Dynamic expression of H19 and MALAT1 and their correlation with tumor progression biomarkers in a multistage hepatocarcinogenesis model

• Published in: Cell biochemistry and function Vol. 41; no. 3; pp. 331 - 343
• Main Authors: El‐Daly, Sherien M., El‐Bana, Mona A., Abd El‐Rahman, Sahar S., Latif, Yasmin Abdel, Medhat, Dalia
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.04.2023
• Subjects: Animal models; Animals; Biomarkers; Biomarkers, Tumor - genetics; Carcinogenesis; Carcinogenesis - genetics; Carcinogens; Carcinoma, Hepatocellular - chemically induced; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Cell Line, Tumor; diethylnitrosamine; Epigenetics; Epithelial-Mesenchymal Transition - genetics; epithelial‐mesenchymal transition; Gene Expression Regulation, Neoplastic; Genes; Genetic markers; Hepatocellular carcinoma; Homeobox; Humans; Immunohistochemistry; Liver; Liver cancer; Liver Neoplasms - chemically induced; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; lncRNA; Matrix metalloproteinase; Matrix metalloproteinases; Mice; MicroRNAs - metabolism; Non-coding RNA; noncoding RNA; Pathogenesis; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Tumors; Vimentin; Vimentin - genetics; Vimentin - metabolism; Zinc finger proteins; diethylnitrosamine; epithelial-mesenchymal transition; lncRNA; noncoding RNA; matrix metalloproteinases; hepatocellular carcinoma
• ISSN: 0263-6484; 1099-0844
• DOI: 10.1002/cbf.3785

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. Significant Statement Using a murine model recapitulating the multistage progression of liver cancer, we demonstrated that the expression of the lncRNAs H19 and MALAT1 are implicated in the pathogenesis of HCC, with an elevated expression parallel with the progression of carcinogenesis. Furthermore, we found a strong correlation between their expression pattern and the tumor‐progression genes that control EMT. Our study provides a molecular mechanistic approach to evaluate the correlation between epigenetic and genetic markers involved in the stepwise stages of hepatocarcinogenesis.