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）有 PCA的最高事件在世界范围内死亡的可能性是PCA的两倍，是欧美（EA）男子。 研究表明，即使在调整后，AA男性中PCA的死亡率也更高 社会经济因素。这就是生物因素在发病率和死亡率的差异中起重要作用 来自AA男子的PCA。 我们已经对AA中的基因表达和拷贝数改变进行了最大的现有合并研究 PCA和匹配的良性组织，以阐明AA PCA中癌变的新机制。我们 已经定义了4p16.3上的损失区域，即在AA PCA中丢失了更常见的损失。详细分析显示 RGS12是这些删除事件的目标。 RGS12（G蛋白信号的调节剂12）为负 G蛋白信号的调节剂先前尚未作为肿瘤抑制基因实施。分析 来自AA和EA的PCA组织以及体外和体内研究表明RGS12是肿瘤 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（GPCR） 在PCA进程中已隐含Gα12和/或Gα13的上游。同样，RGS12与高结合 对CXCL8（IL-8）受体CXCR2的亲和力，即GPCR。配体与CXCR2结合可以激活多个 包括PI3K/AKT，MAPK，PLC和RHO在内的途径。有一个非常广泛的文献，暗示CXCL8， PCA中的其他CXCR2结合趋化因子和/或CXCR2。但是，RGS12可以抑制的程度 PCA中涉及Gα12，Gα13和CXCR2的特定途径以及这种抑制的生物学影响不是 已知，但显然与PCA中RGS12的肿瘤抑制活性有关。 RGS12的敲低导致HSP27和ATF2的磷酸化增加。这两个途径很好 已知与致癌转化和耐药性有关。另外，RGS12表达 显着下降的雄激素受体和Akt蛋白表达。 PCA肿瘤显示标记 与AA PCA中的良性前列腺相比，MNX1蛋白表达的增加，但增加的增加数量较小 EA PCA。体外和体内研究表明MNX1是癌基因。那是RGS12是肿瘤 抑制器的损失导致多种重要途径激活（AR，AKT，HSP27，ATF2，MNX1） 与致癌转化和耐药性有关。 在AIM 1中，我们将检查介导RGS12肿瘤抑制的途径。我们将系统地检查 由RGS12损失诱导的信号通路，包括已知的RGS12目标Gα12，Gα13和CXCR2信号传导 以及我们在初步研究中确定的更具识别的信号传导途径。在目标2中，我们将 进一步检查RGS12降低的表型效应。损失RGS12激活的几种途径 与侵袭和转移和/或耐药性的增加有关。因此，我们会 确定RGS12损失是否会导致转移和使用合适的体外和/或体内的治疗性 型号。在AIM 3中，我们将在AA PCA中评估RGS12及其目标。途径和蛋白质 我们已经确定的可能是AA PCA疾病侵略性的重要生物标志物，因此可能是 有助于识别患有懒惰与侵略性疾病的AA男性。我们将确定RGS12和 AA PCA中涉及该致癌轴的关键蛋白质和磷蛋白会改变，如果是这样，它们是 使用我们出色的AA和EA组织微阵列与AA PCA中的疾病侵略性相关 这种分析的资源和专家。我们还将确定它们与每个相关的程度 西非的其他和百分比。这些相关研究可以验证 这种致癌轴并识别出可能对AA男性治疗计划有用的新型生物标志物。

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