Abstract
Gastric cancer (GC) is the most common cancer throughout the world. Despite advances of the treatments, detailed oncogenic mechanisms are largely unknown. In our previous study, we investigated microRNA (miR) expression profiles in human GC using miR microarrays. We found miR-192/215 were upregulated in GC tissues. Then gene microarray was implemented to discover the targets of miR-192/215. We compared the expression profile of BGC823 cells transfected with miR-192/215 inhibitors, and HFE145 cells transfected with miR-192/-215 mimics, respectively. SET8 was identified as a proposed target based on the expression change of more than twofold. SET8 belongs to the SET domain-containing methyltransferase family and specifically catalyzes monomethylation of H4K20me. It is involved in diverse functions in tumorigenesis and metastasis. Therefore, we focused on the contributions of miR-192/215/SET8 axis to the development of GC. In this study, we observe that functionally, SET8 regulated by miR-192/215 is involved in GC-related biological activities. SET8 is also found to trigger oncogene-induced senescence (OIS) in GC in vivo and in vitro, which is dependent on the DDR (DNA damage response) and p53. Our findings reveal that SET8 functions as a negative regulator of metastasis via the OIS-signaling pathway. Taken together, we investigated the functional significance, molecular mechanisms, and clinical impact of miR-192/215/SET8/p53 in GC.
Highlights
Gastric cancer (GC) is one of the most common cancers all over the world, especially in Asia
Correlation analyses between miR-192/215 and SET8 indicated that miR-192 and -215 were highly expressed in GC tissues, a finding that was consistent with our previous results[1,2] (Fig. 1B down)
SET8 was found to be expressed at low levels in GC tissues and cells, which suggests that it may function as a suppressor of GC
Summary
Gastric cancer (GC) is one of the most common cancers all over the world, especially in Asia. Despite the improved surgical and adjuvant treatment approaches[1], the microRNA (miR) is a small, single-stranded RNA, and negatively regulates the target genes by interacting with the untranslated regions (UTRs) of targets[2]. It plays a critical role in cancer-related proliferation, migration, apoptosis, and cell-cycle progression. We investigated the miR expression profiles in human GC using miR microarrays. We found miR-192/ 215 were upregulated in GC tissues[1,2].
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