YAP promotes erlotinib resistance in human non-small cell lung cancer cells
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Ping-Chih Hsu1,2,*, Bin You1,3,*, Yi-Lin Yang1, Wen-Qian Zhang1,3, Yu-Cheng Wang1, Zhidong Xu1, Yuyuan Dai1, Shu Liu1, Cheng-Ta Yang2, Hui Li3, Bin Hu3, David M. Jablons1, Liang You1
1Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA, USA
2Department of Thoracic Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
3Department of Thoracic Surgery, Beijing Chao-Yang Hospital, Affiliated with Capital University of Medical Science, Beijing, People’s Republic of China
*These authors have contributed equally to this work
Liang You, email: [email protected]
Keywords: Hippo pathway, yes-associated protein, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance, erlotinib, non-small cell lung cancer
Received: September 28, 2015 Accepted: June 17, 2016 Published: July 07, 2016
Yes-associated protein (YAP) is a main mediator of the Hippo pathway, which promotes cancer development. Here we show that YAP promotes resistance to erlotinib in human non-small cell lung cancer (NSCLC) cells. We found that forced YAP overexpression through YAP plasmid transfection promotes erlotinib resistance in HCC827 (exon 19 deletion) cells. In YAP plasmid-transfected HCC827 cells, GTIIC reporter activity and Hippo downstream gene expression of AREG and CTGF increased significantly (P<0.05), as did ERBB3 mRNA expression (P<0.05). GTIIC reporter activity, ERBB3 protein and mRNA expression all increased in HCC827 erlotinib-resistance (ER) cells compared to parental HCC827 cells. Inhibition of YAP by small interfering RNA (siRNA) increased the cytotoxicity of erlotinib to H1975 (L858R+T790M) cells. In YAP siRNA-transfected H1975 cells, GTIIC reporter activity and downstream gene expression of AREG and CTGF decreased significantly (P<0.05). Verteporfin, YAP inhibitor had an effect similar to that of YAP siRNA; it increased sensitivity of H1975 cells to erlotinib and in combination with erlotinib, synergistically reduced migration, invasion and tumor sphere formation abilities in H1975 cells. Our results indicate that YAP promotes erlotinib resistance in the erlotinib-sensitive NSCLC cell line HCC827. Inhibition of YAP by siRNA increases sensitivity of erlotinib-resistant NSCLC cell line H1975 to erlotinib.
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