Androgen-regulated microRNA-135a decreases prostate cancer cell migration and invasion through downregulating ROCK1...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Androgen signaling, mediated by the androgen receptor (AR), is critical for prostate cancer (PCa) development and progression.
• Identifying novel downstream effectors of the AR pathway is essential for understanding PCa mechanisms and developing new therapeutic strategies.

Purpose of the Study:

• To identify novel microRNA (miRNA) effectors in androgen signaling relevant to prostate cancer.
• To investigate the role of miR-135a in PCa cell invasion and its potential as a prognostic marker.

Main Methods:

• High-throughput reverse transcriptase-quantitative PCR to profile miRNA expression in response to androgen stimulation.
• Androgen stimulation of LNCaP cells and AR binding analysis to confirm direct transcriptional activation of miR-135a.
• In vitro and in vivo assays (xenografts, wound-healing) to assess the effect of miR-135a on prostate cancer cell invasion.
• Analysis of ROCK1 and ROCK2 gene expression as direct targets of miR-135a.
• Immunohistochemistry and analysis of human prostatectomy samples to correlate miR-135a and ROCK1 expression with clinicopathological features.

Main Results:

• Androgen stimulation upregulated miR-135a expression in LNCaP cells.
• The androgen receptor (AR) directly activates the transcription of the miR-135a gene.
• Overexpression of miR-135a reduced in vivo and in vitro invasion of PC-3 prostate cancer cells.
• miR-135a directly targets and downregulates ROCK1 and ROCK2 expression.
• Lower miR-135a expression and higher ROCK1 protein levels were observed in high-grade (Gleason score ⩾8) and invasive prostate tumors compared to normal tissues.

Conclusions:

• miR-135a is a novel downstream effector of the androgen/AR signaling pathway in prostate cancer.
• The miR-135a/ROCK1 axis plays a role in regulating prostate cancer cell invasion.
• Reduced miR-135a expression is associated with increased disease aggressiveness and may serve as a prognostic biomarker for human PCa.