A novel oncogenic axis in African American prostate cancer

非裔美国人前列腺癌的新致癌轴

基本信息

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
项目类别：
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

项目摘要

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) 是非裔美国 (AA) 男性退伍军人中最常见的恶性肿瘤。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，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。在 4p16.3 上定义了一个丢失区域，详细分析表明它在 AA PCa 中更常见。 RGS12 是这些缺失事件的目标，这一点是负面的。 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。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。 Gα12 和/或 Gα13 的上游与 PCa 进展有关，类似地，RGS12 与高结合。与 CXCL8 (IL-8) 受体 CXCR2 的亲和力，CXCR2 是一种与 CXCR2 结合的 GPCR 可以激活多个。通路包括 PI3K/AKT、MAPK、PLC 和 Rho 有大量文献涉及 CXCL8、然而，RGS12 可以抑制 PCa 中的其他 CXCR2 结合趋化因子和/或 CXCR2。 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，这两条途径效果良好。此外，RGS12 的表达与致癌转化和治疗耐药性有关。显着降低雄激素受体和 AKT 蛋白表达。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。 RGS12 缺失诱导的信号通路，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确定的更远端的信号通路。进一步研究 RGS12 减少对表型的影响。因此，我们将与增加的侵袭和转移和/或治疗耐药性相关。使用合适的体外和/或体内确定 RGS12 丢失是否会导致转移和治疗耐药在目标 3 中，我们将评估 RGS12 及其靶标作为 AA PCa 的生物标志物。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位于 AA PCa 中，如果是的话，它们也在使用我们出色的 AA 和 EA 组织微阵列与 AA PCa 的疾病侵袭性相关我们还将确定此类分析中的资源和专业知识。其他和百分比西非血统这些相关研究可以验证其重要性。并确定可能有助于 AA 男性治疗计划的新型生物标志物。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
Ban K;Feng S;Shao L;Ittmann M
通讯作者：
Ittmann M