The DLK1/MEG3 Locus is Related to the Differentiation of Pituitary Neuroendocrine Tumors

Abstract Background: Pituitary neuroendocrine tumors (PitNETs) represent the neoplastic proliferation of the anterior pituitary gland. Transcription factors play a key role in the differentiation of PitNETs according to the 2017 WHO classification of tumors of endocrine organs. However, for a substantial proportion of PitNETs, the etiology is poorly understood.Methods: To analyze the diversity genes and pathways based on transcriptomic data of 172 patients by transcriptome sequencing, difference, correlation, and enrichment analysis. The transcriptomic data and clinical characteristics are applied to find the clinical significance of key genes by correlation analysis and ROC curve. Series functional experiments demonstrated the role of DLK1/MEG3 locus through antibody blocking and RNA interference in GH3, MMQ and ATT20 cell line.Results: In this study, we found the imprinting disorders of the 14q32.2 region and DLK1/MEG3 locus associated with the differentiation of PitNETs. As being specific feature change in somatotroph adenomas compared with other subtype adenomas, DLK1/MEG3 locus promoted somatotroph differentiation and inhibited tumor proliferation in PIT1(+) PitNET patients, furthermore, the level of DLK1 played a critical role in the trend of somatotroph differentiation or lactotroph differentiation in PIT1(+) PitNET patients. Anti-DLK1 monoclonal antibody blockade or siMEG3 both indicated that the DLK1/MEG3 domain significantly induced the synthesis and secretion of growth hormone/insulin-like growth factor-1 (GH/IGF-1) and inhibited cell growth and colony formation and that the loss of DLK1 activated the mTOR signaling pathway in high DLK1-expressing and PIT1(+) GH3 cell lines. There was a mild effect in the low DLK1-expressing and PIT1(+) MMQ cell lines and no effect in the PIT1(-) ATT20 cell line, regardless of whether anti-DLK1 monoclonal antibody blockade or siMEG3 was used. Conclusions: These findings emphasize that expression at the DLK1/MEG3 locus plays a key role in the differentiation of PitNETs in patients depending on the level of PIT1. In addition, these findings provide potential molecular target data for patient stratification and treatment in the future.