Cytokines regulate neoplastic cell growth in vivo either by inducing the expression of growth suppressor genes in tumors or by mounting an immune response against them. The interferon family of cytokines regulates several physiologic responses such as antiviral, antitumor, and immune functions. By interacting with other cytokines, IFNs become an integral part of a large of intercellular signaling network that promotes anti-tumor and anti-pathogen surveillance system in vivo. In an earlier study, we demonstrated that the IFN-induced anti-tumor actions, especially apoptosis, could be synergistically augmented by all-trans retinoic acid (RA). This vitamin-A metabolite by itself acts as a growth inhibitor in many experimental and clinical models. Some clinical studies also demonstrated the potent tumor inhibitory effects of IFN/RA. We hypothesized that IFN/RA employs novel gene products for suppressing tumor growth. To identify the critical molecules involved in IFN/RA-induced apoptosis, we have used a genetic strategy and identified several Genes associated with Retinoid-Interferon-induced Mortality (GRIM). One such novel gene product, GRIM-19, suppresses growth via apoptosis. Previous studies by us and others showed that its activity suppressed by DNA viral oncoproteins and some cellular proteins. These observations indicate its potent anti-oncogenic characteristics. During the last funding period we have shown that GRIM-19 binds to Signal Transducer and Activator of Transcription 3 (STAT3) and suppresses its growth promoting action using cell line models. STAT3, a dormant cytokine-regulated transcription factor, is constitutively activated in a number of human tumors by oncogenic signals. STAT3 activity is regulated in normal cells by feedback inhibitors. Persistent STAT3 activity promotes survival, proliferation, metastasis of tumor cells by stimulating the expression of various cellular genes involved in those responses. Although oncogenic activation of STAT3 is an important step, we suggest that loss or inactivation of its inhibitors may also play a critical step in this process prior to the promotion of tumor growth. In preliminary studies, we showed that GRIM-19 suppress constitutive STAT3- induced tumor growth and metastasis using xenograft models. Consistent with these, we observed a loss of expression and mutations in GRIM-19 in several primary human tumors, which correlated with a strong upregulation of STAT3-inducible genes and promotion of cell growth. In this renewal application, we will investigate the biological relevance of GRIM-19 to tumor growth in vivo using knockout and transgenic mice. We will investigate the impact of grim19 mutations (found in primary tumors) on oncogene-induced tumor growth promotion using in vitro and in vivo models. Although a deregulation of STAT3 is known in many tumors, the molecular mechanisms of its deregulation, specifically the role of its inhibitors in tumor development are poorly studied. The studies proposed in this application will define how tumor- specific dysfunctions in GRIM-19 affect the functioning of this new growth regulatory pathway.
Cases of Squamous cell carcinoma (SCC), a from of non-melanoma skin cancer (NMSC), are on the rise, with over a million new cases annually in U.S.A. Persistently activated STAT3 is found in many SCCs and other cancers, which correlates with an aggressive growth of tumors. This proposal for the first time will define the importance of GRIM-19, an inhibitor of STAT3, in tumor suppression. The information gained from these studies will be useful in developing designer therapies for treating SCCs and other cancers, where abnormal STAT3 activities are observed.
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