Validation of the four-miRNA biomarker panel MiCaP for prediction of long-term prostate cancer outcome

Abstract

Improved prostate cancer prognostic biomarkers are urgently needed. We previously identified the four-miRnA prognostic biomarker panel MiCaP ((miR-23a-3p × miR-10b-5p)/(miR-133a-3p × miR-374b-5p)) for prediction of biochemical recurrence (BCR) after radical prostatectomy (RP). Here, we identified an optimal numerical cutoff for MiCaP dichotomisation using a training cohort of 475 RP patients and tested this in an independent cohort of 281 RP patients (PCA281). Kaplan-Meier, uni-and multivariate Cox regression analyses were conducted for multiple endpoints: BCR, metastatic-(mPC) and castration-resistant prostate cancer (CRPC), prostate cancer-specific (PCSS) and overall survival (OS). Functional effects of the four MiCaP miRNAs were assessed by overexpression and inhibition experiments in prostate cancer cell lines. We found the numerical value 5.709 optimal for MiCaP dichotomisation. This was independently validated in PCA281, where a high MiCaP score significantly [and independent of the Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) score] predicted BCR, progression to mPC and CRPC, and PCSS, but not OS. Harrell's C-index increased upon addition of MiCaP to CAPRA-S for all endpoints. Inhibition of miR-23a-3p and miR-10b-5p, and overexpression of miR-133a-3p and miR-374b-5p significantly reduced cell survival. Our results may promote future implementation of a MiCaP-based test for improved prostate cancer risk stratification. Prostate cancer is a significant healthcare problem, globally causing > 300,000 deaths/year 1. While many prostate cancers are indolent, a subset progress to metastatic (mPC) and castration-resistant (CRPC) disease, causing significant morbidity and mortality. Routine prognostic tools for early-stage prostate cancer are suboptimal, causing overtreatment of indolent prostate cancer and undertreatment of aggressive prostate cancer 2. Thus, novel prognostic biomarkers are urgently needed to improve risk stratification and guide individualised treatment. MicroRNAs (miRNAs) are small noncoding RNAs that bind complementary sequences in target messenger RNAs (mRNAs), inhibiting mRNA translation and stability 3. miRNAs regulate genes involved in key cellular processes, including differentiation, cell-cycle control, and migration. Furthermore, dysregulation of miRNA expression is a hallmark of cancer development and progression 3,4 , and miRNAs have shown promising prognostic biomarker potential in prostate cancer 5-9. We recently identified the four-miRNA prognostic model MiCaP ((miR-23a-3p × miR-10b-5p)/(miR-133a-3p × miR-374b-5p)) 9 as an independent predictor of biochemical recurrence (BCR) in radical prostatectomy (RP) patients 9. Here, to promote future clinical implementation of a MiCaP test, we identified an optimal numerical cutoff value for MiCaP dichotomisation using a merged training cohort of 475 RP patients (PCA475)

MiRNA biomarkers in cancers of the male reproductive system: Are we approaching clinical application?

“…As a proof‐of‐principle, the authors also showed that the MiCaP score significantly associated with BCR in plasma samples of 111 RP patients 33 . Such results were independently validated in yet another study with RP specimens from 475 patients 34 . Moreover, levels of several other miRNAs assessed in RP samples (in tumour and/or adjacent tissue) also associated with BCR, some even after adjusting for classical clinicopathological variables 35–46 …”

MicroRNA-32 Suppression: its Effects on Prostate Cancer Cells’ Capability to Proliferate and Migrate

“…Similarly, miRNAs have demonstrated predictive solid biomarker potential in PCa, and the dysregulation of these miRNA expressions is a hallmark of neoplasia formation and progression [14]. Though numerous miRNAs, such as miR-20b, miR-30, miR-32, miR-34, miR-199b, miR-210, miR-532, and miR-622 have been established to encourage or repress metastasis in PCa, many other miRNAs that play critical regulatory roles in metastasis have not yet been discovered [15][16][17][18][19][20]. MiR-32 is an intronic miRNA located in intron 14 of c9orf5, the gene encoding transmembrane protein 245 (TMEM245), on chromosome 9.…”

Integrative Analysis and Experimental Validation Indicated That SNHG17 Is a Prognostic Marker in Prostate Cancer and a Modulator of the Tumor Microenvironment via a Competitive Endogenous RNA Regulatory Network

“…More importantly, they have been demonstrated as prognostic biomarkers in prostate cancer and were proven to influence the malignant behavior of PC cells. Strand et al identified a four-miRNA prognostic biomarker panel for the prediction of long-term prostate cancer, and they found that inhibition of miR-23a-3p significantly reduced survival of PC3 and DU145 cells, indicating the oncogenic role of miR-23a-3p in PC [ 37 ]. In contrast, Cai et al reported that downregulation of miR-23a suppresses prostate cancer metastasis by targeting the PAK9-LIMK signaling pathway, suggesting the antitumor function of miR-23a in PC [ 38 ].…”