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Increased SPON1 promotes pancreatic ductal adenocarcinoma progression by enhancing IL‐6 trans‐signalling

OBJECTIVES: This study investigated the specific molecular mechanism and the roles of extracellular matrix protein Spondin 1 (SPON1) in the development of pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: The expression pattern and clinical relevance of SPON1 was determined in GEO, Ren...

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Autores principales: Huo, Yanmiao, Yang, Jian, Zheng, Jiahao, Xu, Dapeng, Yang, Minwei, Tao, Lingye, Yao, Hongfei, Fu, Xueliang, Yang, Jianyu, Liu, Dejun, Hua, Rong, Zhang, Junfeng, Sun, Yongwei, Hu, Lipeng, Liu, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9136514/
https://www.ncbi.nlm.nih.gov/pubmed/35487760
http://dx.doi.org/10.1111/cpr.13237
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author Huo, Yanmiao
Yang, Jian
Zheng, Jiahao
Xu, Dapeng
Yang, Minwei
Tao, Lingye
Yao, Hongfei
Fu, Xueliang
Yang, Jianyu
Liu, Dejun
Hua, Rong
Zhang, Junfeng
Sun, Yongwei
Hu, Lipeng
Liu, Wei
author_facet Huo, Yanmiao
Yang, Jian
Zheng, Jiahao
Xu, Dapeng
Yang, Minwei
Tao, Lingye
Yao, Hongfei
Fu, Xueliang
Yang, Jianyu
Liu, Dejun
Hua, Rong
Zhang, Junfeng
Sun, Yongwei
Hu, Lipeng
Liu, Wei
author_sort Huo, Yanmiao
collection PubMed
description OBJECTIVES: This study investigated the specific molecular mechanism and the roles of extracellular matrix protein Spondin 1 (SPON1) in the development of pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: The expression pattern and clinical relevance of SPON1 was determined in GEO, Ren Ji and TCGA datasets, further validated by immunohistochemical staining and Kaplan‐Meier analysis. Loss and gain of function experiments were employed to investigate the cellular function of SPON1 in vitro. Gene set enrichment analysis, luciferase assay, immunofluorescence and Western blot and immunoprecipitation were applied to reveal the underlying molecular mechanisms. Subcutaneous xenograft model was used to test the role of SPON1 in tumour growth and maintenance in vivo. RESULTS: SPON1 is significantly upregulated in PDAC tumour tissues and correlated with progression of PDAC. Loss and gain of function experiments showed that SPON1 promotes the growth and colony formation ability of pancreatic cancer cells. Combining bioinformatics assays and experimental signalling evidences, we found that SPON1 can enhance the IL‐6/JAK/STAT3 signalling. Mechanistically, SPON1 exerts its oncogenic roles in pancreatic cancer by maintaining IL‐6R trans‐signalling through stabilizing the interaction of soluble IL‐6R (sIL‐6R) and glycoprotein‐130 (gp130) in PDAC cells. Furthermore, SPON1 depletion greatly reduced the tumour burden, exerted positive effect with gemcitabine, prolonging PDAC mice overall survival. CONCLUSIONS: Our data indicate that SPON1 expression is dramatically increased in PDAC and that SPON1 promotes tumorigenicity by activating the sIL‐6R/gp130/STAT3 axis. Collectively, our current work suggests SPON1 may be a potential therapy target for PDAC patient.
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spelling pubmed-91365142022-06-04 Increased SPON1 promotes pancreatic ductal adenocarcinoma progression by enhancing IL‐6 trans‐signalling Huo, Yanmiao Yang, Jian Zheng, Jiahao Xu, Dapeng Yang, Minwei Tao, Lingye Yao, Hongfei Fu, Xueliang Yang, Jianyu Liu, Dejun Hua, Rong Zhang, Junfeng Sun, Yongwei Hu, Lipeng Liu, Wei Cell Prolif Original Articles OBJECTIVES: This study investigated the specific molecular mechanism and the roles of extracellular matrix protein Spondin 1 (SPON1) in the development of pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: The expression pattern and clinical relevance of SPON1 was determined in GEO, Ren Ji and TCGA datasets, further validated by immunohistochemical staining and Kaplan‐Meier analysis. Loss and gain of function experiments were employed to investigate the cellular function of SPON1 in vitro. Gene set enrichment analysis, luciferase assay, immunofluorescence and Western blot and immunoprecipitation were applied to reveal the underlying molecular mechanisms. Subcutaneous xenograft model was used to test the role of SPON1 in tumour growth and maintenance in vivo. RESULTS: SPON1 is significantly upregulated in PDAC tumour tissues and correlated with progression of PDAC. Loss and gain of function experiments showed that SPON1 promotes the growth and colony formation ability of pancreatic cancer cells. Combining bioinformatics assays and experimental signalling evidences, we found that SPON1 can enhance the IL‐6/JAK/STAT3 signalling. Mechanistically, SPON1 exerts its oncogenic roles in pancreatic cancer by maintaining IL‐6R trans‐signalling through stabilizing the interaction of soluble IL‐6R (sIL‐6R) and glycoprotein‐130 (gp130) in PDAC cells. Furthermore, SPON1 depletion greatly reduced the tumour burden, exerted positive effect with gemcitabine, prolonging PDAC mice overall survival. CONCLUSIONS: Our data indicate that SPON1 expression is dramatically increased in PDAC and that SPON1 promotes tumorigenicity by activating the sIL‐6R/gp130/STAT3 axis. Collectively, our current work suggests SPON1 may be a potential therapy target for PDAC patient. John Wiley and Sons Inc. 2022-04-29 /pmc/articles/PMC9136514/ /pubmed/35487760 http://dx.doi.org/10.1111/cpr.13237 Text en © 2022 The Authors. Cell Proliferation published by John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Huo, Yanmiao
Yang, Jian
Zheng, Jiahao
Xu, Dapeng
Yang, Minwei
Tao, Lingye
Yao, Hongfei
Fu, Xueliang
Yang, Jianyu
Liu, Dejun
Hua, Rong
Zhang, Junfeng
Sun, Yongwei
Hu, Lipeng
Liu, Wei
Increased SPON1 promotes pancreatic ductal adenocarcinoma progression by enhancing IL‐6 trans‐signalling
title Increased SPON1 promotes pancreatic ductal adenocarcinoma progression by enhancing IL‐6 trans‐signalling
title_full Increased SPON1 promotes pancreatic ductal adenocarcinoma progression by enhancing IL‐6 trans‐signalling
title_fullStr Increased SPON1 promotes pancreatic ductal adenocarcinoma progression by enhancing IL‐6 trans‐signalling
title_full_unstemmed Increased SPON1 promotes pancreatic ductal adenocarcinoma progression by enhancing IL‐6 trans‐signalling
title_short Increased SPON1 promotes pancreatic ductal adenocarcinoma progression by enhancing IL‐6 trans‐signalling
title_sort increased spon1 promotes pancreatic ductal adenocarcinoma progression by enhancing il‐6 trans‐signalling
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9136514/
https://www.ncbi.nlm.nih.gov/pubmed/35487760
http://dx.doi.org/10.1111/cpr.13237
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