Magi2 in aggressive prostate cancer

Magi2 在侵袭性前列腺癌中的作用

• 批准号: 9024983
• 负责人: Paul C Marker
• 金额: $ 16.18万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9024983
• 关键词: Activin Receptor; Adenocarcinoma; Agar; Allografting; Androgens; Apoptosis; Bicalutamide; Biological Markers; Cancer Patient; Castration; Cell Line; Cells; Cessation of life; DNA Sequence Rearrangement; DRPLA protein; Data; Disease; Disease Resistance; Epithelial Cells; Goals; Human; Immunohistochemistry; In Vitro; Indolent; Length; Light; Literature; Malignant Neoplasms; Malignant neoplasm of prostate; Molecular; Molecular Analysis; Morbidity - disease rate; Mus; Mutagenesis; N-terminal; Names; Neoplasm Metastasis; Outcome; PTEN gene; Pathology; Pathway interactions; Patients; Phenotype; Prostate; Prostatic Epithelium; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-akt; Publishing; RIPK1 gene; Resistance; Risk; Role; Scanning; Slide; Synapses; System; Testing; Tissue Microarray; Transcript; Transforming Growth Factor beta; Transgenic Mice; Work; Xenograft procedure; advanced disease; base; beta catenin; cancer recurrence; castration resistant prostate cancer; combat; data mining; deprivation; follow-up; genome sequencing; knock-down; liquid crystal polymer; loss of function; male; meetings; membrane-associated guanylate kinase; men; mouse model; novel therapeutics; overexpression; potential biomarker; prostate cancer cell line; protein expression; public health relevance; research study; resistance mechanism; response; scaffold; transcriptome sequencing; whole genome

 DESCRIPTION (provided by applicant): Most prostate cancers initially respond to androgen deprivation therapy but eventually progress to castration-resistant disease. Once castration-resistant prostate cancer (CRPC) arises, it cannot be effectively treated. This fact creates a need to better understand mechanisms of CRPC to enable new therapies for patients with advanced disease. In preliminary studies, we used transposon-based mutagenesis of androgen-sensitive prostate epithelial cells to derive sub-lines that were resistant to absence of androgens or the presence of bicalutamide. Molecular analysis of transposon insertions in the castration-resistant sub-lines identified MAGI2 as a potential driver of the castration resistant phenotype. Previous whole genome sequencing of human prostate cancers also found genomic rearrangements in MAGI2. Both the transposon insertions observed in our study and the rearrangements observed in human prostate cancers could potentially cause both loss of full-length MAGI2 expression and gain of expression for a truncated N-terminal fragment of MAGI2. Data mining the results of published RNA-seq studies of CRPC also identified candidate fusion transcripts involving the MAGI2 N-terminus. These data fit with additional preliminary studies of protein expression for the N-terminus of MAGI2 on human prostate cancer tissue microarrays. In these studies we observed that high expression of the MAGI2 N-terminus was associated with an increased risk of death from prostate cancer. In light of these findings, we hypothesize that over-expression of the N-terminus of MAGI2 drives progression to CRPC. We will test this hypothesis via gain- and loss-of-function approaches in cell line and mouse models (Aim 1) and by further investigating expression of the MAGI2 protein and candidate MAGI2-regulated pathways in human prostate cancer (Aim 2). This project will have high-impact outcomes for the effort to combat prostate cancer by furthering the goal of understanding mechanisms of resistance for men with prostate cancer. This project will also further the goal of distinguishing aggressive from indolent disease because our preliminary studies support the concept that MAGI2 and MAGI2-regulated pathways as potential biomarkers to distinguish aggressive from indolent disease.

 描述（由申请人提供）：大多数前列腺癌最初对雄激素剥夺治疗有反应，但最终进展为去势抵抗性疾病。一旦出现去势抵抗性前列腺癌（CRPC），就无法得到有效治疗。这一事实需要更好地了解CRPC的机制，以便为晚期疾病患者提供新的治疗方法。在初步的研究中，我们使用转座子为基础的突变雄激素敏感的前列腺上皮细胞，以获得亚系，这是抵抗缺乏雄激素 或存在比卡鲁胺。在去势抗性亚系中的转座子插入的分子分析鉴定MAGI 2为去势抗性表型的潜在驱动因子。先前对人类前列腺癌的全基因组测序也发现了MAGI 2中的基因组重排。在我们的研究中观察到的转座子插入和在人前列腺癌中观察到的重排都可能导致全长MAGI 2表达的丧失和MAGI 2的截短N末端片段的表达的获得。对已发表的CRPC的RNA-seq研究结果进行数据挖掘，还鉴定了涉及MAGI 2 N-末端的候选融合转录物。这些数据与MAGI2的N-末端在人前列腺癌组织微阵列上的蛋白表达的额外初步研究相吻合。在这些研究中，我们观察到MAGI 2 N-末端的高表达与前列腺癌死亡风险增加相关。根据这些发现，我们假设MAGI2的N-末端的过表达驱动CRPC的进展。我们将通过在细胞系和小鼠模型中获得和丧失功能的方法（Aim 1）以及通过进一步研究MAGI 2蛋白和候选MAGI 2调节途径在人前列腺癌中的表达（Aim 2）来测试这一假设。该项目将通过进一步了解前列腺癌男性抵抗机制的目标，为对抗前列腺癌的努力产生高影响力的结果。该项目还将进一步实现区分侵袭性疾病和惰性疾病的目标，因为我们的初步研究支持MAGI2和MAGI2调节途径作为区分侵袭性疾病和惰性疾病的潜在生物标志物的概念。