Tumor-Associated Macrophage Exosomal miR-142-5p Drives Prostate Cancer Neuroendocrine Differentiation...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Androgen deprivation therapy (ADT) for prostate cancer (PCa) can induce lineage plasticity, leading to aggressive neuroendocrine prostate cancer (NEPC).
• Tumor-associated macrophages (TAMs) communicate via exosomes, influencing tumor progression.
• The gene RERG was previously identified as a suppressor of neuroendocrine differentiation (NED) in PCa.

Purpose of the Study:

• To investigate the role of RERG in NEPC development and its regulation by TAM-derived factors.
• To elucidate the molecular mechanisms by which TAMs promote NEPC.
• To identify potential therapeutic targets for NEPC.

Main Methods:

• Analysis of RERG expression in castration-resistant PCa (CRPC) and NEPC tissues.
• Investigating the effect of RERG downregulation on the Ras/ERK pathway.
• Studying the transfer of miR-142-5p from TAMs to PCa cells via exosomes.
• In vitro experiments assessing the impact of miR-142-5p and RERG on PCa cell behavior.
• In vivo xenograft models to evaluate the role of RERG in tumor growth and NED.

Main Results:

• RERG expression is significantly reduced in CRPC and NEPC, and its downregulation activates the Ras/ERK pathway, promoting NED.
• TAM-derived exosomal miR-142-5p downregulates RERG, activating the Ras/ERK pathway and promoting PCa progression and NED.
• In vitro, miR-142-5p enhanced PCa cell proliferation, migration, invasion, and NED; RERG overexpression reversed these effects.
• In vivo, RERG knockdown promoted tumor growth and NED.

Conclusions:

• TAM-derived miR-142-5p plays a critical role in promoting NEPC by downregulating RERG and activating the Ras/ERK pathway.
• Targeting the RERG/Ras/ERK axis presents a potential therapeutic strategy for NEPC.