Headpin: a serpin with endogenous and exogenous suppression of angiogenesis.
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.
Shellenberger
Thomas D
TD
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, 77030, USA.
Mazumdar
Abhijit
A
Henderson
Ying
Y
Briggs
Katrina
K
Wang
Mary
M
Chattopadhyay
Chandrani
C
Jayakumar
Arumugam
A
Frederick
Mitchell
M
Clayman
Gary L
GL
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D003315:Cornea / Q000098:blood supply / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D013347:Subcellular Fractions; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D016209:Interleukin-8; D012333:RNA, Messenger; D011994:Recombinant Proteins; C530652:SERPINB13 protein, human; C530653:Serpinb13 protein, mouse; D015843:Serpins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A