FoxO3a inhibiting expression of EPS8 to prevent progression of NSCLC: A new negative loop of EGFR signalingResearch in context
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
Affiliations
Qiang Wen
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan 450001, China; Institute of Engineering and Medicine, Virginia Commonwealth University, Richmond, VA 23284, USA
Xinwei Jiao
Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Henan Eye Institute, Henan Eye Hospital, Zhengzhou, 450003, China
Fei Kuang
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan 450001, China
Beibei Hou
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan 450001, China
Yajing Zhu
Department of Breast, Xuchang Maternal and Child Health-Care Hospital of Henan Province, Xuchang, Henan 461000, China
Wenyu Guo
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan 450001, China
Guangxin Sun
Department of Respiratory Medicine, The First People's Hospital of Zhengzhou, Zhengzhou, Henan 450000, China
Yufeng Ba
The Department of Thoracic Surgery, Henan Cancer Hospital, Zhengzhou, Henan 450003, China
Dandan Yu
Department of Oncology, Henan General Hospital of the Chinese People's Armed Police Force, Zhengzhou, Henan 450001, China
David Wang
National Teleratiology Program, Veterans Affairs, Durham, NC 27705, USA
Faya Zhang
Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99210, USA
Hui Chao Qiao
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan 450001, China
Shuolin Wang
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan 450001, China
Shu Tang
Department 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.
Hailing Qiao
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)
