Ali Kamkar Maisa Mahmoud, Ahmad Rasheed, Alsmadi Osama, Behbehani Kazem
Dasman Genome Center, Biomedical Research Department, Dasman Diabetes Institute, Dasman, Kuwait ; Department of Biomedical Research, Genetics and Genomics Unit/Dasman Genome Center, Dasman Diabetes Institute, P.O.Box 1180, Dasman 15462, Kuwait.
Immunology and Innovative Cell Therapy Unit, Biomedical Research Department, Dasman Diabetes Institute, Dasman, Kuwait.
J Diabetes Metab Disord. 2014 May 22;13:57. doi: 10.1186/2251-6581-13-57. eCollection 2014.
Hepatocellular carcinoma is a multifactorial disease which is associated with a background of many causal risk factors. Diabetes mellitus however is one of the most common co-morbid illnesses found in hepatocellular carcinoma patients that are significantly associated with worsening of hepatocellular carcinoma development, patient prognosis and survival. Therefore, efforts have been focused on understanding the mechanisms underlying progression of hepatocellular carcinoma onset and development especially in diabetic patients. To our knowledge, there are no reports which address the impact of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) along with epigenetic regulations associated with increased risk of hepatocellular carcinoma confounded by diabetes mellitus. Therefore, this mini-review focuses on the possible intermediary mechanisms involved in worsening the onset and progression of hepatocellular carcinoma development confounded by diabetes mellitus. The first approach is to look at the role of inflammatory mediators (TNF-α and IL-6) in apoptosis and inflammation during hepatocarcinogenesis through monitoring levels of apoptotic regulators, B-cell lymphoma 2 protein which is encoded by BCL2 gene and apoptosis regulator BAX known as bcl-2-like protein 4 which is encoded by the BAX gene. The second approach is to focus on the possible epigenomic reprogramming that drives hepatocellular transformation since epigenetic modification of DNA is a key feature in the pathogenesis of hepatocarcinogenesis. Both approaches may suggest role of using Bcl2 and Bax as apoptotic and inflammatory markers for hepatocellular carcinoma detection as well as the importance impact of DNA methylation, hypomethylation or histone modifications as attractive candidates for early-detection biomarkers of hepatocellular carcinoma.
肝细胞癌是一种多因素疾病，与许多因果风险因素背景相关。然而，糖尿病是肝细胞癌患者中最常见的合并疾病之一，与肝细胞癌发展恶化、患者预后和生存显著相关。因此，研究重点一直放在了解肝细胞癌发病和发展进程的潜在机制上，尤其是在糖尿病患者中。据我们所知，尚无报告探讨肿瘤坏死因子α（TNF-α）和白细胞介素-6（IL-6）以及与糖尿病导致肝细胞癌风险增加相关的表观遗传调控的影响。因此，本综述聚焦于糖尿病导致肝细胞癌发病和发展恶化过程中可能涉及的中间机制。第一种方法是通过监测凋亡调节因子、由BCL2基因编码的B细胞淋巴瘤2蛋白以及由BAX基因编码的凋亡调节因子BAX（即bcl-2样蛋白4）的水平，研究炎症介质（TNF-α和IL-6）在肝癌发生过程中的凋亡和炎症作用。第二种方法是关注可能驱动肝细胞转化的表观基因组重编程，因为DNA的表观遗传修饰是肝癌发病机制的关键特征。这两种方法都可能表明，Bcl2和Bax作为肝细胞癌检测的凋亡和炎症标志物的作用，以及DNA甲基化、去甲基化或组蛋白修饰作为肝细胞癌早期检测生物标志物的有吸引力候选物的重要影响。
