Oncogenic role of EAPII in lung cancer development and its activation of the MAPK-ERK pathway

• Published in: Oncogene Vol. 30; no. 35; pp. 3802 - 3812
• Main Authors: Li, C, Fan, S, Owonikoko, T K, Khuri, F R, Sun, S-Y, Li, R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2011; Nature Publishing Group
• Subjects: 631/67/395; 631/80/86; 692/699/67/1612; Angiogenesis; Antibodies; Apoptosis; Apoptosis - genetics; Biological and medical sciences; c-Jun amino-terminal kinase; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Biology; Cell culture; Cell cycle; Cell Line, Tumor; Cell physiology; Cell Proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; cyclin D1; Enzyme Activation; Extracellular signal-regulated kinase; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Knockdown Techniques; Human Genetics; Humans; Internal Medicine; Kinases; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; MAP kinase; Medical sciences; Medicine; Medicine & Public Health; Metastases; Mitogen-Activated Protein Kinase Kinases - biosynthesis; Molecular and cellular biology; mRNA; Myc protein; Non-small cell lung carcinoma; Nuclear Proteins - genetics; Nuclear Proteins - physiology; Oncogenes - genetics; Oncogenes - physiology; Oncology; Original; original-article; Pneumology; Proteins; Signal transduction; Transcription Factors - genetics; Transcription Factors - physiology; Tumors; Tumors of the respiratory system and mediastinum; Xenografts; United States; NSCLC; MAPK–ERK pathway; EAPII; Lung disease; Extracellular signal-regulated protein kinase; Enzyme; Respiratory disease; Transferases; Lung cancer; Mitogen-activated protein kinase; Activation; Malignant tumor; Carcinogenesis; Development; Bronchus disease; MAPK-ERK pathway; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2011.94

Cancer progression involves multiple complex and interdependent steps, including progressive proliferation, angiogenesis and metastases. The complexity of these processes requires a comprehensive elucidation of the integrated signaling networks for better understanding. EAPII interacts with multiple cancer-related proteins, but its biological significance in cancer development remains unknown. In this report we identified the elevated level of EAPII protein in non-small-cell lung carcinoma (NSCLC) patients and NSCLC cell lines in culture. The oncogenic role of EAPII in lung cancer development was demonstrated using NSCLC cells with genetic manipulations that influence EAPII expression: EAPII overexpression increases proliferation of NSCLC cells with an accelerated transition of cell cycle and facilitates xenograft tumor growth in vivo ; EAPII knockdown results in apoptosis of NSCLC cells and reduces xenograft tumor formation. To further explore the mechanism of EAPII's oncogenic role in lung cancer development and to elucidate the potential signaling pathway(s) that EAPII may impact, we employed antibody array to investigate the alternation of the major signaling pathways in NSCLC cells with altered EAPII level. We found that EAPII overexpression significantly activated Raf1 and ERK1/2, but not c-Jun N-terminal kinase and p38 pathways. Consistently, the protein and mRNA levels of MYC and cyclin D1, which are targets of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK–ERK) pathway, are significantly increased by EAPII overexpression. Taken together, we demonstrated that EAPII is an oncogenic factor and the activation of MAPK–ERK signaling pathway by EAPII may contribute to lung cancer development.