title: 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.
authors.affiliation: Department of Surgery, Kyushu University, Beppu Hospital, Beppu, Oita, Japan.
authors.forename: Hisateru
authors.initials: H
authors.lastname: Komatsu
authors.affiliation: Department of Surgery, Kyushu University, Beppu Hospital, Beppu, Oita, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Iguchi
authors.affiliation: Department of Surgery, Kyushu University, Beppu Hospital, Beppu, Oita, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Surgery, Kyushu University, Beppu Hospital, Beppu, Oita, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Nambara
authors.affiliation: Department of Surgery, Kyushu University, Beppu Hospital, Beppu, Oita, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Surgery, Kyushu University, Beppu Hospital, Beppu, Oita, Japan.
authors.forename: Hidenari
authors.initials: H
authors.lastname: Hirata
authors.affiliation: Department of Surgery, Kyushu University, Beppu Hospital, Beppu, Oita, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Sakimura
authors.affiliation: Department of Surgery, Kyushu University, Beppu Hospital, Beppu, Oita, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takano
authors.affiliation: Department of Surgery, Kyushu University, Beppu Hospital, Beppu, Oita, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Uchi
authors.affiliation: Department of Surgery, Kyushu University, Beppu Hospital, Beppu, Oita, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Shinden
authors.affiliation: Department of Surgery, Kyushu University, Beppu Hospital, Beppu, Oita, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Eguchi
authors.affiliation: Department of Surgery, Kyushu University, Beppu Hospital, Beppu, Oita, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Masuda
authors.affiliation: Department of Surgery, Kyushu University, Beppu Hospital, Beppu, Oita, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Sugimachi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Eguchi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Surgery, Kyushu University, Beppu Hospital, Beppu, Oita, Japan.
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012335:RNA, Ribosomal / Q000235:genetics*; D016019:Survival Analysis; D014157:Transcription Factors; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D012335:RNA, Ribosomal; C504003:TTF1 protein, human; D014157:Transcription Factors