Abstract
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.
Highlights
Gastric cancer (GC) is one of the most frequently diagnosed cancers and the second leading cause of cancerrelated mortality worldwide [1]
Synthetic siRNAs directed against different regions of HER3 (HER3.1, HER3.2, HER3.3 and HER3.4) were tested for their ability to suppress HER3 mRNA expression, and the results showed that HER3.3 siRNA was more effective than the others
To ensure that the reduction in mRNA was associated with a reduction of protein expression, we conducted a Western blotting analysis of cellular lysates, and the results showed that HER3.3 downmodulated the HER3 protein levels (Figure 1C)
Summary
Gastric cancer (GC) is one of the most frequently diagnosed cancers and the second leading cause of cancerrelated mortality worldwide [1]. The human epidermal growth factor receptor (EGFR/HER) family is involved in multiple complex and tightly controlled signalling pathways that regulate various cellular functions, including cell proliferation, organ development, and organ repair [3,4,5]. At least nine cancer therapeutics [monoclonal antibodies (mAbs) and small-molecule tyrosine kinase inhibitors (TKIs)] targeting EGFR and/or HER2 are currently in clinical use [3, 9,10,11,12,13]. Their clinical benefits have been demonstrated, these drugs induce different www.impactjournals.com/oncotarget patient responses, and drug resistance is often encountered [14]. Different models, including genetic mutations of key genes in the HER pathway, such as KRAS and PTEN, and upregulation of oncogenes, such as cMET and HER3, have been proposed [15,16,17]
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