Up regulation of GW112 Gene by NFκB promotes an antiapoptotic property in gastric cancer cells

Abstract

To clarify the regulatory mechanism of GW112 gene expression, 5'-flanking region of the human GW112 gene was isolated and characterized in the present study. 5'-RACE analysis showed a single transcription start site, which is located 142 nucleotides upstream of the translation initiation site. Transient transfection studies with serial deletion constructs and close examination of the sequences identified a putative NF kappaB binding sequence between -442 and -430, which could be responsible for efficient expression of the GW112 gene. Indeed, GW112 gene was found to be regulated by NF kappaB signals including overexpressed p65 and I kappaB alpha, IKK inhibitor, and proteasome inhibitor. Binding of NF kappaB to its putative site was confirmed by EMSA and ChIP assays. These results suggest that NF kappaB is an essential regulatory factor for GW112 transcription. Based on this finding, we next confirmed that inhibition of GW112 expression could induce apoptosis in the presence of cytotoxic agent in gastric cancer cells. Furthermore, knocking-down or overexpression of GW112 gene in gastric cancer cells demonstrated that GW112 has an antiapoptotic property against the cytotoxic agents-induced apoptosis. Taken together, these results suggest that GW112 could be an important mediator in NF kappaB-dependent tumorigenesis of digestive tract tissues.

Genomic Loss ofmiR-486Regulates Tumor Progression and theOLFM4Antiapoptotic Factor in Gastric Cancer

“…Functionally, OLFM4 has also been shown to behave as an antiapoptotic factor and to promote tumor growth and invasion (see Discussion;refs. 42,43). Confirming previous reports, we found that OLFM4 was indeed highly expressed in GCs compared with gastric normals (P < 0.001; Fig.…”

“…OLFM4 has been reported to be overexpressed in various cancers including GC but also colon, breast, and lung cancers (41), and has been proposed as a potential serum biomarker of GC (39). Functionally, OLFM4 has been shown to interact with GRIM19 (a cell-death regulatory protein), cadherins, and lectins, and OLFM4 has been shown to inhibit apoptosis and promote tumor growth and invasion (41)(42)(43). However, a recent finding showed that OLFM4 has a proapoptotic effect in myeloid leukemia cells (49).…”

“…OLFM4 expression promotes GC cell proliferation and inhibits the antioncogenic effects of miR-486 OLFM4 has been proposed to promote tumor growth by functioning as an antiapoptotic protein (42,43) attenuating the apoptotic function of GRIM-19, a cell-death regulatory protein. To establish a functional role for OLFM4 in GC, we silenced OLFM4 in YCC3 and SCH cells, and conducted cell proliferation assays.…”

DNA methylation is required for the control of stem cell differentiation in the small intestine

“…To our knowledge, nothing is currently known about the role of distal enhancer elements in the regulation of Olfm4 expression. However, there are multiple transcription factor-binding sites in the proximal promoter important for Olfm4 expression, including nuclear factor-kB (NF-kB) (Huang et al 2010;Kim et al 2010b) and RBP-J, the main transcriptional mediator of Notch signaling (VanDussen et al 2012). In the DMR at the proximal promoter, CpGs are directly adjacent to the NFkB-and predicted RBP-J- binding sites.…”

Olfactomedin III expression contributes to anoikis-resistance in clonal variants of a human lung squamous carcinoma cell line

“…Both OLFM1 and OLFM4 have been implicated in apoptosis. Mutations in OLFM1 [28] and silencing of OLFM1 resulted in increased apoptosis [29]. OLFM4 may have differing roles depending on the tissue, being antiapoptotic in gastric cancers [30] and growth promoting in pancreas and lung cancer cells [31,21].…”