REGULATION OF ANDROGEN RECEPTOR and erbB-2 GENE EXPRESSION IN PROSTATE CANCER: ROLE OF THE HU PROTEINS

前列腺癌(PCA)是影响男性的最常见的恶性肿瘤，在澳大利亚造成巨大的发病率和死亡率。在西方国家，它是导致男性死亡的第二大原因。大约三分之一的男性在根治性前列腺切除术后复发，原因是以前无法发现的转移性疾病。雄激素通过雄激素受体(AR)发挥作用，AR是一种核转录因子，调节一组基本上未知的雄激素反应基因，促进前列腺癌细胞的生长。因此，AR是治疗的主要靶点。即使当疾病对雄激素停用无反应时，AR也存在。此外，我们知道这些前列腺癌细胞招募其他雄激素不依赖的途径来激活生长。其中一个途径是erbB-2信号级联，它驱动细胞走向增殖。与细胞信使RNA结合的蛋白质在癌症生物学中发挥着越来越大的作用。HUR是Hu-Elav家族的成员，它促进结肠癌细胞的生长，并与卵巢和脑恶性肿瘤的不良预后有关。我们最近发现了第一个与AR和erbB-2mRNA结合的蛋白质。值得注意的是，HUR与这两个序列都有结合。此外，通常只在大脑中发现的Hu-Elav家族的另一成员HUD在人类前列腺癌中异常表达。在这个项目中，我们将确定这些蛋白质在培养和整个动物模型中对人前列腺癌细胞生长的影响。我们还将评估它们在大量的人类前列腺癌标本中的存在。据设想，这项工作将在这两条道路之间建立新的联系，以一种以前未被认识到的方式将它们结合在一起。我们还旨在解决与AR mRNA结合的HU蛋白的分子结构。这项工作的成果将包括前列腺癌的新的潜在测试和改善的预后预测，以及为开发新的治疗靶点奠定基础。

Carcinoma of the prostate (PCa) is the most common malignancy affecting males and causes enormous morbidity and mortality in Australia. It is the second leading cause of death in men in Western countries. About one third of men relapse after radical prostatectomy because of previously undetectable metastatic disease. Androgens, acting via the androgen receptor (AR) a nuclear transcription factor that regulates a set of largely unknown androgen-responsive genes, promote the growth of prostate cancer cells. Thus the AR is a major target for therapy. Even when the disease is unresponsive to androgen withdrawal, the AR is present. Furthermore, we know that these PCa cells recruit other androgen-independent pathways to activate growth. One such pathway is the erbB-2 signaling cascade, which drives the cells towards proliferation. Proteins that bind to RNA, the cellular messenger, are playing an increasing role in the biology of cancer. HuR, a member of the Hu-Elav family, augments growth of colon cancer cells, and is associted with poor outcomes in ovarian and brain malignancies. We have recently identified the first proteins that bind to AR and erbB-2 mRNA. Remarkably, HuR binds to both sequences. Furthermore, HuD, another member of the Hu-Elav family which is normally only found in the brain, is aberrantly expressed in human PCa. In this Project we will determine the effects of these proteins on the growth of human PCa cells in culture and in whole animal models. We will also evaluate their presence in a large array of human PCa specimens. It is envisaged that this work will develop novel links between the two pathways bringing them together in a previously unrecognised manner. We also aim to solve the molecular structure of Hu proteins bound to the AR mRNA. Outcomes of the work will include new potential tests for prostate cancer and improved prognosis prediction, and establishment of a foundation for the development of novel targets for therapy.