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Headpin: a serpin with endogenous and exogenous suppression of angiogenesis
Thomas D Shellenberger1, Abhijit Mazumdar, Ying Henderson
1Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, 77030, USA.
Abstract:
Headpin is a novel serine proteinase inhibitor (serpin) with constitutive mRNA expression in histologically normal oral mucosa but with lost or down-regulated expression in head and neck squamous cell carcinoma. Several serpin family members are similarly lost in multiple cancer types and hold tumor suppressor functions including the inhibition of angiogenesis. However, the functional significance for the loss of headpin expression in cancer is not known. Using immunohistochemical analysis of invasive squamous cell carcinoma and matched normal squamous mucosa of patient specimens, headpin expression was lost or down-regulated in the vast majority of tumor specimens. We investigated the functions of exogenous recombinant headpin and endogenously expressed headpin related to angiogenesis. In a rat corneal assay of neovascularization, recombinant headpin protein blocked in vivo angiogenesis mediated by interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF). In assays of cellular events in angiogenesis, headpin blocked the invasion, migration, and tube formation of endothelial cells. In light of our findings of nuclear subcellular localization of headpin, we investigated the expression and secretion of angiogenic factors and found reduced mRNA, protein, and promoter activities of IL-8 and VEGF. Finally, using a murine flank tumor model, headpin expression reduced growth and microvessel density in tumors derived from headpin-expressing UMSCC1 cells relative to those from vector control cells. These findings of nuclear regulatory functions of a serpin in the inhibition of angiogenesis bring new understanding to the cellular and molecular mechanisms of serpins. Therefore, this novel serpin targets diverse mechanisms against tumor angiogenesis on which to base therapeutic strategies.
Insights
Headpin, a novel serine proteinase inhibitor (serpin), is downregulated in head and neck cancers. Its expression inhibits tumor angiogenesis by blocking endothelial cell invasion and reducing key growth factors like IL-8 and VEGF.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Headpin is a novel serine proteinase inhibitor (serpin) with reduced expression in head and neck squamous cell carcinoma.
- Serpins often function as tumor suppressors, inhibiting processes like angiogenesis.
- The role of headpin loss in cancer development and its impact on angiogenesis remain unclear.
Purpose of the Study:
- To investigate the functional significance of headpin loss in head and neck squamous cell carcinoma.
- To determine headpin's role in regulating angiogenesis and tumor growth.
- To explore headpin's potential as a therapeutic target against tumor angiogenesis.
Main Methods:
- Immunohistochemical analysis of headpin expression in patient tumor specimens.
- In vivo angiogenesis assays using recombinant headpin protein in a rat corneal model.
- In vitro assays assessing endothelial cell invasion, migration, and tube formation.
- Analysis of IL-8 and VEGF expression, secretion, and promoter activity.
- In vivo tumor growth and microvessel density assessment in a murine flank tumor model.
Main Results:
- Headpin expression was significantly lost or downregulated in most head and neck squamous cell carcinoma specimens compared to normal tissue.
- Recombinant headpin inhibited in vivo angiogenesis and key cellular events of angiogenesis, including endothelial cell invasion, migration, and tube formation.
- Headpin expression reduced mRNA, protein levels, and promoter activity of pro-angiogenic factors IL-8 and VEGF.
- Tumor growth and microvessel density were reduced in a murine model when headpin was expressed.
Conclusions:
- Headpin acts as a novel inhibitor of tumor angiogenesis through multiple mechanisms, including nuclear regulation of angiogenic factors.
- The loss of headpin expression in cancer contributes to tumor angiogenesis and growth.
- Headpin represents a potential therapeutic target for developing anti-angiogenic strategies in cancer treatment.
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