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: 10158403
• 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/10158403
• 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)是退伍军人最常见的恶性肿瘤。非裔美国人(AA)男性有 前列腺癌的发病率是世界上最高的，死于前列腺癌的可能性是欧洲裔美国人(EA)的两倍。 研究表明，即使在调整了以下因素后，再障男性患前列腺癌的死亡率也更高 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患者中来自PCA。 我们进行了现存最大规模的再生障碍性贫血基因表达和拷贝数改变的联合研究。 为了阐明AA-PCa致癌的新机制，对AA-PCa的致癌机制进行了研究。我们 在4p16.3上定义了一个丢失区域，它在AA PCA中更常见地丢失。详细的分析显示 RGS12是这些删除事件的目标。RGS12(G蛋白信号12的调节因子)为阴性 G蛋白信号的调节器，以前没有被认为是肿瘤抑制基因。分析 来自AA和EA男性的Pca组织以及体内外研究表明RGS12是一种肿瘤 在AA-PCa中优先降低的抑制基因。 RGS12抑制Gα12和Gα13SRF介导的转录。G蛋白偶联受体(GPCRs) G-α12和/或G-α13的上游与前列腺癌的进展有关。同样，RGS12与HIGH结合 与CXCL8(IL-8)受体CXCR2的亲和力，这是一种GPCR。与CXCR2结合的配体可以激活多个 途径包括PI3K/AKT、MAPK、PLC和Rho。有非常广泛的文献涉及CXCL8， 其他与CXCR2结合的趋化因子和/或PCa中的CXCR2。然而，RGS12可以在多大程度上抑制 前列腺癌中涉及Gα12、Gα13和CXCR2的特定通路以及这种抑制的生物学影响 已知，但显然与RGS12在前列腺癌中的肿瘤抑制活性有关。 RGS12的敲除导致HSP27和ATF2的磷酸化增加。这两条路走得很好 已知与致癌转化和治疗耐药有关。此外，RGS12表达 显著降低雄激素受体和AKT蛋白的表达。PCa肿瘤显示明显 与良性前列腺相比，AA-PCa中MNX1蛋白的表达增加，但在 EA PCA。体内外研究表明，MNX1是一种癌基因。因此，RGS12是一种肿瘤 其缺失导致多个重要通路(AR、AKT、HSP27、ATF2、MNX1)激活的抑制因子 与致癌转化和治疗耐药有关。 在目标1中，我们将研究介导RGS12肿瘤抑制的途径。我们将系统地研究 RGS12缺失诱导的信号通路包括已知的RGS12靶标Gα12、Gα13和CXCR2信号 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》中我们将 进一步研究RGS12降低的表型效应。RGS12缺失激活的几条通路 与侵袭和转移增加和/或治疗耐药有关。因此，我们将 使用合适的体外和/或体内实验确定RGS12缺失是否会导致转移和治疗耐药 模特们。在目标3中，我们将评估RGS12及其靶点作为AA-PCa的生物标志物。途径和蛋白质 我们已经确定可能是AA-PCa疾病侵袭性的重要生物标志物，因此可能是 有助于识别患有惰性疾病和攻击性疾病的AA患者。我们将确定RGS12和 参与这一致癌轴的关键蛋白和磷蛋白在AA-PCa中发生变化，如果是这样的话，它们是否会发生变化 使用我们杰出的AA和EA组织芯片研究AA PCA与疾病侵袭性的相关性 在这种分析方面的资源和专业知识。我们还将确定它们之间的关联程度 其他和百分比的西非血统。这些相关的研究可以证实 这一致癌轴和识别可能对AA男性的治疗计划有用的新的生物标记物。