Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China.
Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China.
Hepatol Commun. 2022 Dec;6(12):3473-3486. doi: 10.1002/hep4.2096. Epub 2022 Sep 27.
Liver cirrhosis represents an advanced stage of chronic liver disease and is associated with significant morbidity, mortality, and risk of cancer development. While sex disparity of liver diseases has been observed, understanding at a genetic level awaits more thorough investigation. In this study, we performed a sex-specific analysis of the microRNA (miR) profiles in hepatitis B virus (HBV)-associated cirrhosis by small RNA-sequencing using clinical tissue samples. Potential associated signaling pathways, downstream gene targets, and upstream regulators were highlighted by computational prediction analyses based on the differentially expressed miRs (DEmiRs). From our results, deregulation of miRs in cirrhosis showed a marked difference between males and females by the degree and pattern. Sixty-five (64 up-regulated, 1 down-regulated) and 12 (6 up-regulated, 6 down-regulated) DEmiRs were found in males and females, respectively, when compared with their respective control group. A number of DEmiRs were only observed in one sex but not the other. In addition, 26 DEmiRs were identified between cirrhosis female and cirrhosis male groups. Fatty acid biosynthesis pathway, extracellular matrix-receptor interaction, p53 signaling, Hippo signaling, tumor necrosis factor signaling, the forkhead box O signaling, as well as gene targets ribosomal protein S27 like, methyl CpG binding protein 2, and estrogen receptor 1, may contribute to the pathogenesis and biological behavior of cirrhosis in a sex-specific manner. Analysis of the Cancer Genome Atlas data set suggested a role of sex-specific DEmiRs in multistep hepatocarcinogenesis. Conclusion: Our findings illustrate that miR profiles in HBV-associated cirrhosis are distinct between the males and females and suggest a potential role of sex-specific biomarkers and molecular mechanisms in disease development and progression.
肝硬化是慢性肝病的晚期阶段，与较高的发病率、死亡率和癌症发展风险相关。虽然已经观察到肝脏疾病的性别差异，但在遗传水平上的理解仍需要更深入的研究。在这项研究中，我们通过小 RNA 测序对乙型肝炎病毒（HBV）相关肝硬化的 microRNA（miR）谱进行了性别特异性分析，使用了临床组织样本。通过基于差异表达的 miRs（DEmiRs）的计算预测分析，突出了潜在相关的信号通路、下游基因靶标和上游调节剂。我们的结果表明，肝硬化中 miRs 的失调在男性和女性之间表现出显著的差异，表现在程度和模式上。与各自的对照组相比，男性和女性分别发现了 65 个（64 个上调，1 个下调）和 12 个（6 个上调，6 个下调）DEmiRs。一些 DEmiRs仅在一个性别中观察到，而在另一个性别中则没有。此外，在肝硬化女性和肝硬化男性组之间鉴定出 26 个 DEmiRs。脂肪酸生物合成途径、细胞外基质-受体相互作用、p53 信号通路、Hippo 信号通路、肿瘤坏死因子信号通路、叉头框 O 信号通路以及核糖体蛋白 S27 样、甲基 CpG 结合蛋白 2 和雌激素受体 1 等基因靶标，可能以性别特异性的方式促进肝硬化的发病机制和生物学行为。对癌症基因组图谱数据集的分析表明，性别特异性 DEmiRs 在多步骤肝癌发生中起作用。结论：我们的研究结果表明，HBV 相关肝硬化的 miR 谱在男性和女性之间存在显著差异，并提示性别特异性生物标志物和分子机制在疾病发展和进展中可能发挥作用。
