Abstract
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Helicobacter pylori infection can induce GC through a serial cascade of events, with emerging evidence suggesting the important role of epigenetic alterations in the development and progression of the disease. Here, we report on mechanisms responsible for Jumonji AT-rich interactive domain1B (JARID1B) upregulation in GC and its role in the malignant transformation induced by H. pylori infection. We found that upregulation of JARID1B was associated with poorer prognosis, greater tumor purity, and less immune cell infiltration into the tumor. Mechanistically, we showed that the upregulation of JARID1B in human GC was attributed to JARID1B amplification and its induction by H. pylori infection. Furthermore, we identified miR-29c as a negative regulator of JARID1B in GC. H. pylori caused downregulation of miR-29c in human GC and thereby contributed to JARID1B upregulation through relieving posttranscriptional regulation. Functionally, we showed that knockdown of JARID1B reduced GC cell proliferation induced by H. pylori infection. Subsequently, cyclinD1 (CCND1), a key molecule in GC, was shown to be a target gene of JARID1B. In conclusion, these results suggest that JARID1B may be an oncogene upregulated in human GC and could represent a novel therapeutic target to prevent malignant transformation induced by H. pylori infection.
Highlights
Gastric cancer (GC) is one of the most common malignancies worldwide, with >950,000 newly diagnosed cases each year [1]
We carried out an analysis of the Gene Expression Omnibus (GEO) databases (e.g., GSE27342 and GSE63089), which showed that Jumonji AT-rich interactive domain1B (JARID1B) expression was upregulated in GC tissues (Figures 1F, G)
The role of histone demethylases in tumorigenesis and progression has become more clearly recognized recently, for example, KDM4B is involved in the growth and progression of tumors such as GC, breast cancer, and ovarian cancer [31,32,33]; HPV16 E7 and miR-342-3p stimulate the expression of KDM2A in tumors, and KDM2A enhances ERK1/2-mediated tumor formation in lung cancer [34,35,36]; KDM4A is abnormally expressed in colorectal cancer, prostate cancer, lung cancer, and breast cancer and promotes their progression [37, 38]
Summary
Gastric cancer (GC) is one of the most common malignancies worldwide, with >950,000 newly diagnosed cases each year [1]. Due to the lack of early diagnostic screening, most patients are diagnosed at an advanced stage [2]. Studying the etiology of GC is of great significance for identifying means of early detection and/or prevention. Gastric carcinogenesis is a complex, multistep, and multifactorial event. Helicobacter pylori infection has long been recognized as a Class I oncogenic factor in GC. H. pylori can cause chronic gastritis, intestinal metaplasia, and even dysplasia, which can be considered precancerous lesions
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