Identification of CREB-regulating microRNAs and the characterization of their function and clinical relevance in HER-2/neu-positive mammary carcinoma

HER-2/neu 阳性乳腺癌中 CREB ​​调节 microRNA 的鉴定及其功能特征和临床相关性

• 批准号: 454020884
• 负责人: Professorin Dr. Barbara Seliger
• 金额: --
• 依托单位: Institut für Medizinische Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/454020884?language=en
• 关键词: Identification; CREB; regulating; microRNAs; characterization

The cAMP response element binding Protein (CREB)1 is a transcription factor involved in many physiological processes including the regulation of cell proliferation, apoptosis and cell cycle. Furthermore, an increased expression and activity of CREB was detected in tumors of distinct origin, which are often associated with disease progression and poor prognosis of tumor patients. Own preliminary work demonstrated a correlation between HER-2/neu and CREB expression in in vitro models of HER-2/neu-mediated transformation as well as in HER-2/neu+ mammary carcinoma, which was accompanied by an increased cell growth as well as a reduced apoptosis in vitro and in vivo. Despite CREB-regulated processes have been well characterized, there exist little information about the posttranscriptional control of CREB. In order to identify whether CREB expression can be controlled by CREB regulating microRNAs (miRNAs), the aim of this project is (i) to identify general CREB regulating miRNAs, (ii) characterize the expression, regulation and function of these miRNAs, (iii) to define HER-2/neu regulated CREB regulating miRNAs, (iv) to analyze the clinical relevance of CREB regulating miRNAs and their association with therapy resistance in HER-2/neu+ tumors as well as (v) to determine their modulation as novel therapy concept for HER-2/neu overexpressing tumors. These analyses will not only extend the knowledge of the miRNA-mediated control of CREB expression, but will also give insights into the functional role of the miRNA/CREB/HER-2/neu network, which might lead to the development of innovative strategies for the treatment of therapy naive as well as therapy resistant HER-2/neu overexpressing tumors.

cAMP 反应元件结合蛋白 (CREB)1 是一种转录因子，参与许多生理过程，包括细胞增殖、凋亡和细胞周期的调节。此外，在不同来源的肿瘤中检测到CREB表达和活性增加，这通常与肿瘤患者的疾病进展和不良预后相关。自己的初步工作表明，在 HER-2/neu 介导的转化体外模型以及 HER-2/neu+ 乳腺癌中，HER-2/neu 和 CREB ​​表达之间存在相关性，并且还伴随着细胞生长的增加作为体外和体内细胞凋亡的减少。尽管 CREB ​​调控过程已得到很好的表征，但有关 CREB ​​转录后控制的信息很少。为了确定 CREB ​​表达是否可以通过 CREB ​​调节 microRNA (miRNA) 来控制，本项目的目的是 (i) 鉴定一般 CREB ​​调节 miRNA，(ii) 表征这些 miRNA 的表达、调节和功能，(iii) ) 定义 HER-2/neu 调节的 CREB ​​调节 miRNA，(iv) 分析 CREB ​​调节 miRNA 的临床相关性及其与 HER-2/neu+ 肿瘤治疗耐药性的关系，以及 (v)确定它们的调节作为 HER-2/neu 过表达肿瘤的新治疗概念。这些分析不仅将扩展 miRNA 介导的 CREB ​​表达控制的知识，还将深入了解 miRNA/CREB/HER-2/neu 网络的功能作用，这可能会导致创新策略的开发治疗未经治疗以及治疗耐药的 HER-2/neu 过表达肿瘤。