scholarly journals Clinical Evaluation of FOXO1 as a Tumor Suppressor in Prostate Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Ning Yang ◽  
Jiawen Wu ◽  
Tiancheng Zhang ◽  
Fan Yang ◽  
Jinyan Shao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Progression ◽  
Specific Antigen ◽  
Cell Counting ◽  
Pcr Analysis ◽  
Clinical Role ◽  
Pathological Staging ◽  
Kaplan Meier

Objective. Prostate cancer (PCa) is considered the most serious cancer in the world. Nevertheless, the accuracy of current biomarkers, such as pathological staging, Gleason’s score, and serum prostate-specific antigen (PSA) levels, is limited. FOXO1 is a key downstream effector of PTEN and a tumor suppressor in PCA, which has been reported extensively. However, the clinical relevance of FOXO1 in PCa remains unclear. Methods. In this study, we first detected its expression in four public databases to explore the clinical role of FOXO1. Verification of the knockdown effect of FOXO1 siRNA was performed by real-time PCR analysis. Changes in cell viability were assessed using cell counting kit-8 (CCK-8) assays. In addition, we verified the effect of FOXO1 on the PCa cell cycle using a cell cycle assay. Results. Herein, we found that FOXO1 was significantly downregulated in PCa tissues and was significantly associated with Gleason’s score, age, biochemical recurrence (BCR), and lymph node (LN) status, while FOXO1 expression was independent of pathological staging and preoperative PSA levels. The Kaplan-Meier survival analysis showed that PCA patients with high FOXO1 expression were less likely to develop BCR compared with patients with low FOXO1 expression. In terms of function, FOXO1 inhibition significantly promoted the proliferation and cell cycle progression of PCa cells. Conclusions. In summary, our study suggests that FOXO1 may be one of the prognostic factors that describe the risk of PCa for BCR. These results suggest that FOXO1 may be a therapeutic target for PCa.

CCP score and risk stratification for prostate cancer patients at biopsy.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 47-47 ◽  
Author(s):  
E. David Crawford ◽  
Neal Shore ◽  
Peter T. Scardino ◽  
John W. Davis ◽  
Jonathan D. Tward ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Risk Stratification ◽  
Gleason Score ◽  
Cell Cycle Progression ◽  
Specific Antigen ◽  
Risk Category ◽  
Cycle Progression ◽  
Aggressive Cancer ◽  
Cancer Aggressiveness

47 Background: New prognostic markers for prostate cancer play an important role in addressing the controversies of over diagnosis and treatment. The cell cycle progression score (CCP) (Prolaris, Myriad Genetic Laboratories, Inc.) is a new RNA-based marker, which improved the prediction of prostate cancer aggressiveness in eight separate cohorts. Each one-unit increase in CCP score corresponds with approximately a doubling of the risk of the studied event (recurrence or death from prostate cancer). In this analysis, we characterized the CCP score distribution from our initial CCP signature commercial testing. Methods: Our current laboratory database was evaluated for patients whose biopsy was analyzed with the CCP test and whose clinicopathologic data was collected by the ordering physician. Formalin fixed, prostate biopsy tissue from 1,648 patients diagnosed with adenocarcinoma ordered by more than 300 physicians were analyzed. The CCP score was calculated by measuring the RNA expression of 31 cell cycle progression genes normalized to 15 housekeeping genes. Results: Of the 1,648 samples that contained sufficient carcinoma (more than 0.5mm linear extent), 1,604 (97.3%) provided quality RNA for analysis. This retrospective analysis showed a normal distribution for the CCP score ranging from −2.9 to 3.1. Correlation with Gleason score was r=0.35. A relative classification of cancer aggressiveness based on CCP of approximately1,200 patients from multiple cohorts was developed to interpret how the patient’s CCP score compared to that of patients within the same AUA risk category. The thresholds between each of the five intervals are one unit of CCP score apart, with the "consistent" interval centered at the median CCP score. Based on the CCP score, 27.9% of men had a less aggressive cancer compared to the clinicopathologic prediction and were assigned to a lower risk group while 27.6% of patients had a more aggressive cancer. Conclusions: The CCP signature test is a novel assay that can improve risk stratification for men with prostate adenocarcinoma independent of the Gleason score and prostate-specific antigen level. Over 50% of men initially tested in the commercial assay were assigned to a different risk category than predicted by clinicopathologic features alone.

scholarly journals The tumor suppressor miR-642a-5p targets Wilms Tumor 1 gene and cell-cycle progression in prostate cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dianne J. Beveridge ◽  
Kirsty L. Richardson ◽  
Michael R. Epis ◽  
Rikki A. M. Brown ◽  
Lisa M. Stuart ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Wilms Tumor ◽  
Tumor Model ◽  
Negative Control ◽  
Wilms Tumor 1

AbstractRNA-based therapeutics are emerging as innovative options for cancer treatment, with microRNAs being attractive targets for therapy development. We previously implicated microRNA-642a-5p (miR-642a-5p) as a tumor suppressor in prostate cancer (PCa), and here we characterize its mode of action, using 22Rv1 PCa cells. In an in vivo xenograft tumor model, miR-642a-5p induced a significant decrease in tumor growth, compared to negative control. Using RNA-Sequencing, we identified gene targets of miR-642a-5p which were enriched for gene sets controlling cell cycle; downregulated genes included Wilms Tumor 1 gene (WT1), NUAK1, RASSF3 and SKP2; and upregulated genes included IGFBP3 and GPS2. Analysis of PCa patient datasets showed a higher expression of WT1, NUAK1, RASSF3 and SKP2; and a lower expression of GPS2 and IGFBP3 in PCa tissue compared to non-malignant prostate tissue. We confirmed the prostatic oncogene WT1, as a direct target of miR-642a-5p, and treatment of 22Rv1 and LNCaP PCa cells with WT1 siRNA or a small molecule inhibitor of WT1 reduced cell proliferation. Taken together, these data provide insight into the molecular mechanisms by which miR-642a-5p acts as a tumor suppressor in PCa, an effect partially mediated by regulating genes involved in cell cycle control; and restoration of miR-642-5p in PCa could represent a novel therapeutic approach.

Predicting radical prostatectomy outcome: Cell cycle progression (CCP) score compared with primary Gleason grade among men with clinical Gleason less than 7 who are upgraded to Gleason 7.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 13-13 ◽  
Author(s):  
Matthew R. Cooperberg ◽  
Stephen J. Freedland ◽  
Thorsten Schlomm ◽  
Julia E. Reid ◽  
Steven Stone ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Risk Assessment ◽  
Radical Prostatectomy ◽  
Cell Cycle Progression ◽  
Specific Antigen ◽  
Gleason Grade ◽  
Cycle Progression ◽  
Major Barrier ◽  
Cancer Aggressiveness

13 Background: Improved prognostic markers for prostate cancer are an important part of addressing the issue of over- and under-treatment in prostate cancer. Gleason score (GS), prostate-specific antigen and clinical stage work well for population risk assessment but lack precision for individual patients. Concern over undergrading on biopsy is felt to be a major barrier to increasing use of active surveillance. Molecular analysis can further refine risk assessment as demonstrated by the cell cycle progression (CCP) score (Prolaris) which has been shown to predict prostate cancer aggressiveness in eight separate cohorts. In these studies, CCP scores typically ranged from −2 to +3 with each one−unit increase in CCP score corresponding to approximately a doubling of the risk of the studied event (recurrence or death from prostate cancer). In the present investigation, we sought to assess how upgrading compared with CCP in predicting failure after radical prostatectomy (RP). Methods: In this study, we examined men from three cohorts (UCSF, Martini Clinic, and Durham VAMC) with clinical GS (cGS) less than 7 who had pathologic GS (pGS) 3+4 or 4+3. The CCP assay was performed using RP specimen from UCSF and biopsy material from the other cohorts. We compared the rates of biochemical recurrence (BCR) as predicted by pGS, CAPRA, or CCP score alone versus CAPRA combined with CCP score using a Cox proportional hazards model stratified by cohort. Results: Among the 230 men with cGS less than 7 and pGS equal to 7 included in this analysis, 207 had pGS 3+4 and 57 had BCR; 23 had pGS 4+3; and eight had BCR. There was no difference in BCR based on GS (p=0.8) or CAPRA (p=0.4). In contrast, CCP score alone and a pre-defined score combining the CCP score and CAPRA were prognostic of BCR (HR=1.82 [95 % CI 1.32-2.52; p<0.001]; HR=1.84 [95 % CI 1.10-3.05; p=0.021] respectively). Conclusions: These data indicate that the risk of BCR is indistinguishable in men with cGS less than 7 who have pGS 3+4 or 4+3. However, the CCP assay does provide stratification of this risk. Tests that can predict BCR on biopsy will aid in initial therapeutic decision making.

Sequential and intermittent docetaxel (D) and imatinib (Im) in hormone-refractory prostate cancer patients (NYU 04–47)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16108-e16108
Author(s):  
A. Gómez-Pinillos ◽  
H. Ballard ◽  
G. Shelton ◽  
M. M. Reilly ◽  
A. Chachoua ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Progression Free Survival ◽  
Symptomatic Improvement ◽  
Treatment Schedule ◽  
Cycle Progression ◽  
Prior Chemotherapy ◽  
Taste Changes ◽  
Kaplan Meier

e16108 Background: Platelet-derived growth factor is frequently expressed in advanced prostate cancer (PC) lesions where it supports PC cell growth and neo-angiogenesis. Im. is a PDGF inhibitor that blocks cell cycle in G1-S due to MEK/erk inhibition. D blocks cell cycle progression in G2-M. Sequential block of the cell cycle progression in G2-M followed by G1-S may increase anti-tumor responses. The phase II study dose of sequential D on day 1 and Im started 24–36h later given daily for 14 d was established in a previous phase I. Methods: Eligibility: at least 2 prior hormone manipulations and up to one prior chemotherapy, PSA>5ng/ml, ECOG PS 0–2. Treatment schedule: D 70mg/m2 day 1 followed 24–36 hours later by Im 600mg PO daily × 14 days. Cycles were repeated every 21d until toxicity or progression. Pegfilgrastim was given each cycle for neutropenia prevention. A two steps design was planned to assess activity (PSA decline >50% and/or measurable or symptomatic response) and tolerance including interim analysis to determine if 37 patients (pts) should be enrolled. Results: Of 15 pts enrolled, 13 had metastasis and 5(33%) received prior chemotherapy. There were 98 cycles of trial therapy administered and 9 events (PSA or bone progression) registered at the time of analysis. Median baseline PSA 73,5ng/ml (2.1–1954.3). Median follow-up estimated by inverse Kaplan Meier: 308 days (CI95%, 133–482). Median of cycles administrated 6 (1–12). PSA decline >50% observed in 7/15pts (46.67%) of which 3 was >80% (20%). PSA decline <50%, observed in 6/15(40%). 2/15(15.3%) were non-responders. Pain scores improved in all symptomatic pts. Median duration of response was 162 days (42- 281). Estimated median progression free survival by Kaplan-Meier was 155 days (CI95%, 80–339). Toxicity: there was G1–2 fatigue, anorexia, weight change in 66% pts; nausea, vomiting, taste changes in 66% pts, anemia in 46% and neuropathy in 46% pts. G3 fatigue in 2 pts, neuropathy and CHF in 1 pt. No G4 toxicities were observed. Conclusions: Sequential and intermittent D every 21 days and Im for 14 days is tolerable and active by PSA decline and symptomatic improvement. Compared to previous report with weekly D and continuous Im, this alternative schedule appears to have similar activity with better tolerance. [Table: see text]

1955-P: GLP-1R Activation Attenuates Prostate Cancer Growth via Inhibiting Cell Cycle Progression

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 1955-P
Author(s):  
TORU SHIGEOKA ◽  
TAKASHI NOMIYAMA ◽  
TAKAKO KAWANAMI ◽  
YURIKO HAMAGUCHI ◽  
TOMOKO TANAKA ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cancer Growth ◽  
Cycle Progression

scholarly journals MiR-5195-3p Functions as a Tumor Suppressor in Prostate Cancer via Targeting CCNL1

2020 ◽  
Author(s):  
Xing Zeng ◽  
Zhiquan Hu ◽  
Yuanqing Shen ◽  
Xian Wei ◽  
Jiahua Gan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Clinical Significance ◽  
Cox Regression ◽  
Tumor Formation ◽  
Luciferase Reporter ◽  
Cell Cycle Distribution ◽  
Survival Prognosis

Abstract BackgroundAccumulating evidence indicates miR-5195-3p exerts tumor suppressive role in several tumors. However, there is limited research on the clinical significance and biological function of miR-5195-3p in prostate cancer (PCa).MethodsExpression levels of miR-5195-3p and Cyclin L1 (CCNL1) were determined using quantitative real-time PCR. The clinical significance of miR-5195-3p in PCa patients was evaluated using Kaplan-Meier survival analysis and Cox regression models. Cell proliferation and cell cycle distribution were measured by CCK-8 assay and flow cytometry, respectively. The association between miR-5195-3p and CCNL1 was analyzed by luciferase reporter assay.ResultsMiR-5195-3p expression levels were significantly downregulated in 69 paired PCa tissues compared with matched adjacent normal tissues. The decreased miR-5195-3p expression was associated with Gleason score and TNM stage, as well as worse survival prognosis. The in vitro experiments showed that miR-5195-3p overexpression suppressed the proliferation and cell cycle G1/S transition in PC-3 and DU145 cells. Elevated miR-5195-3p abundance was also demonstrated to impair tumor formation in vivo using PC-3 xenografts. Mechanistically, Cyclin L1 (CCNL1) was a direct target of miR-5195-3p in PCa cells, which was inversely correlated with miR-5195-3p in PCa tissues. Importantly, CCNL1 knockdown imitated, while overexpression reversed the effects of miR-5195-3p overexpression on PCa cell proliferation and cell cycle G1/S transition.ConclusionsOur data suggests that miR-5195-3p functions as a tumor suppressor via downregulating G1/S related CCNL1 expression in PCa.

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