Role of RUNX2 in prostate cancer intratumoral androgen synthesis and progression

RUNX2在前列腺癌瘤内雄激素合成和进展中的作用

基本信息

批准号：
9537435
负责人：
Haojie Huang
金额：
$ 36.37万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9537435
关键词：
Address American Anabolism Biology Cancer Etiology Cancer Patient Cancer Relapse Castration Cell Proliferation Cessation of life Clinical DNA Polymerase II Data Development Disease Progression Epithelial Cells Foundations Gene Targeting Genes Genetic Transcription Genetic study Goals Hormones Human Knock-out Knockout Mice Knowledge Lead Malignant Neoplasms Malignant neoplasm of prostate Mediating Molecular Mus Oncogenic Osteocalcin Outcome PTEN gene Patients Phenotype Phosphorylation Phosphotransferases Play Preventive Prostate Prostatic Intraepithelial Neoplasias Prostatic Neoplasms Proteins Proto-Oncogene Proteins c-akt RNA Resistance Role Runx2 protein Sampling Serine Specimen Steroid biosynthesis Testing Testis Testosterone Therapeutic Transactivation Transgenic Mice Tumor Suppressor Proteins Up-Regulation Work androgen deprivation therapy base bone castration resistant prostate cancer cell motility cell transformation chemokine receptor clinically significant cohort design gene function genome-wide improved in vivo innovation intratumoral androgen knock-down loss of function men mortality mouse model novel novel therapeutic intervention overexpression programs prostate cancer cell prostate carcinogenesis public health relevance testosterone biosynthesis transcription factor tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the second leading cause of cancer death among American men. The high mortality is mainly caused by castration-resistant PCa (CRPC) relapsed after androgen deprivation therapy. Complete or partial loss of the PTEN tumor suppressor frequently occurs in localized and metastatic, castration-resistant PCa, suggesting that PTEN deficiency plays an important role in both PCa development and progression. Mouse genetic studies show that loss-of-function of Pten is sufficient for emergence of CRPC. However, how PTEN loss promotes development of CRPC is largely unclear. Runt-related transcription factor 2 (RUNX2) has been implicated in human PCa. However, whether or not it plays a causal role in prostate tumorigenesis and castration-resistant progression remains elusive. Motivated by our previous finding that RUNX2 overexpression correlates with decreased PTEN expression in human PCa specimens, we generate a Runx2 conditional transgenic mouse model and demonstrate that overexpression of Runx2 alone induces prostate epithelial cell transformation and low-grade prostate intraepithelial neoplasia (PIN), but in combination with Pten heterozygous deletion, causes high-grade PIN and cancer. We also show that the Akt kinase is hyperphosphorylated/hyperactivated in Runx2-Pten heterozygous tumors in mice and that concomitant RUNX2 overexpression and PTEN loss induce upregulation of the chemokine receptor CXCR7. We further demonstrate that testosterone is synthesized in murine Pten-knockout prostate tumors and PTEN-null, RUNX2-overexpressing human PCa cells and that this effect is abrogated by knockdown of RUNX2 or restored expression of PTEN in cultured PCa cells. These preliminary data lead to our central hypothesis that PTEN loss and RUNX2 overexpression work cooperatively to confer an aberrantly-activated transcriptional program of RUNX2, which in turn contributes AKT hyper activation, intratumoral androgen biosynthesis, prostate tumorigenesis and castration-resistant progression. To test this hypothesis, we will determine the molecular mechanism and downstream effectors that mediate concomitant RUNX2 overexpression and PTEN deficiency- induced prostate oncogenesis (Aim 1) and determine the cooperativity of RUNX2 overexpression and PTEN deficiency in development of aggressive and castration-resistant PCa in mice and human patient samples (Aim 2). Findings from this innovative proposal will provide a major advance in our understanding of the molecular mechanisms underlying prostate tumorigenesis and castration-resistant progression and novel aspects of PTEN tumor suppressor activity, in addition to conceptually advancing the field of RUNX2 biology in steroidogenesis and cancer, particularly in PCa. This knowledge will lay the foundation for development of new therapeutic strategies that will improve the clinical outcome of PCa patients, especially those with PTEN and RUNX2 alterations.

描述（申请人提供）：前列腺癌（PCa）是美国男性癌症死亡的第二大原因，其高死亡率主要是由于雄激素剥夺治疗后复发的去势抵抗性前列腺癌（CRPC）。 PTEN 肿瘤抑制基因经常出现在局部和转移性去势抵抗性 PCa 中，这表明 PTEN 缺陷在 PCa 的发育和进展中发挥着重要作用。小鼠遗传学研究表明 PTEN 的功能丧失。 Pten 足以促进 CRPC 的发生，但目前尚不清楚 Runt 相关转录因子 2 (RUNX2) 的缺失是否与前列腺肿瘤发生有关。受我们之前发现 RUNX2 过度表达与人类 PCa 标本中 PTEN 表达减少相关的启发，我们生成了 Runx2 条件转基因小鼠模型并证明了这一点。 Runx2 的过度表达单独诱导前列腺上皮细胞转化和低度前列腺上皮内瘤变 (PIN)，但与 Pten 杂合性缺失结合，会导致高级别 PIN 和癌症。我们还表明，Akt 激酶在 Runx2 中过度磷酸化/过度激活。 -小鼠中的 Pten 杂合肿瘤以及伴随的 RUNX2 过度表达和 PTEN 缺失会诱导趋化因子受体 CXCR7 的上调。进一步证明，睾酮在 Pten 敲除的小鼠前列腺肿瘤和 PTEN 缺失、RUNX2 过表达的人 PCa 细胞中合成，并且通过敲低 RUNX2 或恢复培养的 PCa 细胞中 PTEN 的表达来消除这种作用。这些初步数据得出了我们的结论。中心假设是 PTEN 缺失和 RUNX2 过度表达协同作用，赋予 RUNX2 异常激活的转录程序，进而导致 AKT 过度表达激活、肿瘤内雄激素生物合成、前列腺肿瘤发生和去势抵抗进展为了检验这一假设，我们将确定介导伴随的 RUNX2 过度表达和 PTEN 缺陷诱导的前列腺肿瘤发生的分子机制和下游效应器（目标 1）并确定 RUNX2 的协同作用。在小鼠和人类患者样本中，过度表达和 PTEN 缺乏会导致侵袭性和去势抵抗性 PCa 的发展（目标 2）。除了从概念上推进 RUNX2 生物学在类固醇生成和癌症领域（特别是 PCa 领域）之外，我们对前列腺肿瘤发生和去势抵抗进展的分子机制以及 PTEN 肿瘤抑制活性的新方面的理解也取得了重大进展。为开发新的治疗策略奠定了基础，这些策略将改善 PCa 患者的临床结果，特别是那些具有 PTEN 和 RUNX2 改变的患者。