TAM-derived miR-142-5p drives neuroendocrine prostate cancer differentiation by suppressing RERG and activating Ras/ERK.

Androgen deprivation therapy (ADT) for prostate cancer (PCa) often leads to the emergence of neuroendocrine prostate cancer (NEPC), a highly aggressive and therapy-resistant subtype with limited treatment options. This lineage plasticity involves androgen receptor-negative cells. Tumor-associated macrophages (TAMs) are known to contribute to tumor progression through exosome-mediated communication, but the specific molecular drivers governing neuroendocrine differentiation (NED) in this context remain poorly understood, representing a critical gap in therapeutic strategies.

Researchers investigated the role of miR-142-5p and RERG in prostate cancer neuroendocrine differentiation (NED). They analyzed RNA-seq data from a previous study to identify RERG as a key gene suppressing NED. In vitro, they evaluated the effects of miR-142-5p on PCa cell proliferation, migration, invasion, and NED, and assessed how RERG overexpression modulated these effects. In vivo, they used a xenograft model to study the impact of RERG knockdown on tumor growth and NED, comparing outcomes to control groups.

The study found that RERG expression is significantly reduced in CRPC cells and NEPC tissues. This downregulation of RERG was shown to activate the Ras/ERK signaling pathway, a crucial driver of NED. Furthermore, miR-142-5p, transferred from TAMs via exosomes, directly downregulates RERG expression and consequently activates the Ras/ERK pathway, thereby promoting PCa progression and NED.

In vitro, miR-142-5p significantly enhanced PCa cell proliferation, migration, invasion, and NED, while RERG overexpression effectively reversed these pro-tumorigenic effects. In vivo, RERG knockdown in a xenograft model significantly promoted tumor growth and NED, confirming its suppressive role. These findings highlight a novel mechanism where TAM-derived miR-142-5p orchestrates NED through the RERG/Ras/ERK axis.