Liquid Biopsy-Based Exo-oncomiRNAs Can Predict Prostate Cancer Aggressiveness
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Extracellular Vesicle-Derived Exo-oncomiRNAs Are Differentially Expressed in Liquid Biopsies from Patients with Prostate Cancer Based on the Degree of Cancer Aggressiveness
2.2. Semen Levels of Exo-oncomiR-221-3p May Help Identify an Aggressive Prostate Cancer Phenotype
2.3. TWEAK Modulates Potential Predicted Targets for oncomiR-221-3p
3. Discussion
4. Materials and Methods
4.1. Cell Culture
4.2. Extracellular Vesicle Isolation from Cell Culture Media and Exo-oncomiRNA Expression Profile Using TaqMan Low-Density Arrays
4.3. Extracellular Vesicle Analysis
4.4. Transmission Electron Microscopy Analysis
4.5. Patients
4.6. Analytical Methods
4.7. Sample Processing
4.8. Extracellular Vesicles Extraction from Liquid Biopsy and Exo-onocomiRNA Quantitative Real-Time PCR Profiling
4.9. Target Search by Bioinformatic Analysis
4.10. Functional Studies
4.11. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Patient’s Characteristics | Mean ± SD | N |
---|---|---|
Age (years) | 63.5 ± 6.35 | 97 |
Prostatic Volume (c.c) | 47.49 ± 23.09 | 97 |
Testosterone (nmol/L) | 14.37 ± 5.07 | 97 |
Total PSA (ng/mL) | 9.57 ± 7.92 | 97 |
N (%) | ||
BMI (kg/m2) | <25 | 25 (25.8) |
25 ≤ x ≤ 29.99 | 50 (51.5) | |
≥30 | 19 (19.6) | |
Total PSA (ng/mL) | ||
<4 | 8 (8.2) | |
4 ≤ x < 10 | 60 (61.9) | |
≥ 10 | 29 (29.9) | |
ISUP-GG | ||
Low Risk | Group I | 32 (33.0) |
Group II | 25 (25.8) | |
High Risk | Group III | 23 (23.7) |
Group IV | 10 (10.3) | |
Group V | 7 (7.2) | |
T pathological stage | ||
≤T2a | 68 (70.1) | |
T3,T4 | 29 (29.9) | |
N pathological stage | ||
NX | 57 (58.8) | |
N0 | 34 (35.1) | |
N1 | 6 (6.2) |
ISUP GG Classification | |||
---|---|---|---|
Patient’s Stratification | Low-Risk | High-Risk | |
(Group I and II) | (Group III, IV and V) | ||
N = 57 | N = 40 | ||
Mean ± SD | Mean ± SD | p-Value | |
Anthropometric parameters | |||
Age (years) | 62.46 ± 6.74 | 64.96 ± 5.52 | 0.066 |
BMI (kg/m2) | 27.97 ± 4.07 | 27.64 ± 3.46 | 0.718 |
Prostatic volume (c.c) | 48.68 ± 24.56 | 45.81 ± 21 | 0.687 |
Glycemic profile | |||
Glucose (mmol/L) | 5.82 ± 1.1 | 6.29 ± 2.26 | 0.388 |
Insulin (pmol/L) | 89.36 ± 58.39 | 87.42 ± 47.09 | 0.841 |
HOMA-IR | 3.46 ± 2.58 | 3.67 ± 2.71 | 0.841 |
HbA1c (%) | 5.74 ± 0.64 | 5.92 ± 0.84 | 0.364 |
Lipid profile | |||
Cholesterol (mmol/L) | 5.03 ± 1.06 | 5.03 ± 1.1 | 0.957 |
HDL cholesterol (mmol/L) | 1.49 ± 0.73 | 1.42 ± 0.39 | 0.672 |
LDL cholesterol (mmol/L) | 3.28 ± 1.3 | 3 ± 0.88 | 0.503 |
Triglycerides (mmol/L) | 1.36 ± 0.74 | 1.55 ± 0.96 | 0.711 |
Hepatic profile | |||
AST (µkat/L) | 0.39 ± 0.19 | 0.33 ± 0.07 | 0.171 |
ALT (µkat/L) | 0.42 ± 0.22 | 0.36 ± 0.11 | 0.402 |
GGT (µkat/L) | 0.7 ± 0.85 | 0.65 ± 0.48 | 0.887 |
Renal profile | |||
Uric acid (µmol/L) | 368.05 ± 83.1 | 456.2 ± 529.55 | 0.376 |
Urea (mmol/L) | 14.26 ± 3.23 | 14.8 ± 5.12 | 0.808 |
Creatinine (μmol/L) | 85.83 ± 18.44 | 80.05 ± 13.97 | 0.072 |
Hormonal profile | |||
SHBG (nmol/L) | 46.13 ± 52.46 | 40.02 ± 16.36 | 0.814 |
Testosterone (nmol/L) | 14.93 ± 4.62 | 13.55 ± 5.63 | 0.101 |
Tumoral marker | |||
Total PSA (μg/L) | 7.71 ± 4.8 | 12.24 ± 10.43 | 0.007 |
Biofluid Biomarker profile | |||
Semen cytokines (pg/mg of total protein) | |||
sTWEAK | 989.62 ± 685.75 | 617.25 ± 447.57 | 0.009 |
Exo-oncomiRNAs in semen—Relative expression levels | |||
miR-221-3p | 0.75 ± 0.6 | 2.17 ± 1.7 | 0.002 |
miR-222-3p | 2.01 ± 2.79 | 3.79 ± 2.92 | 0.006 |
miR-31-5p | 1.05 ± 0.73 | 2.75 ± 2.27 | 0.004 |
Exo-oncomiRNAs in urine—Relative expression levels | |||
miR-193-3p | 0.12 ± 0.12 | 0.06 ± 0.05 | 0.037 |
miR-423-5p | 0.05 ± 0.05 | 0.04 ± 0.03 | 0.034 |
95% CI | ||||||||
---|---|---|---|---|---|---|---|---|
ROC Model | AUC | Error | p-Value | Lower | Upper | Sensivity (%) | Specificity (%) | % Correct Diagnosis |
Age | 0.610 | 0.058 | 0.066 | 0.496 | 0.724 | 85 | 75.4 | 62.9 |
Total PSA | 0.662 | 0.056 | 0.007 | 0.552 | 0.772 | 85 | 31.6 | 63.9 |
sTWEAK | 0.708 | 0.072 | 0.009 | 0.567 | 0.848 | 85.7 | 52.8 | 71.9 |
exo-oncomiR-221-3p | 0.79 | 0.078 | 0.002 | 0.638 | 0.943 | 86.7 | 55.6 | 78.6 |
exo-oncomiR-222-3p | 0.758 | 0.08 | 0.006 | 0.601 | 0.915 | 86.7 | 74.1 | 66.7 |
exo-oncomiR-31-5p | 0.768 | 0.082 | 0.004 | 0.607 | 0.929 | 86.7 | 48.1 | 76.2 |
Total PSA + Age | 0.704 | 0.054 | 0.001 | 0.597 | 0.810 | 85 | 70.2 | 67 |
Total PSA + sTWEAK | 0.738 | 0.072 | 0.003 | 0.597 | 0.879 | 85.7 | 47.2 | 71.9 |
Total PSA + exo-oncomiR-221-3p | 0.864 | 0.063 | <0.001 | 0.74 | 0.998 | 86.7 | 55.6 | 83.3 |
Total PSA + exo-oncomiR-222-3p | 0.78 | 0.071 | 0.003 | 0.641 | 0.919 | 86.7 | 55.6 | 73.8 |
Total PSA + exo-oncomiR-31-5p | 0.832 | 0.07 | <0.001 | 0.695 | 0.969 | 86.7 | 51.9 | 81 |
sTWEAK + Age | 0.709 | 0.069 | 0.009 | 0.574 | 0.844 | 85.7 | 50 | 66.7 |
sTWEAK + exo-oncomiR-221-3p | 0.841 | 0.073 | <0.001 | 0.698 | 0.983 | 85.7 | 69.2 | 82.5 |
sTWEAK + exo-oncomiR-222-3p | 0.745 | 0.086 | 0.012 | 0.576 | 0.913 | 85.7 | 42.3 | 70 |
sTWEAK + exo-oncomiR-31-5p | 0.808 | 0.077 | 0.001 | 0.657 | 0.958 | 85.7 | 61.5 | 77.5 |
exo-oncomiR-221-3p + Age | 0.802 | 0.077 | 0.001 | 0.651 | 0.954 | 86.7 | 33.3 | 76.2 |
exo-oncomiR-221-3p + exo-oncomiR-222-3p | 0.802 | 0.078 | 0.001 | 0.65 | 0.955 | 86.7 | 63 | 76.2 |
exo-oncomiR-221-3p + exo-oncomiR-31-5p | 0.8 | 0.079 | 0.001 | 0.646 | 0.954 | 86.7 | 55.6 | 81 |
exo-oncomiR-222-3p + Age | 0.751 | 0.081 | 0.008 | 0.592 | 0.909 | 86.7 | 66.7 | 73.8 |
exo-oncomiR-222-3p + exo-oncomiR-31-5p | 0.8 | 0.077 | 0.001 | 0.649 | 0.951 | 86.7 | 55.6 | 81 |
exo-oncomiR-31-5p + Age | 0.778 | 0.078 | 0.003 | 0.625 | 0.930 | 86.7 | 44.4 | 73.8 |
Total PSA + sTWEAK + Age | 0.746 | 0.067 | 0.002 | 0.614 | 0.878 | 85.7 | 44.4 | 73.7 |
Total PSA + sTWEAK + exo-oncomiR-221-3p | 0.863 | 0.068 | <0.001 | 0.73 | 0.996 | 85.7 | 69.2 | 85 |
Total PSA + sTWEAK + exo-oncomiR-222-3p | 0.758 | 0.086 | 0.008 | 0.59 | 0.926 | 85.7 | 46.2 | 75 |
Total PSA + sTWEAK + exo-oncomiR-31-5p | 0.824 | 0.076 | 0.001 | 0.675 | 0.974 | 85.7 | 73.1 | 77.5 |
Total PSA + exo-oncomiR-221-3p + Age | 0.889 | 0.056 | <0.001 | 0.780 | 0.998 | 85.7 | 37 | 83.3 |
Total PSA + exo-oncomiR-221-3p + exo-oncomiR-222-3p | 0.872 | 0.06 | <0.001 | 0.755 | 0.988 | 86.7 | 59.3 | 83.3 |
Total PSA + exo-oncomiR-221-3p + exo-oncomiR-31-5p | 0.854 | 0.067 | <0.001 | 0.724 | 0.985 | 86.7 | 51.9 | 83.3 |
Total PSA + exo-oncomiR-222-3p + Age | 0.840 | 0.064 | <0.001 | 0.714 | 0.965 | 86.7 | 37 | 83.3 |
Total PSA + exo-oncomiR-222-3p + exo-oncomiR-31-5p | 0.849 | 0.069 | <0.001 | 0.713 | 0.985 | 86.7 | 59.3 | 83.3 |
Total PSA + exo-oncomiR-31-5p + Age | 0.862 | 0.061 | <0.001 | 0.743 | 0.981 | 86.7 | 37 | 83.3 |
sTWEAK + exo-oncomiR-221-3p + Age | 0.854 | 0.067 | <0.001 | 0.723 | 0.986 | 85.7 | 23.7 | 77.5 |
sTWEAK + exo-oncomiR-221-3p + exo-oncomiR-222-3p | 0.857 | 0.069 | <0.001 | 0.721 | 0.993 | 85.7 | 76.9 | 87.5 |
sTWEAK + exo-oncomiR-221-3p + exo-oncomiR-31-5p | 0.841 | 0.073 | <0.001 | 0.698 | 0.983 | 85.7 | 69.2 | 82.5 |
sTWEAK + exo-oncomiR-222-3p + Age | 0.764 | 0.078 | 0.006 | 0.611 | 0.917 | 85.7 | 50 | 72.5 |
sTWEAK + exo-oncomiR-222-3p + exo-oncomiR-31-5p | 0.83 | 0.073 | 0.001 | 0.687 | 0.972 | 85.7 | 53.8 | 82.5 |
sTWEAK + exo-oncomiR-31-5p + Age | 0.821 | 0.074 | 0.001 | 0.677 | 0.966 | 85.7 | 34.6 | 75 |
exo-oncomiR-221-3p + exo-oncomiR-222-3p + exo-oncomiR-31-5p | 0.807 | 0.076 | 0.001 | 0.658 | 0.956 | 86.7 | 51.9 | 83.3 |
exo-oncomiR-221-3p + exo-oncomiR-222-3p + Age | 0.820 | 0.074 | 0.001 | 0.675 | 0.965 | 86.7 | 25.9 | 76.2 |
exo-oncomiR-221-3p + exo-oncomiR-31-5p + Age | 0.812 | 0.074 | 0.001 | 0.668 | 0.957 | 86.7 | 37 | 78.6 |
exo-oncomiR-222-3p + exo-oncomiR-31-5p + Age | 0.802 | 0.075 | 0.001 | 0.655 | 0.950 | 86.7 | 44 | 78.6 |
Total PSA + sTWEAK + exo-oncomiR-221-3p + exo-oncomiR-222-3p | 0.86 | 0.071 | <0.001 | 0.721 | 0.999 | 85.7 | 69.2 | 85 |
Total PSA + sTWEAK + exo-oncomiR-221-3p + exo-oncomiR-31-5p | 0.86 | 0.069 | <0.001 | 0.724 | 0.995 | 85.7 | 69.2 | 85 |
Total PSA + sTWEAK + exo-oncomiR-222-3p + exo-oncomiR-31-5p | 0.83 | 0.076 | 0.001 | 0.682 | 0.978 | 85.7 | 65.4 | 82.5 |
Age + Total PSA + sTWEAK + exo-oncomiR-221-3p | 0.879 | 0.62 | <0.001 | 0.757 | 1 | 85.7 | 23.1 | 85 |
Age + Total PSA + sTWEAK + exo-oncomiR-222-3p | 0.808 | 0.074 | 0.001 | 0.662 | 0.953 | 85.7 | 50 | 82.5 |
Age + Total PSA + sTWEAK + exo-oncomiR-31-5p | 0.849 | 0.069 | <0.001 | 0.715 | 0.983 | 85.7 | 53.2 | 82.5 |
Age + Total PSA + exo-oncomiR-221-3p + exo-oncomiR-222-3p | 0.894 | 0.053 | <0.001 | 0.789 | 0.998 | 86.7 | 56.7 | 83.3 |
Age + Total PSA + exo-oncomiR-221-3p + exo-oncomiR-31-5p | 0.879 | 0.059 | <0.001 | 0.764 | 0.994 | 86.7 | 54.3 | 83.3 |
Age + Total PSA + exo-oncomiR-222-3p + exo-oncomiR-31-5p | 0.867 | 0.059 | <0.001 | 0.752 | 0.982 | 86.7 | 49.2 | 81 |
Age + sTWEAK + exo-oncomiR-221-3p + exo-oncomiR-222-3p | 0.868 | 0.061 | <0.001 | 0.748 | 0.988 | 86.7 | 46.5 | 80 |
Age + sTWEAK + exo-onxomiR-221-3p + exo-oncomiR-31-5p | 0.857 | 0.067 | <0.001 | 0.726 | 0.988 | 85.7 | 76.9 | 80 |
Age + sTWEAK + exo-oncomiR-222-3p + exo-oncomiR-31-5p | 0.832 | 0.070 | 0.001 | 0.695 | 0.969 | 86.7 | 46.5 | 80 |
Age + exo-oncomiR-221-3p + exo-oncomiR-222-3p + exo-oncomiR-31-5p | 0.820 | 0.072 | 0.001 | 0.678 | 0.962 | 86.7 | 48.1 | 81 |
Total PSA + exo-oncomiR-221-3p + exo-oncomiR-222-3p + exo-oncomiR-31-5p | 0.874 | 0.061 | <0.001 | 0.754 | 0.995 | 86.7 | 55.6 | 83.3 |
sTWEAK + exo-oncomiR-221-3p + exo-oncomiR-222-3p + exo-oncomiR-31-5p | 0.86 | 0.068 | <0.001 | 0.726 | 0.994 | 85.7 | 73.1 | 85 |
Total PSA + sTWEAK + exo-oncomiR-221-3p + exo-oncomiR-222-3p + exo-oncomiR-31-5p | 0.865 | 0.069 | <0.001 | 0.73 | 1 | 85.7 | 69.2 | 85 |
Age + Total PSA + sTWEAK + exo-oncomiR-221-3p + exo-oncomiR-222-3p | 0.879 | 0.062 | <0.001 | 0.757 | 1 | 86.7 | 70.4 | 87.5 |
Age + Total PSA + sTWEAK + exo-oncomiR-221-3p + exo-oncomiR-31-5p | 0.879 | 0.062 | <0.001 | 0.758 | 1 | 86.7 | 57.9 | 85 |
Age + Total PSA + sTWEAK + exo-oncomiR-222-3p + exo-oncomiR-31-5p | 0.857 | 0.065 | <0.001 | 0.729 | 0.985 | 85.7 | 58.3 | 85 |
Age + Total PSA + exo-oncomiR-221-3p + exo-oncomiR-222-3p + exo-oncomiR-31-5p | 0.896 | 0.053 | <0.001 | 0.793 | 0.999 | 86.7 | 57.9 | 83.3 |
Age + sTWEAK + exo-oncomiR-221-3p + exo-oncomiR-222-3p + exo-oncomiR-31-5p | 0.874 | 0.061 | <0.001 | 0.755 | 0.992 | 85.7 | 63.8 | 82.5 |
Age + Total PSA + sTWEAK + exo-oncomiR-221-3p + exo-oncomiR-222-3p + exo-oncomiR-31-5p | 0.879 | 0.062 | <0.001 | 0.757 | 1 | 85.7 | 68.9 | 87.5 |
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Ruiz-Plazas, X.; Altuna-Coy, A.; Alves-Santiago, M.; Vila-Barja, J.; García-Fontgivell, J.F.; Martínez-González, S.; Segarra-Tomás, J.; Chacón, M.R. Liquid Biopsy-Based Exo-oncomiRNAs Can Predict Prostate Cancer Aggressiveness. Cancers 2021, 13, 250. https://doi.org/10.3390/cancers13020250
Ruiz-Plazas X, Altuna-Coy A, Alves-Santiago M, Vila-Barja J, García-Fontgivell JF, Martínez-González S, Segarra-Tomás J, Chacón MR. Liquid Biopsy-Based Exo-oncomiRNAs Can Predict Prostate Cancer Aggressiveness. Cancers. 2021; 13(2):250. https://doi.org/10.3390/cancers13020250
Chicago/Turabian StyleRuiz-Plazas, Xavier, Antonio Altuna-Coy, Marta Alves-Santiago, José Vila-Barja, Joan Francesc García-Fontgivell, Salomé Martínez-González, José Segarra-Tomás, and Matilde R. Chacón. 2021. "Liquid Biopsy-Based Exo-oncomiRNAs Can Predict Prostate Cancer Aggressiveness" Cancers 13, no. 2: 250. https://doi.org/10.3390/cancers13020250