siRNA-mediated inactivation of HER3 improves the antitumour activity and sensitivity of gefitinib in gastric cancer cells
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Heng-Heng Yuan1,*, Ying-Nan Yang2,*, Jian-Hua Zhou1, Yan-Jing Li1, Li-Ying Wang3, Jun-Wei Qin4, Tao Liu5, Zhen-Zhen Li1, Qing-Xin Zhou1, Xiao-Li Wei1, Ting-Ting Zhang1, Peng Huang1, Wen-Jie Zhang1, Lei Liu1, Xiao-Xue Du1 and Yu Han1
1Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China
2Department of Chest Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China
3Department of Oncology, Chaoyang Central Hospital, Shenyang, Liaoning Province, China
4Department of Oncology, Qingdao Municipal Hospital, Qingdao, Shandong Province, China
5The Third Department of Oncology, Xinxiang Central Hospital, Xinxiang, Henan Province, China
*These authors contributed equally to this work
Yu Han, email: email@example.com
Keywords: HER3, siRNA, gefitinib, gastric cancer, PI3K/AKT
Received: March 21, 2017 Accepted: April 17, 2017 Published: April 29, 2017
The human EGFR family consists of four type-1 transmembrane tyrosine kinase receptors: HER1 (EGFR, ErbB1), HER2 (Neu, ErbB2), HER3 (ErbB3), and HER4 (ErbB4). HER3 can dimerize with EGFR, HER2 and even c-Met and likely plays a central role in the response to EGFR-targeted therapy. Because HER3 lacks significant kinase activity and cannot be inhibited by tyrosine kinase inhibitors, neutralizing antibodies and alternative inhibitors of HER3 have been sought as cancer therapeutics. Here, we describe the stable suppression of HER3 mRNA and protein using siRNA. The inhibition of HER3 expression decreased cell proliferation, suppressed cell cycle progression, induced apoptosis and inhibited cell motility, migration, invasiveness, and soft agar growth. In addition, we found that gefitinib treatment increased the HER3 and HER2 mRNA levels. The administration of various concentrations of gefitinib to HER3-knockdown cells enhanced antitumour activity and sensitivity due to the downregulation of protein phosphorylation via PI3K/AKT and ERK signalling. Our results support the use of combined treatments targeting multiple EGFR receptors, particularly the use of HER3 inhibitors combined with EGFR inhibitors, such as gefitinib.
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