Abstract
BackgroundA healthy gastric mucosal epithelium exhibits tumor-suppressive properties. Gastric epithelial cell dysfunction contributes to gastric cancer development. Oxysterols provided from food or cholesterol oxidation in the gastric epithelium may be further sulfated by hydroxysteroid sulfotransferase 2B1 (SULT2B1), which is highly abundant in the gastric epithelium. However, the effects of SULT2B1 on gastric epithelial function and gastric carcinogenesis are unclear.MethodsA mouse gastric tumor model was established using carcinogenic agent 3-methylcholanthrene (3-MCA). A SULT2B1 deletion (SULT2B1−/−) human gastric epithelial line GES-1 was constructed by CRISPR/CAS9 genome editing system.ResultsThe gastric tumor incidence was higher in the SULT2B1−/− mice than in the wild-type (WT) mice. In gastric epithelial cells, adenovirus-mediated SULT2B1b overexpression reduced the levels of oxysterols, such as 24(R/S),25-epoxycholesterol (24(R/S),25-EC) and 27-hydroxycholesterol (27HC). This condition also increased PI3K/AKT signaling to promote gastric epithelial cell proliferation, epithelization, and epithelial development. However, SULT2B1 deletion or SULT2B1 knockdown suppressed PI3K/AKT signaling, epithelial cell epithelization, and wound healing and induced gastric epithelial cell malignant transition upon 3-MCA induction.ConclusionsThe abundant SULT2B1 expression in normal gastric epithelium might maintain epithelial function via the PI3K/AKT signaling pathway and suppress gastric carcinogenesis induced by a carcinogenic agent.
Highlights
Gastric cancer is the fifth most common cancer worldwide and the second most common cancer in China [1,2,3,4,5,6,7,8]
sulfotransferase 2B1 (SULT2B1)-deficient mice were susceptible to gastric tumors upon induction with the carcinogenic agent 3-MCA In the fundus, corpus and antrum of the human stomach, SULT2B1 was highly expressed in the gastric epithelium as evidenced by immunohistochemical staining and Western blotting analysis
Nodules were found in only 22% of the WT mice, Fig. 1 SULT2B1-deficient mice were susceptible to gastric tumors upon induction with the carcinogenic agent 3-MCA. a SULT2B1 expression in human normal gastric mucosal tissue was studied by immunohistochemical staining and Western blotting analysis. b The SULT2B1 mRNA level in different murine organs was detected by : Quantitative real-time polymerase chain reaction (qRT-PCR). c The SULT2B1 mRNA expression level in the gastric tissues of WT and SULT2B1−/− mice was measured by qRT-PCR
Summary
Gastric cancer is the fifth most common cancer worldwide and the second most common cancer in China [1,2,3,4,5,6,7,8]. Patients with gastric cancer generally have a poor prognosis, with a less than 30% 5-year survival rate in advanced stage [9]. The mechanism underlying gastric carcinogenesis remains to be elucidated. Gastric mucosal epithelium controls important digestive, absorptive, and secretory functions and forms the first barrier against gastric juice, dietary irritants, and the microbiota. A healthy epithelium is composed of a polarized epithelial cell layer, which is maintained by the integrity of the apical-basal polarity, a highly organized actin cytoskeleton, and a junctional complex exhibiting tumor-suppressive properties [10]. The gastric epithelial cells of the gastric mucosa undergo dynamic changes, such as differentiation, growth, migration, and shedding. A healthy gastric mucosal epithelium exhibits tumor-suppressive properties. Gastric epithelial cell dysfunction contributes to gastric cancer development. The effects of SULT2B1 on gastric epithelial function and gastric carcinogenesis are unclear
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