INSERM U 954, Faculté de Médecine – BP 184, 54511 Vandoeuvre les Nancy, France.
Clin Chem Lab Med. 2013 Mar 1;51(3):617-21. doi: 10.1515/cclm-2012-0689.
Carcinogenesis is a multi-step and multifactorial process. It includes genetic, epigenetic, nutritional and environmental factors, which are closely interconnected. Human hepatocellular carcinoma (HCC) is among the most frequent and lethal cancers. Imbalance in the S-adenosylmethionine (SAM) concentration, the main methyl group donor, strongly influences the development of HCC. Key enzymes of carbon metabolism are greatly reduced in patients with cirrhosis and HCC. These alterations play a role in genetic instability and epigenetic modifications (DNA methylation, and histone modifications), however, the molecular underlying mechanisms are still poorly understood. We aimed to investigate betaine homocysteine methyltransferase (BHMT) expression in HepG2 cells and human hepatocarcinoma tissues. Tumor and surrounding healthy tissue were compared. HepG2 cells and tumor samples showed a strong decrease in BHMT transcripts resulting from the transcription of a splicing variant that contained a frameshift mutation generating a premature termination codon and gene loss of function. This splicing variant, not detected in normal adult and fetal liver, cannot be explained by any mechanism involving the known splicing consensus sequences. BHMT activity was abolished in HepG2 cells and protein expression was detected neither in HepG2 cells nor in five of the six tumor samples investigated. Further investigation is needed to elucidate whether this abnormal BHMT transcription is part of cause or consequence of liver carcinogenesis.
癌症发生是一个多步骤和多因素的过程。它包括遗传、表观遗传、营养和环境因素，这些因素密切相关。人肝细胞癌（HCC）是最常见和最致命的癌症之一。S-腺苷甲硫氨酸（SAM）浓度的平衡，主要的甲基供体，强烈影响 HCC 的发展。肝硬化和 HCC 患者的碳代谢关键酶大大减少。这些改变在遗传不稳定性和表观遗传修饰（DNA 甲基化和组蛋白修饰）中起作用，但分子潜在机制仍知之甚少。我们旨在研究 HepG2 细胞和人肝癌组织中甜菜碱同型半胱氨酸甲基转移酶（BHMT）的表达。比较肿瘤和周围健康组织。HepG2 细胞和肿瘤样本显示 BHMT 转录本的强烈减少，这是由于包含移码突变的剪接变体的转录导致的，该突变产生过早终止密码子和基因功能丧失。这种剪接变体在正常成人和胎儿肝脏中未检测到，不能用任何涉及已知剪接一致序列的机制来解释。BHMT 活性在 HepG2 细胞中被废除，并且在 HepG2 细胞中和在六个研究的肿瘤样本中的五个中均未检测到蛋白质表达。需要进一步研究以阐明这种异常的 BHMT 转录是否是肝癌发生的原因或后果的一部分。
