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Downregulation of PRRX1 Confers Cancer Stem Cell-Like Properties and Predicts Poor Prognosis in Hepatocellular Carcinoma

Hidenari Hirata MD, Keishi Sugimachi MD, PhD, Yusuke Takahashi MD, PhD, Masami Ueda MD, Shotaro Sakimura MD, Ryutaro Uchi MD, Junji Kurashige MD, PhD, Yuki Takano MD, Sho Nanbara MD, Hisateru Komatsu MD, Tomoko Saito MD, Yoshiaki Shinden MD, Tomohiro Iguchi MD, PhD, Hidetoshi Eguchi MD, PhD, Kazushige Atsumi MD, PhD, Katsumi Sakamoto MD, PhD, Toshiro Doi MD, PhD, Masakazu Hirakawa MD, PhD, Hiroshi
Translational Research and Biomarkers
Volume 22, Issue 3 / December , 2015

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.

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