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COL5A2 Promotes Proliferation and Invasion in Prostate Cancer and Is One of Seven Gleason-Related Genes That Predict Recurrence-Free Survival.

ABSTRACT: Extensive research has revealed that the score derived from the Gleason grading system plays a pivotal role in predicting prostate cancer (PCa) progression. However, the underlying involvement of Gleason-related genes in PCa requires further investigation. This study aimed to identify Gleason-related genes with the potential to guide PCa therapy and future research. Differentially expressed genes (DEGs) were identified by comparing PCa tissues with high or low Gleason scores using the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases. R v3.6.1, SPSS v23, and ImageJ software were used for all analyses. An effective recurrence-free survival (RFS) predictive model based on seven Gleason-related genes was established and validated (TCGA, AUC = 0.803; five years, AUC = 0.740; three years, AUC = 0.722; one year, AUC = 0.711; GSE46602, AUC = 0.766; five years, AUC = 0.808; three years, AUC = 0.723; one year, AUC = 0.656; GSE116918, AUC = 0.788; five years, AUC = 0.704; three years, AUC = 0.693; one year, AUC = 0.996). Calibration and nomogram plots were conducted. Weighted correlation network analysis (WGCNA) was used, and COL5A2 was selected for further analysis. The results from in vitro experiments demonstrated that COL5A2 was upregulated in PCa with high Gleason scores. The knockdown of COL5A2 inhibited cell proliferation and invasion in PC-3 and LNCaP cell lines. Meanwhile, COL5A2 displayed a strong association with immune infiltration, which might be an underlying immunotherapy target for PCa. We successfully established a robust RFS predictive model. The findings from this study indicated that COL5A2 could promote cell proliferation and invasion in PCa.

SUBMITTER: Ren X

PROVIDER: S-EPMC8012814 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe incidence rate of prostate cancer is increasing rapidly. This study aims to explore the gene-associated mechanism of prostate cancer biochemical recurrence (BCR) after radical prostatectomy and to construct a biochemical recurrence of prostate cancer prognostic model.MethodsThe DEseq2 R package was used for the differential expression of mRNA. The ClusterProfiler R package was used to analyze the functional enrichment of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to explore related mechanisms. The Survival, Survminer, and My.stepwise R packages were used to construct the prognostic model to predict the biochemical recurrence-free probability. The RMS R package was used to draw the nomogram. For evaluating the prognostic model, the timeROC R package was used to draw the time-dependent ROC curve (receiver operating characteristic curve).ResultTo investigate the association between mRNA and prostate cancer, we performed differential expression analysis on the TCGA (The Cancer Genome Atlas) database. Seven protein-coding genes (VWA5B2, ARC, SOX11, MGAM, FOXN4, PRAME, and MMP26) were picked as independent prognostic genes by regression analysis. Based on their Cox coefficient, a risk score formula was proposed. According to the risk scores, patients were divided into high- and low-risk groups based on the median score. Kaplan-Meier plot curves showed that the low-risk group had a better biochemical recurrence-free probability compared to the high-risk group. The 1-year, 3-year, and 5-year AUCs (areas under the ROC curve) of the model were 77%, 81%, and 86%, respectively. In addition, we built a nomogram based on the result of multivariate Cox regression analysis. Furthermore, we select the GSE46602 dataset as our external validation. The 1-year, 3-year, and 5-year AUCs of BCR-free probability were 83%, 82%, and 80%, respectively. Finally, the levels of seven genes showed a difference between PRAD tissues and adjacent non-tumorous tissues.ConclusionsThis study shows that establishing a biochemical recurrence prediction prognostic model comprising seven protein-coding genes is an effective and precise method for predicting the progression of prostate cancer.

Project description:ObjectivesAlthough the incidence of prostate cancer (PCa) is rapidly increasing in Korea, there are few suitable prediction models for disease recurrence after radical prostatectomy (RP). We established pre- and post-operative nomograms estimating biochemical recurrence (BCR)-free probability after RP in Korean men with clinically localized PCa.Patients and methodsOur sampling frame included 3,034 consecutive men with clinically localized PCa who underwent RP at our tertiary centers from June 2004 through July 2011. After inappropriate data exclusion, we evaluated 2,867 patients for the development of nomograms. The Cox proportional hazards regression model was used to develop pre- and post-operative nomograms that predict BCR-free probability. Finally, we resampled from our study cohort 200 times to determine the accuracy of our nomograms on internal validation, which were designated with concordance index (c-index) and further represented by calibration plots.ResultsOver a median of 47 months of follow-up, the estimated BCR-free rate was 87.8% (1 year), 83.8% (2 year), and 72.5% (5 year). In the pre-operative model, Prostate-Specific Antigen (PSA), the proportion of positive biopsy cores, clinical T3a and biopsy Gleason score (GS) were independent predictive factors for BCR, while all relevant predictive factors (PSA, extra-prostatic extension, seminal vesicle invasion, lymph node metastasis, surgical margin, and pathologic GS) were associated with BCR in the post-operative model. The c-index representing predictive accuracy was 0.792 (pre-) and 0.821 (post-operative), showing good fit in the calibration plots.ConclusionsIn summary, we developed pre- and post-operative nomograms predicting BCR-free probability after RP in a large Korean cohort with clinically localized PCa. These nomograms will be provided as the mobile application-based SNUH Prostate Cancer Calculator. Our nomograms can determine patients at high risk of disease recurrence after RP who will benefit from adjuvant therapy.

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COL5A2 Promotes Proliferation and Invasion in Prostate Cancer and Is One of Seven Gleason-Related Genes That Predict Recurrence-Free Survival.

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