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）是退伍军人中最常见的恶性肿瘤。非裔美国人 (AA) 男性有 世界上 PCa 发病率最高，死于 PCa 的可能性是欧洲裔美国人 (EA) 男性的两倍。 研究表明，即使在调整了 AA 男性的 PCa 死亡率后， 社会经济因素。因此，生物因素在发病率和死亡率的差异中发挥着重要作用 AA 男性中的 PCa。 我们对 AA 中的基因表达和拷贝数改变进行了现有最大规模的联合研究 PCa 和匹配的良性组织，以阐明 AA PCa 致癌的新机制。我们 在 4p16.3 上定义了一个丢失区域，它在 AA PCa 中丢失更常见。详细分析表明 RGS12 是这些删除事件的目标。 RGS12（G 蛋白信号传导调节剂 12）是一种阴性 G 蛋白信号传导的调节因子，之前并未被认为是肿瘤抑制基因。分析 来自 AA 和 EA 男性的 PCa 组织的体外和体内研究表明，RGS12 是一种肿瘤 AA PCa 中优先减少的抑制基因。 RGS12 抑制 Gα12 和 Gα13 SRF 介导的转录。 G 蛋白偶联受体 (GPCR) Gα12 和/或 Gα13 的上游与 PCa 进展有关。同样，RGS12 与高 与 CXCL8 (IL-8) 受体 CXCR2 的亲和力，CXCR2 是一种 GPCR。配体与 CXCR2 结合可以激活多个 通路包括 PI3K/AKT、MAPK、PLC 和 Rho。有大量文献涉及 CXCL8， 其他 CXCR2 结合趋化因子和/或 PCa 中的 CXCR2。然而，RGS12 可以抑制的程度 PCa 中涉及 Gα12、Gα13 和 CXCR2 的特定途径，并且这种抑制的生物学影响并不明显 已知，但显然与 PCa 中 RGS12 的肿瘤抑制活性潜在相关。 RGS12 的敲低会导致 HSP27 和 ATF2 的磷酸化增加。这两条路都很好 已知与致癌转化和治疗耐药性有关。此外，RGS12表达 显着降低雄激素受体和 AKT 蛋白的表达。 PCa 肿瘤显示明显 与 AA PCa 中的良性前列腺相比，MNX1 蛋白表达增加，但 EA PCa。体外和体内研究表明MNX1是一种癌基因。因此，RGS12是一种肿瘤 抑制因子的丢失会导致多个重要通路（AR、AKT、HSP27、ATF2、MNX1）的激活 与致癌转化和治疗耐药性有关。 在目标 1 中，我们将检查介导 RGS12 肿瘤抑制的途径。我们将系统地考察 RGS12 丢失诱导的信号通路，包括已知的 RGS12 靶标 Gα12、Gα13 和 CXCR2 信号传导 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 进一步检查 RGS12 减少的表型效应。 RGS12 缺失激活的几种途径 与侵袭和转移和/或治疗耐药性增加有关。因此我们将 使用合适的体外和/或体内确定 RGS12 缺失是否会导致转移和治疗耐药 模型。在目标 3 中，我们将评估 RGS12 及其靶标作为 AA PCa 中的生物标志物。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，因此可以 有助于识别患有惰性疾病和侵袭性疾病的 AA 男性。我们将确定 RGS12 和 参与该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，它们也是如此 使用我们出色的 AA 和 EA 组织微阵列与 AA PCa 的疾病侵袭性相关 此类分析的资源和专业知识。我们还将确定它们与每个的相关程度 其他和百分比西非血统。这些相关研究可以验证 并确定可能有助于 AA 男性治疗计划的新型生物标志物。