Epithelial splicing regulator protein 1 and alternative splicing in somatotroph adenomas

Endocrinology. 2013 Sep;154(9):3331-43. doi: 10.1210/en.2013-1051. Epub 2013 Jul 3.


Somatotroph adenomas secrete supraphysiological amounts of GH, causing acromegaly. We have previously hypothesized that epithelial mesenchymal transition (EMT) may play a central role in the progression of these adenomas and that epithelial splicing regulator 1 (ESRP1) may function prominently as a master regulator of the EMT process in pituitary adenomas causing acromegaly. To further elucidate the role of ESRP1 in somatotroph adenomas and in EMT progression, we used RNA sequencing (RNAseq) to sequence somatotroph adenomas characterized by high and low ESRP1 levels. Transcripts identified by RNAseq were analyzed in 65 somatotroph adenomas and in GH-producing pituitary rat cells with a specific knockdown of Esrp1. The clinical importance of the transcripts was further investigated by correlating mRNA expression levels with clinical indices of disease activity and treatment response. Many of the transcripts and isoforms identified by RNAseq and verified by quantitative PCR were involved in vesicle transport and calcium signaling and were associated with clinical outcomes. Silencing Esrp1 in GH3 cells resulted in changes of gene expression overlapping the data observed in human somatotroph adenomas and revealed a decreased granulation pattern and attenuated GH release. We observed an alternative splicing pattern for F-box and leucine-rich repeat protein 20, depending on the ESPR1 levels and on changes in circulating IGF-I levels after somatostatin analog treatment. Our study indicates that ESRP1 in somatotroph adenomas regulates transcripts that may be essential in the EMT progression and in the response to somatostatin analog treatment.

MeSH terms

  • Acromegaly / etiology
  • Adenoma / drug therapy
  • Adenoma / metabolism*
  • Adenoma / pathology
  • Adenoma / physiopathology
  • Adult
  • Alternative Splicing*
  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Cell Line, Tumor
  • Cohort Studies
  • Epithelial-Mesenchymal Transition*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Growth Hormone-Secreting Pituitary Adenoma / drug therapy
  • Growth Hormone-Secreting Pituitary Adenoma / metabolism*
  • Growth Hormone-Secreting Pituitary Adenoma / pathology
  • Growth Hormone-Secreting Pituitary Adenoma / physiopathology
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / antagonists & inhibitors
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Rats
  • Somatostatin / analogs & derivatives
  • Somatostatin / pharmacology
  • Somatostatin / therapeutic use
  • Somatotrophs / drug effects
  • Somatotrophs / metabolism*
  • Somatotrophs / pathology


  • Antineoplastic Agents, Hormonal
  • ESRP1 protein, human
  • Neoplasm Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Somatostatin