Functional characterization of DLK1/MEG3 locus on chromosome 14q32.2 reveals the differentiation of pituitary neuroendocrine tumors

Aging (Albany NY). 2020 Dec 29;13(1):1422-1439. doi: 10.18632/aging.202376. Epub 2020 Dec 29.

Abstract

Pituitary neuroendocrine tumors (PitNETs) represent the neoplastic proliferation of the anterior pituitary gland. Transcription factors play a key role in the differentiation of PitNETs. However, for a substantial proportion of PitNETs, the etiology is poorly understood. According to the transcription data of 172 patients, we found the imprinting disorders of the 14q32.2 region and DLK1/MEG3 locus associated with the differentiation of PitNETs. DLK1/MEG3 locus promoted somatotroph differentiation and inhibited tumor proliferation in PIT1(+) patients, furthermore, the level of DLK1 played a critical role in the trend of somatotroph or lactotroph differentiation. Anti-DLK1 monoclonal antibody blockade or siMEG3 both indicated that the DLK1/MEG3 significantly promoted the synthesis and secretion of GH/IGF-1 and inhibited cell proliferation. In addition, loss of DLK1 activated the mTOR signaling pathway in high DLK1-expressing and PIT1(+) GH3 cell lines, a mild effect in the low DLK1-expressing and PIT1(+) MMQ cell lines and no effect in the PIT1(-) ATT20 cell line. These findings emphasize that expression at the DLK1/MEG3 locus plays a key role in the differentiation of PitNETs, especially somatotroph adenomas, and provide potential molecular target data for patient stratification and treatment in the future.

Keywords: DLK1/MEG3 locus; differentiation; growth hormone secreting; pituitary neuroendocrine tumors; somatotroph adenomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ACTH-Secreting Pituitary Adenoma / genetics*
  • ACTH-Secreting Pituitary Adenoma / metabolism
  • ACTH-Secreting Pituitary Adenoma / pathology
  • Adenoma / genetics
  • Adenoma / metabolism
  • Adenoma / pathology
  • Adult
  • Aged
  • Animals
  • Calcium-Binding Proteins / genetics*
  • Calcium-Binding Proteins / metabolism
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Female
  • Gene Expression Profiling
  • Genomic Imprinting
  • Gonadotropins, Pituitary / metabolism
  • Growth Hormone / metabolism
  • Growth Hormone-Secreting Pituitary Adenoma / genetics*
  • Growth Hormone-Secreting Pituitary Adenoma / metabolism
  • Growth Hormone-Secreting Pituitary Adenoma / pathology
  • Humans
  • Insulin-Like Growth Factor I / metabolism
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Middle Aged
  • Neuroendocrine Tumors / genetics
  • Neuroendocrine Tumors / metabolism
  • Neuroendocrine Tumors / pathology
  • Pituitary Neoplasms / genetics*
  • Pituitary Neoplasms / metabolism
  • Pituitary Neoplasms / pathology
  • Prolactinoma / genetics*
  • Prolactinoma / metabolism
  • Prolactinoma / pathology
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • Rats
  • TOR Serine-Threonine Kinases / metabolism
  • Young Adult

Substances

  • Calcium-Binding Proteins
  • DLK1 protein, human
  • Dlk1 protein, mouse
  • Dlk1 protein, rat
  • Gonadotropins, Pituitary
  • Intercellular Signaling Peptides and Proteins
  • MEG3 non-coding RNA, human
  • MEG3 non-coding RNA, mouse
  • MEG3 non-coding RNA, rat
  • Membrane Proteins
  • RNA, Long Noncoding
  • Insulin-Like Growth Factor I
  • Growth Hormone
  • TOR Serine-Threonine Kinases