Gene Expression Signature Predictive of Neuroendocrine Transformation in Prostate Adenocarcinoma
Abstract
:1. Introduction
2. Results
2.1. Sample Selection
2.2. Identification of Differentially Expressed mRNAs, lncRNAs and miRs
2.3. Functional Enrichment Analysis
2.4. Estrogen Pathway in Neuroendocrine Transdifferentiation of Prostate Cancer
2.5. LncRNA and miRNA Expression Profiling
2.6. Gene Signature of Neuroendocrine Prostate Cancer
3. Discussion
4. Materials and Methods
4.1. Prostate Samples Recruitment
4.2. Organotypic Slice Culture (OSC) Preparation and Treatment
4.3. Gene Expression Analysis
4.4. Cluster and Principal Component Analysis
4.5. Functional Analysis
4.6. Gene Set Enrichment Analysis (GSEA)
4.7. External Datasets
4.8. Statistical Analysis
4.9. NEPC Classifier
5. Conclusions
Supplementary Materials
Author Contributions
Acknowledgments
Conflicts of Interest
Abbreviations
NE | neuroendocrine |
NEPC | neuroendocrine prostate cancer |
PCa | prostate cancer |
PSA | prostate specific antigen |
pcRNA | protein-coding RNA |
lncRNA | long non-coding RNA |
miRNA | microRNA |
AUC | area under the curve |
GS | Gleason score |
DEG | differentially expressed gene |
PDX | patient-derived xenograft |
OSC | organotypic slice culture |
GO | gene ontology |
CRPC | castration-resistant prostate cancer |
SERMS | Selective estrogen receptor modulators |
BCR | biochemical relapse |
ROC | receiver operating characteristic |
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NE-like (n = 22) | AdenoPCa (n = 32) | Fisher’s Exact Test p-Value | |
---|---|---|---|
Biochemical relapse | 12 (55%) | 15 (47%) | 0.78 |
Gleason Score | 0.02 | ||
6 | 3 (14%) | 8 (25%) | |
7 | 11 (50%) | 22 (69%) | |
8–9 | 8 (36%) | 2 (6%) | |
Grade | 0.067 | ||
2 | 12 (55%) | 26 (81%) | |
3 | 10 (45%) | 6 (19%) | |
Age at surgery | 65.91 ± 5.1 | 65.86 ± 5.08 | 0.5 |
Initial PSA | 14.2 ± 15.8 | 12.9 ± 12.98 | 0.37 |
# pcRNAs | # lncRNAs | # miRNAs | |
---|---|---|---|
UP | 295 | 24 | 6 |
DOWN | 206 | 15 | 1 |
NAME | EDGES |
---|---|
ESR1 (NUCLEAR) ↑ | 88 |
ANDROGEN RECEPTOR ↓ | 82 |
TFCP2L1 ↑ | 46 |
RUNX2 ↑ | 30 |
CDX2 ↑ | 28 |
C-MYB ↑ | 16 |
DNMT3A ↑ | 15 |
KLF5 ↑ | 14 |
MTOR ↓ | 13 |
NKX2-1 ↑ | 12 |
BCL-3 ↑ | 9 |
MIR-200A-3P ↑ | 9 |
MIR-200B-3P ↑ | 9 |
C-REL ↑ | 8 |
TAF7L ↓ | 8 |
ASCL2 ↑ | 7 |
NR6A1↑ | 7 |
MECOM ↑ | 7 |
BATF ↑ | 6 |
LDHA ↓ | 6 |
MALAT1 ↑ | 6 |
MIR-99A-5P ↓ | 6 |
HOTAIR ↑ | 5 |
IGF-1 ↓ | 5 |
UP-Regulated Genes | DOWN-Regulated Genes |
---|---|
HCAR3 (Nicotinic acid) CXCR2 (Elubrixin, Navarixin, Reparixin, SB332235) KCNQ1 (Azimilide, Indapamide) KCND2 (Dalfampridine) REL (Apilimod) AMD1 (N(1),N(11)-Diethylnorspermine) DDC (Carbidopa) ESR1 (Afimoxifene, Clomifene, Diethylstilbestrol, Megestrol, Raloxifene) NOS2 (GW274150) ADRA2C (Apraclonidine, Azepexole, Besipirdine, Brimonidine, Deriglidole, Dipivefrine, Efaroxan, Fipamezole, Guanethidine, Idazoxan, Lusaperidone, Mianserin, Naphazoline, OPC28326, Piperoxan, Tramazoline, Yohimbine) LPL (Gemfibrozil, Ibrolipim) GPNMB (Glembatumumab vedotin) CACNA1H (Mibefradil, Sipatrigine) GPC3 (Codrituzumab) | PPIE (Ciclosporin) S1PR1 (Fingolimod) CA3 (Acetazolamide) KCNMA1 (Cromoglicic acid, Diazoxide, Hydroflumethiazide, Trichlormethiazide) AR (Androstanolone, Bicalutamide, BMS564929, Cyproterone acetate, Dehydroepiandrosterone, Diethylstilbestrol, Drospirenone, Finasteride, Flutamide, HE3235, LGD-2226, Megestrol O-acetate, Metandienone, Methyltestosterone, Osaterone, Oxandrolone, Oxendolone, RU58841, Silibinin, Testosterone, Zanoterone) MTOR (AZD8055, Everolimus, Ridaforolimus, Sirolimus, Temsirolimus) PTGS1 (Acemetacin, Aspirin, Benoxaprofen, Bromfenac, butibufen, Celecoxib, Diflunisal, Droxicam, Etodolac, Fenbufen, Fenflumizol, Fenoprofen, Ibufenac, Ibuprofen, Indoprofen, Ketorolac, Lornoxicam, Loxoprofen, Meclofenamic acid, Meloxicam, Mesalazine, Nabumetone, NCX701, Nitroaspirin, Oxaprozin, Parsalmide, Phenacetin, Piroxicam, Salsalate, Sulindac, Tarenflurbil, Tenidap, Tenoxicam, Tiaprofenic acid, Timegadine, Tolfenamic acid, Tolmetin, Zaltoprofen, Zomepirac) EPHX2 (AR9281) |
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Ostano, P.; Mello-Grand, M.; Sesia, D.; Gregnanin, I.; Peraldo-Neia, C.; Guana, F.; Jachetti, E.; Farsetti, A.; Chiorino, G. Gene Expression Signature Predictive of Neuroendocrine Transformation in Prostate Adenocarcinoma. Int. J. Mol. Sci. 2020, 21, 1078. https://doi.org/10.3390/ijms21031078
Ostano P, Mello-Grand M, Sesia D, Gregnanin I, Peraldo-Neia C, Guana F, Jachetti E, Farsetti A, Chiorino G. Gene Expression Signature Predictive of Neuroendocrine Transformation in Prostate Adenocarcinoma. International Journal of Molecular Sciences. 2020; 21(3):1078. https://doi.org/10.3390/ijms21031078
Chicago/Turabian StyleOstano, Paola, Maurizia Mello-Grand, Debora Sesia, Ilaria Gregnanin, Caterina Peraldo-Neia, Francesca Guana, Elena Jachetti, Antonella Farsetti, and Giovanna Chiorino. 2020. "Gene Expression Signature Predictive of Neuroendocrine Transformation in Prostate Adenocarcinoma" International Journal of Molecular Sciences 21, no. 3: 1078. https://doi.org/10.3390/ijms21031078