title: Downregulation of PRRX1 Confers Cancer Stem Cell-Like Properties and Predicts Poor Prognosis in Hepatocellular Carcinoma.
abstract: BACKGROUND
  Downregulation of paired related homeobox 1 (PRRX1) is associated with the acquisition of cancer stem cell (CSC)-like properties and poor prognosis in cancers. The purpose of this study is to clarify the role of PRRX1 expression in predicting prognosis and mediating CSC-like properties in hepatocellular carcinoma (HCC).
  
  
  METHODS
  The association between PRRX1 expression and overall survival (OS) of patients with HCC was analyzed in three independent datasets: 62 resected primary cases, 242 cases from GSE14520, and 162 cases from The Cancer Genome Atlas (TCGA). A cell line expressing PRRX1 (HuH7) was established for the functional analyses. The ability to form spheres, the expression levels of the hepatic CSC surface markers (CD13, CD133, and EpCAM), in vitro chemosensitivity to 5-fluorouracil (FU), and radiosensitivity were evaluated.
  
  
  RESULTS
  Univariate and multivariate analyses showed that the 5-year OS of the low PRRX1 expression group was significantly poorer than that of the high PRRX1 expression group (P = 0.024 and P = 0.045, respectively). Consistent with this, the low PRRX1 expression group in GSE14520 and TCGA datasets showed significantly shorter OS (P = 0.027 and P = 0.010, respectively). Gene set enrichment analysis on GSE14520 and TCGA datasets indicated that downregulation of PRRX1 was correlated with the stemness signature. The number of spheres and the expression levels of CSC markers were significantly decreased when PRRX1 was expressed. Moreover, PRRX1 impaired resistance to 5-FU and radiation.
  
  
  CONCLUSIONS
  Downregulation of PRRX1 expression contributes to the poor prognosis of patients with HCC through acquisition of CSC-like properties.
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.|Department of Radiology, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Hidenari
authors.initials: H
authors.lastname: Hirata
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Sugimachi
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.|Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Sakimura
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Uchi
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Kurashige
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takano
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Nanbara
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Hisateru
authors.initials: H
authors.lastname: Komatsu
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Shinden
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Iguchi
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Eguchi
authors.affiliation: Department of Radiology, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Kazushige
authors.initials: K
authors.lastname: Atsumi
authors.affiliation: Department of Radiology, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Department of Orthopedic Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Doi
authors.affiliation: Department of Radiology, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Hirakawa
authors.affiliation: Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Honda
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan. kmimori@beppu.kyushu-u.ac.jp.
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; C082157:PRRX1 protein, human; D012333:RNA, Messenger; D005472:Fluorouracil