2. Academic Validation
  3. Hyperglycemia accelerated the metastasis of triple-negative breast cancer via promoting TNFα/Gli-1 axis in endothelial cells

Hyperglycemia accelerated the metastasis of triple-negative breast cancer via promoting TNFα/Gli-1 axis in endothelial cells

  • Biochim Biophys Acta Gen Subj. 2026 Jan;1870(1):130875. doi: 10.1016/j.bbagen.2025.130875.
Xiyu Mei 1,  Chuang Ke 2,  Ziyun Gao 3,  Fan Yang 2,  Zhenlin Huang 2,  Bin Lu 4,  Lili Ji 2
Affiliations

Affiliations

  • 1 Key Laboratory of Pharmacodynamic Material Basis Research in Chinese Medicine of Zhejiang Province, Institute of Basic Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou 310007, China; The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: [email protected].
  • 2 The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 3 School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou 310007, Zhejiang, China.
  • 4 The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: [email protected].
PMID: 41183624 DOI: 10.1016/j.bbagen.2025.130875
Abstract

Diabetes mellitus (DM) is associated with a poor prognosis of aggressive breast Cancer. Vascular dysfunction is commonly found during the development of both Cancer and diabetes. We previously reported that the disruption of vascular endothelial phenotype induced by tumor necrosis factor-α (TNFα) accelerated the trans-endothelial metastasis of triple-negative breast Cancer (TNBC). Herein, we explored the role of vascular endothelial cells in diabetes-induced TNBC metastasis. Both type 2 DM (T2DM) and type 1 DM (T1DM) enhanced the metastasis of TNBC in vivo. T2DM increased the expression of endothelial phenotype vascular endothelial Cadherin (VE-cadherin), platelet-endothelial cell adhesion molecule (PECAM-1/CD31), and mesenchymal markers including vimentin and fibroblast specific protein-1 (FSP-1/S100A4) in tumor vessels. T1DM increased the expression of vimentin and FSP-1, but suppressed the expression of VE-cadherin in tumor vessels. Hyperglycemia elevated the production of TNFα in vivo and in vitro. TNFα reduced the trans-endothelial electrical resistance (TEER) value of both human mammary microvascular endothelial cells (HMMECs) and human umbilical vein endothelial cells (HUVECs). Expressions of vimentin and α-smooth muscle actin (α-SMA) were also increased in TNFα-treated both HMMECs and HUVECs. The number of trans-endothelial migrated MDA-MB-231 cells through TNFα-treated HMMECs or HUVECs monolayer was elevated. Moreover, glioma-associated oncogene 1 (Gli-1) was remarkably accumulated in the nucleus of TNFα-stimulated HMMECs and DM-induced tumor vessels. Both Gli-1 siRNA and GANT61 (an inhibitor of Gli-1) could abrogate the increased TNBC trans-endothelial migration through TNFα-treated ECs. We demonstrated that DM might promote TNBC metastasis via activating the TNFα/Gli-1 axis initiated vascular endothelial mesenchymal-like phenotype.

Keywords

Diabetes mellitus; Endothelial cells; Gli-1; TNBC metastasis; TNFα.

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