A novel oncogenic axis in African American prostate cancer

非裔美国人前列腺癌的新致癌轴

• 批准号: 10455444
• 负责人: Michael M Ittmann
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455444
• 关键词: ATF2 gene; Address; Affinity; African; African American; Agar; American; Androgen Receptor; Androgens; Behavior; Benign; Binding; Biological; Biological Factors; Biological Markers; Cancer Etiology; Carcinogenesis Mechanism; Cell Line; Cells; Cessation of life; Clinical; Correlative Study; Data; Disease; Distal; Epithelial Cells; European; Evaluation; Event; FASN gene; G-Protein-Coupled Receptors; GTP-Binding Protein Regulators; GTP-Binding Protein alpha Subunits, Gs; Gene Expression; Genetic Transcription; Growth; HSPB1 gene; IL8 gene; IL8RB gene; In Vitro; Incidence; Individual; Indolent; Interleukin-8B Receptor; LNCaP; Ligand Binding; Link; Lipids; Literature; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Neoplasm Metastasis; Oncogenes; Oncogenic; PI3K/AKT; Pathway interactions; Phenotype; Phosphoproteins; Phosphorylation; Play; Prostate; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Resistance; Resources; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Socioeconomic Factors; Tissue Microarray; Tissues; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Validation; Veterans; Visceral; Work; anticancer research; base; chemokine; in vivo; in vivo Model; knock-down; men; mortality; novel; novel marker; overexpression; predictive tools; prostate cancer cell line; prostate cancer progression; protein expression; receptor; rho; small hairpin RNA; treatment planning; tumor; tumor growth; tumor xenograft; tumorigenesis

Prostate cancer (PCa) is the most common malignancy in veterans. African American (AA) men have the highest incidence of PCa in the world and are twice as likely to die of PCa as European American (EA) men. Studies have shown that there is a higher mortality from PCa in AA men even after adjustment for socioeconomic factors. Thus, biological factors play a significant role in the disparity in incidence and mortality from PCa in AA men. We have carried out the largest existing combined study of gene expression and copy number alterations in AA PCa and matched benign tissues in order to elucidate novel mechanisms of carcinogenesis in AA PCa. We have defined a region of loss on 4p16.3 that it is lost more commonly in AA PCa. Detailed analysis showed that RGS12 is the target of these deletion events. RGS12 (regulator of G-protein signaling 12) is a negative regulator of G-protein signaling that has not been previously implicated as a tumor suppressor gene. Analysis of PCa tissues from AA and EA men and in vitro and in vivo studies have shown that RGS12 is a tumor suppressor gene that is preferentially decreased in AA PCa. RGS12 inhibits Gα12 and Gα13 SRF mediated transcription. G-protein coupled receptors (GPCRs) that are upstream of Gα12 and/or Gα13 have been implicated in PCa progression. Similarly, RGS12 binds with high affinity to the CXCL8 (IL-8) receptor CXCR2, which is a GPCR. Ligand binding to CXCR2 can activate multiple pathways including PI3K/AKT, MAPK, PLC and Rho. There is a very extensive literature implicating CXCL8, other CXCR2 binding chemokines and/or CXCR2 in PCa. However, the extent to which RGS12 can inhibit the specific pathways involving Gα12, Gα13 and CXCR2 in PCa and the biological impact of this inhibition is not known, but is clearly potentially relevant to the tumor suppressor activities of RGS12 in PCa. Knockdown of RGS12 results in increased phosphorylation of HSP27 and ATF2. These two pathways are well known to be linked to oncogenic transformation and therapy resistance. In addition, RGS12 expression markedly decreases both androgen receptor and AKT protein expression. PCa tumors shows marked increases in MNX1 protein expression compared to benign prostate in AA PCa but much smaller increases in EA PCa. In vitro and in vivo studies have shown that MNX1 is an oncogene. Thus, RGS12 is a tumor suppressor whose loss results in activation of multiple important pathways (AR, AKT, HSP27, ATF2, MNX1) linked to oncogenic transformation and therapy resistance. In Aim 1 we will examine the pathways mediating RGS12 tumor suppression. We will systematically examine signaling pathways induced by RGS12 loss including known RGS12 targets Gα12, Gα13 and CXCR2 signaling as well as the more distal signaling pathways we have identified in our preliminary studies. In Aim 2 we will further examine the phenotypic effects of decreased RGS12. Several pathways activated by loss of RGS12 have been associated with increased invasion and metastasis and/or therapy resistance. We will therefore determine if RGS12 loss leads to metastasis and therapy resistance using suitable in vitro and/or in vivo models. In Aim 3 we will evaluate RGS12 and its targets as biomarkers in AA PCa. The pathways and proteins we have identified may be important biomarkers of disease aggressiveness in AA PCa and thus could be useful in identifying AA men with indolent versus aggressive disease. We will determine whether RGS12 and key proteins and phosphoproteins involved in this oncogenic axis are altered in AA PCa and if so are they correlated with disease aggressiveness in AA PCa using our outstanding AA and EA tissue microarray resources and expertise in such analysis. We will also determine the extent which they correlate with each other and percent West African lineage. These correlative studies can provide validation of the importance of this oncogenic axis and identify novel biomarkers that may be useful for treatment planning in AA men.

前列腺癌（PCa）是退伍军人中最常见的恶性肿瘤。非裔美国人（AA）男性有 在世界上PCa的发病率最高，并且死于PCa的可能性是欧洲美国（EA）男性的两倍。 研究表明，即使在调整后，AA男性中PCa的死亡率也较高， 社会经济因素。因此，生物因素在发病率和死亡率的差异中起着重要作用 在AA男性中的PCa 我们已经进行了最大的现有的基因表达和拷贝数的变化在AA的联合研究 前列腺癌和匹配的良性组织，以阐明新的机制，在AA前列腺癌的致癌作用。我们 在4p16.3上定义了一个丢失区域，该区域在AA PCa中更常见。详细分析显示， RGS 12是这些删除事件的目标。RGS 12（G蛋白信号转导调节因子12）是一种负性调节因子。 G蛋白信号转导的调节子，以前未涉及作为肿瘤抑制基因。分析 体外和体内研究表明，RGS 12是一种肿瘤， 在AA PCa中优先减少的抑制基因。 RGS 12抑制Gα12和Gα13 SRF介导的转录。G蛋白偶联受体（GPCR）， Gα12和/或Gα13上游与PCa进展有关。类似地，RGS 12与高水平的 与CXCL 8（IL-8）受体CXCR 2（其为GPCR）的亲和力。与CXCR 2结合的配体可以激活多个 信号通路包括PI 3 K/AKT、MAPK、PLC和Rho。有大量文献涉及CXCL 8， 其他CXCR 2结合趋化因子和/或PCa中的CXCR 2。然而，RGS 12可以在多大程度上抑制 PCa中涉及Gα12、Gα13和CXCR 2的特异性途径，这种抑制的生物学影响不是 已知，但显然可能与PCa中RGS 12的肿瘤抑制活性相关。 RGS 12的敲低导致HSP 27和ATF 2的磷酸化增加。这两种途径 已知与致癌转化和治疗抗性有关。此外，RGS 12表达 显著降低雄激素受体和AKT蛋白表达。前列腺癌肿瘤显示 与良性前列腺相比，AA PCa中MNX 1蛋白表达增加，但 EA PCa.体外和体内研究表明，MNX 1是一种致癌基因。因此，RGS 12是肿瘤 一种抑制因子，其缺失导致多个重要途径（AR、AKT、HSP 27、ATF 2、MNX 1）的激活 与致癌转化和治疗抗性有关。 在目标1中，我们将研究介导RGS 12肿瘤抑制的途径。我们将系统地研究 RGS 12缺失诱导的信号通路，包括已知的RGS 12靶点Gα12、Gα13和CXCR 2信号通路 以及我们在初步研究中发现的更远端的信号通路。在目标2中， 进一步检查降低的RGS 12的表型效应。RGS 12缺失激活的几种途径 与增加的侵袭和转移和/或治疗抗性相关。因此我们将 使用合适的体外和/或体内方法确定RGS 12损失是否导致转移和治疗抗性 模型在目标3中，我们将评估RGS 12及其靶标作为AA PCa中的生物标志物。这些通路和蛋白质 我们已经确定了可能是AA PCa疾病侵袭性的重要生物标志物，因此可能是 用于识别患有惰性与侵袭性疾病的AA男性。我们将确定RGS 12和 参与致癌轴的关键蛋白和磷蛋白在AA PCa中发生改变，如果是这样， 使用我们杰出的AA和EA组织微阵列， 资源和专业知识在这样的分析。我们还将确定它们与每个 其他和百分之西非血统。这些相关的研究可以验证的重要性， 这一致癌轴，并确定新的生物标志物，可能是有用的治疗计划，在AA男子。

项目成果

RET Signaling in Prostate Cancer.

• DOI: 10.1158/1078-0432.ccr-17-0528
• 发表时间: 2017-08-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Ban K;Feng S;Shao L;Ittmann M
• 通讯作者: Ittmann M