Shp2 regulates migratory behavior and response to EGFR-TKIs through ERK1/2 pathway activation in non-small cell lung cancer cells
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Yu-Jing Sun1,2,*, Zhong-Ling Zhuo1,*, Hai-Peng Xian1, Ke-Zhong Chen3, Fan Yang3 and Xiao-Tao Zhao1
1Department of Clinical Laboratory, Peking University People’s Hospital, Beijing 100044, China
2Department of Clinical Laboratory, Peking University International Hospital, Beijing 100044, China
3Department of Thoracic Surgery, Peking University People’s Hospital, Beijing 100044, China
*These authors contributed equally to this work and should be regarded as joint first authors
Xiao-Tao Zhao, email: firstname.lastname@example.org
Keywords: Shp2, non-small cell lung cancer, epidermal growth factor receptor, tyrosine kinase inhibitors, ERK1/2
Received: February 01, 2017 Accepted: July 25, 2017 Published: August 14, 2017
In the clinical treatment of lung cancer, therapy failure is mainly caused by cancer metastasis and drug resistance. Here, we investigated whether the tyrosine phosphatase Shp2 is involved in the development of metastasis and drug resistance in non-small cell lung cancer (NSCLC). Shp2 was overexpressed in a subset of lung cancer tissues, and Shp2 knockdown in lung cancer cells inhibited cell proliferation and migration, downregulated c-Myc and fibronectin expression, and upregulated E-cadherin expression. In H1975 cells, which carry double mutations (L858R + T790M) in epidermal growth factor receptor (EGFR) that confers resistance toward the tyrosine kinase inhibitor gefitinib, Shp2 knockdown increased cellular sensitivity to gefitinib; conversely, in H292 cells, which express wild-type EGFR and are sensitive to gefitinib, Shp2 overexpression increased cellular resistance to gefitinib. Moreover, by overexpressing Shp2 or using U0126, a small-molecule inhibitor of extracellular signal-regulated kinase 1/2 (ERK1/2), we demonstrated that Shp2 inhibited E-cadherin expression and enhanced the expression of fibronectin and c-Myc through activation of the ERK1/2 pathway. Our findings reveal that Shp2 is overexpressed in clinical samples of NSCLC and that Shp2 knockdown reduces the proliferation and migration of lung cancer cells, and further suggest that co-inhibition of EGFR and Shp2 is an effective approach for overcoming EGFR T790M mutation acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Thus, we propose that Shp2 could serve as a new biomarker in the treatment of NSCLC.
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