ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis
Human bladder cancer (BC) is the fourth most common cancer in the United States. Investigation of the strategies aiming to elucidate the tumor growth and metastatic pathways in BC is critical for the management of this disease. Here we found that ATG7 expression was remarkably elevated in human blad...
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Elsevier
2017-06-01
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Series: | Molecular Therapy: Nucleic Acids |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253117301622 |
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author | Junlan Zhu Yang Li Zhongxian Tian Xiaohui Hua Jiayan Gu Jingxia Li Claire Liu Honglei Jin Yulei Wang Guosong Jiang Haishan Huang Chuanshu Huang |
author_facet | Junlan Zhu Yang Li Zhongxian Tian Xiaohui Hua Jiayan Gu Jingxia Li Claire Liu Honglei Jin Yulei Wang Guosong Jiang Haishan Huang Chuanshu Huang |
author_sort | Junlan Zhu |
collection | DOAJ |
description | Human bladder cancer (BC) is the fourth most common cancer in the United States. Investigation of the strategies aiming to elucidate the tumor growth and metastatic pathways in BC is critical for the management of this disease. Here we found that ATG7 expression was remarkably elevated in human bladder urothelial carcinoma and N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced mouse invasive BC. Knockdown of ATG7 resulted in a significant inhibitory effect on tumorigenic growth of human BC cells both in vitro and in vivo by promoting p27 expression and inducing cell cycle arrest at G2/M phase. We further demonstrated that knockdown of ATG7 upregulated FOXO1 (forkhead box protein O 1) expression, which specifically promoted p27 transcription. Moreover, mechanistic studies revealed that inhibition of ATG7 stabilized ETS2 mRNA and, in turn, reduced miR-196b transcription and expression of miR-196b, which was able to bind to the 3′ UTR of FOXO1 mRNA, consequently stabilizing FOXO1 mRNA and finally promoting p27 transcription and attenuating BC tumorigenic growth. The identification of the ATG7/FOXO1/p27 mechanism for promoting BC cell growth provides significant insights into understanding the nature of BC tumorigenesis. Together with our most recent discovery of the crucial role of ATG7 in promoting BC invasion, it raises the potential for developing an ATG7-based specific therapeutic strategy for treatment of human BC patients. |
first_indexed | 2024-04-12T18:30:04Z |
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institution | Directory Open Access Journal |
issn | 2162-2531 |
language | English |
last_indexed | 2024-04-12T18:30:04Z |
publishDate | 2017-06-01 |
publisher | Elsevier |
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series | Molecular Therapy: Nucleic Acids |
spelling | doaj.art-2c565dc8daef452088598fa662d708c72022-12-22T03:21:07ZengElsevierMolecular Therapy: Nucleic Acids2162-25312017-06-017C29931310.1016/j.omtn.2017.04.012ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 AxisJunlan Zhu0Yang Li1Zhongxian Tian2Xiaohui Hua3Jiayan Gu4Jingxia Li5Claire Liu6Honglei Jin7Yulei Wang8Guosong Jiang9Haishan Huang10Chuanshu Huang11Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, ChinaZhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, ChinaZhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, ChinaZhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, ChinaZhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, ChinaNelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USANelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USAZhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, ChinaNelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USANelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USAZhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, ChinaZhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, ChinaHuman bladder cancer (BC) is the fourth most common cancer in the United States. Investigation of the strategies aiming to elucidate the tumor growth and metastatic pathways in BC is critical for the management of this disease. Here we found that ATG7 expression was remarkably elevated in human bladder urothelial carcinoma and N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced mouse invasive BC. Knockdown of ATG7 resulted in a significant inhibitory effect on tumorigenic growth of human BC cells both in vitro and in vivo by promoting p27 expression and inducing cell cycle arrest at G2/M phase. We further demonstrated that knockdown of ATG7 upregulated FOXO1 (forkhead box protein O 1) expression, which specifically promoted p27 transcription. Moreover, mechanistic studies revealed that inhibition of ATG7 stabilized ETS2 mRNA and, in turn, reduced miR-196b transcription and expression of miR-196b, which was able to bind to the 3′ UTR of FOXO1 mRNA, consequently stabilizing FOXO1 mRNA and finally promoting p27 transcription and attenuating BC tumorigenic growth. The identification of the ATG7/FOXO1/p27 mechanism for promoting BC cell growth provides significant insights into understanding the nature of BC tumorigenesis. Together with our most recent discovery of the crucial role of ATG7 in promoting BC invasion, it raises the potential for developing an ATG7-based specific therapeutic strategy for treatment of human BC patients.http://www.sciencedirect.com/science/article/pii/S2162253117301622ATG7bladder cancertumorigenic growthmiR-196bFOXO1p27 |
spellingShingle | Junlan Zhu Yang Li Zhongxian Tian Xiaohui Hua Jiayan Gu Jingxia Li Claire Liu Honglei Jin Yulei Wang Guosong Jiang Haishan Huang Chuanshu Huang ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis Molecular Therapy: Nucleic Acids ATG7 bladder cancer tumorigenic growth miR-196b FOXO1 p27 |
title | ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis |
title_full | ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis |
title_fullStr | ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis |
title_full_unstemmed | ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis |
title_short | ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis |
title_sort | atg7 overexpression is crucial for tumorigenic growth of bladder cancer in vitro and in vivo by targeting the ets2 mirna196b foxo1 p27 axis |
topic | ATG7 bladder cancer tumorigenic growth miR-196b FOXO1 p27 |
url | http://www.sciencedirect.com/science/article/pii/S2162253117301622 |
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