Abstract
Gastric cancer (GC) is one of the most common types of cancer. The n-butanol extract of Huaier (NEH) is the alcohol-soluble part extracted by the systematic solvent method, which is effective against gastric cancer (GC). However, the mechanism of action of NEH remains unclear. In this study, we aim to evaluate the clinical relevance of GPR30 expression in GC patients and the role of the GPR30/PI3K/AKT signalling pathway in the anti-GC effect of NEH. The expression of GPR30 was examined using immunohistochemistry. Cell counting kit 8 (CCK-8) assay, wound healing, and transwell experiments were used to investigate the viability, migration, and invasion of gastric cancer cells. Western blotting was used to detect the expression of GPR30 and its downstream signalling molecules of the PI3K/AKT signalling pathway. Gastric cancer patient-derived xenografts (PDX) mouse model was used to evaluate the antitumor effect of NEH in vivo. In addition, the graded doses and the maximum tolerated dose of NEH were administered intraperitoneally into the mice for acute toxicity test. We demonstrate that GPR30 expression in GC tissues was significantly higher than that in corresponding adjacent noncancerous tissues and the expression of GPR30 was correlated with a poor prognosis in GC patients. Moreover, GPR30 expression was involved in the migration and invasion of GC cells in vitro. Additionally, we found that NEH can suppress the growth of GC in patient-derived xenograft tumors in vivo. Furthermore, NEH inhibited the proliferation, migration, and invasion in GC cells in a concentration-dependent manner through inhibiting the GPR30-mediated PI3K/AKT signalling pathway in vitro. Acute toxicity test showed that NEH caused no toxic reaction or death and the maximum tolerated dose of NEH in mice was greater than 1600 mg/kg. Our results demonstrate that the high expression of GPR30 is an independent factor of poor prognosis in patients with GC and NEH could be a new agent for the treatment of gastric cancer.
Highlights
Gastric cancer (GC) is one of the most common types of cancers [1]
We found that n-butanol extract of Huaier (NEH) significantly inhibited the proliferation, migration, and invasion of gastric cancer cells through the PI3K/AKT signalling pathway mediated by GPR30
We found that 51 (56.04%) GC patients had a high expression of GPR30 in tumor tissues, and 40 (43.96%) patients had a low expression
Summary
Gastric cancer (GC) is one of the most common types of cancers [1]. Despite significant progress in the treatment of GC, the prognosis remains poor. Two-thirds of patients with GC are already in advanced stage when they are first diagnosed, and there is no chance of surgery. Erefore, finding effective potential targeted therapy is the key to the treatment of advanced GC. GPR30, a new type of estrogen receptor, is different from the classic estrogen receptors (ERα and ERβ) in structure and function. It participates in the rapid activation of intracellular signalling transduction pathways through the G protein βc heterodimer and Gα subunit, including the mobilization of intracellular calcium storage, the transactivation of human epidermal growth factor receptor (EGFR), and the activation of downstream signalling pathways such as PI3K/AKT signalling pathway [3]. Our previous studies demonstrated that GPR30 was a key factor
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