转录因子Slug体内调控前列腺癌生长的机制研究

Prostate cancer is a leading cause of illness and death among men all around the world. Recently, the standard therapies include androgen ablation that initially cause tumor regressioin. However, cancer cells eventually recur and develop into hormone refractory prostate cancer. New strategies developed to treat patients with advanced prostate cancer require a thorough understanding of the molecular mechanisms that regulate prostate cancer development and progression. Slug is a transcription factor of the Snail/Slug zinc-finger family and is implicated in metastasis of some tumors, but its role in prostate cancer is unclear. We previously demonstrated that Slug protein was highly expressed in tumor samples from transgenic adenocarcinoma of the mouse prostate (TRAMP) and human prostate cancer cell lines and Slug inhibits proliferation of human prostate cancer cells via downregulation of Cyclin D1 expression. Together, our data strongly suggest that Slug may represent a prognostic marker and a potential therapeutic target of this highly aggressive tumor. However, it is not enough to disclose the nature of prostate cancer via study in vitro, and it remains to be tested whether forced expression of Slug inhibits tumorigenesis of prostate cancer cells in vivo. Furthermore, because genetically defined mouse prostate cancer models such as TRAMP mouse are available, we should investigate the role of endogenous Slug in the initation, promotion, and progression of prostate tumors. These future studies will add substantively to the knowledge of the underlying molecular mechanisms by which Slug regulates tumorigenesis of prostate cancer.

研究显示Slug与多种恶性肿瘤的进展有关，但Slug与前列腺癌关系的研究目前报道甚少。我们在前期体外实验中发现前列腺腺癌小鼠模型的前列腺肿瘤组织以及人前列腺癌细胞系中Slug是呈高表达的；Slug通过下调细胞周期因子Cyclin D1抑制前列腺癌细胞增殖。这些发现预示了Slug在前列腺癌的发生发展中扮演着重要角色，但是仅从体外水平对肿瘤细胞系进行研究是不能完全代表肿瘤的实际情况的，因此我们将从体内进一步研究内源性转录因子Slug调控前列腺癌生长的分子机制。我们将采取Western-Blot、Real-Time PCR以及免疫组化的方法研究Slug对前列腺癌小鼠模型和子一代Slug基因敲除前列腺癌小鼠模型前列腺病变发生发展的作用以及研究Slug基因敲除前列腺癌小鼠模型对去势治疗的反应，最大限度的模拟体内Slug基因发挥作用的真实环境，从而为前列腺癌的治疗提供新颖的理论基础。

前列腺癌泌尿外科常见疾病，尤其是在欧美发达国家男性中，是仅次于肺癌发病率的第二高发疾病，其发病率及致死率都居高不下，因此对于其发生的机制及治疗靶点的研究一直是泌尿外科研究的热点。先前的研究显示Slug与多种恶性肿瘤的进展有关，而Slug与前列腺癌关系的研究目前报道甚少。我们从体内及体外实验进一步研究内源性转录因子Slug调控前列腺癌生长的分子机制。发现Lipocalin 2、ERK通路及PI3K-akt-mTOR信号通路均与SLUG相关，并阐述了其分子机制。通过研究，我们找到了一个潜在的治疗前列腺癌的分子靶点，从而为前列腺癌的治疗提供新颖的理论基础。