Inflammation, Prostate Cancer and Negative Regulation of Androgen Receptor Expression

摘要

My study involved two aspects of androgen receptor (AR) regulation- 1) molecular mechanism underlying negative regulation of AR expression and activity, 2) microRNA-mediated regulation of prostate cancer cell proliferation. My data establish that the human AR level is negatively regulated by nuclear factor kB (NF-kB) following its activation by TNF-alpha- induced signaling. I have defined the regulatory region in the human AR promoter that responds to the TNF-alpha-controlled negative transcriptional regulation. I show that TNF-alpha-controlled inhibition of AR expression occurs in androgen-dependent LNCaP human prostate cancer cells, but not in the androgen-independent C4-2 human prostate cancer cells. I further show that TNF- alpha treatment caused recruitment of corepressor complexes on negative response region in LNCaP cells, but not in C4-2 cells. To search for the microRNA effect on prostate cancer, scanning of the cancer microRNA array shows that miR-454 is up regulated in androgen-independent C4-2 cells and overexpression of miR-454 enhanced prostate cancer cell proliferation. In addition, Slain1 is identified as a miR-454 target protein using bioinformatics approaches.