Abstract
The long non-coding RNA (lncRNA) H19 represents a maternally expressed and epigenetically regulated imprinted gene product and is discussed to have either tumor-promoting or tumor-suppressive actions. Recently, H19 was shown to be regulated under inflammatory conditions. Therefore, aim of this study was to determine the function of H19 in hepatocellular carcinoma (HCC), an inflammation-associated type of tumor. In four different human HCC patient cohorts H19 was distinctly downregulated in tumor tissue compared to normal or non-tumorous adjacent tissue. We therefore determined the action of H19 in three different human hepatoma cell lines (HepG2, Plc/Prf5, and Huh7). Clonogenicity and proliferation assays showed that H19 overexpression could suppress tumor cell survival and proliferation after treatment with either sorafenib or doxorubicin, suggesting chemosensitizing actions of H19. Since HCC displays a highly chemoresistant tumor entity, cell lines resistant to doxorubicin or sorafenib were established. In all six chemoresistant cell lines H19 expression was significantly downregulated. The promoter methylation of the H19 gene was significantly different in chemoresistant cell lines compared to their sensitive counterparts. Chemoresistant cells were sensitized after H19 overexpression by either increasing the cytotoxic action of doxorubicin or decreasing cell proliferation upon sorafenib treatment. An H19 knockout mouse model (H19Δ3) showed increased tumor development and tumor cell proliferation after treatment with the carcinogen diethylnitrosamine (DEN) independent of the reciprocally imprinted insulin-like growth factor 2 (IGF2). In conclusion, H19 suppresses hepatocarcinogenesis, hepatoma cell growth, and HCC chemoresistance. Thus, mimicking H19 action might be a potential target to overcome chemoresistance in future HCC therapy.
Highlights
Non-coding sequences constitute the considerably larger part of the transcribed human genome compared to coding sequences since only 2% of the genome encode for proteins [1].Recently, RNA-seq datasets were used to identify long non-coding RNAs aberrantly expressed under inflammatory conditions
Since cholangiocarcinoma represents a tumor type that develops under inflammatory conditions and in settings of oxidative stress, the authors investigated the role of H19 in cholangiocarcinoma cell lines and observed tumor-promoting and pro-inflammatory actions of LncRNA H19 in hepatocellular carcinoma (HCC) and chemoresistance
Based on recent reports suggesting H19 as an inflammation-inducible long non-coding RNA (lncRNA) and HCC representing a disease developing in an inflammatory environment, we sought to determine H19 expression in human HCC
Summary
RNA-seq datasets were used to identify long non-coding RNAs (lncRNAs) aberrantly expressed under inflammatory conditions. The well-described lncRNA H19 (long intergenic non-protein coding RNA 8), a maternally expressed imprinted gene product, was the lncRNA with the most consistent overexpression among all conditions investigated [2]. Since cholangiocarcinoma represents a tumor type that develops under inflammatory conditions and in settings of oxidative stress, the authors investigated the role of H19 in cholangiocarcinoma cell lines and observed tumor-promoting and pro-inflammatory actions of LncRNA H19 in HCC and chemoresistance. HCC represents the second most common cause of cancer-related death worldwide [12], which is not least due to its high chemoresistance.
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