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Inhibition of mTORC1 by lncRNA H19 via disrupting 4E-BP1/Raptor interaction in pituitary tumours

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机构: [1]Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. [2]Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, 325000 Wenzhou, China. [3]Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. [4]Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 100050 Beijing, China. [5]Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. [6]Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, 410000 Chongqing, China. [7]Department of Neurosurgery, Zhongshan Hospital, Fudan University, 200032 Shanghai, China. [8]Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200127 Shanghai, China. [9]State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
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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.

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出版当年[2017]版:
大类 | 1 区 综合性期刊
小类 | 1 区 综合性期刊
最新[2023]版:
大类 | 1 区 综合性期刊
小类 | 1 区 综合性期刊
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出版当年[2016]版:
Q1 MULTIDISCIPLINARY SCIENCES
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Q1 MULTIDISCIPLINARY SCIENCES

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第一作者机构: [1]Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. [2]Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, 325000 Wenzhou, China.
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通讯机构: [1]Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. [2]Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, 325000 Wenzhou, China. [3]Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
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