Headpin: A Serpin with Endogenous and Exogenous Suppression of Angiogenesis

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 downregulated 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. (Cancer Res 2005; 65(24): 11501-9)

Blocking the Wnt pathway, a unifying mechanism for an angiogenic inhibitor in the serine proteinase inhibitor family

“…A number of serpin members have been identified as endogenous angiogenic inhibitors (20)(21)(22)(23). Some of these serpin angiogenic inhibitors have also displayed anti-inflammatory activities (38).…”

“…However, a number of natural antiangiogenic factors or angiogenic inhibitors have been identified (18). The identified angiogenic inhibitors include several serine proteinase inhibitors (SERPIN), such as pigment epithelium-derived factor (PEDF), α1-antitrypsin (AAT), maspin, SERPINA3K, and headpin (19)(20)(21)(22)(23)(24)(25).…”

Development of a survival prediction model for gastric cancer using serine proteases and their inhibitors

“…Most serpins act as inhibitors of chymotrypsin-like SPs, others as cross-class serine protease inhibitors of papain-like cysteine proteases and caspases (10)(11)(12)(13). Certain serpins have been identified to be involved in the progression of malignant tumor; these include SERPINB3 and SERPINB4 in squamous cell carcinoma (14,15), SERPINB5 in human breast cancer (16), SERPINB13 in head and neck squamous cell carcinoma (17), SERPINH1 in head and neck carcinomas (18), SERPINI2 in breast cancer (19), SERPINB2 and SERPINE1 in breast cancer and other cancers (20), and SERPINB2, SERPINB3, SERPINB4, SERPINB7, SERPINB11, SERPINB12 and SERPINB13 in oral squamous cell carcinoma (21).…”

Down-regulated expression of SERPIN genes located on chromosome 18q21 in oral squamous cell carcinomas

“…In oral carcinoma, Xia et al suggested that higher SERPINB5 expression was significantly associated with better overall survival (11). Furthermore, down-regulated expression of the SERPINB13 (headpin/ hurpin) gene has been demonstrated in head and neck malignancies (12)(13)(14). Both SERPINB5 and SERPINB13 genes are located on chromosome 18q, which is the location of the serpin gene cluster and other members of serpin family.…”