Regulator of G Protein Signaling 1 Trastuzumab Resistance and Malignant Behaviors of Gastric Cancer Cells by Regulating Gαq Signaling and Activating the MEK/ERK Pathway

Abstract

Background: Trastuzumab resistance poses a challenge to the treatment of patients with Human epidermal growth factor receptor-2 (HER2)-positive gastric cancer (GC). The aim of this study was to determine the function and possible mechanism of Regulator of G Protein Signaling 1 (RGS1) on trastuzumab resistance in GC. Methods: There were 20 cases each of tumor tissue (GC) and histologically normal paracancerous tissue (Adjacent) from GC patients. Trastuzumab-resistant human gastric cancer cells SNU216 cell line (SNU216-TR) was constructed by Etest, and then quantitative real-time polymerase chain reaction (qRT-PCR) was responsible for expression measurement of RGS1 in GC clinical tissues and different cells lines. The viability of cells treated with trastuzumab of 0, 1, 10, 100, and 200 µg/mL was observed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Transwell and scratch assays were performed to examine the cells migration and invasion abilities. Additionally, the expression of RGS1, Gαq, as well as related proteins of epithelial-mesenchymal transition (EMT) and MEK/ERK (mitogen-activated extracellular signal-regulated kinase/extracellular signal-regulated kinase) pathway were estimated, using western blot. Results: RGS1 expression had a significant upregulation in GC tissues and trastuzumab-resistant GC tissues and cells (p < 0.05). Overexpression of RGS1 could enhance the resistance to trastuzumab, migration and invasion of SNU216-TR cells and promote EMT progression (p < 0.05). Moreover, overexpression of RGS1 could activate the MEK/ERK pathway in SNU216-TR cells, while knockdown of RGS1 significantly inhibited the pathway (p < 0.05). In addition, RGS1 significantlyup-regulated Gαq expression and activated the MEK/ERK signaling pathway (p < 0.05). Conclusions: RGS1 activated the MEK/ERK pathway by regulating Gαq signaling, thereby promoting trastuzumab resistance and malignant behaviors of GC cells SNU216.