Targeting Relaxin Signaling in Prostate Cancer

靶向前列腺癌中的松弛素信号传导

• 批准号: 7212754
• 负责人: Alexander I Agoulnik
• 金额: $ 18万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-19 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7212754
• 关键词: Ablation; Affect; Androgens; Apoptosis; Attention; Cancer Cell Growth; Cancer Etiology; Cancer Model; Cells; Cessation of life; Data; Development; Disease; Endogenous Factors; Exploratory/Developmental Grant; Future; G Protein-Coupled Receptor Genes; Genetic Transcription; Growth; Human; In Vitro; Intervention; Invasive; Laboratories; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Membrane; Men' s Role; Metastatic Prostate Cancer; Modeling; Mus; NIH Program Announcements; Neoplasm Metastasis; Phenotype; Prognostic Marker; Prostate; Prostate Adenocarcinoma; Prostate carcinoma; Protein Overexpression; Rate; Recurrent Malignant Neoplasm; Relaxin; Reporting; Sampling; Signal Transduction; Small Interfering RNA; Staging; Testing; Tissues; Transgenic Mice; Transgenic Organisms; United States; anti-cancer therapeutic; base; cancer cell; cancer recurrence; extracellular; in vivo; lymph nodes; men; migration; mutant; novel; outcome forecast; receptor; relaxin receptor; response; steroid hormone; therapeutic target; tumor; tumor growth; tumor progression; tumorigenesis

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.

描述（由申请人提供）：前列腺癌是美国男性癌症死亡的第二大原因。癌细胞对前列腺的局部浸润以及向区域淋巴结的扩散是预后不良的关键因素。晚期转移性前列腺癌目前无法治愈。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，在进展到雄激素非依赖性阶段后，前列腺癌变得对雄激素消融治疗无反应。因此，鉴定负责前列腺癌细胞增殖、存活和迁移的新型内源性因子可能会产生潜在的治疗靶点。该项目的主要目的是证明松弛素（RLN）信号在前列腺癌进展中的重要性。最近在我们实验室和其他实验室获得的实验数据表明，RLN刺激前列腺癌细胞在体外和体内的侵袭和增殖的增加。通过siRNA抑制内源性RLN或其受体LGR 7在癌细胞中的表达显著降低了体外癌细胞的侵袭性表型并增加了凋亡。我们已经确定LGR 7的RNA表达在前列腺癌的不同阶段维持，而RLN的表达在人类癌症样品中增加，特别是在复发性癌症中。在TRAMP小鼠前列腺癌模型中，RLN的转基因过表达降低了小鼠的存活率，增加了转移率，并减少了癌细胞凋亡。据报道，RLN直接介导p53依赖性前列腺细胞雄激素非依赖性生长的增加。该提案的主要假设是松弛素信号传导的抑制可以减少体内前列腺癌的进展。该假设将通过以下具体目标进行检验：具体目标1。确定RLN信号传导的消融是否影响体内小鼠转基因前列腺腺癌（TRAMP）的肿瘤发生和转移潜力。分析RLN在该模型中的作用机制。具体目标2。在人前列腺癌进展的原位模型中确定RLN信号传导的抑制是否影响生长、侵袭和转移。RLN信号抑制的抗肿瘤活性的证明可能为这种致命疾病的治疗干预提供新的靶点。