| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2009: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2008: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
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| Research Abstract |
Interferon-γ (IFN-γ) is a pleiotropic cytokine that exerts anti-tumor activity to various cancer cells. IFNγ induces Mig/CXCL9 and IP10/CXCL10, members of the CXC chemokine family, have been shown to induce potent lymphocyte chemotaxis and play an important role in tumor rejection. In the tumor microenvironment, most solid tumors develop regions of low oxygen tension called hypoxia, which is due to an imbalance in oxygen supply and consumption. We have previously shown that hypoxia inhibited the IFN-γ induced expression of chemokines CXCL9 and CXCL10 in human tumor cell lines. Although hypoxia (1% O2) markedly inhibited IFN-γ -induced expression of CXCL9 and CXCL10 mRNAs in human oral squamous carcinoma cell line, hypoxia had no effect on the levels of tyrosine-phosphorylated and nuclear-translocated STAT1. Furthermore,Chromatin immunoprecipitation assay demonstrated that although STAT1 was recruited to the promoter region of the CXCL9 and CXCL10 gene under hypoxia, recruitments of RNA polymerase II and coactivator SRC-1 was inhibited under hypoxia. In the present study, we further investigated the mechanisms by which hypoxia down-regulates the IFN-y-induced CXCL9 and CXCL10 gene expression. IFNγ-induced phosphorylation of STAT1 (Ser727) was down-regulated under the hypoxia in HSC-2 cell. However, the inhibitory effect of hypoxia on the phosphorylation was not observed in HSC-3 and T98G cells, suggesting that the inhibition of STAT1 Ser727 by hypoxia is a cell-type specific phenomenon. Furthermore, U3A cells transfected with mutant STAT1 in which Ser727 had been mutated to Glu, which mimics the phosphorylated status of Ser727, were also inhibited by hypoxia for the IFN-y-induced CXCL9 and CXCL10 gene expression. Taken together these results suggest that the inhibition of STAT1 Ser727 does not involved in the inhibition of IFN-γ-induced gene expression.
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