Targeting Relaxin Signaling in Prostate Cancer

描述(申请人提供)：前列腺癌是美国男性癌症死亡的第二大原因。癌细胞对前列腺癌的局部侵袭和区域淋巴转移是影响预后的关键因素。晚期转移性前列腺癌目前是无法治愈的。男性类固醇激素在癌症进展中的作用受到了极大的关注。然而，在发展到雄激素非依赖性阶段后，前列腺癌对雄激素消融治疗变得没有反应。因此，识别与前列腺癌细胞的增殖、存活和迁移有关的新的内源性因素可能会为治疗创造潜在的治疗靶点。这个项目的主要目的是证明松弛蛋白(RLN)信号在前列腺癌进展中的重要性。我们实验室和其他实验室最近的实验数据表明，RLN在体外和体内都能刺激前列腺癌细胞侵袭和增殖。通过siRNA抑制肿瘤细胞内源性RLN或其受体LGR7的表达，可显著减少肿瘤细胞的侵袭表型，增加体外癌细胞的凋亡率。我们已经证实，在前列腺癌的不同阶段，LGR7的RNA表达保持不变，而RLN在人类癌症标本中的表达增加，特别是在复发的癌症中。在TRAMP小鼠前列腺癌模型中，转基因过表达的RLN降低了小鼠的存活率，增加了转移率，减少了癌细胞的凋亡。据报道，RLN直接介导了P53依赖的雄激素非依赖性前列腺细胞生长的增加。该提议的主要假设是，在体内抑制松弛素信号可以减缓前列腺癌的进展。该假说将通过以下特定目的进行验证：特定目的1.确定RLN信号的阻断是否影响转基因小鼠前列腺癌(TRAMP)的体内成瘤和转移潜能。分析了RLN在该模型中的作用机制。具体目的2：在人类前列腺癌进展的原位模型中，确定抑制RLN信号是否影响生长、侵袭和转移。RLN信号抑制的抗肿瘤活性可能为这种致命疾病的治疗干预提供新的靶点。

DESCRIPTION (provided by applicant): Prostate cancer is the second cause of cancer deaths in men in the United States. Local invasion of prostate by cancer cells as well as the spread to regional lymph nodes are the key factors related to poor prognosis. Advanced metastatic prostate cancer is currently not curable. Significant attention was devoted to the role of male steroid hormones in cancer progression. However, after advancing to the androgen-independent stage, prostate cancer becomes unresponsive to androgen ablation therapy. Therefore, identification of novel endogenous factors responsible for proliferation, survival, and migration of the prostate cancer cells may create potential therapeutic targets for treatment. The key aim of this project is to demonstrate the significance of relaxin (RLN) signaling in progression of prostate cancer. Recent experimental data obtained in our laboratory and others indicate that RLN stimulates increase in prostate carcinoma cell invasiveness and proliferation in vitro and in vivo. The suppression of endogenous RLN or its receptor LGR7 expression in cancer cells by siRNA drastically reduced an invasive phenotype and increased apoptosis of cancer cells in vitro. We have established that the RNA expression of LGR7 is maintained at different stages of prostate cancer, whereas the expression of RLN is increased in human cancer samples, and especially in recurrent cancers. The transgenic overexpression of RLN in mice decreased the survival, increased the rate of metastasis, and decreased cancer cell apoptosis in TRAMP mouse prostate cancer model. It was reported that RLN directly mediates p53-dependent increase in androgen-independent growth of prostate cells. The main hypothesis of the proposal is that the inhibition of relaxin signaling can reduce the progression of prostate cancer in vivo. The hypothesis will be tested by the following specific aims:Specific Aim 1. Determine whether ablation of RLN signaling affects tumorigenesis and metastatic potentials of mouse transgenic adenocarcinoma of prostate (TRAMP) in vivo. Analyze the mechanisms of RLN action in this model. Specific Aim 2. Determine whether the suppression of RLN signaling affects growth, invasiveness, and metastasis in an orthotopic model of human prostate cancer progression. Demonstration of the anti- tumor activity of RLN signaling suppression may provide a novel target for therapeutical intervention in this deadly disease.