Abstract Castration-resistant prostate cancer (CRPC), which is considered to contain cancer stem cells (CSCs), leads to a high relapse rate in patients with prostate cancer (PCa). However, the markers of prostate CSCs are controversial. Here we demonstrate that CD51, in part, correlates with the poor prognosis of PCa patients. Further, we find that CD51 is a functional molecule that is able to promote the malignancy of PCa through enhancing tumor initiation, metastatic potential, and chemoresistance. Moreover, we find that elevated CD51 expression in PCa specimens correlates with p53 loss of function. Mechanistically, we demonstrate that p53 acts via Sp1/3 to repress CD51 transcription, and CD51 is required for PCa stemness and metastasis properties, and is downregulated by p53. Taken together, these results indicate that CD51 is a novel functional marker for PCa, which may provide a therapeutic target for the efficiently restricting PCa progression.
Perturbations of the expression of transporters and drug-metabolizing enzymes (DMEs) by opioids can be the locus of deleterious drug-drug interactions (DDIs). Many transporters and DMEs are regulated by xenobiotic receptors [XRs; e.g., pregnane X receptor (PXR), constitutive androstane receptor (CAR), and Aryl hydrocarbon receptor (AhR)]; however, there is a paucity of information regarding the influence of opioids on XRs. The objective of this study was to determine the influence of oxycodone administration (15 mg/kg intraperitoneally twice daily for 8 days) on liver expression of XRs, transporters, and DMEs in rats. Microarray, quantitative real-time polymerase chain reaction and immunoblotting analyses were used to identify significantly regulated genes. Three XRs (e.g., PXR, CAR, and AhR), 27 transporters (e.g., ABCB1 and SLC22A8), and 19 DMEs (e.g., CYP2B2 and CYP3A1) were regulated (P < 0.05) with fold changes ranging from −46.3 to 17.1. Using MetaCore (computational platform), we identified a unique gene-network of transporters and DMEs assembled around PXR, CAR, and AhR. Therefore, a series of transactivation/translocation assays were conducted to determine whether the observed changes of transporters/DMEs are mediated by direct activation of PXR, CAR, or AhR by oxycodone or its major metabolites (noroxycodone and oxymorphone). Neither oxycodone nor its metabolites activated PXR, CAR, or AhR. Taken together, these findings identify a signature hepatic gene-network associated with repeated oxycodone administration in rats and demonstrate that oxycodone alters the expression of many transporters and DMEs (without direct activation of PXR, CAR, and AhR), which could lead to undesirable DDIs after coadministration of substrates of these transporters/DMEs with oxycodone.
Significance Epithelial barrier integrity is dependent on progenitor cells that either divide to replenish themselves or differentiate into a functional epithelium. In the placenta, cytotrophoblast cells comprise this progenitor population, but the differentiation program they undertake is unlike any other in human tissues: acquisition of hormonogenesis and cell fusion to form a syncytialized (syncytio)trophoblast. Syncytiotrophoblast forms the primary epithelial barrier separating maternal and fetal tissue and performs functions vital for pregnancy. In the present study, we found that OVO-like 1 (OVOL1), a transcription factor homolog of Drosophila ovo, regulates the transition between progenitor and differentiated cytotrophoblast. It does so by repressing genes that maintain cytotrophoblast progenitor traits. This study provides insight into the role of OVOL1 in human trophoblast development.
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