Division of Hepatology and Gene Therapy, Proteomics, Genomics & Bioinformatics Unit, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Funct Integr Genomics. 2011 Sep;11(3):419-29. doi: 10.1007/s10142-011-0230-7. Epub 2011 May 12.
Hepatocellular carcinoma (HCC) represents a major health problem as it afflicts an increasing number of patients worldwide. Albeit most of the risk factors for HCC are known, this is a deadly syndrome with a life expectancy at the time of diagnosis of less than 1 year. Definition of the molecular principles governing the neoplastic transformation of the liver is an urgent need to facilitate the clinical management of patients, based on innovative methods to detect the disease in its early stages and on more efficient therapies. In the present study, we have combined the analysis of a murine model and human samples of HCC to identify genes differentially expressed early in the process of hepatocarcinogenesis, using a microarray-based approach. Expression of 190 genes was impaired in murine HCC from which 65 were further validated by low-density array real-time polymerase chain reaction (RT-PCR). The expression of the best 45 genes was then investigated in human samples resulting in 18 genes in which expression was significantly modified in HCC. Among them, JUN, methionine adenosyltransferase 1A and 2A, phosphoglucomutase 1, and acyl CoA dehydrogenase short/branched chain indicate defective cell proliferation as well as one carbon pathway, glucose and fatty acid metabolism, both in HCC and cirrhotic liver, a well-known preneoplastic condition. These alterations were further confirmed in public transcriptomic datasets from other authors. In addition, vasodilator-stimulated phosphoprotein, an actin-associated protein involved in cytoskeleton remodeling, was also found to be increased in the liver and serum of cirrhotic and HCC patients. In addition to revealing the impairment of central metabolic pathways for liver homeostasis, further studies may probe the potential value of the reported genes for the early detection of HCC.
肝细胞癌（HCC）是一个严重的健康问题，因为它在全球范围内影响了越来越多的患者。尽管大多数 HCC 的风险因素已经知晓，但这仍然是一种致命的综合征，在诊断时的预期寿命不到 1 年。定义控制肝脏肿瘤发生的分子原理是当务之急，这有助于根据创新方法在疾病早期进行检测，并提供更有效的治疗方法，从而对患者进行临床管理。在本研究中，我们结合了对 HCC 的小鼠模型和人类样本的分析，使用基于微阵列的方法，鉴定了在肝癌发生过程中早期差异表达的基因。在来自小鼠 HCC 的 190 个基因表达受损中，通过低密度阵列实时聚合酶链反应（RT-PCR）进一步验证了 65 个基因。然后在人类样本中研究了最佳的 45 个基因的表达情况，结果发现 18 个基因在 HCC 中表达显著改变。其中，JUN、甲硫氨酸腺苷转移酶 1A 和 2A、磷酸葡萄糖变位酶 1 和酰基辅酶 A 脱氢酶短/支链表明，细胞增殖以及一碳途径、葡萄糖和脂肪酸代谢在 HCC 和肝硬化肝脏中都存在缺陷，肝硬化是一种众所周知的癌前病变。这些改变在其他作者的公共转录组数据集也得到了进一步证实。此外，血管扩张刺激磷蛋白，一种参与细胞骨架重塑的肌动蛋白相关蛋白，也被发现增加在肝硬化和 HCC 患者的肝脏和血清中。除了揭示肝脏内稳态的中央代谢途径受损之外，进一步的研究可能会探究报告基因在 HCC 早期检测中的潜在价值。
