Clinical and biological significance of transcription termination factor, RNA polymerase I in human liver hepatocellular carcinoma.

Abstract

Recent studies have indicated that increased ribosomal activity contributes to cancer progression. Transcription termination factor, RNA polymerase I (TTF1) acts as a transcription factor for RNA polymerase I. However, the role which TTF1 plays in cancer progression still remains unknown. The present study aimed to determine whether TTF1 plays a critical role in the progression of human liver hepatocellular carcinoma (HCC). In the present study, quantitative real-time reverse transcription polymerase chain reaction was conducted to evaluate TTF1 mRNA expression in 60 HCC tissue samples in order to determine the clinicopathological significance of TTF1. To investigate whether the expression levels of TTF1 were associated known gene signatures which represented ribosomal activity, we applied gene set enrichment analysis (GSEA) to HCC cases in The Cancer Genome Atlas (TCGA) a. We also performed in vitro proliferation assays using TTF1‑overexpressing HCC cells. TTF1 expression was significantly higher in HCC tumor tissues than in adjacent liver tissues (P<0.001). The overall survival (OS) of patients with high TTF1 expression levels was significantly shorter than that of patients with low TTF1 expression (P=0.027). Multivariate analysis indicated that TTF1 expression was an independent prognostic factor for OS (P=0.020). GSEA revealed significant associations between TTF1 expression and gene sets involved in ribosomal function. In vitro, cell proliferation and rRNA transcription were significantly promoted by overexpression of TTF1 in the HCC cell lines HuH-7 and HepG2. From these results, it was suggested that TTF1 participate in poor prognoses and play a role in tumor cell growth in HCC, possibly by upregulating ribosomal activity. In conclusion, we first propose that TTF1 may be a novel biomarker and therapeutic target in HCC. Increased expression of TTF1 was significantly associated with poor prognosis in two independent sets of HCC cases. Furthermore, in vitro experiments provided an explanation for clinical data showing that overexpression of TTF1 contributed to the proliferation of cancer cells.