Long noncoding RNAs (lncRNAs) are an emerging class of relatively underexplored oncogenic molecules with biological and clinical significance. Current inadequacies for stratifying patients with aggressive disease presents a strong rationale to systematically identify lncRNAs as clinical predictors in localized prostate cancer.
To identify RNA biomarkers associated with aggressive prostate cancer researchers from the Washington University School of Medicine obtained radical prostatectomy microarray and clinical data from 910 patients in three published institutional cohorts: Mayo Clinic I (N=545, median follow-up 13.8 yr), Mayo Clinic II (N=235, median follow-up 6.7 yr), and Thomas Jefferson University (N=130, median follow-up 9.6 yr). The primary clinical endpoint was distant metastasis-free survival. Secondary endpoints include prostate cancer-specific survival and overall survival. Univariate and multivariate Cox regression were used to evaluate the association of lncRNA expression and these endpoints.
An integrative analysis revealed Prostate Cancer Associated Transcript-14 (PCAT-14) as the most prevalent lncRNA that is aberrantly expressed in prostate cancer patients. Down-regulation of PCAT-14 expression significantly associated with Gleason score and a greater probability of metastatic progression, overall survival, and prostate cancer-specific mortality across multiple independent datasets and ethnicities. Low PCAT-14 expression was implicated with genes involved in biological processes promoting aggressive disease. In-vitro analysis confirmed that low PCAT-14 expression increased migration while overexpressing PCAT-14 reduced cellular growth, migration, and invasion.
Integrative analysis reveals Prostate Cancer Associated Transcript-14
(PCAT-14) expression associates with prostate cancer
(A) Differentially expressed (DE) long noncoding RNAs (lncRNAs) between normal and tumor samples of prostate cancer in one Affymetrix dataset and two RNA-seq datasets (Supplementary Table 1). The Venn diagram shows the number of up-regulated (orange arrow) and down-regulated (blue arrow) DE lncRNAs identified in one to three datasets. Heatmaps of the normalized Affymetrix expression and normalized RNA-seq log fragments per kilobase of exon per million fragments mapped (FPKM) of the five DE lncRNAs from all three datasets are shown across normal, tumor, and metastatic samples in each datasets. Four of the five DE lncRNAs are up-regulated in the tumor dataset and one is down-regulated in all three datasets. Among these five lncRNAs, PCAT-14 is the only one that shows an association with tumor progression (Supplementary Table 2). (B) Boxplot of normalized Affymetrix expression of PCAT-14 in Gleason 6 through 9. Expression of PCAT-14 is anticorrelated with Gleason score (correlation [cor] = −0.22). Expression of PCAT-14 is significantly decreases from Gleason 6 to 9 (p = 0.00013). (C) Boxplot of normalized Affymetrix expression of PCAT-14 in normal, tumor, and metastatic prostate samples. PCAT-14 is up-regulated in tumor samples compared with normal samples (p = 1.3e-15), and its expression goes down again in metastatic patients from the tumor dataset (p = 9.7e-06).