Circulating microRNA profiles in plasma: identification of miR-224 as a novel diagnostic biomarker in hepatocellular carcinoma independent of hepatic function
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Wataru Okajima1,*, Shuhei Komatsu1,*, Daisuke Ichikawa1, Mahito Miyamae1, Tsutomu Kawaguchi1, Shoji Hirajima1, Takuma Ohashi1, Taisuke Imamura1, Jun Kiuchi1, Tomohiro Arita1, Hirotaka Konishi1, Atsushi Shiozaki1, Ryo Moriumura1, Hisashi Ikoma1, Kazuma Okamoto1, Hiroki Taniguchi2, Yoshito Itoh3, Eigo Otsuji1
1Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
2Department of Surgery, Kyoto Second Red Cross Hospital, Haruobicho, Kamigyo-ku, 602-8026, Kyoto, Japan
3Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
*These authors contributed equally to this work
Shuhei Komatsu, email: email@example.com
Keywords: plasma, circulating microRNA, liquid biopsy, liver cirrhosis, tumor marker
Received: February 17, 2016 Accepted: July 09, 2016 Published: July 22, 2016
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.
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