Promoter methylation of the Wnt/β‐catenin signaling antagonist Dkk‐3 is associated with poor survival in gastric cancer

Abstract

Objective Infliximab treatment results in a decrease in synovial cellularity as early as 48 hours after initiation of therapy in patients with rheumatoid arthritis (RA). This study was undertaken to investigate whether infliximab induces apoptosis within the first 24 hours after infusion. Methods The percentage of apoptotic cells was determined by flow cytometry in blood drawn from 21 patients directly before, 1 hour after, and 24 hours after infliximab infusion. Synovial tissue samples obtained before, 1 hour after (n = 5), or 24 hours after (n = 5) initiation of therapy were subjected to immunohistochemistry to detect active caspase 3 and to TUNEL assay and electron microscopy to detect apoptosis. In addition, plasma levels of nucleosomes (generated during apoptosis) and C4b/c (an indicator of complement activation) were measured. Results There were no signs of apoptosis induction in peripheral blood monocytes or lymphocytes after infliximab treatment. Circulating lymphocyte counts were increased within 1 hour after infusion (P < 0.05). There was no definite evidence of apoptosis induction in the synovium, except in 1 patient 24 hours after the infliximab infusion. Consistent with these results, there was no increase in nucleosome levels nor were there signs of complement activation. Conclusion Our findings indicate that the rapid decrease in synovial cellularity observed after initiation of anti–tumor necrosis factor antibody therapy cannot be explained by apoptosis induction at the site of inflammation. It is tempting to speculate that the striking effects on synovial inflammation may be explained by other mechanisms, such as decreased migration toward the synovial compartment and reduced retention in the inflamed synovium.

Methylation of BNIP3 and DAPK indicates lower response to chemotherapy and poor prognosis in gastric cancer

“…Furthermore, methylation could provide useful information regarding prognosis. Yu et al reported that patients with methylation of Dkk-3, a Wnt/b-Catenin signaling antagonist, had a significantly shorter survival than patients with no methylation, in a study of primary gastric cancers (18). There have been many studies on the relationship between the methylation of tumor-suppressor genes and the response to chemotherapy in gastric cancer.…”

Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review

“…Homeostasis of the gastrointestinal epithelium is 87 [47,[69][70][71][72][73][74][75]232] Fzd-3 [78] CTNNB1 [9,[88][89][90][91][92][93]96,97] LRP6 [228] TCF7L2 [98][99][100] PPN [79] CDH17 [80] EZH2 [81] HMGA1, HMGA2 [210,211] YY1 [86] TC1 (C8orf4) [201,202] miR-17-92 [161] mir-10a [168] has-miR-335 [166] hsa-miR-375 [163] Downregulation or function inhibition in gastric cancer Downregulation by hypermethylation Inactivation by miRNAs APC [145,146] APC [175] sFRP1, sFRP2, sFRP4, sFRP5 [78,96,149] AXIN2 [159] WIF-1 [144,149] EZF1 [78] Dkk-1, Dkk-2, Dkk-3 [59,144,148,…”

“…Several other tumor suppressor genes that function through modulating Wnt/b-catenin signaling were found silenced in gastric cancer, such as members of the sFRP and Dkk gene families. CpG methylation-depending silencing of sFRP1, sFRP2, sFRP4, sFRP5, HSulf-1, WIF-1, RUNX3 as well as, Dkk-1, Dkk-2 and Dkk-3 has been frequently observed among gastric cancer cells lines and primary specimens [59,96,108,144,147,148] . In addition, Yu et al [148] showed by multivariate analysis that Dkk-3 methylation was associated significantly and independently with poor disease survival in gastric cancer, but not in colorectal cancer.…”

Expression of orphan nuclear receptor NR4A2 in gastric cancer cells confers chemoresistance and predicts an unfavorable postoperative survival of gastric cancer patients with chemotherapy

“…15 Wnt/b-catenin signaling and bcatenin target molecule cyclin D1 are important in promoting GC progression and chemoresistance. [16][17][18] We hypothesize that NR4A2 is activated in an inflammatory microenvironment, participates in an evolutionary process from inflammation to cancer via affecting PKA and/ or OPN-b-catenin-cyclin D1 pathways, and promotes the progression of GC. However, the role of NR4A2 in the pathogenesis of GC remains unknown.…”