Ask about this productRelated genes to: TWEAK protein
- Gene:
- TNFSF12 NIH gene
- Name:
- TNF superfamily member 12
- Previous symbol:
- -
- Synonyms:
- TWEAK, DR3LG, APO3L
- Chromosome:
- 17p13.1
- Locus Type:
- gene with protein product
- Date approved:
- 1998-12-04
- Date modifiied:
- 2019-04-23
Related products to: TWEAK protein
Related articles to: TWEAK protein
- Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with metastasis representing a major determinant of poor prognosis. Epithelial-mesenchymal transition (EMT) promotes metastatic progression by enhancing tumor cell migration and invasion. This study aimed to identify EMT-associated malignant epithelial programs in CRC and define the macrophage-tumor cell signaling mechanisms contributing to EMT and apoptosis resistance. We integrated single-cell RNA sequencing, bulk RNA-seq, spatial transcriptomics, immunohistochemistry, and functional validation experiments. Malignant epithelial subpopulations were identified using inferCNV and reclustering analyses, and EMT-related programs were evaluated by gene set scoring. Transcriptional regulation was assessed using pySCENIC, public ChIP-seq data, ChIP-qPCR, and TNFRSF12A promoter luciferase reporter assays. Cell-cell communication and ligand activity were analyzed using CellPhoneDB and NicheNet. Functional validation included western blotting, conditioned-medium assays, TNFSF12 neutralization, and Transwell migration assays. We identified an EMT-associated malignant epithelial subgroup enriched for TNFRSF12A expression. FOSL2 was highly active in this subgroup and positively associated with TNFRSF12A expression. ChIP-qPCR and promoter luciferase assays supported direct FOSL2-mediated transcriptional activation of TNFRSF12A. APOE+ macrophages were identified as a potential source of TNFSF12 in the tumor microenvironment. TNFSF12 acted on TNFRSF12A-expressing CRC cells and was associated with BCL2L1 upregulation, EMT-like changes, and enhanced migration. TNFSF12 overexpression increased BCL2L1 expression, whereas APOE+ macrophage-conditioned medium promoted E-cadherin downregulation, Vimentin and BCL2L1 upregulation, and tumor cell migration. These effects were attenuated by anti-TNFSF12 neutralization. Clinically, combined high TNFSF12 and TNFRSF12A expression was associated with advanced disease stage and poorer survival. Together, these findings identify a macrophage-tumor cell signaling axis in which FOSL2 upregulates TNFRSF12A in CRC cells, while APOE+ macrophage-derived TNFSF12 activates downstream BCL2L1-associated survival and EMT-related programs. The TNFSF12-TNFRSF12A-BCL2L1 pathway may represent a potential therapeutic vulnerability in metastatic CRC. NOVELTY AND IMPACT: This study identifies a previously undercharacterized macrophage-tumor cell signaling mechanism in colorectal cancer (CRC), in which APOE+ macrophage-derived TNFSF12 acts on TNFRSF12A-expressing malignant epithelial cells to promote EMT-associated progression. By integrating single-cell transcriptomics, bulk RNA-seq, spatial transcriptomics, and functional validation, we show that FOSL2 directly enhances TNFRSF12A transcription in EMT-associated tumor cells, thereby increasing their responsiveness to TNFSF12. Functionally, TNFSF12/TNFRSF12A signaling promotes BCL2L1-associated survival signaling, EMT-like changes, and tumor cell migration, while combined high TNFSF12 and TNFRSF12A expression is associated with advanced disease stage and poor patient survival. These findings reveal a clinically relevant macrophage-tumor cell communication axis and highlight the TNFSF12-TNFRSF12A-BCL2L1 pathway as a potential therapeutic vulnerability in metastatic CRC. - Source: PubMed
Publication date: 2026/05/20
Song ChuanjunSun HongyuGan WenyuanLiu QuanzhongWu LingxiangZhu MengyanZhu Lingjun - Vascular remodeling, a pathological hallmark of hypertensive target-organ damage, is critically modulated by autophagy. Given the emerging role of TWEAK (tumor necrosis factor-like weak inducer of apoptosis)/TWEAK receptor (TWEAKR) signaling in cardiovascular pathogenesis, this study investigates the relationship between TWEAK/TWEAKR and autophagy in hypertension-associated vascular remodeling. - Source: PubMed
Publication date: 2026/05/14
Lan QingsuHan WenqiangWang TianyuWang JinxiaoYao LinaDi MingxueDi Qin Selina HZhong JingquanHao Li - The causal relationship between milk consumption and a broad spectrum of health outcomes remains incompletely elucidated. This study aimed to investigate potential causal effects and explore the underlying biological pathways using an integrative multi-omics framework. We conducted a large-scale 2-sample Mendelian randomization study. Genetic predisposition for milk consumption was instrumented by the lactase persistence variant (rs4988235). We assessed causal relationships with 2459 disease phenotypes from FinnGen, and 91 inflammatory proteins, 211 gut microbial taxa, 731 immunophenotypes, and 1091 plasma metabolites. Genetically predicted higher milk consumption demonstrated robust effects on different disease outcomes. It was associated with a reduced risk of intestinal diseases, particularly colorectal cancer and its subtypes (all P <2.03 × 10-5) and a decreased risk of malnutrition (OR: 0.998, 95% confidence interval: 0.996-0.999, P = 6.02 × 10-8). Multi-omics analyses revealed nominally significant associations with specific gut microbes (e.g., Lactobacillus), inflammatory proteins (TNFSF12, CXCL5), immunophenotypes, and plasma metabolites (all P <.05). After false discovery rate correction, milk consumption significantly increased levels of N,N,N- trimethyl-5-aminovalerate (TMAVA, OR: 1.001, 95% confidence interval: 1.001-1.002, P = 5.74 × 10-5). This study provides genetic evidence supporting a potential causal relationship between milk consumption and health outcomes, exhibiting a strong protective role against intestinal diseases while also implicating potential pathways involving gut microbiota, host metabolism, and immune response. - Source: PubMed
Shao MingLu HanliZhang RuixiuZhang TaoYu Lingxiang - Heart failure (HF) is a critical condition characterized by the heart's inability to pump blood effectively, leading to significant morbidity and mortality. Inflammation and metabolic disturbances play key roles in its progression. This study is aimed at elucidating the causal relationships between inflammatory cytokines, metabolites, and HF using Mendelian randomization (MR). - Source: PubMed
Yao YanbingTang LinghuiZhou PeilinHuang FengZeng Zhiyu - Ligand-receptor (LR) signaling shapes immune dynamics and tumor behavior in nephrotic kidney disease. However, LR-based subtype classification and therapeutic prediction remain underexplored. - Source: PubMed
Publication date: 2026/04/22
Chen JieLin KunLi HaiYueJia LiangLiangNiu YanXia