Background and Aims: Little is known about metabolic dysfunction-associated steatotic liver disease (MASLD) as a risk factor for hepatocellular carcinoma (HCC) in non-cirrhotic (HCC-NC) patients. In-house developed mouse models with defective lipid-metabolizing enzyme long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD), coded by hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) gene, result in MASLD (steatosis) without cirrhosis leading to HCC-NC. The aims of the current investigations are to assess molecular markers and the associated molecular events that may lead to HCC-NC.Methods: cDNA array study of HCC patients was conducted to assess the expression of HADHA transcripts. Differentially expressed proteins identified between wild-type (WT) and heterozygous mice with no cancer (HT) from a previous study were subjected to Ingenuity Pathway Analysis (IPA). Western blotting was performed to assess the expression of proteins.Results: IPA of the differentially expressed proteins between WT and HT mice results in two biological networks (network 1 and network 2), which pointed to an important role of p53 in HCC-NC. Validation of the levels of MDM2 and p53 also highlights the role of MDM2-p53 axis in HCC-NC. All the focus molecules in network 1 and network 2 are either presented as tumor suppressor/promoter of carcinogenesis or serum markers for early HCC diagnosis. The hepatotoxicity report from IPA further identified four functional groups including liver steatosis, glutathione depletion, hepatocellular carcinoma, and liver hyperplasia/hyperproliferation.Conclusions: This study suggests that impaired fatty oxidation may play a role in the development of HCC associated with steatosis but without cirrhosis (HCC-NC). Defective LCHAD is a novel etiology for HCC.
背景与目的：目前对于代谢功能障碍相关脂肪性肝病（MASLD）作为非肝硬化性肝细胞癌（HCC-NC）患者危险因素的认知尚不充分。本实验室构建的脂质代谢酶长链3-羟基酰基辅酶A脱氢酶（LCHAD）缺陷小鼠模型（该酶由羟基酰基辅酶A脱氢酶三功能多酶复合物α亚基[HADHA]基因编码），可形成不伴肝硬化的MASLD（脂肪变性）并最终发展为HCC-NC。本研究旨在评估可能导致HCC-NC的分子标志物及相关分子事件。方法：通过cDNA芯片分析HCC患者HADHA转录本表达水平。对既往研究中野生型（WT）与未患癌杂合子（HT）小鼠的差异表达蛋白进行Ingenuity通路分析（IPA）。采用蛋白质印迹法检测蛋白表达。结果：WT与HT小鼠差异表达蛋白的IPA分析显示两个生物网络（网络1和网络2），提示p53在HCC-NC中具有重要作用。MDM2与p53水平的验证进一步凸显MDM2-p53轴在HCC-NC中的关键作用。网络1和网络2中的所有核心分子均被证实可作为肿瘤抑制因子/致癌促进因子或早期HCC诊断的血清标志物。IPA肝毒性报告进一步识别出四个功能组：肝脏脂肪变性、谷胱甘肽耗竭、肝细胞癌及肝脏增生/过度增殖。结论：本研究表明脂肪酸氧化障碍可能在伴脂肪变性但不伴肝硬化的HCC（HCC-NC）发生发展中发挥作用。LCHAD缺陷是HCC的新型病因学机制。
肿瘤(癌症)患者之家