Identification and Validation of a Five MicroRNA Signature Predictive of Prostate Cancer Recurrence and Metastasis: A Cohort Study

Abstract

Background: MicroRNA (miRNA) have been shown to be important in regulating gene expression in prostate cancer. We used next generation miRNA sequencing to conduct a whole miRNome analysis to identify miRNAs associated with prostate cancer metastasis.Methods: We conducted discovery and validation analyses of miRNAs among a total of 546 men who underwent surgery for prostate cancer using the development of metastasis as an endpoint. Genome wide analysis was conducted among the discovery group (n=31) to identify new miRNAs associated with prostate cancer metastasis. Selected miRNAs were then analyzed using qPCR on prostatectomy specimens from an independent cohort (n=515) to determine whether their expression could predict the development of metastasis after surgery. To examine the biology underlying these associations, we created prostate cancer cell lines which overexpressed miR-301a for in vitro and in vivo functional assays.Results: We identified 33 miRNAs associated with prostate cancer metastasis and selected a panel comprising miRs-301a, 652, 454, 223 and 139 which strongly predicted metastasis (AUC=95.3%, 95%C.I.:84%-99%). Among the validation cohort, the 15-year metastasis-free survival was 77.5% (95% C.I.:63.9%-86.4%) for patients with a high miRNA panel score and 98.8% (95% C.I.:94.9%-99.7%, p<0.0001 for difference) for those with a low score. After adjusting for grade, stage, and PSA, the hazard ratio for metastasis was 4.3 (95% C.I.: 1.7-11.1, p=0.002) for patients with a high miRNA panel score, compared to those with a low score. Prostate cancer cell lines overexpressing miR-301a had in significantly higher tumor growth and metastasis in a xenograft mouse model.Conclusions: A panel of miRNAs is associated with prostate cancer metastasis. These could be used as potential new prognostic factors in the surgical management of prostate cancer.

MicroRNA‐139 is a predictor of prostate cancer recurrence and inhibits growth and migration of prostate cancer cells through cell cycle arrest and targeting IGF1R and AXL

“…The secondary endpoint was the development of biochemical recurrence based on serum PSA levels. The baseline characteristics of the Study Cohort have been described previously …”

“…4,8 By whole miRNome sequencing we previously identified 33 miRNAs associated with metastatic PCa following prostatectomy. 9 Out of 33 miRNAs a panel of five miRs-301a, 652, 454, 223, and 139 was selected that strongly predicted metastasis (area under the curve = 95.3%, 95% confidence interval [CI]: 84%-99%). 9 Three of these miRNAs were overexpressed, while two were underexpressed in prostate tumors.…”

“…9 Out of 33 miRNAs a panel of five miRs-301a, 652, 454, 223, and 139 was selected that strongly predicted metastasis (area under the curve = 95.3%, 95% confidence interval [CI]: 84%-99%). 9 Three of these miRNAs were overexpressed, while two were underexpressed in prostate tumors. We have already determined the mechanism of action of miRNAs that were upregulated in our panel, miR-301a, miR-454, and miR-652.…”

“…The secondary endpoint was the development of biochemical recurrence based on serum PSA levels. The baseline characteristics of the Study Cohort have been described previously 9. The median miR-139 normalized gene expression was significantly lower among patients who developed recurrence compared with patients who did not (0.317 vs 0.377, P < .0001) and among…”

miR-301a expression: A prognostic marker for prostate cancer

“…Recently, Xie et al reported that miR301 increases the invasiveness of CaP cells by activating TGF-β1/Smad/MMP9 signaling [30], and another cohort study confirmed that the expression of miR301 could be a predictive marker for the recurrence and metastasis of CaP [31]. These studies highlight the importance of miR301a, and analyzing more samples and identifying potential targets of miR-301a may suggest whether miR-301a could be prognostic marker for prostate cancer.…”