Abstract
Gastric cancer is one of the most prevalent human cancers with poor prognosis. Trastuzumab is a well-used targeted drug for gastric cancer with HER2 amplification. Trastuzumab resistance restrains the clinical use of trastuzumab. In this study, we reported human Gse1 coiled-coil protein (GSE1) promoted trastuzumab resistance in HER2-positive gastric cancer cells. Acquired trastuzumab-resistant gastric cancer cells overexpressed GSE1, and depletion of GSE1 decreased the trastuzumab resistance of trastuzumab-resistant gastric cancer cells. BCL-2 was a downstream gene positively regulated by GSE1 and also performed promoting the role of trastuzumab resistance in HER2-positive gastric cancer cells. A high level of GSE1 was associated with a high risk of tumor lymph node metastasis and higher clinical stage in HER2-positive gastric cancer patients. GSE1 was a potential target that could be used for HER2-positive gastric cancer therapy.
Highlights
Gastric cancer is one of the most prevalent human cancers and has a high lethality worldwide [1, 2]
We reported that Gse1 coiled-coil protein (GSE1) promoted proliferation and metastasis of human gastric cancer cells both in vitro and in vivo; a high level of GSE1 was associated with worse clinicopathological parameters including lymph node metastasis, histological grade, depth of invasion, and clinical stage in gastric cancer patients; overexpression of GSE1 was associated with decreased relapse-free survival rate and overall survival rate in gastric cancer patients [12]
We have observed that the forced expression of GSE1 in HER2-positive gastric cancer cells MKN45 and NCI-N8 dramatically enhanced the resistance to trastuzumab as determined by MTT assay and 3-D matrigel cell culture assay
Summary
Gastric cancer is one of the most prevalent human cancers and has a high lethality worldwide [1, 2]. Surgical resection and chemotherapy are the main treatments for gastric cancer, but the survival rate of advanced gastric cancer patients is less than 1 year [3, 4]. HER2 (human epidermal growth factor receptor 2 (ERBB2)) amplification is found in 10-15% of gastric cancer patients, and trastuzumab is a monoclonal antibody drug that directly targets HER2 [5, 6]. Acquired drug resistance retarded the use of trastuzumab in gastric cancer [7]. Contributed to trastuzumab resistance of gastric cancer. The mechanisms involved in trastuzumab resistance of gastric cancer are complex; further study of the detailed molecular mechanisms of trastuzumab resistance in gastric cancer is desirable and urgent
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