lncRNA H19 binds VGF and promotes pNEN progression via PI3K/AKT/CREB signaling
in Endocrine-Related Cancer
Authors: Meng Ji 1 , Yanli Yao 2 , 3 , Anan Liu 1 , Ligang Shi 1 , Danlei Chen 1 , Liang Tang 1 , Guang Yang 1 , Xing Liang 1 , Junfeng Peng 1 and Chenghao Shao 1
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1 Department of General Surgery (Department of Pancreatic-Biliary Surgery), Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China 2 Glycochemistry & Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai, China 3 University of the Chinese Academy of Sciences, Beijing, China
Correspondence should be addressed to C Shao: shaochenghao_czyy@163.com
*(M Ji and Y Yao contributed equally to this work)
DOI: https://doi.org/10.1530/ERC-18-0552
Page(s): 643–658
Volume/Issue: Volume 26: Issue 7
Article Type: Research Article
Online Publication Date: Jul 2019
Copyright: © 2019 Society for Endocrinology 2019
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Abstract/Excerpt
Supplementary Materials
Pancreatic neuroendocrine neoplasms (pNENs) are endocrine tumors arising in pancreas and is the most common neuroendocrine tumors. Mounting evidence indicates lncRNA H19 could be a determinant of tumor progression. However, the expression and mechanism of H19 and the relevant genes mediated by H19 in pNENs remain undefined. Microarray analysis was conducted to identify the differentially expressed lncRNAs in pNENs. H19 expression was analyzed in 39 paired pNEN tissues by qPCR. The biological role of H19 was determined by functional experiments. RNA pulldown, mass spectroscopy and RNA immunoprecipitation were performed to confirm the interaction between H19 and VGF. RNA-seq assays were performed after knockdown H19 or VGF. H19 was significantly upregulated in pNEN tissues with malignant behaviors, and the upregulation predicted poor prognosis in pNENs. In vitro and in vivo data showed that H19 overexpression promoted tumor growth and metastasis, whereas H19 knockdown led to the opposite phenotypes. H19 interacted with VGF, which was significantly upregulated in pNENs, and higher VGF expression was markedly related to poor differentiation and advanced stage. Furthermore, VGF was downregulated when H19 was knocked down, and VGF promoted cell proliferation, migration and invasion. Mechanistic investigations revealed that H19 activated PI3K/AKT/CREB signaling and promoted pNEN progression by interacting with VGF. These findings indicate that H19 is a promising prognostic factor in pNENs with malignant behaviors and functions as an oncogene via the VGF-mediated PI3K/AKT/CREB pathway. In addition, our study implies that VGF may also serve as a candidate prognostic biomarker and therapeutic target in pNENs.
in Endocrine-Related Cancer
Authors: Meng Ji 1 , Yanli Yao 2 , 3 , Anan Liu 1 , Ligang Shi 1 , Danlei Chen 1 , Liang Tang 1 , Guang Yang 1 , Xing Liang 1 , Junfeng Peng 1 and Chenghao Shao 1
View Less
1 Department of General Surgery (Department of Pancreatic-Biliary Surgery), Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China 2 Glycochemistry & Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai, China 3 University of the Chinese Academy of Sciences, Beijing, China
Correspondence should be addressed to C Shao: shaochenghao_czyy@163.com
*(M Ji and Y Yao contributed equally to this work)
DOI: https://doi.org/10.1530/ERC-18-0552
Page(s): 643–658
Volume/Issue: Volume 26: Issue 7
Article Type: Research Article
Online Publication Date: Jul 2019
Copyright: © 2019 Society for Endocrinology 2019
Restricted access
48-hour access to this article
USD $30.00
Buy
Check for updates
Citation Alert Citation Alerts
Get Permissions
Abstract/Excerpt
Supplementary Materials
Pancreatic neuroendocrine neoplasms (pNENs) are endocrine tumors arising in pancreas and is the most common neuroendocrine tumors. Mounting evidence indicates lncRNA H19 could be a determinant of tumor progression. However, the expression and mechanism of H19 and the relevant genes mediated by H19 in pNENs remain undefined. Microarray analysis was conducted to identify the differentially expressed lncRNAs in pNENs. H19 expression was analyzed in 39 paired pNEN tissues by qPCR. The biological role of H19 was determined by functional experiments. RNA pulldown, mass spectroscopy and RNA immunoprecipitation were performed to confirm the interaction between H19 and VGF. RNA-seq assays were performed after knockdown H19 or VGF. H19 was significantly upregulated in pNEN tissues with malignant behaviors, and the upregulation predicted poor prognosis in pNENs. In vitro and in vivo data showed that H19 overexpression promoted tumor growth and metastasis, whereas H19 knockdown led to the opposite phenotypes. H19 interacted with VGF, which was significantly upregulated in pNENs, and higher VGF expression was markedly related to poor differentiation and advanced stage. Furthermore, VGF was downregulated when H19 was knocked down, and VGF promoted cell proliferation, migration and invasion. Mechanistic investigations revealed that H19 activated PI3K/AKT/CREB signaling and promoted pNEN progression by interacting with VGF. These findings indicate that H19 is a promising prognostic factor in pNENs with malignant behaviors and functions as an oncogene via the VGF-mediated PI3K/AKT/CREB pathway. In addition, our study implies that VGF may also serve as a candidate prognostic biomarker and therapeutic target in pNENs.
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