Abstract:
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.
