A novel oncogenic axis in African American prostate cancer

点击翻译按钮获取中文摘要

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.