Hepatocarcinogenesis is a long-term process that results in hepatic function decline. Our goal is to learn more about the processes involved in this disease process so that we may help create novel diagnostic markers and treatment targets. We discovered a group of Long non-coding RNAs (lncRNAs) that are highly downregulated in Hepatocellular Carcinoma (HCC) and are associated with the grade of tumour dedifferentiation and patients' poor prognosis in this study. Our findings suggest that they are linked to hepatic differentiation, and that at least a subset of those lncRNAs is necessary for the expression of other hepato-specific genes required for liver function. Furthermore, we show that DNA methylation silences the expression of these lncRNAs in HCC. Overall, we discover linked epigenetic changes that are implicated in the progression of liver cancer and identify potential new biomarkers.
Long noncoding RNAs (lncRNAs) are becoming more prominent in cancers, such as Hepatocellular Carcinoma (HCC). The mechanism implicated in the HCC inhibition of a group of lncRNAs, as well as their contribution to the hepatocarcinogenesis process, are described here. Several human HCC cohorts were used to validate the top 35 lncRNAs downregulated in HCC (Top35 LNDH). We show that their inhibition is linked to promoter hypermethylation in HCC human cell lines compared to primary hepatocytes and in HCC human cell lines compared to control tissue. Demethylating HCC human cell lines also resulted in the expression of these lncRNAs. The Top35 LNDH were generated in well-differentiated HepaRG cells and were preferentially expressed in the adult healthy liver compared to other tissues including foetal liver. Surprisingly, knocking down these genes interfered with the production of other hepato-specific genes. Finally, Top35 LNDH expression is associated with a higher grade of tumour differentiation and, more crucially, a better patient prognosis. Conclusions: Our findings show that the Top35 LNDH are not only part of the genes that make up the hepatic differentiated signature, but also play a role in its formation. Furthermore, their downregulation by DNA methylation happens during the hepatocarcinogenesis process, jeopardising hepatocellular differentiation and the prognosis of HCC patients.