTA、TATTAT 和 TAATAA。我们还比较了 AT-TTU 形成的菌落数(连续 AT-TTU 之间的距离):我们发现,大部分 AT-TTU (> 96%)分布在约 140 万个菌落中,遍布整个人类基因组。与 CG-TTU 群体相比,AT-TTU 群体明显更多,规模也更大。在同一菌落中很容易检测到纯合单元和纯合单元的重叠单元,这表明这些单元是不平等交叉的位点。我们发现,在所研究的灵长类物种中,有几个菌落具有动态共享性,主要是在人类中达到了最大的复杂性和规模:我们报告了具有最精细分子分辨率的新型交叉和重组热点,它们在人类和其他几种灵长类动物的基因组中大规模分布和共享。在交叉和重组方面,这些基因组的动态性远远超过了之前的设想。
{"title":"Novel crossover and recombination hotspots massively spread across primate genomes.","authors":"Mina Ohadi, Masoud Arabfard, Safoura Khamse, Samira Alizadeh, Sara Vafadar, Hadi Bayat, Nahid Tajeddin, Ali M A Maddi, Ahmad Delbari, Hamid R Khorram Khorshid","doi":"10.1186/s13062-024-00508-8","DOIUrl":"10.1186/s13062-024-00508-8","url":null,"abstract":"<p><strong>Background: </strong>The recombination landscape and subsequent natural selection have vast consequences forevolution and speciation. However, most of the crossover and recombination hotspots are yet to be discovered. We previously reported the relevance of C and G trinucleotide two-repeat units (CG-TTUs) in crossovers and recombination.</p><p><strong>Methods: </strong>On a genome-wide scale, here we mapped all combinations of A and T trinucleotide two-repeat units (AT-TTUs) in human, consisting of AATAAT, ATAATA, ATTATT, TTATTA, TATTAT, and TAATAA. We also compared a number of the colonies formed by the AT-TTUs (distance between consecutive AT-TTUs < 500 bp) in several other primates and mouse.</p><p><strong>Results: </strong>We found that the majority of the AT-TTUs (> 96%) resided in approximately 1.4 million colonies, spread throughout the human genome. In comparison to the CG-TTU colonies, the AT-TTU colonies were significantly more abundant and larger in size. Pure units and overlapping units of the pure units were readily detectable in the same colonies, signifying that the units were the sites of unequal crossover. We discovered dynamic sharedness of several of the colonies across the primate species studied, which mainly reached maximum complexity and size in human.</p><p><strong>Conclusions: </strong>We report novel crossover and recombination hotspots of the finest molecular resolution, massively spread and shared across the genomes of human and several other primates. With respect to crossovers and recombination, these genomes are far more dynamic than previously envisioned.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"70"},"PeriodicalIF":5.7,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016341","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}