Noguchi Kozo, Konno Masamitsu, Koseki Jun, Nishida Naohiro, Kawamoto Koichi, Yamada Daisaku, Asaoka Tadafumi, Noda Takehiro, Wada Hiroshi, Gotoh Kunihito, Sakai Daisuke, Kudo Toshihiro, Satoh Taroh, Eguchi Hidetoshi, Doki Yuichiro, Mori Masaki, Ishii Hideshi
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Oncol Lett. 2018 Aug;16(2):1827-1834. doi: 10.3892/ol.2018.8795. Epub 2018 May 24.
The expression levels of one-carbon metabolic enzymes were investigated and observed to be correlated with clinicopathological parameters in patients with pancreatic cancer. Mitochondrial one-carbon metabolism comprises a network of biological reactions that integrate nutrient status with nucleotide synthesis, amino acid metabolism, antioxidant reduced nicotinamide adenine dinucleotide phosphate production and epigenetic methylation processes. Previous studies have reported that the hyper-activation of mitochondrial one-carbon metabolism serves a significant role in malignant cancer phenotypes. A total of 103 patients underwent surgical resection of pancreatic ductal adenocarcinomas (PDAC) at Osaka University Hospital between April 2007 and December 2013 and were enrolled in this study. Subsequently, the expression of the one-carbon metabolic enzymes methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), aldehyde dehydrogenase 1 family member L2 (ALDH1L2), and serine hydroxymethyltransferase (SHMT2) was examined using immunohistochemical analysis. The immunohistochemical analyses demonstrated that patients with high expression levels of MTHFD2, ALDH1L2 or SHMT2 had significantly poor overall survival (OS) and disease-free survival (DFS) rates, as compared with patients with low expression levels. Furthermore, multivariate Cox proportional hazards analysis indicated that MTHFD2 and ALDH1L2 were independent prognostic factors for OS and DFS, whereas SHMT2 was not predictive of DFS. However, high and low expression levels of all three folate metabolic enzymes were significantly associated with improved OS and DFS, compared with the high expression of one or two folate metabolic enzymes. The expression levels of mitochondrial one-carbon metabolic enzymes are independent prognostic factors and potential therapeutic targets for future pancreatic cancer treatments.
研究了一碳代谢酶的表达水平，并观察到其与胰腺癌患者的临床病理参数相关。线粒体一碳代谢包括一个生物反应网络，该网络将营养状态与核苷酸合成、氨基酸代谢、抗氧化还原型烟酰胺腺嘌呤二核苷酸磷酸生成以及表观遗传甲基化过程整合在一起。先前的研究报道，线粒体一碳代谢的过度激活在恶性肿瘤表型中起重要作用。2007年4月至2013年12月期间，共有103例患者在大阪大学医院接受了胰腺导管腺癌（PDAC）的手术切除，并纳入本研究。随后，采用免疫组织化学分析检测了一碳代谢酶亚甲基四氢叶酸脱氢酶2（MTHFD2）、醛脱氢酶1家族成员L2（ALDH1L2）和丝氨酸羟甲基转移酶（SHMT2）的表达。免疫组织化学分析表明，与低表达水平的患者相比，MTHFD2、ALDH1L2或SHMT2高表达水平的患者总生存期（OS）和无病生存期（DFS）率显著较差。此外，多变量Cox比例风险分析表明，MTHFD2和ALDH1L2是OS和DFS的独立预后因素，而SHMT2不能预测DFS。然而，与一种或两种叶酸代谢酶的高表达相比，所有三种叶酸代谢酶的高表达和低表达水平均与OS和DFS的改善显著相关。线粒体一碳代谢酶的表达水平是未来胰腺癌治疗的独立预后因素和潜在治疗靶点。
