Abstract B39: Role of hepatoma upregulated Protein (HURP) in prostate cancer tumorigenesis.

Abstract

Abstract Hepatoma up-regulated protein (HURP) is a cell cycle-regulated and microtubule-associated protein. It functions as a Ran GTPase effector and is involved in the stabilization of the mitotic kinetochore fibers. The expression of this protein is elevated in different tumor types and associated with tumor progression and aggressiveness. Also, a significant elevation of HURP expression was reported in normal stem cells including haematopoietic stem cells, mesenchymal stem cells, and mouse embryonic stem cells but not in differentiated cells, an evidence for HURP as stemness maintenance factor. The aim of this study is to analyze the oncogenic potential of HURP in prostate cancer (PCa). We analyzed the expression level of HURP in PCa patients and found the transcripts of HURP were overexpressed in PCa. The elevated expression of HURP in PCa was found to be associated with higher Gleason score, systemic progression and poor prognosis. Furthermore, using a case-control cohort study we demonstrated the overall prognostic ability of HURP mRNA in advanced PCa, as tested in receiver operating characteristic analysis [AUC 0.74 (95% CL, 0.68 to 0.8)]. In addition, we analyzed the expression level of HURP protein in tumor tissue and in prostate benign and cancer cell lines; we found that the level of HURP protein was almost 5-fold higher (p<0.005) relative to control (cystoprostatectomy) tissue and in cancer cell lines compared to the benign cells. Overall, these data suggest a strong relationship between the elevated expression of HURP and the development and progression of PCa. Next, we set out a tetracyclin-regulated transient expression system model to study the effects of HURP overexpression in LNCaP cells. Data obtained from western blot revealed that HURP overexpression was associated with the phosphorylation of C-Jun-N-Terminal kinase (JNK) and the induction of both Fra1 and c-JUN proteins as well as with the suppression of pro-apoptotic protein Bcl-Xs, and p53 without influencing the negative regulator MDM2. Also, the overexpression of HURP in CaP cell lines was found to enhance the expression of the anti-apoptotic protein Bcl-2 without influencing the anti-apoptotic protein. Conversely, viral titer of shHURP was found to inhibit the basal phosphorylation of JNK, to suppress the basal level of cyclin A, to increase the degradation of the inhibitor of NF-κB, to decrease the expression of PKC. Furthermore, down regulation of HURP was found to enhance the expression of p53 and to abolish its negative regulator MDM2, suggesting a central role for p53 in the modulation of HURP-induced cell proliferation and tumor progression. Also, the overexpression of HURP promoted the expression of the stemness markers Oct3/4 and Nanog, an evidence for the involvement of HURP in the maintenance of stemness properties in PCa cells. This idea is supported by the reported role of Nanog and Oct3/4 in promoting PCa stem cell characteristics as well as prostate resistance to androgen deprivation, and by our results showing decreased p53, with demonstrated roles in reprogramming, dedifferentiation, self-renewal, and pluripotency. Overall, our data suggest a potential role of HURP in PCa tumorigenesis. In addition, these findings suggest that HURP's stemness properties can contribute to its role in the etiology of PCa. Support: DOD PC094680 (CRG), PCF Creativity Award (CRG). Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B39. Citation Format: Abdelouahid El-Khattouti, Tangeng Ma, James R. Kent, Ingrid Espinoza, Christian R. Gomez. Role of hepatoma upregulated Protein (HURP) in prostate cancer tumorigenesis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B39.