title: Hypoxia regulates Toll-like receptor-9 expression and invasive function in human brain cancer cells in vitro.
abstract: Toll-like receptor-9 (TLR9) is a cellular DNA sensor of the innate immune system. TLR9 is widely expressed in a number of tumors, including brain cancer; however, little is known regarding its regulation and involvement in cancer pathophysiology. The present study demonstrated that hypoxia upregulates and downregulates TLR9 expression in human brain cancer cellsin vitro, in a cell-specific manner. In addition, hypoxia-induced TLR9 upregulation was associated with hypoxia-induced invasion; however, such invasion was not detected in cells where hypoxia had suppressed TLR9 expression. Furthermore, suppression of TLR9 expression through TLR9 siRNA resulted in an upregulation of matrix metalloproteinase (MMP)-2, -9 and -13 and tissue inhibitor of matrix metalloproteinases-3 (TIMP-3) mRNA, and a decreased invasion of cells in normoxia, in a cell-specific manner. In cells where hypoxia induced TLR9 expression, TLR9 expression and invasion were reduced by TLR9 siRNA. The decreased invasion observed in hypoxia was associated with the decreased expression of the MMPs and a concomitant increase in TIMP-3 expression. In conclusion, hypoxia regulates the invasion of brain cancer cellsin vitroin a TLR9-dependent manner, which is considered to be associated with a complex expression pattern of TLR9-regulated mediators and inhibitors of invasion.
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Jouko
authors: J
authors: Sandholm
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Johanna
authors: J
authors: Tuomela
authors: Department of Pathology, Oulu University Hospital, Oulu 90029, Finland ; Department of Surgery, Oulu University Hospital, Oulu 90029, Finland ; Department of Anatomy and Cell Biology, University of Oulu, Oulu 90570, Finland.
authors: Joonas H
authors: JH
authors: Kauppila
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Birmingham Veterans Affairs Medical Center, Birmingham, AL 35233, USA.
authors: Kevin W
authors: KW
authors: Harris
authors: Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: David
authors: D
authors: Graves
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Katri S
authors: KS
authors: Selander
keywords: Toll-like receptor-9; brain cancer; hypoxia; invasion