title: CD44 variant 9 expression as a predictor for gastric cancer recurrence: immunohistochemical and metabolomic analysis of surgically resected tissues.
abstract: CD44 variant 9 (CD44v9) and the heavy chain of 4F2 cell-surface antigen (CD98hc) appear important for regulation of reactive oxygen species defence and tumor growth in gastric cancer. This study examined the roles of CD44v9 and CD98hc as markers of gastric cancer recurrence, and investigated associations with energy metabolism. We applied capillary electrophoresis time-of-flight mass spectrometry to metabolome profiling of gastric cancer specimens from 103 patients who underwent resection with no residual tumor or microscopic residual tumor, and compared metabolite levels to immunohistochemical staining for CD44v9 and CD98hc. Positive expression rates were 40.7% for CD44v9 and 42.7% for CD98hc. Various tumor characteristics were significantly associated with CD44v9 expression. Five-year recurrence-free survival rate was significantly lower for CD44v9-positive tumors (39.1%) than for CD44v9-negative tumors (73.5%; P < 0.0001), but no significant differences in recurrence-free survival were seen according to CD98hc expression. Uni- and multivariate analyses identified positive CD44v9 expression as an independent predictor of poorer recurrence-free survival. Metabolome analysis of 110 metabolites found that levels of glutathione disulfide were significantly lower and reduced glutathione (GSH)/ glutathione disulfide (GSSG) ratio was significantly higher in CD44v9-positive tumors than in CD44v9-negative tumors, suggesting that CD44v9 may enhance pentose phosphate pathway flux and maintain GSH levels in cancer cells.
authors.affiliation: Division of Colon and Rectal Surgery, Shizuoka Cancer Center.
authors.forename: Yushi
authors.initials: Y
authors.lastname: Yamakawa
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kusuhara
authors.forename: Masanori
authors.initials: M
authors.lastname: Terashima
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kinugasa
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugino
authors.forename: Masato
authors.initials: M
authors.lastname: Abe
authors.forename: Toru
authors.initials: T
authors.lastname: Mochizuki
authors.forename: Keiichi
authors.initials: K
authors.lastname: Hatakeyama
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kami
authors.forename: Ken
authors.initials: K
authors.lastname: Yamaguchi
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D005260:Female; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics*; D008297:Male; D055442:Metabolome; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D016016:Proportional Hazards Models; D017382:Reactive Oxygen Species / Q000378:metabolism; D013274:Stomach Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000601:surgery; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D017382:Reactive Oxygen Species; D005978:Glutathione; D019803:Glutathione Disulfide