Research Paper Volume 13, Issue 1 pp 1422—1439
Functional characterization of DLK1/MEG3 locus on chromosome 14q32.2 reveals the differentiation of pituitary neuroendocrine tumors
- 1 Department of Cell Biology, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China
- 2 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
- 3 Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- 4 Department of Neurosurgery, People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang 830001, China
- 5 China National Clinical Research Center for Neurological Diseases, Beijing 100070, China
- 6 Brain Tumor Center, Beijing Institute for Brain Disorders, Beijing 100070, China
Received: August 14, 2020 Accepted: November 10, 2020 Published: December 29, 2020
https://doi.org/10.18632/aging.202376How to Cite
Copyright: © 2020 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.
Abbreviations
ACTH: Adrenocorticotropic hormone; DIO3: Iodothyronine deiodinase 3; DLK1: Delta like non-canonical Notch ligand 1; ESR1, ER-α: Estrogen receptor 1; GATA2: Endothelial transcription factor GATA-2; GH: Growth hormone; GHR: GH receptor; IGF-1: Insulin-like growth factor 1; lncRNA: Long noncoding RNAs; MEGs: Maternally expressed genes; miRNA: microRNA; PEG: Paternally expressed genes; PitNET: Pituitary neuroendocrine tumor; POU1F1, PIT1: POU class 1 homeobox 1; PRL: Prolactin; ROC: Receiver operating characteristic; RTL1: Retrotransposon gag like 1 (RTL1); siRNA: small interfering RNA; SF1: Splicing factor 1; SNV: Single nucleotide variations; SSTR2: Somatostatin receptor 2; TBX19, TPIT: T-box transcription factor 19; WGS: Whole genome sequencing.