Journal Article

Effects of 1α,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells

Wang, Wei-Lin W, Welsh, JoEllen, Chatterjee, Namita, Chittur, Sridar V, Tenniswood, Martin P

2011

Overview

Background There is evidence from epidemiological and in vitro studies that the biological effects of testosterone (T) on cell cycle and survival are modulated by 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) in prostate cancer. To investigate the cross talk between androgen- and vitamin D-mediated intracellular signaling pathways, the individual and combined effects of T and 1,25(OH) 2 D 3 on global gene expression in LNCaP prostate cancer cells were assessed. Results Stringent statistical analysis identifies a cohort of genes that lack one or both androgen response elements (AREs) or vitamin D response elements (VDREs) in their promoters, which are nevertheless differentially regulated by both steroids (either additively or synergistically). This suggests that mechanisms in addition to VDR- and AR-mediated transcription are responsible for the modulation of gene expression. Microarray analysis shows that fifteen miRNAs are also differentially regulated by 1,25(OH) 2 D 3 and T. Among these miR-22, miR-29ab, miR-134, miR-1207-5p and miR-371-5p are up regulated, while miR-17 and miR-20a, members of the miR-17/92 cluster are down regulated. A number of genes implicated in cell cycle progression, lipid synthesis and accumulation and calcium homeostasis are among the mRNA targets of these miRNAs. Thus, in addition to their well characterized effects on transcription, mediated by either or both cognate nuclear receptors, 1,25(OH) 2 D 3 and T regulate the steady state mRNA levels by modulating miRNA-mediated mRNA degradation, generating attenuation feedback loops that result in global changes in mRNA and protein levels. Changes in genes involved in calcium homeostasis may have specific clinical importance since the second messenger Ca 2+ is known to modulate various cellular processes, including cell proliferation, cell death and cell motility, which affects prostate cancer tumor progression and responsiveness to therapy. Conclusions These data indicate that these two hormones combine to drive a differentiated phenotype, and reinforce the idea that the age dependent decline in both hormones results in the de-differentiation of prostate tumor cells, which results in increased proliferation, motility and invasion common to aggressive tumors. These studies also reinforce the potential importance of miRNAs in prostate cancer progression and therapeutic outcomes.

• Publisher: BioMed Central,BMC
• Subject: Age / Androgens / Androgens - pharmacology / Biomedical and Life Sciences / Biomedicine / Calcitriol / Calcium homeostasis / Cancer Research / Cell cycle / Cell Cycle - drug effects / Cell Death / Cell Line, Tumor / Cell migration / Cell proliferation / Cell survival / Data processing / Dihydroxyvitamin D3 / DNA microarrays / Feedback / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Neoplastic - drug effects / Homeostasis - genetics / Hormones / Humans / Intracellular signalling / Lipids / Male / MicroRNAs - genetics / MicroRNAs - metabolism / miRNA / Molecular Sequence Annotation / Nuclear receptors / Oncology / Promoters / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - physiopathology / Regulatory sequences / Reproducibility of Results / RNA, Messenger - genetics / RNA, Messenger - metabolism / Second messengers / Statistical analysis / Steroid hormones / Testosterone / Testosterone - pharmacology / Transcription / Tumor cells / Tumors / Vitamin D / Vitamin D - analogs & derivatives / Vitamin D - pharmacology / Vitamins - pharmacology