Yamakawa Yushi, Kusuhara Masatoshi, Terashima Masanori, Kinugasa Yusuke, Sugino Takashi, Abe Masato, Mochizuki Toru, Hatakeyama Keiichi, Kami Kenjiro, Yamaguchi Ken
Division of Colon and Rectal Surgery, Shizuoka Cancer Center.
Biomed Res. 2017;38(1):41-52. doi: 10.2220/biomedres.38.41.
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.
CD44变异体9（CD44v9）和4F2细胞表面抗原重链（CD98hc）似乎对胃癌中活性氧防御调节和肿瘤生长至关重要。本研究检测了CD44v9和CD98hc作为胃癌复发标志物的作用，并研究了其与能量代谢的关联。我们应用毛细管电泳飞行时间质谱对103例接受无残留肿瘤或微小残留肿瘤切除的胃癌标本进行代谢组分析，并将代谢物水平与CD44v9和CD98hc的免疫组化染色结果进行比较。CD44v9的阳性表达率为40.7%，CD98hc的阳性表达率为42.7%。多种肿瘤特征与CD44v9表达显著相关。CD44v9阳性肿瘤的5年无复发生存率（39.1%）显著低于CD44v9阴性肿瘤（73.5%；P<0.0001），但根据CD98hc表达情况，无复发生存率无显著差异。单因素和多因素分析确定CD44v9阳性表达是无复发生存较差的独立预测因素。对110种代谢物的代谢组分析发现，CD44v9阳性肿瘤中谷胱甘肽二硫化物水平显著降低，还原型谷胱甘肽（GSH）/谷胱甘肽二硫化物（GSSG）比值显著升高，这表明CD44v9可能增强癌细胞中的磷酸戊糖途径通量并维持GSH水平。
