Proto-oncogene WNT10B is up-regulated by tumor necrosis factor α in human gastric cancer cell line MKN45

WNT10A and WNT10B genes are human orthologues of mouse proto-oncogene Wnt-10b. We have previously cloned and characterized WNT10A, and demonstrated upregulation of WNT10A by tumor necrosis factor a (TNF alpha) in gastric cancer. Here, we cloned and characterized human WNT10B, which showed Gly60Asp amino-acid substitution compared with human WNT10B previously reported by another group. Gly60 WNT10B allele was identified in 2 human genome draft sequences and 7 human ESTs, while Asp60 WNT10B allele was not identified in any human genome draft sequences or ESTs. The Gly60-type WNT10B cDNA isolated in this study might be derived from more common WNT10B allele. WNT10B was most homologous to WNT10A (64.5% total amino-acid identity) among human WNTs. Variable region in the WNT core domain of WNT10B and WNT10A were longer than that of other WNTs, such as WNT2B1 I, WNT2B2, WNT3, WNT3A, WNT5B, WNT7B, WNT8A, WNT 11, WNT 14, and WNT 14B/WNT 15. We next investigated expression of WNT10B in human gastric cancer. WNT10B was moderately expressed in MKN45 and MKN74 cells, and weakly expressed in OKAJIMA, TMK1, MKN7, MKN28, and KATO-III cells. Because interferon gamma (IFN gamma) and TNF alpha were frequently elevated in gastric mucosa with Helicobacter pylori infection, effects of IFN gamma and TN-Fa on WNT10B expression in MKN45 cells were investigated. TNFa induced transient up-regulation of WNT10B mRNA in MKN45 cells. Up-regulation of WNT10B in human gastric mucosa might lead to gastric carcinogenesis through activation of the beta -catenin - TCF signaling pathway, just like up-regulation of Wnt-10b in mouse mammary gland leads to mammary carcinogenesis.