Estrogen Aggravates Tumor Growth in a Diffuse Gastric Cancer Xenograft Model

Abstract

Gastric cancer has the fifth-highest incidence rate and is the third leading cause of cancer-related deaths worldwide. The incidence of gastric cancer is higher in men than in women, but for the diffuse types of gastric cancer, the trend is opposite. Estrogen is considered the prime culprit behind these differences. Nevertheless, the action of estrogen in gastric cancers remains unclear. In this study, we investigated the effect of estrogen on diffuse-type gastric cancer. Human female diffuse gastric cancer SNU-16 cells were transplanted into male and female mice to analyze the effect of endogenous estrogen on tumor growth. Furthermore, the effect of exogenous estrogen was evaluated in ovariectomized mice. Expressed genes were compared between female and male xenograft models using RNA sequencing analysis. Furthermore, human gene expression omnibus databases were utilized to examine the effect of our target genes on overall survival. SNU-16-derived tumor growth was faster in female mice than in male mice. In total RNA sequencing, interferon gamma receptor 2 (IFNGR2), IQ motif containing E (IQCE), transient receptor potential cation channel subfamily M member 4 (TRPM4), and structure-specific endonuclease subunit SLX4 (SLX4) were found. These genes could be associated with the tumor growth in female diffuse-type gastric cancer which was affected by endogenous estrogen. In an ovariectomized gastric cancer xenograft model, exogenous estrogen promoted tumor growth. Especially, our results indicated that estrogen induced G protein-coupled estrogen receptor expression in these mice. These results suggest that estrogen aggravates tumor progression in female diffuse gastric cancer.

Risk of gastric cancer in relation with serum cholesterol profiles: A nationwide population-based cohort study

“…This may simply have been due to the smaller number of gastric cancer patients in the female population. Additionally, considering that estrogen exerts a tumorigenic effect on diffuse-type gastric cancer, [30][31][32] and that diffuse-type gastric cancers are more prevalent in younger patients, [33] the elevated estrogen levels in young obese men may contribute to the stronger correlation between LDL-C and gastric cancer in young men.…”

Prognostic significance of preoperative osteopenia on outcomes after gastrectomy for gastric cancer

“… 20 Lee suggested that estrogen aggravates tumor progression in females with GC. 21 Thus, vitamin D and estrogen are suggested to be associated with GC prevalence and mortality, and further investigation is needed in relation to osteopenia.…”

“…A review by Du et al reported that vitamin D may inhibit GC cell viability, proliferation, and metastasis and may inhibit Helicobacter pylori infection and Helicobacter‐associated GC 20 . Lee suggested that estrogen aggravates tumor progression in females with GC 21 . Thus, vitamin D and estrogen are suggested to be associated with GC prevalence and mortality, and further investigation is needed in relation to osteopenia.…”

Sex Disparity in Patients with Gastric Cancer: A Systematic Review and Meta-Analysis

“…The estrogen receptor (ER) positive rate has been reported to be slightly higher in young females and in poorly differentiated gastric cancer. This may be the reason that poorly differentiated histological results have been found more common in female gastric cancer patients [ 30 , 35 , 94 , 95 ]. One study detailed the tumorigenic mechanism of estrogen in the development of ER α -positive diffuse-type gastric adenocarcinoma [ 94 ].…”