Biology Direct最新文献

{"title":"Single-cell RNA sequencing reveals the critical role of alternative splicing in cattle testicular spermatagonia.","authors":"Xiuge Wang, Chunhong Yang, Xiaochao Wei, Yaran Zhang, Yao Xiao, Jinpeng Wang, Qiang Jiang, Zhihua Ju, Yaping Gao, Yanqin Li, Yundong Gao, Jinming Huang","doi":"10.1186/s13062-024-00579-7","DOIUrl":"10.1186/s13062-024-00579-7","url":null,"abstract":"<p><p>Spermatogonial stem cells (SSCs) form haploid gametes through the precisely regulated process of spermatogenesis. Within the testis, SSCs undergo self-renewal through mitosis, differentiation, and then enter meiosis to generate mature spermatids. This study utilized single-cell RNA sequencing on 26,888 testicular cells obtained from five Holstein bull testes, revealing the presence of five distinct germ cell types and eight somatic cell types in cattle testes. Gene expression profiling and enrichment analysis were utilized to uncover the varied functional roles of different cell types involved in cattle spermatogenesis. Additionally, unique gene markers specific to each testicular cell type were identified. Moreover, differentially expressed genes in spermatogonia exhibited notable enrichment in GO terms and KEGG pathway linked to alternative splicing. Notably, our study has shown that the activity of the YY1 regulation displays distinct expression patterns in spermatogonia, specifically targeting spliceosome proteins including RBM39, HNRNPA2B1, HNRNPH3, CPSF1, PCBP1, SRRM1, and SRRM2, which play essential roles in mRNA splicing. These results emphasize the importance of mRNA processing in spermatogonia within cattle testes, providing a basis for further investigation into their involvement in spermatogonial development.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"145"},"PeriodicalIF":5.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892109","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":"Enhanced itaconic acid secretion from macrophages mediates the protection of mesenchymal stem cell-derived exosomes on lipopolysaccharide-induced acute lung injury mice.","authors":"Yanmei Wen, Zong'an Liang","doi":"10.1186/s13062-024-00586-8","DOIUrl":"10.1186/s13062-024-00586-8","url":null,"abstract":"<p><strong>Background: </strong>Alveolar macrophages (AMs) is critical to exacerbate acute lung injury (ALI) induced by lipopolysaccharide (LPS) via inhibiting inflammation, which could by shifted by mesenchymal stem cell-derived exosomes (MSC-exos). But the underlying rationale is not fully clarified. Our study aimed to analyze the significance of itaconic acid (ITA) in mediating the protective effects of MSC-exos on LPS-induced ALI.</p><p><strong>Methods: </strong>MSC-exos were used to treat pulmonary microvascular endothelial cells (PMVECs) co-cultured with AMs under LPS stimulation. si-IRG1 was transfected to AMs. PMVEC permeability, apoptosis rates, and inflammatory cytokine levels were assessed. In vivo, C57BL/6 wild-type (WT) and Irg1-/- mice were employed to explore the protection of MSC-exos against LPS-induced ALI. The lung injury was determined by histological and biochemical assays. ITA levels were measured using gas chromatography-mass spectrometry. Western blot and flow cytometry analyses were performed to assess M1/M2 polarization.</p><p><strong>Results: </strong>Co-culture with AMs significantly increased PMVEC permeability, apoptosis rates, IL-6, TNF-α levels and Claudin-5 and ZO-1 expression induced by LPS treatment, which were attenuated by MSC-exos accompanied by enhanced ITA level. After si-IRG1 transfection, MSC-exos' protective efficacy was reversed, with suppressed M2 polarization. In vivo, MSC-exos alleviated alveolar structure disruption, pulmonary edema, inflammation and increased ITA concentration in WT mice but had reduced effects in Irg1-/- mice, with neglected M2 polarization.</p><p><strong>Conclusions: </strong>ITA secretion facilitated the MSC-exos' protective benefits on LPS-induced PMVEC damage and ALI in mice by promoting AM M2 polarization, highlighting a potential therapeutic strategy for ALI and related inflammatory lung diseases.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"138"},"PeriodicalIF":5.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891626","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":"USP44 regulates HEXIM1 stability to inhibit tumorigenesis and metastasis of oral squamous cell carcinoma.","authors":"Shuai Chen, Kefan Wu, Yingrui Zong, Zhenzhen Hou, Zhifen Deng, Zongping Xia","doi":"10.1186/s13062-024-00573-z","DOIUrl":"10.1186/s13062-024-00573-z","url":null,"abstract":"<p><p>Oral squamous cell carcinoma (OSCC) is the most frequent type of oral malignancy with high metastasis and poor prognosis. The deubiquitinating enzyme Ubiquitin Specific Peptidase 44 (USP44) regulates the mitotic checkpoint, and its deficiency leads to aneuploidy and increases tumor incidence. However, the role of USP44 in OSCC is not well understood. Herein, we analyzed mRNA sequencing data of OSCC samples downloaded from the TCGA and GEO databases and found that USP44 was decreased in human OSCC tissues and was positively correlated to the survival of OSCC patients. To investigate the biological impact of USP44, we used recombinant lentiviruses to overexpress or knockdown USP44 expression in OSCC cell lines, which were also injected subcutaneously or into the lateral tail vein of Male BALB/c nude mice to model tumorigenesis or lung metastasis in vivo, respectively. The results showed that overexpression of USP44 inhibited malignant cell phenotypes in vitro and suppressed tumor growth and lung metastasis in vivo, while its downregulation had the opposite effects. Comprehensive proteomic analyses through Co-IP mass spectrometry and label-free quantitative LC-MS/MS methods identified 112 differentially expressed proteins positively regulated by USP44, among which 13 were involved in cancer-related pathways including apoptotic signaling and cell cycle regulation. PPI analysis identified Hexamethylene Bis-Acetamide-Inducible Protein 1 (HEXIM1) as the hub protein. Upregulation of USP44 enhanced HEXIM1 protein stability, leading to its higher expression in OSCC cells. Silencing of HEXIM1 further enhanced the malignant phenotype of OSCC cells. At the same time, HEXIM1 knockdown reversed the antitumor effects of USP44. These findings demonstrated that USP44 acted as a critical tumor suppressor in OSCC by inhibiting cell proliferation and metastasis through the stabilization of HEXIM1 protein, suggesting that USP44-HEXIM1 axis is a promising target for OSCC therapy.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"143"},"PeriodicalIF":5.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892070","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":"PTGES3 proteolysis using the liposomal peptide-PROTAC approach.","authors":"Shiwei Liu, Fukang Yuan, Hui Dong, Jiaqi Zhang, Xinyu Mao, Yangsui Liu, Huansong Li","doi":"10.1186/s13062-024-00580-0","DOIUrl":"10.1186/s13062-024-00580-0","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide, and the lack of effective biomarkers for early detection leads to poor therapeutic outcomes. Prostaglandin E Synthase 3 (PTGES3) is a putative prognostic marker in many solid tumors; however, its expression and biological functions in HCC have not been determined. The proteolysis-targeting chimera (PROTAC) is an established technology for targeted protein degradation. Compared to the small-molecule PROTAC, the peptide PROTAC (p-PROTAC) utilizes peptides bound to target proteins to mediate the ubiquitination and degradation of undruggable proteins. This study aimed to use the PROTAC technology to develop a PTGES3 degrader liposome complex containing a PTGES3-binding peptide and the E3 ubiquitin ligase ligand pomalidomide for regulating cell function and provide a novel pathway for treating HCC.</p><p><strong>Results: </strong>In this study, we demonstrated that PTGES3 is highly expressed in HCC at the transcriptional and protein levels; furthermore, PTGES3 was identified as a novel drug target that could potentially treat HCC. Hence, we developed PTGES3-PROTACs by adjusting the ligand ratio to optimize the efficacy of degradation agents. The results revealed that PTGES3-PROTAC effectively degraded PTGES3 protein and strongly weakened the HCC malignant phenotype in vitro and in vivo.</p><p><strong>Conclusions: </strong>Our findings revealed that the highly selective PTGES3 proteolysis is a potential therapeutic strategy for HCC, and PTGES3 degraders PTGES3-PROTACs can be developed as safe and effective drugs for HCC treatment.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"144"},"PeriodicalIF":5.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892103","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":"LINC01094 promotes gastric cancer through dual targeting of CDKN1A by directly binding RBMS2 and HDAC1.","authors":"Xinyi Zhou, Cheng Gu, Linmei Xiao, Li Hu, Guanhua Chen, Fei Zuo, Hongan Shao, Bojian Fei","doi":"10.1186/s13062-024-00582-y","DOIUrl":"10.1186/s13062-024-00582-y","url":null,"abstract":"<p><strong>Background: </strong>Accumulating studies have focused on long noncoding RNAs (lncRNAs) because of their regulatory effects on multiple cancers. However, the biological functions and molecular mechanisms of lncRNAs in gastric cancer (GC) remain to be elucidated in depth.</p><p><strong>Methods: </strong>Long intergenic nonprotein coding RNA 1094 (LINC01094), a differentially expressed lncRNA between GC tissues and adjacent normal tissues, was identified. Moreover, gain- and loss-of-function experiments in vitro and in vivo were carried out. To understand the mechanisms underlying the regulatory effects of LINC01094, we performed RNA pull-down assays, RNA immunoprecipitation assays, chromatin immunoprecipitation assays, luciferase reporter assays, etc. RESULTS: LINC01094 was markedly upregulated in GC tissues and cell lines, and LINC01094 upregulation was positively correlated with GC malignant behaviours in vitro and in vivo. Mechanistically, LINC01094 downregulated the expression of CDKN1A by interacting with RNA binding motif single stranded interacting protein 2 (RBMS2) and histone deacetylase 1 (HDAC1). Additionally, LINC01094 was confirmed to sponge miR-128-3p and participate in the LINC01094-miR-128-3p-RUNX family transcription factor 1 (RUNX1) feedback loop. Finally, Ro 5-3335, a validated RUNX1 inhibitor, was explored for anticancer drug development in GC.</p><p><strong>Conclusions: </strong>The LINC01094-miR-128-3p-RUNX1 feedback loop downregulates CDKN1A and promotes GC cooperatively with RBMS2 and HDAC1. Furthermore, Ro 5-3335 may hold promising therapeutic potential in the treatment of GC. Hence, our study found an oncogenic lncRNA, LINC01094, which could be a promising target for cancer treatment and diagnosis.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"137"},"PeriodicalIF":5.7,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11669238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885138","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":"Integrated Mendelian randomization and single-cell RNA-sequencing analyses identified OAS1 as a novel therapeutic target for erectile dysfunction via targeting fibroblasts.","authors":"Yi Wang, Guihua Chen, Deng Li","doi":"10.1186/s13062-024-00587-7","DOIUrl":"10.1186/s13062-024-00587-7","url":null,"abstract":"<p><p>Clinically, phosphodiesterase type 5 inhibitors (PDE5-Is) remain the first-line therapy for erectile dysfunction (ED) patients; however, approximately 35% of these patients are still failing to respond to the therapeutic effects. So, urgent needs are required to identify novel therapeutic targets for ED. Hence, in this report, it was the first time for us to integrate single-cell RNA-sequencing (scRNA-Seq), mendelian randomization (MR) analysis with expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) data to find new treatment targets for ED. Disease-causing changes were revealed by MR analysis, and it showed that the OAS1 eQTL/cis-eQTL/cis-pQTL was causally related to ED, significantly reducing its risks (all P < 0.05). Disease-induced changes were revealed by scRNA-Seq, and it suggested that OAS1 mainly played its role in ED via targeting fibroblasts. We further concluded that the positive regulation of OAS1 gene expression could lead to the vicious circle of ED. As a result, drugs targeting OAS1 in the future might provide more potential opportunities and flexibility for treating ED. In conclusion, our study identified OAS1 as a gene of interest in the context of ED via targeting fibroblasts through integrated MR and scRNA-Seq analyses. While these findings highlighted the potential of OAS1 as a therapeutic target, further experimental and clinical studies were still required to validate its functional role and therapeutic relevance in ED pathology.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"136"},"PeriodicalIF":5.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880896","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":"TFAP2C-mediated transcriptional activation of STEAP3 promotes lung squamous cell carcinoma progression by regulating the β-catenin pathway.","authors":"Tong Sun, Zhiguang Yang","doi":"10.1186/s13062-024-00584-w","DOIUrl":"10.1186/s13062-024-00584-w","url":null,"abstract":"<p><p>Six-transmembrane epithelial antigen of prostate 3 (STEAP3) is associated with the progression of several human malignancies. However, its role in lung squamous cell carcinoma (LUSC) remains unclear. We measured STEAP3 expression in LUSC cell lines and tissues. LUSC cells with stable STEAP3 overexpression and knockdown were obtained through G418 selection. Multiple assays were used to evaluate the malignant phenotypes of LUSC cells and the activation of the β-catenin signaling. The potential transcriptional regulatory factors of STEAP3 were predicted using the JASPAR database, and the correlation between transcription factor AP-2 gamma (TFAP2C) and STEAP3 was analyzed through the GEPIA database. The study evaluated the regulatory relationship between a potential transcription factor and STEAP3 through ChIP and luciferase reporter assays. Additionally, rescue assays were utilized to ascertain whether TFAP2C serves as the upstream regulatory factor of STEAP3, contributing to LUSC progression. Finally, tumor growth and metastasis were evaluated in vivo. STEAP3 expression was notably higher in LUSC, and its overexpression was linked to a poor prognosis. Moreover, STEAP3 overexpression activated the β-catenin pathway, thereby accelerating cell proliferation and metastasis. Conversely, STEAP3 knockdown had an anti-tumor effect in LUSC. Additionally, TFAP2C bound directly to the STEAP3 promoter and positively regulate its expression in LUSC. The anti-tumor effects of TFAP2C knockdown were partially reversed by STEAP3 overexpression. The study indicates that the TFAP2C/STEAP3 axis may be a therapeutic target for LUSC treatment. This enhances our understanding of lung carcinogenesis.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"135"},"PeriodicalIF":5.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881130","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 functional approach to homeostatic regulation.","authors":"Clemente F Arias, Francisco J Acosta, Federica Bertocchini, Cristina Fernández-Arias","doi":"10.1186/s13062-024-00577-9","DOIUrl":"10.1186/s13062-024-00577-9","url":null,"abstract":"<p><p>In this work, we present a novel modeling framework for understanding the dynamics of homeostatic regulation. Inspired by engineering control theory, this framework incorporates unique features of biological systems. First, biological variables often play physiological roles, and taking this functional context into consideration is essential to fully understand the goals and constraints of homeostatic regulation. Second, biological signals are not abstract variables, but rather material molecules that may undergo complex turnover processes of synthesis and degradation. We suggest that the particular nature of biological signals may condition the type of information they can convey, and their potential role in shaping the dynamics and the ultimate purpose of homeostatic systems. We show that the dynamic interplay between regulated variables and control signals is a key determinant of biological homeostasis, challenging the necessity and the convenience of strictly extrapolating concepts from engineering control theory in modeling the dynamics of homeostatic systems. This work provides a simple, unified framework for studying biological regulation and identifies general principles that transcend molecular details of particular homeostatic mechanisms. We show how this approach can be naturally applied to apparently different regulatory systems, contributing to a deeper understanding of homeostasis as a fundamental process in living systems.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"134"},"PeriodicalIF":5.7,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11663359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871339","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":"MLL1 promotes placental trophoblast ferroptosis and aggravates preeclampsia symptoms through epigenetic regulation of RBM15/TRIM72/ADAM9 axis.","authors":"Lingling Li, Haining He, Zhenrong Zheng, Xiaolan Zhao","doi":"10.1186/s13062-024-00572-0","DOIUrl":"10.1186/s13062-024-00572-0","url":null,"abstract":"<p><p>This study explores the epigenetic mechanism of MLL1 regulating trophoblast ferroptosis in preeclampsia (PE). A murine model of PE was established, and HTR-8/SVneo cells were induced by Erastin to establish an in vitro cell model. GSH, MDA, Fe²⁺, and ROS levels were measured to assess ferroptosis. MLL1, RBM15, TRIM72, ADMAM9, ASCL4, GPX4, and FTH1 expressions were detected by qRT-PCR or Western blot. ChIP analyzed H3K4me3 enrichment and MLL1 enrichment on RBM15 promoter. The binding of YTHDF2 or m6A to TRIM72 mRNA was determined by RIP. TRIM72 mRNA stability was detected after actinomycin D treatment. The binding of TRIM72 to ADAM9 and the ADAM9 ubiquitination level were detected by Co-IP. MLL1 was highly expressed in placental tissues of PE mice. Inhibition of MLL1 improved PE symptoms in mice, repressed ferroptosis in placental tissues, and inhibited Erastin-induced ferroptosis in vitro. MLL1 elevated RBM15 expression by increasing H3K4me3 on RBM15 promoter. RBM15 promoted the binding of TRIM72 to YTHDF2 by enhancing m6A modification on TRIM72 mRNA, thereby repressing TRIM72 expression. TRIM72 bound to ADAM9 and ubiquitinated it for degradation. In conclusion, MLL1 promotes placental trophoblast ferroptosis and aggravates PE symptoms via epigenetic regulation of RBM15/TRIM72/ADAM9 axis.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"133"},"PeriodicalIF":5.7,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11663353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871349","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":"Integrated machine learning reveals the role of tryptophan metabolism in clear cell renal cell carcinoma and its association with patient prognosis.","authors":"Fan Li, Haiyi Hu, Liyang Li, Lifeng Ding, Zeyi Lu, Xudong Mao, Ruyue Wang, Wenqin Luo, Yudong Lin, Yang Li, Xianjiong Chen, Ziwei Zhu, Yi Lu, Chenghao Zhou, Mingchao Wang, Liqun Xia, Gonghui Li, Lei Gao","doi":"10.1186/s13062-024-00576-w","DOIUrl":"10.1186/s13062-024-00576-w","url":null,"abstract":"<p><strong>Background: </strong>Precision oncology's implementation in clinical practice faces significant constraints due to the inadequacies in tools for detailed patient stratification and personalized treatment methodologies. Dysregulated tryptophan metabolism has emerged as a crucial factor in tumor progression, encompassing immune suppression, proliferation, metastasis, and metabolic reprogramming. However, its precise role in clear cell renal cell carcinoma (ccRCC) remains unclear, and predictive models or signatures based on tryptophan metabolism are conspicuously lacking.</p><p><strong>Methods: </strong>The influence of tryptophan metabolism on tumor cells was explored using single-cell RNA sequencing data. Genes involved in tryptophan metabolism were identified across both single-cell and bulk-cell dimensions through weighted gene co-expression network analysis (WGCNA) and its single-cell data variant (hdWGCNA). Subsequently, a tryptophan metabolism-related signature was developed using an integrated machine-learning approach. This signature was then examined in multi-omics data to assess its associations with patient clinical features, prognosis, cancer malignancy-related pathways, immune microenvironment, genomic characteristics, and responses to immunotherapy and targeted therapy. Finally, the genes within the signature were validated through experiments including qRT-PCR, Western blot, CCK8 assay, and transwell assay.</p><p><strong>Results: </strong>Dysregulated tryptophan metabolism was identified as a potential driver of the malignant transformation of normal epithelial cells. The tryptophan metabolism-related signature (TMRS) demonstrated robust predictive capability for overall survival (OS) and progression-free survival (PFS) across multiple datasets. Moreover, a high TMRS risk score correlated with increased tumor malignancy, significant metabolic reprogramming, an inflamed yet dysfunctional immune microenvironment, heightened genomic instability, resistance to immunotherapy, and increased sensitivity to certain targeted therapeutics. Experimental validation revealed differential expression of genes within the signature between RCC and adjacent normal tissues, with reduced expression of DDAH1 linked to enhanced proliferation and metastasis of tumor cells.</p><p><strong>Conclusion: </strong>This study investigated the potential impact of dysregulated tryptophan metabolism on clear cell renal cell carcinoma, leading to the development of a tryptophan metabolism-related signature that may provide insights into patient prognosis, tumor biological status, and personalized treatment strategies. This signature serves as a valuable reference for further exploring the role of tryptophan metabolism in renal cell carcinoma and for the development of clinical applications based on this metabolic pathway.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"19 1","pages":"132"},"PeriodicalIF":5.7,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871342","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}