PUBLICATION
HIF1α Counteracts TGFβ1-Driven TSP1 Expression in Endothelial Cells to Stimulate Angiogenesis in the Hypoxic Tumor Microenvironment
- Authors
- Luo, Y.W., Fang, Y., Zeng, H.X., Ji, Y.C., Wu, M.Z., Li, H., Chen, J.Y., Zheng, L.M., Fang, J.H., Zhuang, S.M.
- ID
- ZDB-PUB-241003-3
- Date
- 2024
- Source
- Cancer research 85(1): 69-83 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Humans
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Chick Embryo
- Zebrafish*
- Animals
- Carcinoma, Hepatocellular*/blood supply
- Carcinoma, Hepatocellular*/genetics
- Carcinoma, Hepatocellular*/metabolism
- Carcinoma, Hepatocellular*/pathology
- Signal Transduction
- Angiogenesis
- Mice
- Transforming Growth Factor beta1*/metabolism
- Liver Neoplasms*/blood supply
- Liver Neoplasms*/genetics
- Liver Neoplasms*/metabolism
- Liver Neoplasms*/pathology
- Thrombospondin 1*/genetics
- Thrombospondin 1*/metabolism
- Gene Expression Regulation, Neoplastic
- Cell Line, Tumor
- Neovascularization, Pathologic*/genetics
- Neovascularization, Pathologic*/metabolism
- Neovascularization, Pathologic*/pathology
- Mice, Nude
- Hypoxia-Inducible Factor 1, alpha Subunit*/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit*/metabolism
- Xenograft Model Antitumor Assays
- Tumor Microenvironment*
- Endothelial Cells*/metabolism
- Endothelial Cells*/pathology
- PubMed
- 39356626 Full text @ Cancer Res.
Citation
Luo, Y.W., Fang, Y., Zeng, H.X., Ji, Y.C., Wu, M.Z., Li, H., Chen, J.Y., Zheng, L.M., Fang, J.H., Zhuang, S.M. (2024) HIF1α Counteracts TGFβ1-Driven TSP1 Expression in Endothelial Cells to Stimulate Angiogenesis in the Hypoxic Tumor Microenvironment. Cancer research. 85(1):69-83.
Abstract
Emerging evidence suggests that transforming growth factor β1 (TGFβ1) can inhibit angiogenesis, contradicting the coexistence of active angiogenesis and high abundance of TGFβ1 in the tumor microenvironment. Here, we investigated how tumors overcome the anti-angiogenic effect of TGFβ1. TGFβ1 treatment suppressed physiological angiogenesis in chick chorioallantoic membrane and zebrafish models but did not affect angiogenesis in mouse hepatoma xenografts. The suppressive effect of TGFβ1 on angiogenesis was recovered in mouse xenografts by a hypoxia-inducible factor 1α (HIF1α) inhibitor. In contrast, a HIF1α stabilizer abrogated angiogenesis in zebrafish, indicating that hypoxia may attenuate the anti-angiogenic role of TGFβ1. Under normoxic conditions, TGFβ1 inhibited angiogenesis by upregulating anti-angiogenic factor thrombospondin 1 (TSP1) in endothelial cells (ECs) via TGFβ type I receptor (TGFβR1)-SMAD2/3 signaling. In a hypoxic microenvironment, HIF1α induced microRNA-145 (miR145) expression; miR145 abolished the inhibitory effect of TGFβ1 on angiogenesis by binding and repressing SMAD2/3 expression and subsequently reducing TSP1 levels in ECs. Primary ECs isolated from human hepatocellular carcinoma (HCC) displayed increased miR145 and decreased SMAD3 and TSP1 compared to ECs from adjacent non-tumor livers. The reduced SMAD3 or TSP1 in ECs was associated with increased angiogenesis in HCC tissues. Collectively, this study identified that TGFβ1-TGFβR1-SMAD2/3-TSP1 signaling in ECs inhibits angiogenesis. This inhibition can be circumvented by a hypoxia-HIF1α-miR145 axis, elucidating a mechanism by which hypoxia promotes angiogenesis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping