Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 14, 2016; 22(22): 5183-5192
Published online Jun 14, 2016. doi: 10.3748/wjg.v22.i22.5183
miR-106b promotes cancer progression in hepatitis B virus-associated hepatocellular carcinoma
Chia-Sheng Yen, Zhi-Ru Su, Yi-Ping Lee, I-Ting Liu, Chia-Jui Yen
Chia-Sheng Yen, Institute of Clinical Medicine, National Cheng Kung University, Tainan 70101, Taiwan
Chia-Sheng Yen, Department of General Surgery, Chi Mei Medical Center, Tainan 71004, Taiwan
Zhi-Ru Su, Yi-Ping Lee, I-Ting Liu, Chia-Jui Yen, Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
Author contributions: Yen CS and Yen CJ designed the study; Su ZR performed the experiments; Lee YP, Su ZR and Liu IT analyzed the data; Liu IT collected the clinical samples; Yen CS, Lee YP, Su ZR and Yen CJ drafted the manuscript.
Supported by National Cheng Kung University Hospital Research Fund, No. NCKUH-10103002.
Institutional review board statement: This study was reviewed and approved through the National Cheng Kung University Hospital Institutional Review Board.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Chia-Jui Yen, MD, PhD, Associate Professor, Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 70403, Taiwan. yencj@mail.ncku.edu.tw
Telephone: +886-6-2353535 Fax: +886-6-2752037
Received: January 27, 2016
Peer-review started: January 28, 2016
First decision: March 7, 2016
Revised: March 24, 2016
Accepted: April 7, 2016
Article in press: April 7, 2016
Published online: June 14, 2016
Processing time: 126 Days and 23.9 Hours
Abstract

AIM: To investigate the effect of miR-106b on tumor progression in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC).

METHODS: A total of 120 patients who underwent liver resection for HCC at National Cheng Kung University Hospital were enrolled in the present study. MicroRNA (miRNA) array was first used to screen the miRNA expression profiles in HCC patients. The clinical records were retrospectively analyzed, and correlations with the miRNA expression profiles were evaluated. The mRNA expression levels of the miR-106b-25 cluster (miR-106b, miR-93 and miR-25), and MCM7 in tumor and non-tumor samples were quantitated using quantitative real-time reverse transcription-polymerase chain reaction (q-RT-PCR) analysis, and correlations in the levels of miR-106b, miR-93 and miR-25 expression were calculated. Kaplan-Meier overall and disease-free survival rates of HBV-associated HCC patients were analyzed using the log-rank test based on miR-106b expression. The comparison of the miR-106b expression levels in patients with different clinical outcomes was analyzed using Mann-Whitney U tests. Furthermore, a hepatitis B virus X protein (HBx) expression plasmid was transfected into Huh7 and Hep 3B cells. The expression levels of the miR-106b-25 cluster and MCM7 in HBx-expressing Huh7 and Hep 3B cells were detected using q-RT-PCR.

RESULTS: miRNA array screening showed that miR-106b and its cluster, miR-93 and miR-25 were up-regulated in HCC patients (P < 0.01). The value of miR-106b expression in HBV-associated HCC patients was significantly higher than that in HCV- (P < 0.05) or non-B/non-C- (P < 0.001) associated HCC patients. The expression of the miR-106b-25 cluster was significantly higher in tumor tissue (P < 0.001) and associated with the host gene, MCM7, in clinical specimens from HBV-associated HCC patients. Furthermore, the expression levels of miR-106b, miR-93 and miR-25 were positively correlated in HBV-associated HCC tissues (miR-106 vs miR-93, r = 0.75; miR-93 vs miR-25, r = 0.69; miR-106b vs miR-25, r = 0.33). The overall and disease-free survival curves showed that high-miR-106b expression was correlated with the poor prognosis of HBV-associated HCC. HCC differentiation was significantly correlated with miR-106b expression (P < 0.05). Lower miR-106b expression levels resulted in the well differentiation of HCC. Moreover, the expression of the miR106b-25 cluster and MCM7 was up-regulated in Huh7 and Hep 3B cells after transfection with the HBx expression plasmid.

CONCLUSION: The data obtained in the present study suggests that HBx enhances miR-106b transcription to promote tumor progression in HBV-associated HCC.

Keywords: miR-106b; Hepatitis B virus; Hepatocellular carcinoma; Tumor progression; Hepatitis B virus X protein

Core tip: The role of miR-106b in tumor progression of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and how it be regulated are still unclear. In this study, we analyzed the expression levels of miR-106b in HBV-associated HCC tissues and correlated the data with clinical records of patients. Our results indicated that miR-106b expression was up-regulated and related with tumor progression in HBV-associated HCC. In addition, hepatitis B virus X protein may contribute to enhance the transcription of miR-106b. These findings provide potential diagnostic and therapeutic targets for HBV-associated HCC.