The effect of hypoxic microenvironment on matrix metalloproteinase expression in xenografts of human oral squamous cell carcinoma.
Hypoxia is a common environmental stress factor and is associated with physiological and pathological conditions related to cancer invasion and metastasis. The process of cancer cell invasion involves degradation of the extracellular matrix. Here, we examine the effect of hypoxic microenvironment on matrix metalloproteinase expression in human oral squamous cell carcinoma under in vitro and in vivo conditions. At first, the expression levels of HIF-1alpha and matrix metalloproteinase (MMP) proteins in human oral squamous cell carcinoma cell lines, SAS and HSC-2 cultured under hypoxic or normoxic condition, were assessed by Western blotting. Enzyme activity and mRNA of MMP under hypoxic or normoxic condition were also investigated. Then the SAS and HSC-2 cells were transplanted subcutaneously into immunodeficient mice and the correlation between hypoxia and protein expression for MMPs, HIF-1alpha and Ki-67 were assessed. Hypoxic region was detected by in situ hypoxic probe, pimonidazole. MMP proteins and mRNA in both SAS and HSC-2 cells were increased under hypoxic condition. In xenograft, MMP-2 was expressed in tumor tissue, especially in hypoxic region. In contrast, MMP-9 expression was recognized in tumor tissue, especially neighboring stromal tissues containing blood vessels. Our study suggests that the hypoxic microenvironment in human oral squamous cell carcinoma plays important roles in expression for HIF-1alpha and MMPs, and proliferative activity of tumor cells.
Miyazaki
Yasuo
Y
Department of Oral and Maxillofacial Sciences, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan.
Hara
Akira
A
Kato
Keizo
K
Oyama
Takeru
T
Yamada
Yasuhiro
Y
Mori
Hideki
H
Shibata
Toshiyuki
T
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000201:enzymology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis; D007150:Immunohistochemistry; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000032:analysis; D020778:Matrix Metalloproteinase 2 / Q000032:analysis*; D020780:Matrix Metalloproteinase 9 / Q000032:analysis*; D051379:Mice; D008807:Mice, Inbred BALB C; D009062:Mouth Neoplasms / Q000201:enzymology* / Q000473:pathology; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14