Sugar Alcohols Have a Key Role in Pathogenesis of Chronic Liver Disease and Hepatocellular Carcinoma in Whole Blood and Liver Tissues
Sugar Alcohols Have a Key Role in Pathogenesis of Chronic Liver Disease and Hepatocellular Carcinoma in Whole Blood and Liver Tissues
复制标题
DOI：
10.3390/cancers12020484
复制
发表时间：
2020-02-01
期刊：
影响因子：
5.2
通讯作者：
El-Said, Hala
中科院分区：
文献类型：
--
作者：
Ismail, Israa T.;Fiehn, Oliver;El-Said, Hala
肝细胞癌（HCC）的主要危险因素是丙型肝炎和B病毒感染，进而发展为慢性肝病（CLD）。然而，肝癌的早期诊断和治疗是具有挑战性的，因为肝癌的发病机制尚未完全确定。为了更好地理解HCC的发生和发展，从切除的人HCC组织及其配对的非肿瘤肝组织（n = 46）获得非靶向GC-TOF MS代谢组学数据。将相同HCC受试者（n = 23）的血液样品与CLD（n = 15）和健康对照（n = 15）血液样品进行比较。参与者是从埃及国家肝脏研究所招募的。GC-TOF MS数据产生了194个结构注释的化合物。最显著的改变是在HCC患者血液中上调的糖醇类，与CLD受试者相比（p < 2.4 x 10（-12）），与健康对照相比（p = 4.1 x 10（-7））。在HCC组织中，糖醇是所有HCC患者中区分切除的HCC组织和非恶性肝组织的最显著（p < 1 × 10（-6））类别。肝组织中糖醇水平的改变也可以从其配对的非恶性肝组织中确定早期HCC（p = 2.7 x 10（-6））。在血液中，糖醇区分HCC和CLD受试者的ROC曲线为0.875，而经典HCC生物标志物甲胎蛋白为0.685。从健康对照到CLD到早期HCC，最后到晚期HCC患者，血糖酒精水平稳步升高。糖醇水平的增加表明醛酮还原酶在HCC发病机制中的作用，在深入验证后可能开辟新的诊断和治疗选择。
The major risk factors for hepatocellular carcinoma (HCC) are hepatitis C and B viral infections that proceed to Chronic Liver Disease (CLD). Yet, the early diagnosis and treatment of HCC are challenging because the pathogenesis of HCC is not fully defined. To better understand the onset and development of HCC, untargeted GC-TOF MS metabolomics data were acquired from resected human HCC tissues and their paired non-tumor hepatic tissues (n = 46). Blood samples of the same HCC subjects (n = 23) were compared to CLD (n = 15) and healthy control (n = 15) blood samples. The participants were recruited from the National Liver Institute in Egypt. The GC-TOF MS data yielded 194 structurally annotated compounds. The most strikingly significant alteration was found for the class of sugar alcohols that were up-regulated in blood of HCC patients compared to CLD subjects (p < 2.4 x 10(-12)) and CLD compared to healthy controls (p = 4.1 x 10(-7)). In HCC tissues, sugar alcohols were the most significant (p < 1 x 10(-6)) class differentiating resected HCC tissues from non-malignant hepatic tissues for all HCC patients. Alteration of sugar alcohol levels in liver tissues also defined early-stage HCC from their paired non-malignant hepatic tissues (p = 2.7 x 10(-6)). In blood, sugar alcohols differentiated HCC from CLD subjects with an ROC-curve of 0.875 compared to 0.685 for the classic HCC biomarker alpha-fetoprotein. Blood sugar alcohol levels steadily increased from healthy controls to CLD to early stages of HCC and finally, to late-stage HCC patients. The increase in sugar alcohol levels indicates a role of aldo-keto reductases in the pathogenesis of HCC, possibly opening novel diagnostic and therapeutic options after in-depth validation.