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Inhibition of mTORC1 by lncRNA H19 via disrupting 4E-BP1/Raptor interaction in pituitary tumours
Ze Rui Wu1,2, Lichong Yan3, Yan Ting Liu1,2
1Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
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.
Insights
Long noncoding RNA H19 downregulation promotes pituitary tumour growth by activating mTORC1. Upregulating H19 inhibits tumour progression, offering a potential therapeutic strategy for pituitary adenomas.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Aberrant expression of long noncoding RNA H19 is linked to tumour progression.
- The specific molecular mechanisms of H19 in pituitary tumourigenesis are not well understood.
Purpose of the Study:
- To investigate the role of H19 in pituitary adenoma development and progression.
- To elucidate the molecular pathways regulated by H19 in pituitary tumour growth.
Main Methods:
- Analysis of H19 expression in human pituitary adenomas.
- In vitro and in vivo studies assessing the effect of H19 upregulation on tumour cell proliferation and growth.
- Investigation of H19 interaction with the mTORC1 pathway components, including 4E-BP1 and Raptor.
Main Results:
- H19 expression is downregulated in pituitary adenomas and correlates negatively with tumour progression.
- H19 upregulation inhibits pituitary tumour cell proliferation and growth.
- H19 suppresses tumour growth by inhibiting mTORC1 activity via interaction with 4E-BP1 and Raptor, independent of mTORC2.
- H19 demonstrates superior efficacy over cabergoline in suppressing pituitary tumours.
Conclusions:
- The H19-mTOR-4E-BP1 axis is crucial for regulating pituitary tumour growth.
- H19 acts as a tumour suppressor in pituitary adenomas.
- Targeting the H19-mTOR-4E-BP1 pathway represents a promising therapeutic strategy for human pituitary tumours.
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