TIMP-1 REGULATORY FACTORS IN HUMAN PROSTATE CANCER

描述（改编自研究者摘要）：规范

DESCRIPTION (Adapted from the Investigator's Abstract): Regulation of expression of the tissue inhibitors of metalloproteinases (TIMPs) is proposed to play a seminal role in the prevention of tumor cell spreading and metastasis. The major focus of this grant application is to characterize the signal transduction pathway regulating TIMP-1 expression in human prostate cancer. In preliminary studies, we have (a) identified a novel cis-acting enhancer element HTE-1, and a putative silencer element, HTE-2, located upstream of the 5' promoter of the TIMP-1 gene; (b) identified an IL-10 responsive novel signal transacting factor (STAT7) that is phosphorylated and transported to nucleus where it binds the HTE-1 element to activate TIMP-1 expression; (c) cloned the STAT7 gene and raised monoclonal antibodies against 3 different STAT7 peptides; (d) demonstrated that STAT7 is expressed in stably transfected PC-3 ML cells and 2 x N.I. PC-3 cells; (e) found both TIMP-1 and STAT7 are associated with low grade human prostate cancer. Since IL-10 activation of STAT7 correlates with the up regulation of TIMP-1 we hypothesize that the STAT7 protein in cooperation with other signal transduction factors might be critical in up regulating TIMP-1 expression in vitro and in vivo to block tumor cell metastasis. The specific aims of this grant application are: Aim 1: Characterize cooperative interactions of positive and negative transcriptional regulatory elements (i.e., HTE-1 and HTE-2) of the human TIMP-1 promoter. Aim 2: Study the role of the IL-10 receptor (IL-10R) signal transduction pathway in the regulation of TIMP-1 expression in human prostatic tumor cells. Aim 3: Evaluate the influence of IL-10 on growth, invasion, metastasis and tumor angiogenesis utilizing rSTAT7 gene transfected PC-3 cells. Aim 4: Evaluate STAT7 and TIMP-1 co-expression in human prostate cancer. In sum, the overall purpose of this grant application is two-fold: to assess whether an IL-10 responsive STAT7 protein can account for up regulation of TIMP-1 via binding to a unique enhancer element of the human TIMP-1 promoter; and to determine the potential importance of STAT7 expression in the tumorigenesis of prostate cancer.