Supplemental Table 1 and Figure 1 from FOXP3–miR-146–NF-κB Axis and Therapy for Precancerous Lesions in Prostate
Runhua LiuBin YiShi WeiWei‐Hsiung YangKaren HartPriyanka ChauhanWei ZhangXicheng MaoXiuping LiuChang-Gong LiuLizhong Wang
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<p>Supplemental Table 1: Primer sequences used in this study. Supplemental Figure 1: The effect of FOXP3, NF-κB p65-siRNA, and NF-κB inhibitor bortezomib on the growth of DU145 cells.</p>Keywords:
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Progression of prostate cancer to the lethal castrate-resistant stage coincides with loss of responsiveness to androgen deprivation and requires development of novel therapies. We previously provided proof-of-concept that Stat5a/b is a therapeutic target protein for prostate cancer. Here, we show that pharmacologic targeting of Jak2-dependent Stat5a/b signaling by the Jak2 inhibitor AZD1480 blocks castrate-resistant growth of prostate cancer.Efficacy of AZD1480 in disrupting Jak2-Stat5a/b signaling and decreasing prostate cancer cell viability was evaluated in prostate cancer cells. A unique prostate cancer xenograft mouse model (CWR22Pc), which mimics prostate cancer clinical progression in patients, was used to assess in vivo responsiveness of primary and castrate-resistant prostate cancer (CRPC) to AZD1480. Patient-derived clinical prostate cancers, grown ex vivo in organ explant cultures, were tested for responsiveness to AZD1480.AZD1480 robustly inhibited Stat5a/b phosphorylation, dimerization, nuclear translocation, DNA binding, and transcriptional activity in prostate cancer cells. AZD1480 reduced prostate cancer cell viability sustained by Jak2-Stat5a/b signaling through induction of apoptosis, which was rescued by constitutively active Stat5a/b. In mice, pharmacologic targeting of Stat5a/b by AZD1480 potently blocked growth of primary androgen-dependent as well as recurrent castrate-resistant CWR22Pc xenograft tumors, and prolonged survival of tumor-bearing mice versus vehicle or docetaxel-treated mice. Finally, nine of 12 clinical prostate cancers responded to AZD1480 by extensive apoptotic epithelial cell loss, concurrent with reduced levels of nuclear Stat5a/b.We report the first evidence for efficacy of pharmacologic targeting of Stat5a/b as a strategy to inhibit castrate-resistant growth of prostate cancer, supporting further clinical development of Stat5a/b inhibitors as therapy for advanced prostate cancer.
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Transcription factor Stat5a/b is highly critical for the viability of human prostate cancer cells in vitro and for prostate tumor growth in vivo. Stat5 is constitutively active in clinical prostate cancers but not in the normal human prostate epithelium. Moreover, Stat5a/b activation in prostate cancer is associated with high histological grade of prostate cancer. However, the molecular mechanisms underlying constitutive activation of Stat5a/b in prostate cancer are unclear. The receptor-associated tyrosine kinase Jak2 is a known key activator of Stat5a/b in prostate cancer cells in response to ligand stimulation. Recently, a single gain-of-function point mutation of JAK2 was described in myeloproliferative diseases leading to constitutive Jak2 kinase activity, subsequent Stat5a/b activation and involvement of V617F Jak2 in the pathogenesis of myeloproliferative disorders.We determined whether JAK2 undergoes the V617F activating mutation during clinical progression of human prostate cancer using a highly sensitive assay (amplification refractory mutation system) and a unique material of fresh specimens from organ-confined or castration-resistant prostate cancers.The JAK2 V617F mutation was not found in any of the normal or malignant prostate samples analyzed in this study.Future work should focus on determining the molecular mechanisms other than V617F mutation of Jak2 resulting in continuous Stat5 activation in clinical prostate cancers.
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We analyzed the levels of selected micro-RNAs in normal prostate tissue to assess their potential to indicate tumor foci elsewhere in the prostate. Histologically normal prostate tissue samples from 31 prostate cancer patients and two cancer negative control groups with either unsuspicious or elevated prostate specific antigen (PSA) levels (14 and 17 individuals, respectively) were analyzed. Based on the expression analysis of 157 microRNAs in a pool of prostate tissue samples and information from data bases/literature, we selected eight microRNAs for quantification by real-time polymerase chain reactions (RT-PCRs). Selected miRNAs were analyzed in histologically tumor-free biopsy samples from patients and healthy controls. We identified seven microRNAs (miR-124a, miR-146a & b, miR-185, miR-16 and let-7a & b), which displayed significant differential expression in normal prostate tissue from men with prostate cancer compared to both cancer negative control groups. Four microRNAs (miR-185, miR-16 and let-7a and let-7b) remained to significantly discriminate normal tissues from prostate cancer patients from those of the cancer negative control group with elevated PSA levels. The transcript levels of these microRNAs were highly indicative for the presence of cancer in the prostates, independently of the PSA level. Our results suggest a microRNA-pattern in histologically normal prostate tissue, indicating prostate cancer elsewhere in the organ.
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Background: Transcription factor Stat5a/b is highly critical for the viability of human prostate cancer cells in vitro and for prostate tumor growth in vivo . Stat5 is constitutively active in clinical prostate cancers but not in the normal human prostate epithelium. Moreover, Stat5a/b activation in prostate cancer is associated with high histological grade of prostate cancer. However, the molecular mechanisms underlying constitutive activation of Stat5a/b in prostate cancer are unclear. The receptor-associated tyrosine kinase Jak2 is a known key activator of Stat5a/b in prostate cancer cells in response to ligand stimulation. Recently, a single gain-of-function point mutation of JAK2 was described in myeloproliferative diseases leading to constitutive Jak2 kinase activity, subsequent Stat5a/b activation and involvement of V617F Jak2 in the pathogenesis of myeloproliferative disorders. Materials and Methods: We determined whether JAK2 undergoes the V617F activating mutation during clinical progression of human prostate cancer using a highly sensitive assay (amplification refractory mutation system) and a unique material of fresh specimens from organ-confined or castration-resistant prostate cancers. Results: The JAK2 V617F mutation was not found in any of the normal or malignant prostate samples analyzed in this study. Conclusions: Future work should focus on determining the molecular mechanisms other than V617F mutation of Jak2 resulting in continuous Stat5 activation in clinical prostate cancers.
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Abstract : The main purpose of our work is to understand the role of Foxm1 in the development of prostate cancer, provide information about molecular mechanisms whereby Foxm1 controls epithelial cell proliferation during PCa, and determine whether the inhibition of Foxm1 may potentially be beneficial during PCa therapy, therefore leading to the development of the novel therapeutic target for prostate cancer chemotherapy. During the second year of grant support, we demonstrated that the deletion of Foxm1 from prostate epithelial cells reduced prostate carcinogenesis in mouse model. Decreased carcinogenesis in epFoxm1-l-l TRAMP mice was associated with decreased proliferation of tumor cells and reduced expression of cell cycle regulatory genes Cdc25b, Cyclin B1, and Plk-1. Moreover, we demonstrated that Foxm1 directly regulates the expression of VEGF-A expression in prostate tumor cells, suggesting the role of Foxm1 in prostate tumor angiogenesis. Furthermore, our data demonstrated that deletion of Foxm1 from prostate epithelium decreased prostate cancer metastatsis in TRAMP mice. Foxm1 transcription factor regulates several genes during prostate cancer progression and metastatsis.
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To evaluate the spatial distribution of prostate cancer detected at a single positive biopsy (PBx) and a repeat PBx (rPBx).We evaluated 533 consecutive men diagnosed with prostate cancer who underwent radical prostatectomy using a clinical map document based on XML (cMDX©)-based map model of the prostate. We determined the number of cancer foci, relative tumour volume, Gleason score, zone of origin, localisation, and pathological stage after stratification according to the number of PBx sessions (PBx vs rPBx). The distribution of 3966 prostate cancer foci was analysed and visualised on heat maps. The colour gradient of the heat map was reduced to six colours representing the frequency classification of prostate cancer using an image posterisation effect. Additionally, the spatial distribution of organ-confined prostate cancer between PBx and rPBx was evaluated.Prostate cancer diagnosed on PBx was mostly localised to the apical portion and the peripheral zone of the prostate. Prostate cancer diagnosed on rPBx was more frequently found in the anterior portion and the base of the prostate. Organ-confined prostate cancer foci were mostly localised in the dorsolateral zone of the prostate in men at PBx, whereas men at rPBx had more prostate cancer foci in the anterior portion.The spatial distribution of prostate cancer with rPBx differs significantly from the spatial distribution of prostate cancer with PBx. The whole anterior portion of the prostate should be considered by rPBx.
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Objective To investigate prostate tissue zinc combination of prostate-specific antigen(PSA) for prostate cancer diagnosis.Methods For prostate cancer treatment guidelines in line with the provisions of the prostate puncture indication system,the patients were examined by prostate biopsy,an organization dedicated by ICP-MS determination of the prostate tissue content of zinc,and the rest of the organization routine pathological examination.At the same time,the data of serum PSA,the prostate through the rectum color ultrasound,and the pathology of the prostate puncture were analyzed.Results According to the results of pathology,the patients were divided into benign prostatic hyperplasia and prostate cancer group.Prostatic hyperplasia(n=20):PSA:(6.691±5.920)ng/mL,prostate Zinc:(125.845±75.600)μg/g(wet).Prostate cancer group(n=22):PSA:(68.390±59.000)ng/mL,prostate tissue zinc content:(54.470±32.690)μg/g(wet).Prostate tissue zinc content comparison between the two groups was statistically significant(P0.05).Conclusion Prostate cancer zinc content was significantly lower than that of prostate hyperplasia.The prostate tissue content of zinc reduce prostate cancer diagnosis has a certain value.
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<div>Abstract<p>Metastatic prostate cancer is lethal and lacks effective strategies for prevention or treatment, requiring novel therapeutic approaches. Interleukin-6 (IL-6) is a cytokine that has been linked with prostate cancer pathogenesis by multiple studies. However, the direct functional roles of IL-6 in prostate cancer growth and progression have been unclear. In the present study, we show that IL-6 is produced in distant metastases of clinical prostate cancers. IL-6–activated signaling pathways in prostate cancer cells induced a robust 7-fold increase in metastases formation in nude mice. We further show that IL-6 promoted migratory prostate cancer cell phenotype, including increased prostate cancer cell migration, microtubule reorganization, and heterotypic adhesion of prostate cancer cells to endothelial cells. IL-6–driven metastasis was predominantly mediated by Stat3 and to lesser extent by ERK1/2. Most importantly, pharmacologic inhibition of Jak1/2 by AZD1480 suppressed IL-6–induced signaling, migratory prostate cancer cell phenotypes, and metastatic dissemination of prostate cancer <i>in vivo</i> in nude mice. In conclusion, we demonstrate that the cytokine IL-6 directly promotes prostate cancer metastasis <i>in vitro</i> and <i>in vivo</i> via Jak–Stat3 signaling pathway, and that IL-6–driven metastasis can be effectively suppressed by pharmacologic targeting of Jak1/2 using Jak1/2 inhibitor AZD1480. Our results therefore provide a strong rationale for further development of Jak1/2 inhibitors as therapy for metastatic prostate cancer. <i>Mol Cancer Ther; 13(5); 1246–58. ©2014 AACR</i>.</p></div>
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Objective
To study the effect of puncture length per cubic centimeter of prostate biopsy on the detection rate of prostate cancer.
Methods
The clinical data of 254 prostate cancer patients who had underwent the first prostate biopsy by transrectal ultrasound guidance from September 2013 to November 2017 were retrospectively analyzed. The patients were divided into prostate cancer group and non prostate cancer group according to biopsy pathologic results. The total prostate specific antigen (TPSA), prostate volume, puncture length per needle, puncture length per cubic centimeter of prostate, volume of per needle and percentage of the sampled prostate volume were compared between 2 groups, and the relationship between puncture length per cubic centimeter of prostate and prostate cancer detection rate were analyzed.
Results
Among the 254 patients, the prostate cancer was in 67 cases (prostate cancer group), and the benign lesion was in 187 cases (non prostate cancer group). The prostate cancer detection rate was 26.4% (67/254). There were no statistical differences in age, puncture length per needle and volume of per needle between 2 groups (P>0.05). The TPSA, puncture length per cubic centimeter of prostate and percentage of the sampled prostate volume in prostate cancer group were significantly higher than those in non prostate cancer group: (13.8 ± 6.8) × 103 ng/L vs. (8.5 ± 3.9) × 103ng/L, (3.42 ± 0.12) mm/cm3 vs. (2.83 ± 0.18) mm/cm3 and (2.75 ± 0.31)% vs. (2.24 ± 0.25)%, the prostate volume was significantly lower than that in non prostate cancer group: (45.8 ± 15.5) cm3 vs. (56.3 ± 13.8) cm3, and there were statistical differences (P<0.05). Receiver operating characteristic curve analysis showed that area under the curve was 0.628, 95% CI 0.561 to 0.695. The cutoff value of puncture length per cubic centimeter of prostate was 3.40 mm/cm3, with the sensitivity of 59.8% and the specificity of 64.8%.
Conclusions
The puncture length per cubic centimeter of prostate and percentage of the sampled prostate volume are important morphometric parameters in the determination of prostate cancer. The detection rate of prostate cancer is the highest, when puncture length per cubic centimeter of prostate is ≥ 3.40 mm/cm3.
Key words:
Prostatic neoplasms; Biopsy, needle; Retrospective studies
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Prostate biopsy
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