MicroRNA 141 is associated to outcome and aggressive tumor characteristics in prostate cancer.

A large number of miRNAs influence key cellular processes involved in prostate tumorigenesis. Previous studies have demonstrated high expression of miRNAs in human prostate cancer (PC) tissues and cell lines. In previous microarray data, we found miR-141 to be upregulated and miR-145 to be downregulated in PC. In this large PC cohort (n = 535), we explored the prognostic role of miR-141 and miR-145 in PC. Tumor epithelial (TE) and tumor stromal (TS) areas were evaluated separately and combined (TE + TS). In situ hybridization was used to evaluate the expression of the miRNAs. We found that miR-141 (TE) correlated significantly to Gleason score ≥8 (p = 0.040) and large tumor size (≥20 mm, p = 0.025) and miR-141 (TE + TS) to Gleason grade (p = 0.001). MiR-145 correlated to pT-stage (p = 0.038), tumor size (p = 0.025), Gleason grade (p = 0.051) and PSA (p = 0.032). In univariate analysis miR-141 (TE + TS) was significantly associated with biochemical failure-free survival (BFFS, p = 0.007) and clinical failure-free survival (CFFS, p = 0.021). For miR-145, there were no differences between patients with high versus low expression. In multivariate analysis overexpression of miR-141 in tumor epithelium and tumor stroma was significantly associated with BFFS (HR = 1.07 CI95% 1.00-1.14, p = 0.007). To conclude, high expression of miR-141 appears associated with increased risk of biochemical PC recurrence.

Elevated expression of a minor isoform of ANK3 is a risk factor for bipolar disorder.

Ankyrin-3 (ANK3) is one of the few genes that have been consistently identified as associated with bipolar disorder by multiple genome-wide association studies. However, the exact molecular basis of the association remains unknown. A rare loss-of-function splice-site SNP (rs41283526*G) in a minor isoform of ANK3 (incorporating exon ENSE00001786716) was recently identified as protective of bipolar disorder and schizophrenia. This suggests that an elevated expression of this isoform may be involved in the etiology of the disorders. In this study, we used novel approaches and data sets to test this hypothesis. First, we strengthen the statistical evidence supporting the allelic association by replicating the protective effect of the minor allele of rs41283526 in three additional large independent samples (meta-analysis p-values: 6.8E-05 for bipolar disorder and 8.2E-04 for schizophrenia). Second, we confirm the hypothesis that both bipolar and schizophrenia patients have a significantly higher expression of this isoform than controls (p-values: 3.3E-05 for schizophrenia and 9.8E-04 for bipolar type I). Third, we determine the transcription start site for this minor isoform by Pacific Biosciences sequencing of full-length cDNA and show that it is primarily expressed in the corpus callosum. Finally, we combine genotype and expression data from a large Norwegian sample of psychiatric patients and controls, and show that the risk alleles in ANK3 identified by bipolar disorder GWAS are located near the transcription start site of this isoform and are significantly associated with its elevated expression. Together, these results point to the likely molecular mechanism underlying ANK3´s association with bipolar disorder.

Stromal expression of VEGF-A and VEGFR-2 in prostate tissue is associated with biochemical and clinical recurrence after radical prostatectomy.

BACKGROUND: There is probably significant overtreatment of patients with prostate cancer due to a lack of sufficient diagnostic tools to predict aggressive disease. Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are potent mediators of angiogenesis and tumor proliferation, but have been examined to a limited extent in large prostate cancer studies. Meanwhile, recent promising results on VEGFR-2 inhibition have highlighted their importance, leading to the need for further investigations regarding their expression and prognostic impact. DESIGN: Using tissue microarray and immunohistochemistry, the expression of VEGFs (VEGF-A and VEGF-C) and their receptors (VEGFR-2 and VEGFR-3) were measured in neoplastic tissue and corresponding stroma from radical prostatectomy specimens in 535 Norwegian patients. Their expression was evaluated semiquantatively and associations with event-free survival were calculated. RESULTS: High expression of VEGFR-2 in either stroma or epithelium was independently associated with a higher incidence of prostate cancer relapse (HR = 4.56, P = 0.038). A high combined expression of either VEGF-A, VEGFR-2 or both in stroma was independently associated with a higher incidence of biochemical failure (HR = 1.77, P = 0.011). CONCLUSIONS: This large study highlights the prognostic importance of VEGF-A and VEGFR-2 stromal expression. Analyses of these biomarkers may help distinguish which patients will benefit from radical treatment. Together with previous studies showing efficiency of targeting VEGFR-2 in prostate cancer, this study highlights its potential as a target for therapy, and may aid in future selection of prostate cancer patients for novel anti-angiogenic treatment.

The prognostic significance of CXCL16 and its receptor C-X-C chemokine receptor 6 in prostate cancer.

The chemokine CXCL16 and its receptor, C-X-C chemokine receptor (CXCR6), affect tumor progression through different pathways, including leukocyte recruitment and function, cellular senescence, tumor cell proliferation, survival, invasion, and metastasis. We examined how the expression of CXCL16/CXCR6 in prostate cancer (PC) was related to clinicopathological features and activation of inflammatory cells. Tissue microarrays from 535 patients were constructed from tumor epithelial and tumor stromal areas of primary PC. Immunohistochemistry was used to evaluate the expression of CXCL16/CXCR6, CD3(+) T cells (CD4(+), CD8(+)), and CD20(+) B cells. Survival analyses were used to evaluate their prognostic impact. Expression of CXCL16 in PC cell lines (DU145 and PC3) and the effect on proliferation and migration were examined. High expression levels of CXCL16 [hazard ratio (HR), 2.52; 95% CI, 1.12-5.68; P = 0.026] and CXCR6 (HR, 2.29; 95% CI, 1.10-4.82; P = 0.028) were each independent predictors for clinical failure. High co-expression of CXCL16 and CXCR6 (HR, 5.1; 95% CI, 1-15.9; P = 0.05) was associated with negative prognostic factors, such as Gleason grade 4 + 3, Gleason score ≥7, vascular infiltration, and positive surgical margins. As a conclusion, high protein expression of CXCL16 and high protein co-expression of CXCL16/CXCR6 in PC were independent predictors for a worse clinical outcome.

High progesterone receptor expression in prostate cancer is associated with clinical failure.

BACKGROUND: Prostate cancer is a highly heterogeneous disease and one of the leading causes of mortality in developed countries. Specific prognostic and predictive markers for prostate cancer patients are still lacking. A causal relationship between androgens and the development of prostate cancer is generally considered biologically plausible, but androgens are not the sole effector in the complexity of prostate carcinogenesis. The aim of this study was to evaluate the prognostic significance of progesterone receptor in tumor tissue of T1-3N0 prostate cancer patients undergoing prostatectomy. METHODS: Tissue microarrays from 535 patients with prostate cancer were constructed. Duplicate cores of tumor cells and tumor stromal tissue from each resected specimen were extracted. Immunohistochemistry was used to evaluate the in-situ expression of progesterone receptor. RESULTS: In univariate analyses, high tumor cell density (p = 0.006) and high tumor stromal cell density level (p = 0.045) of progesterone receptor were both significantly associated with tumor progression and clinical failure. In multivariate analysis, progesterone receptor expression in tumor cells was an independent negative prognostic factor for clinical failure (HR: 2.5, 95% CI: 1.2-5.2, p = 0.012). CONCLUSION: High progesterone receptor density in tumor cells of the prostate cancer tumor is an independent negative prognostic factor for clinical failure.

Stromal expression of MiR-21 predicts biochemical failure in prostate cancer patients with Gleason score 6.

AIM: microRNAs (miRNAs) are involved in various neoplastic diseases, including prostate cancer (PCs). The aim of this study was to investigate the miRNA profile in PC tissue, to assess their association with clinicopathologic data, and to evaluate the potential of miRNAs as diagnostic and prognostic markers. MATERIALS AND METHODS: From a cohort of 535 patients submitted to radical prostatectomy (RP), a sample of 30 patients (14 patients with rapid biochemical failure (BF) and 16 patients without BF) with Gleason score 7 were analyzed. A total of 1435 miRNAs were quantified by microarray hybridization, and selected miRNAs with the highest Standard deviation (n = 50) were validated by real-time quantitative PCR (qRT-PCR). In situ hybridization (ISH) was used to evaluate the expression of miR-21. RESULTS: miR-21 was the only miR that was significantly up-regulated in the BF group (p = 0.045) miR-21 was up-regulated in patients with BF compared with non-BF group (p = 0.05). In univariate analyses, high stromal expression of miR-21 had predictive impact on biochemical failure-free survival (BFFS) and clinical failure-free survival (CFFS) (p = 0.006 and p = 0.04, respectively). In the multivariate analysis, high stromal expression of miR-21 expression was found to be an independent prognostic factor for BFFS in patients with Gleason score 6 (HR 2.41, CI 95% 1.06-5.49, p = 0.037). CONCLUSION: High stromal expression of miR-21 was associated with poor biochemical recurrence-free survival after RP. For patients with Gleason score 6, miR-21 may help predict the risk of future disease progression and thereby help select patients for potential adjuvant treatment or a more stringent follow-up.