Expression of Cellular and Extracellular TERRA, TERC and TERT in Hepatocellular Carcinoma

Abstract

Non-coding RNAs are transcribed from telomeres and the telomeric repeat-containing RNAs (<i>TERRA</i>) are implicated in telomere homeostasis and in cancer. In this study, we aimed to assess in hepatocellular carcinoma (HCC) the cellular and extracellular expression of <i>TERRA</i>, the telomerase RNA subunit (<i>TERC</i>) and the telomerase catalytic subunit (<i>TERT</i>). We determined by qPCR the expression level of <i>TERRA</i> 1_2_10_13q, <i>TERRA</i> 15q, <i>TERRA</i> XpYp, <i>TERC</i> and of <i>TERT</i> mRNA in HCC tissues and in the plasma of HCC patients. Further, we profiled the same transcripts in the HCC cell lines, HA22T/VGH and SKHep1C3, and in the extracellular vesicles (EVs) derived from their secretomes. We found that the expression of <i>TERRA</i> and <i>TERT</i> mRNA was significantly deregulated in HCC, being <i>TERRA</i> downregulated and <i>TERT</i> mRNA upregulated in HCC tissues vs. the peritumoral (PT) ones, and the receiver operating characteristic (ROC) curve analyses revealed a significant ability in discriminating HCC from PT tissue. Further, the determinations of circulating <i>TERRA</i> and <i>TERC</i> showed higher amounts of these transcripts in the plasma of HCC patients vs. controls and ROC analyses gave significant results. The expression characterization of the cultured HCC cells showed their ability to produce and secrete <i>TERRA</i> and <i>TERC</i> into the EVs; the ability to produce <i>TERT</i> mRNA that was not detectable in the EVs; and the ability to respond to sorafenib treatment increasing <i>TERRA</i> expression. Our results highlight that: (i) both cellular and extracellular expressions of <i>TERRA</i> and <i>TERC</i> are dysregulated in HCC as well as the cellular expression of <i>TERT</i> mRNA and (ii) the combined detection of <i>TERRA</i> and <i>TERC</i> in plasma may represent a promising approach for non-invasive diagnostic molecular indicators of HCC.