Circulating microRNA profiles in plasma: identification of miR-224 as a novel diagnostic biomarker in hepatocellular carcinoma independent of hepatic function

Abstract

// Wataru Okajima 1, * , Shuhei Komatsu 1, * , Daisuke Ichikawa 1 , Mahito Miyamae 1 , Tsutomu Kawaguchi 1 , Shoji Hirajima 1 , Takuma Ohashi 1 , Taisuke Imamura 1 , Jun Kiuchi 1 , Tomohiro Arita 1 , Hirotaka Konishi 1 , Atsushi Shiozaki 1 , Ryo Moriumura 1 , Hisashi Ikoma 1 , Kazuma Okamoto 1 , Hiroki Taniguchi 2 , Yoshito Itoh 3 , Eigo Otsuji 1 1 Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan 2 Department of Surgery, Kyoto Second Red Cross Hospital, Haruobicho, Kamigyo-ku, 602-8026, Kyoto, Japan 3 Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan * These authors contributed equally to this work Correspondence to: Shuhei Komatsu, email: skomatsu@koto.kpu-m.ac.jp Keywords: plasma, circulating microRNA, liquid biopsy, liver cirrhosis, tumor marker Received: February 17, 2016     Accepted: July 09, 2016     Published: July 22, 2016 ABSTRACT Aims: This study was designed to identify novel microRNAs (miRNAs) in plasma for detecting and monitoring hepatocellular carcinoma (HCC), independent of hepatic function and background liver diseases with different etiologies. Results: (1) Four oncogenic miRNAs (miR-151, 155, 191 and 224) with high expression in HCC tissues were selected as candidates. (2) Quantitative RT-PCR using plasma samples from 107 HCC patients and 75 healthy volunteers revealed a significantly higher level of plasma miR-224 in HCC patients than in healthy volunteers according to a small-scale analysis (P < 0.0001), two independent large-scale cohort analysis (P < 0.0001, AUC 0.908). (3) miR-224 expression was significantly higher in HCC tissues and HCC cell lines than in normal hepatic tissues and fibroblasts, respectively. (P = 0.0011, 0.0150) (4) Plasma miR-224 reflected tumor dynamics; preoperative plasma levels of miR-224 were significantly reduced in postoperative samples (P = 0.0058), and plasma miR-224 levels were significantly correlated with paired miR-224 levels in HCC tissues (P = 0.0005). (5) Furthermore, plasma miR-224 levels significantly discriminated HCC patients from patients with chronic liver disease (P = 0.0008). A high plasma miR-224 level was significantly correlated with larger tumor size (P = 0.0005) and recurrences (P = 0.0027). The plasma miR-224 level could accurately detect small tumors less than 18 mm preoperatively. Methods: We performed a systematic review of the NCBI database and selected candidate miRNAs reported as highly expressed in HCC tissue. Conclusions: Plasma miR-224 may be a sensitive biomarker for screening HCC and monitoring tumor dynamics.