Dysregulation of stem cell signaling network due to germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer

Genetic factors, Helicobacter pylori infection, salt over-uptake, decreased vegetable fruit consumption, smoking, and metabolic syndrome are risk factors of human gastric cancer. Germline mutations of CDH1 gene, and SNPs of PTPN11 (SHP2), TLR4, IL1 B TNFA, BMP6, GDF15 and RUNX3 genes are associated with gastric cancer. Helicobacte pylori activates CagA-SHP2-ERK and peptidoglycan-NOD1-NF kappa B signaling cascades in gastric epithelial cells using type IV secretion system, and also TRAF6-MAP3K7-NF kappa B and TRAF6-MAP3K7-AP-1 signaling cascades in epithelial and immune cells through lipopoly saccharide recognition by TLR2 or TLR4. IL-1 beta, IL-6, IL-8, TNF alpha and IFN gamma are elevated it gastric mucosa with Helicobacter pylori infection. IL-6 and TNFa induce upregulation of WNT5A and WNT10B, respectively. WNT signals are transduced to beta-catenin-TCF/LEF RhoA, JNK, PKC, NFAT and NLK signaling cascades. WNT-beta-catenin-TCF/LEF signaling induces upregulation of MYC, CCND1, WISP 1, FGF20, JAG 1 and DKK1 genes. Notch signals are transduced to CSL-NICD-MAML and NF kappa B signaling cascades. FGF signals are transduced to ERK, PI3K-AKT, PKC and NEAT signaling cascades. Helicobacter pylor infection induces SHH upregulation in parietal cell lineage, while BMP signals induce IHH upregulation in pit cell lineage. Hedgehog signals induce upregulation of GLl1, PTCH1 CCND2, FOXL1, JAG2 and SFRP1 genes. JAG1 and JAG2 activate Notch signaling while DKK1 and SFRP1 inhibit WNT signaling. Stem cell signaling network, consisting, of WNT, Notch, FGF, Hedgehog and BMP signaling pathways, is activated during chronic Helicobacter pylori infection. Epigenetic silencing of SFRP1 gene occurs in the earlier stage of carcinogenesis in the stomach, while amplification and overexpression of FGFR2 gene in the later stage. Dysregulation of the stem cell signaling network due to the accumulation of germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration gives rise to gastric cancer. SNP typing and custom-made microarray analyses on genes encoding stem cell signaling molecules could be utilized for the personalized medicine.