Clinical Significance of Retinoic Acid Receptor Beta Promoter Methylation in Prostate Cancer: A Meta-Analysis

Abstract

Background/Aims: Retinoic acid receptor beta (RAR beta) is a retinoic acid receptor gene that has been shown to play key roles during multiple cancer processes, including cell proliferation, apoptosis, migration and invasion. Numerous studies have found that methylation of the RAR beta promoter contributed to the occurrence and development of malignant tumors. However, the connection between RAR beta promoter methylation and prostate cancer (PCa) remains unknown. This meta-analysis evaluated the clinical significance of RAR beta promoter methylation in PCa. Materials and Methods: We searched all published records relevant to RAR beta and PCa in a series of databases, including PubMed, Embase, Cochrane Library, ISI Web of Science and CNKI. The rates of RAR beta promoter methylation in the PCa and control groups (including benign prostatic hyperplasia and normal prostate tissues) were summarized. In addition, we evaluated the source region of available samples and the methods used to detect methylation. To compare the incidence and variation in RAR beta promoter methylation in PCa and non-PCa tissues, the odds ratio (OR) and 95% confidence interval (CI) were calculated accordingly. All the data were analyzed with the statistical software STATA 12.0. Results: Based on the inclusion and exclusion criteria, 15 articles assessing 1,339 samples were further analyzed. These data showed that the RAR beta promoter methylation rates in PCa tissues were significantly higher than the rates in the non-PCa group (OR=21.65, 95% CI: 9.27-50.57). Subgroup analysis according to the source region of samples showed that heterogeneity in Asia was small (I²=0.0%, P=0.430). Additional subgroup analysis based on the method used to detect RAR beta promoter methylation showed that the heterogeneity detected by MSP (methylation-specific PCR) was relatively small (I²=11.3%, P=0.343). Conclusion: Although studies reported different rates for RAR beta promoter methylation in PCa tissues, the total analysis demonstrated that RAR beta promoter methylation may be correlated with PCa carcinogenesis and that the RAR beta gene is particularly susceptible. Additional studies with sufficient data are essential to further evaluate the clinical features and prognostic utility of RAR beta promoter methylation in PCa.

The Role of Nuclear Receptors in Prostate Cancer

“…Data from Memorial Sloan Kettering Cancer Center [21] and TCGA Prostate Adenocarcinoma showed that RARγ was significantly and uniquely downregulated in prostate cancer compared with other cancers [22]. In addition, the RARβ promoter methylation status was higher in prostate cancer compared with nonmalignant tissues, suggesting reduced expression of RARβ in prostate cancer [23]. In LNCaP cells, RARγ signaling was shown to suppress AR signaling by competitive binding to AR-binding sites (Figure 1) [24,25].…”

The miR-96 and RARγ signaling axis governs androgen signaling and prostate cancer progression

“…To dissect the impact of the miR-96 regulation of RARg further we examined how the correlations of each of the seven RARg network genes were altered by expression levels of miR-96. Specifically, we identified the significant correlations between each of the 19 seven RARg network genes (EIF4G2, ONECUT2, PRKAR1A, RARG, TACC1, YAP1, ZIC2 50 ) alongside FOXA1 with all RARg dependent genes in the upper (miR-96high, n=123) and lower (miR-96low, n=122) quartile miR-96 expression TCGA-PRAD tumors.…”

“…There are three human RAR paralogs, namely RARa, RARb and RARg. In PCa, RARb appears to act as a tumor suppressor silenced by DNA methylation 10,19 . Curiously, while there are observed roles for RARg in prostatic development 44 , its role and regulatory functions in prostate cells and PCa remain enigmatic, as do its upstream control mechanisms.…”

Promoter Methylation Status of the Retinoic Acid Receptor-Beta 2 Gene in Breast Cancer Patients: A Case Control Study and Systematic Review

“…Reduced expression of RARB2 by genetic or epigenetic mechanisms is linked to many human cancers such as cervical [9,10], head and neck [11], non-small cell lung [12], prostate [13], bladder, brain, and breast cancers [4,14,15,16]. Knowledge of the DNA methylation status in the promoter regions of some candidate genes such as RARB2 may be useful for early detection, prognosis, and drug response prediction in breast cancer patients [6,17].…”