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
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Research Support, Non-U.S. Gov't
MeSH terms
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ACTH-Secreting Pituitary Adenoma / genetics*
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ACTH-Secreting Pituitary Adenoma / metabolism
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ACTH-Secreting Pituitary Adenoma / pathology
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Adenoma / genetics
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Adenoma / metabolism
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Adenoma / pathology
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Adult
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Aged
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Animals
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Calcium-Binding Proteins / genetics*
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Calcium-Binding Proteins / metabolism
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Cell Differentiation / genetics
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Cell Line, Tumor
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Cell Proliferation / genetics
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Female
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Gene Expression Profiling
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Genomic Imprinting
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Gonadotropins, Pituitary / metabolism
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Growth Hormone / metabolism
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Growth Hormone-Secreting Pituitary Adenoma / genetics*
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Growth Hormone-Secreting Pituitary Adenoma / metabolism
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Growth Hormone-Secreting Pituitary Adenoma / pathology
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Humans
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Insulin-Like Growth Factor I / metabolism
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Male
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Mice
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Middle Aged
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Neuroendocrine Tumors / genetics
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Neuroendocrine Tumors / metabolism
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Neuroendocrine Tumors / pathology
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Pituitary Neoplasms / genetics*
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Pituitary Neoplasms / metabolism
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Pituitary Neoplasms / pathology
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Prolactinoma / genetics*
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Prolactinoma / metabolism
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Prolactinoma / pathology
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RNA, Long Noncoding / genetics*
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RNA, Long Noncoding / metabolism
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Rats
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TOR Serine-Threonine Kinases / metabolism
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Young Adult
Substances
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Calcium-Binding Proteins
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DLK1 protein, human
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Dlk1 protein, mouse
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Dlk1 protein, rat
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Gonadotropins, Pituitary
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Intercellular Signaling Peptides and Proteins
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MEG3 non-coding RNA, human
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MEG3 non-coding RNA, mouse
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MEG3 non-coding RNA, rat
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Membrane Proteins
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RNA, Long Noncoding
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Insulin-Like Growth Factor I
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Growth Hormone
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TOR Serine-Threonine Kinases