Gene Expression Signature Predictive of Neuroendocrine Transformation in Prostate Adenocarcinoma

Int J Mol Sci. 2020 Feb 6;21(3):1078. doi: 10.3390/ijms21031078.


Neuroendocrine prostate cancer (NEPC) can arise de novo, but much more commonly occurs as a consequence of a selective pressure from androgen deprivation therapy or androgen receptor antagonists used for prostate cancer (PCa) treatment. The process is known as neuroendocrine transdifferentiation. There is little molecular characterization of NEPCs and consequently there is no standard treatment for this kind of tumors, characterized by highly metastases rates and poor survival. For this purpose, we profiled 54 PCa samples with more than 10-years follow-up for gene and miRNA expression. We divided samples into two groups (NE-like vs. AdenoPCa), according to their clinical and molecular features. NE-like tumors were characterized by a neuroendocrine fingerprint made of known neuroendocrine markers and novel molecules, including long non-coding RNAs and components of the estrogen receptor signaling. A gene expression signature able to predict NEPC was built and tested on independently published datasets. This study identified molecular features (protein-coding, long non-coding, and microRNAs), at the time of surgery, that may anticipate the NE transformation process of prostate adenocarcinoma. Our results may contribute to improving the diagnosis and treatment of this subgroup of tumors for which traditional therapy regimens do not show beneficial effects.

Keywords: estrogen signaling pathway; long non coding RNAs; neuroendocrine prostate cancer; neuroendocrine transdifferentiation; predictive gene signature; prostate cancer.

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics*
  • Aged
  • Androgen Receptor Antagonists / adverse effects
  • Androgen Receptor Antagonists / therapeutic use
  • Androgens / metabolism
  • Carcinoma, Neuroendocrine / drug therapy
  • Carcinoma, Neuroendocrine / genetics*
  • Cell Transdifferentiation / physiology
  • Estrogen Receptor alpha / metabolism
  • Estrogens / metabolism
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Male
  • MicroRNAs / genetics*
  • Middle Aged
  • Prostate / pathology
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics*
  • RNA, Long Noncoding / genetics*
  • Receptors, Androgen / metabolism
  • Signal Transduction


  • Androgen Receptor Antagonists
  • Androgens
  • Estrogen Receptor alpha
  • Estrogens
  • HOTAIR long untranslated RNA, human
  • MicroRNAs
  • RNA, Long Noncoding
  • Receptors, Androgen
  • estrogen receptor alpha, human