FoxO3a inhibiting expression of EPS8 to prevent progression of NSCLC: A new negative loop of EGFR signalingResearch in context
Background: The resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKI) is a major challenge in the treatment of non-small cell lung cancer (NSCLC). Understanding the molecular mechanisms behind resistance is therefore an important issue. Here we assessed the role of EGFR pathway substrat...
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Format: | Article |
Language: | English |
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Elsevier
2019-02-01
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Series: | EBioMedicine |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396419300611 |
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doaj-b8fc6ed8a54c4381bcc82f6442ca3a31 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Qiang Wen Xinwei Jiao Fei Kuang Beibei Hou Yajing Zhu Wenyu Guo Guangxin Sun Yufeng Ba Dandan Yu David Wang Faya Zhang Hui Chao Qiao Shuolin Wang Shu Tang Hailing Qiao |
spellingShingle |
Qiang Wen Xinwei Jiao Fei Kuang Beibei Hou Yajing Zhu Wenyu Guo Guangxin Sun Yufeng Ba Dandan Yu David Wang Faya Zhang Hui Chao Qiao Shuolin Wang Shu Tang Hailing Qiao FoxO3a inhibiting expression of EPS8 to prevent progression of NSCLC: A new negative loop of EGFR signalingResearch in context EBioMedicine |
author_facet |
Qiang Wen Xinwei Jiao Fei Kuang Beibei Hou Yajing Zhu Wenyu Guo Guangxin Sun Yufeng Ba Dandan Yu David Wang Faya Zhang Hui Chao Qiao Shuolin Wang Shu Tang Hailing Qiao |
author_sort |
Qiang Wen |
title |
FoxO3a inhibiting expression of EPS8 to prevent progression of NSCLC: A new negative loop of EGFR signalingResearch in context |
title_short |
FoxO3a inhibiting expression of EPS8 to prevent progression of NSCLC: A new negative loop of EGFR signalingResearch in context |
title_full |
FoxO3a inhibiting expression of EPS8 to prevent progression of NSCLC: A new negative loop of EGFR signalingResearch in context |
title_fullStr |
FoxO3a inhibiting expression of EPS8 to prevent progression of NSCLC: A new negative loop of EGFR signalingResearch in context |
title_full_unstemmed |
FoxO3a inhibiting expression of EPS8 to prevent progression of NSCLC: A new negative loop of EGFR signalingResearch in context |
title_sort |
foxo3a inhibiting expression of eps8 to prevent progression of nsclc: a new negative loop of egfr signalingresearch in context |
publisher |
Elsevier |
series |
EBioMedicine |
issn |
2352-3964 |
publishDate |
2019-02-01 |
description |
Background: The resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKI) is a major challenge in the treatment of non-small cell lung cancer (NSCLC). Understanding the molecular mechanisms behind resistance is therefore an important issue. Here we assessed the role of EGFR pathway substrate 8 (EPS8) and Forkhead box O 3a (FoxO3a) as potentially valuable targets in the resistance of NSCLC . Methods: The expression levels of EPS8 and FoxO3a in patients with NSCLC (n = 75) were examined by immunohistochemistry staining, while in cells were detected by qPCR and western blot. The effects of EPS8 and FoxO3a on resistance, migration and invasion, cell cycle arrest were detected by MTT, transwell and flow cytometry, respectively. Chromatin immunoprecipitation and luciferase reporter assays were performed to determine the mechanisms of EPS8 expression and FoxO3a regulation. Findings: We observed that the expression of EPS8 inversely correlated with FoxO3a in NSCLC cell lines and NSCLC patients. FoxO3a levels were significantly decreased in tumor tissues compared with para-carcinoma tissues, while EPS8 is opposite. Besides, they play reverse roles in the resistance to gefitinib, the migration and invasion abilities, the cell cycle arrest in vitro and the tumor growth in vivo. Mechanistically, FoxO3a inhibits EPS8 levels by directly binding its gene promoter and they form a negative loop in EGFR pathway. Interpretation: Targeting FoxO3a and EPS8 in EGFR signaling pathway prevents the progression of NSCLC, which implied that the negative loop they formed could served as a therapeutic target for overcoming resistance in NSCLC. Funds: National Natural Science Foundation of China, Science and Technology Project of Henan, Outstanding Young Talent Research Fund of Zhengzhou University and the National Scholarship Fund. Keywords: Forkhead box O 3a (FoxO3a), Epidermal growth factor receptor (EGFR), EGFR pathway substrate 8 (EPS8), Gefitinib, Tumor resistance, Non-small cell lung cancer (NSCLC) |
url |
http://www.sciencedirect.com/science/article/pii/S2352396419300611 |
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doaj-b8fc6ed8a54c4381bcc82f6442ca3a312020-11-25T01:49:34ZengElsevierEBioMedicine2352-39642019-02-0140198209FoxO3a inhibiting expression of EPS8 to prevent progression of NSCLC: A new negative loop of EGFR signalingResearch in contextQiang Wen0Xinwei Jiao1Fei Kuang2Beibei Hou3Yajing Zhu4Wenyu Guo5Guangxin Sun6Yufeng Ba7Dandan Yu8David Wang9Faya Zhang10Hui Chao Qiao11Shuolin Wang12Shu Tang13Hailing Qiao14Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan 450001, China; Institute of Engineering and Medicine, Virginia Commonwealth University, Richmond, VA 23284, USAHenan Provincial People's Hospital and People's Hospital of Zhengzhou University, Henan Eye Institute, Henan Eye Hospital, Zhengzhou, 450003, ChinaInstitute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan 450001, ChinaInstitute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan 450001, ChinaDepartment of Breast, Xuchang Maternal and Child Health-Care Hospital of Henan Province, Xuchang, Henan 461000, ChinaInstitute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan 450001, ChinaDepartment of Respiratory Medicine, The First People's Hospital of Zhengzhou, Zhengzhou, Henan 450000, ChinaThe Department of Thoracic Surgery, Henan Cancer Hospital, Zhengzhou, Henan 450003, ChinaDepartment of Oncology, Henan General Hospital of the Chinese People's Armed Police Force, Zhengzhou, Henan 450001, ChinaNational Teleratiology Program, Veterans Affairs, Durham, NC 27705, USADepartment of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99210, USAInstitute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan 450001, ChinaInstitute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan 450001, ChinaDepartment of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450001, China; Institute of Engineering and Medicine, Virginia Commonwealth University, Richmond, VA 23284, USA; Correspondence to: Shu Tang, Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450001, China.Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan 450001, China; Corresponding author.Background: The resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKI) is a major challenge in the treatment of non-small cell lung cancer (NSCLC). Understanding the molecular mechanisms behind resistance is therefore an important issue. Here we assessed the role of EGFR pathway substrate 8 (EPS8) and Forkhead box O 3a (FoxO3a) as potentially valuable targets in the resistance of NSCLC . Methods: The expression levels of EPS8 and FoxO3a in patients with NSCLC (n = 75) were examined by immunohistochemistry staining, while in cells were detected by qPCR and western blot. The effects of EPS8 and FoxO3a on resistance, migration and invasion, cell cycle arrest were detected by MTT, transwell and flow cytometry, respectively. Chromatin immunoprecipitation and luciferase reporter assays were performed to determine the mechanisms of EPS8 expression and FoxO3a regulation. Findings: We observed that the expression of EPS8 inversely correlated with FoxO3a in NSCLC cell lines and NSCLC patients. FoxO3a levels were significantly decreased in tumor tissues compared with para-carcinoma tissues, while EPS8 is opposite. Besides, they play reverse roles in the resistance to gefitinib, the migration and invasion abilities, the cell cycle arrest in vitro and the tumor growth in vivo. Mechanistically, FoxO3a inhibits EPS8 levels by directly binding its gene promoter and they form a negative loop in EGFR pathway. Interpretation: Targeting FoxO3a and EPS8 in EGFR signaling pathway prevents the progression of NSCLC, which implied that the negative loop they formed could served as a therapeutic target for overcoming resistance in NSCLC. Funds: National Natural Science Foundation of China, Science and Technology Project of Henan, Outstanding Young Talent Research Fund of Zhengzhou University and the National Scholarship Fund. Keywords: Forkhead box O 3a (FoxO3a), Epidermal growth factor receptor (EGFR), EGFR pathway substrate 8 (EPS8), Gefitinib, Tumor resistance, Non-small cell lung cancer (NSCLC)http://www.sciencedirect.com/science/article/pii/S2352396419300611 |