Recalde Miriam, Gárate-Rascón María, Herranz José María, Elizalde María, Azkona María, Unfried Juan P, Boix Loreto, Reig María, Sangro Bruno, Fernández-Barrena Maite G, Fortes Puri, Ávila Matías A, Berasain Carmen, Arechederra María
Program of Hepatology, Centre of Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain.
Cancers (Basel). 2022 Apr 19;14(9):2048. doi: 10.3390/cancers14092048.
Long noncoding RNAs (lncRNAs) are emerging as key players in cancer, including hepatocellular carcinoma (HCC). Here we identify the mechanism implicated in the HCC inhibition of a set of lncRNAs, and their contribution to the process of hepatocarcinogenesis.
The top-ranked 35 lncRNAs downregulated in HCC (Top35 LNDH) were validated in several human HCC cohorts. We demonstrate that their inhibition is associated with promoter hypermethylation in HCC compared to control tissue, and in HCC human cell lines compared to primary hepatocytes. Moreover, demethylating treatment of HCC human cell lines induced the expression of these lncRNAs. The Top35 LNDH were preferentially expressed in the adult healthy liver compared to other tissues and fetal liver and were induced in well-differentiated HepaRG cells. Remarkably, their knockdown compromised the expression of other hepato-specific genes. Finally, the expression of the Top35 LNDH positively correlates with the grade of tumor differentiation and, more importantly, with a better patient prognosis.
Our results demonstrate that the selected Top35 LNDH are not only part of the genes that compose the hepatic differentiated signature but participate in its establishment. Moreover, their downregulation through DNA methylation occurs during the process of hepatocarcinogenesis compromising hepatocellular differentiation and HCC patients' prognosis.
长链非编码RNA（lncRNA）正在成为癌症（包括肝细胞癌，HCC）中的关键角色。在此，我们确定了一组lncRNA在HCC抑制中涉及的机制及其对肝癌发生过程的作用。
在多个肝癌队列中验证了在HCC中下调的排名前35的lncRNA（Top35 LNDH）。我们证明，与对照组织相比，以及与原代肝细胞相比的HCC人细胞系中，它们的抑制与启动子高甲基化有关。此外，对HCC人细胞系进行去甲基化处理可诱导这些lncRNA的表达。与其他组织和胎儿肝脏相比，Top35 LNDH在成年健康肝脏中优先表达，并在分化良好的HepaRG细胞中被诱导。值得注意的是，它们的敲低会损害其他肝特异性基因的表达。最后，Top35 LNDH的表达与肿瘤分化程度呈正相关，更重要的是，与患者的更好预后相关。
我们的结果表明，所选的Top35 LNDH不仅是构成肝分化特征的基因的一部分，而且参与其建立。此外，在肝癌发生过程中，它们通过DNA甲基化而下调，从而损害肝细胞分化和HCC患者的预后。
