ABSTRACT
KEY POINTS: Angiopoietin-like 4 (ANGPTL4) modulates tendon neovascularization. Cyclic loading stimulates the activity of transforming growth factor-ß and hypoxia-inducible factor 1α and thereby increases the expression and release of ANGPTL4 from human tendon cells. Targeting ANGPTL4 and its regulatory pathways is a potential avenue for regulating tendon vascularization to improve tendon healing or adaptation. ABSTRACT: The mechanisms that regulate angiogenic activity in injured or mechanically loaded tendons are poorly understood. The present study examined the potential role of angiopoietin-like 4 (ANGPTL4) in the angiogenic response of tendons subjected to repetitive mechanical loading or injury. Cyclic stretching of human tendon fibroblasts stimulated the expression and release of ANGPTL4 protein via transforming growth factor-ß (TGF-ß) and hypoxia-inducible factor 1α (HIF-1α) signalling, and the released ANGPTL4 was pro-angiogenic. Angiogenic activity was increased following ANGPTL4 injection into mouse patellar tendons, whereas the patellar tendons of ANGPTL4 knockout mice displayed reduced angiogenesis following injury. In human rotator cuff tendons, the expression of ANGPTL4 was correlated with the density of tendon endothelial cells. To our knowledge, this is the first study characterizing a role of ANGPTL4 in the tendon. ANGPTL4 may assist in the regulation of vascularity in the injured or mechanically loaded tendon. TGF-ß and HIF-1α comprise two signalling pathways that modulate the expression of ANGPTL4 by mechanically stimulated tendon fibroblasts and, in the future, these could be manipulated to influence tendon healing or adaptation.
Subject(s)
Angiopoietins/biosynthesis , Fibroblasts/metabolism , Neovascularization, Physiologic/physiology , Tendons/metabolism , Weight-Bearing/physiology , Amino Acids, Dicarboxylic/pharmacology , Angiopoietin-Like Protein 4 , Animals , Cells, Cultured , Dose-Response Relationship, Drug , Fibroblasts/drug effects , HeLa Cells , Human Umbilical Vein Endothelial Cells , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Neovascularization, Physiologic/drug effects , Tendons/drug effectsABSTRACT
Human cutaneous melanoma is a devastating skin cancer because of its invasive nature and high metastatic potential. We used tissue microarray to study the role of human eukaryotic translation initiation factor 4E (eIF4E) in melanoma progression in 448 melanocytic lesions and found that high eIF4E expression was significantly increased in primary melanomas compared with dysplastic nevi (P<0.001), and further increased in metastatic melanomas (P<0.001). High eIF4E expression was associated with melanoma thickness (P=0.046), and poor overall and disease-specific 5-year survival of all, and primary melanoma patients, especially those with tumors ≥1 mm thick. Multivariate Cox regression analysis revealed that eIF4E is an independent prognostic marker. eIF4E knockdown (KD) in melanoma cells resulted in a significant increase in apoptosis (sub-G1 populations) and decrease in cell proliferation, and also resulted in downregulation of mesenchymal markers and upregulation of E-cadherin. In addition, eIF4E KD led to a decrease in melanoma cell invasion, matrix metalloproteinase-2 expression and activity, c-myc and BCL2 expression, and an increase in cleaved PARP and cleaved caspase-3 expression and chemosensitivity. Taken together, our data suggest that the eIF4E may promote melanoma cell invasion and metastasis, and may also serve as a promising prognostic marker and a potential therapeutic target for melanoma.
