EGFR-L858R mutant enhances lung adenocarcinoma cell invasive ability and promotes malignant pleural effusion formation through activation of the CXCL12-CXCR4 pathway.
Malignant pleural effusion (MPE) is a common clinical problem in non-small cell lung carcinoma (NSCLC) patients; however, the underlying mechanisms are still largely unknown. Recent studies indicate that the frequency of the L858R mutant form of the epidermal growth factor receptor (EGFR-L858R) is higher in lung adenocarcinoma with MPE than in surgically resected specimens, suggesting that lung adenocarcinoma cells harboring this mutation tend to invade the adjacent pleural cavity. The purpose of this study was to clarify the relationship between the EGFR-L858R mutation and cancer cell invasion ability and to investigate the molecular mechanisms involved in the formation of MPE. We found that expression of EGFR-L858R in lung cancer cells resulted in up-regulation of the CXCR4 in association with increased cancer cell invasive ability and MPE formation. Ectopic expression of EGFR-L858R in lung cancer cells acted through activation of ERK signaling pathways to induce the expression of CXCR4. We also indicated that Inhibition of CXCR4 with small interfering RNA, neutralizing antibody, or receptor antagonist significantly suppressed the EGFR-L858R-dependent cell invasion. These results suggest that targeting the production of CXCR4 and blocking the CXCL12-CXCR4 pathway might be effective strategies for treating NSCLCs harboring a specific type of EGFR mutation.
Department of Molecular Biotechnology, College of Biotechnology and Bioresources, Dayeh University, Changhua 51591, Taiwan.
Meng-Feng
MF
Tsai
Department of Internal Medicine, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei 10002, Taiwan.
Tzu-Hua
TH
Chang
Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yunlin 64041, Taiwan.
Shang-Gin
SG
Wu
Department of Internal Medicine, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei 10002, Taiwan.
Hsiao-Yin
HY
Yang
Institute of Statistical Science, Academia Sinica, Taipei 11529, Taiwan.
Yi-Chiung
YC
Hsu
Department of Internal Medicine, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei 10002, Taiwan.|Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan.
Pan-Chyr
PC
Yang
Department of Internal Medicine, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei 10002, Taiwan.|Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan.
Jin-Yuan
JY
Shih
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness; D016066:Pleural Effusion, Malignant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction
C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; C512478:EGFR protein, human; D066246:ErbB Receptors