<b>CD44 variant 9 expression as a predictor for gastric cancer recurrence: immunohistochemical and metabolomic analysis of surgically resected </b><b>tissues </b>

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. Uniand 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.Gastric cancer is the fifth most common malignancy (952,000 cases in 2012) and the third leading cause of cancer-related deaths (723,000 deaths in 2012) worldwide (1). Despite the decline in global patient numbers, gastric cancer remains one of the most prevalent cancers in Japan. Although progress in early diagnosis and adjuvant therapy has improved outcomes for gastric cancer patients, radical surgery remains the primary approach for gastric cancer treatment. Outcomes are still unsatisfactory, because gastric cancers relapse with local or distant metastasis even after radical gastrectomy. More specific diagnostic and therapeutic targets are urgently needed to achieve better clinical applications in this field. CD44, a major adhesion molecule for the extracellular matrix, is a single-pass type I transmembrane protein that serves as a cell surface receptor for hyaluronic acid, and has been implicated in vari-

Identification of novel biomarkers, MUC5AC, MUC1, KRT7, GAPDH, CD44 for gastric cancer

“…Different from the typical CD44 standard isomers, CD44 variants (CD44v) are considered to be the key molecules in the process of malignant transformation, and their expression is highly restricted and specific [52,53]. In general, CD44v, is considered to be a marker of GC cells [54,55], which help to increase resistance to chemotherapy or radiation-induced cell death [56][57][58][59][60][61][62][63][64][65]. Our results indicated that the expression of CD44 in GC was higher than that in normal tissues, and there was a positive correlation between CD44 and GAPDH.…”

Recent advances in capillary electrophoresis‐mass spectrometry: Instrumentation, methodology and applications

“…Yamakawa et al. performed metabolic profiling to differentiate tumor types of gastric cancer and Saito et al. profiled low molecular weight compounds in hepatocellular carcinoma .…”

Impact of Truncated O-glycans in Gastric-Cancer-Associated CD44v9 Detection

“…CD44 expression has been associated with gastric cancer disease progression and aggressiveness [12,31,32], revealing its importance in these types of malignancies. In order to evaluate the impact of truncated O-glycans cellular profile, we first determined the product of alternative splicing of the CD44 gene in the presented models.…”

“…The CD44v8-10 has been claimed to be the predominant CD44 variant found in gastric CSCs from patient tumor samples [9], and its expression was shown to promote resistance against reactive oxygen species (ROS) and contributed to cell proliferation [10]. Particularly, CD44v9, contained in CD44v8-10, is one of the major isoforms in human gastrointestinal cancer [11], and its presence is related to elevated tumor sizes and poor prognosis and survival [12,13]. Moreover, the mechanistic importance of CD44v9 highlights its potential as a promising biomarker and potential target in therapeutic strategies in GC.…”