Abstract
Aberrant expression of long noncoding RNA H19 has been associated with tumour progression, but the underlying molecular tumourigenesis mechanisms remain largely unknown. Here, we report that H19 expression is frequently downregulated in human primary pituitary adenomas and is negatively correlated with tumour progression. Consistently, upregulation of H19 expression inhibits pituitary tumour cell proliferation in vitro and tumour growth in vivo. Importantly, we uncover a function of H19, which controls cell/tumour growth through inhibiting function of mTORC1 but not mTORC2. Mechanistically, we show that H19 could block mTORC1-mediated 4E-BP1 phosphorylation without affecting S6K1 activation. At the molecular level, H19 interacted with 4E-BP1 at the TOS motif and competitively inhibited 4E-BP1 binding to Raptor. Finally, we demonstrate that H19 is more effective than cabergoline treatment in the suppression of pituitary tumours. Together, our study uncovered the role of H19-mTOR-4E-BP1 axis in pituitary tumour growth regulation that may be a potential therapeutic target for human pituitary tumours.
Highlights
Aberrant expression of long noncoding RNA H19 has been associated with tumour progression, but the underlying molecular tumourigenesis mechanisms remain largely unknown
H19 expression is downregulated in human primary pituitary adenomas and is correlated with tumour progression
Analysis of a previously studied microarray dataset from the Gene Expression Omnibus (GEO) repository database showed that H19 expression was decreased in gonadotrope tumours compared with that in normal pituitary tissues (GSE26966) (Fig. 1b)
Summary
Aberrant expression of long noncoding RNA H19 has been associated with tumour progression, but the underlying molecular tumourigenesis mechanisms remain largely unknown. We report that H19 expression is frequently downregulated in human primary pituitary adenomas and is negatively correlated with tumour progression. Upregulation of H19 expression inhibits pituitary tumour cell proliferation in vitro and tumour growth in vivo. Our study uncovered the role of H19-mTOR-4E-BP1 axis in pituitary tumour growth regulation that may be a potential therapeutic target for human pituitary tumours. MTOR regulates a wide range of cellular processes, including cell growth, proliferation and metabolism, by integrating both extracellular and intracellular cues. We revealed that H19 acted as a tumour suppressor, inhibiting pituitary tumour growth by negatively regulating 4E-BP1 phosphorylation. Mechanistic studies demonstrated that H19 bound to and masked the 4E-BP1 TOR signalling (TOS) motif, inhibiting 4E-BP1 recruitment to mTORC1 by disrupting the binding of 4E-BP1 to Raptor
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
