| 1. |
- Nowak, Michael, et al.
(author)
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Prognostic significance of phospho-histone H3 in prostate carcinoma
- 2014
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In: World journal of urology. - : Springer-Verlag New York. - 0724-4983 .- 1433-8726. ; 32:3, s. 703-707
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Journal article (peer-reviewed)abstract
- Prostate cancer is the second most common cancer in men and the sixth most common cause of death from cancer in men worldwide. Currently, a sufficient pathological distinction between patients requiring further treatment and those for which active surveillance remains an option is still lacking, which leads to the problem of overtreatment. Cell proliferation is routinely assessed by detecting Ki-67 antigen. While Ki-67 is expressed throughout the interphase of proliferating cells, phosphorylation of the chromatin constituent histone H3 occurs only during the late G2 phase and mitosis thus providing a more strict assessment of the mitotic activity. We undertook this study to test whether expression of the recently introduced proliferation marker phospho-histone H3 (pHH3) in prostate carcinoma tissue sections exhibits prognostic significance in comparison with Ki-67. Protein expression of pHH3 and Ki-67 was assessed on TMA consisting of paraffin-embedded tissue from men that had undergone radical prostatectomy. The analysis included triplicate tissue cores of a total of 339 tumor foci. Immunohistochemical staining of pHH3 and Ki-67 was performed and analyzed using Definiens imaging software. Prostate cancer tissue exhibited a significantly higher frequency of pHH3-positive cells compared to benign prostate tissue. pHH3 expression was significantly correlated with Ki-67 expression. Furthermore, statistical analysis revealed positive correlation between pHH3 expression and PSA levels at diagnosis and in addition negatively correlated with overall survival. In contrast to Ki-67 staining, pHH3 expression did not correlate with Gleason grade. Our data point to a conceivable role of pHH3 as prognostic biomarker in prostate carcinoma.
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| 2. |
- Shaikhibrahim, Zaki, et al.
(author)
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MED15, encoding a subunit of the mediator complex, is overexpressed at high frequency in castration-resistant prostate cancer
- 2014
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In: International Journal of Cancer. - Hoboken : Wiley-Blackwell. - 0020-7136 .- 1097-0215. ; 135:1, s. 19-26
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Journal article (peer-reviewed)abstract
- The mediator complex is an evolutionary conserved key regulator of transcription of protein-coding genes and an integrative hub for diverse signaling pathways. In this study, we investigated whether the mediator subunit MED15 is implicated in castration-resistant prostate cancer (CRPC). MED15 expression and copy number/rearrangement status were assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively on 718 prostate cancer (PCa) specimens and sequenced by Sanger on a subset. Furthermore, SMAD3 phosphorylation, androgen receptor (AR) and proliferation markers were evaluated by IHC. In PCa cells, siRNA/shRNA knockdown of MED15 was followed by proliferation assays with/without dihydrotestosterone (DHT), and treatments with recombinant TGF-beta 3. Our results show that MED15 is overexpressed in 76% of distant metastatic CRPC (CRPCMET) and 70% of local-recurrent CRPC (CRPCLOC), in contrast to low frequencies in androgen-sensitive PCa, and no expression in benign prostatic tissue. Furthermore, MED15 overexpression correlates with worse clinical outcome thus defining a highly lethal phenotype. Moreover, TGF-beta signaling activation associates with MED15 overexpression in PCa tissues, and leads to increased expression of MED15 in PCa cells. MED15 knockdown effects phosphorylation and shuttling of p-SMAD3 to the nucleus as well as TGF-beta-enhanced proliferation. In PCa tissues, MED15 overexpression associates with AR overexpression/amplification and correlates with high proliferative activity. MED15 knockdown decreases both androgen-dependent and -independent proliferation in PCa cells. Taken together, these findings implicate MED15 in CRPC, and as MED15 is evolutionary conserved, it is likely to emerge as a lethal phenotype in other therapeutic-resistant diseases, and not restricted to our disease model.
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