肝细胞癌（HCC）呈逐步递进的阶梯状发展。长链非编码RNA（lncRNA）可以调节复杂的肝癌发生过程。本研究旨在阐明H19和MALAT1在肝癌发生不同阶段的表达谱及其与相关基因的关联性。我们使用化学诱导的小鼠肝癌模型模拟人类HCC发展的连续阶段。使用实时PCR分析了H19和MALAT1的表达模式以及表皮间充质转化（EMT）相关生物标志物的表达情况。使用免疫组化评估了介质标记物波形蛋白在逐步诱导阶段中的蛋白表达情况。肝组织切片的组织病理学评估显示实验期间有显着变化，最终形成肝癌。在不同阶段中，H19和MALAT1的表达与正常对照相比动态显著增加。然而，每个阶段与前一个阶段之间没有显着差异。肿瘤进展生物标志物（基质金属蛋白酶，波形蛋白和β-连环蛋白）表现出相同的稳定增长趋势。但是，在锌指E-box结合蛋白1和2（ZEB1和ZEB2）的情况下，显著的升高仅在诱导的最后阶段被检测到。lncRNAs和肿瘤进展生物标志物之间的相关性表明，H19和MALAT1的表达模式与基质金属蛋白酶2、9和波形蛋白呈强烈的正相关。我们的研究结果表明，遗传和表观遗传改变以逐步进展的方式影响HCC的发展。© 2023 John Wiley＆Sons Ltd。

Hepatocellular carcinoma (HCC) progresses sequentially in a stepwise pattern. Long noncoding RNA (lncRNA) can regulate the complex cascade of hepatocarcinogenesis. Our study aimed to elucidate the expression profile of H19 and MALAT1 during the different stages of hepatocarcinogenesis and the correlation between H19 and MALAT1 with the genes implicated in the carcinogenesis cascade. We employed a chemically induced hepatocarcinogenesis murine model to mimic the successive stages of human HCC development. Using real-time PCR, we analyzed the expression patterns of H19 and MALAT1, as well as the expression of biomarkers implicated in the Epithelial-Mesenchymal transition (EMT). The protein expression of the mesenchymal marker vimentin was also evaluated using immunohistochemistry in the stepwise induced stages. The histopathological evaluation of the liver tissue sections revealed significant changes during the experiment, with HCC developing at the final stage. Throughout the stages, there was a dynamic significant increase in the expression of H19 and MALAT1 compared to the normal control. Nevertheless, there was no significant difference between each stage and the preceding one. The tumor progression biomarkers (Matrix Metalloproteinases, vimentin, and β-catenin) exhibited the same trend of steadily increasing levels. However, in the case of Zinc finger E-box-binding homeobox 1 and 2 (ZEB1 and ZEB2), the significant elevation was only detected at the last stage of induction. The correlation between lncRNAs and the tumor progression biomarkers revealed a strong positive correlation between the expression pattern of H19 and MALAT1 with Matrix Metalloproteinases 2 and 9 and vimentin. Our findings imply that genetic and epigenetic alterations influence HCC development in a stepwise progressive pattern.© 2023 John Wiley & Sons Ltd.