Cancer Lett. 2018 Jul 16. pii: S0304-3835(18)30477-4. doi: 10.1016/j.canlet.2018.07.019. [Epub ahead of print]
Dysregulation of miRNA in chronic hepatitis B is associated with hepatocellular carcinoma risk after nucleos(t)ide analogue treatment.
Wakasugi H1, Takahashi H2, Niinuma T3, Kitajima H3, Oikawa R4, Matsumoto N5, Takeba Y5, Otsubo T6, Takagi M7, Ariizumi Y7, Suzuki M8, Okuse C8, Iwabuchi S9, Nakano M10, Akutsu N11, Kang JH12, Matsui T12, Yamada N13, Sasaki H11, Yamamoto E1, Kai M3, Sasaki Y14, Sasaki S11, Tanaka Y15, Yotsuyanagi H16, Tsutsumi T17, Yamamoto H4, Tokino T14, Nakase H11, Suzuki H18, Itoh F4.
Author information
1
Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
2
Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan; Division of Gastroenterology, Department of Internal Medicine, St. Marianna University School of Medicine Yokohama City Seibu Hospital, Yokohama, Japan.
3
Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
4
Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
5
Department of Pharmacology, St. Marianna University School of Medicine, Kawasaki, Japan.
6
Department of Gastroenterological and General Surgery, St. Marianna University School of Medicine, Kawasaki, Japan.
7
Department of Pathology, St. Marianna University, Kawasaki, Japan.
8
Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan; Division of Gastroenterology and Hepatology, Kawasaki Municipal Tama Hospital, Japan.
9
Center for Hepato-Biliary-Pancreatic and Digestive Disease, Shonan Fujisawa Tokushukai Hospital, Kanagawa, Japan.
10
Department of Pathology, Shonan Fujisawa Tokushukai Hospital, Kanagawa, Japan.
11
Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan.
12
Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan.
13
Department of Internal Medicine, Center for Liver Diseases, Kiyokawa Hospital, Tokyo, Japan.
14
Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
15
Department of Virology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
16
Division of Infectious Diseases and applied immunology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
17
Division of Infectious Diseases, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Japan.
18
Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan. Electronic address: [email protected].
Abstract
Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). Nucleos(t)ide analogue (NA) therapy effectively reduces the incidence of HCC, but it does not completely prevent the disease. Here, we show that dysregulation of microRNAs (miRNAs) is involved in post-NA HCC development. We divided chronic hepatitis B (CHB) patients who received NA therapy into two groups: 1) those who did not develop HCC during the follow-up period after NA therapy (no-HCC group) and 2) those who did (HCC group). miRNA expression profiles were significantly altered in CHB tissues as compared to normal liver, and the HCC group showed greater alteration than the no-HCC group. NA treatment restored the miRNA expression profiles to near-normal in the no-HCC group, but it was less effective in the HCC group. A number of miRNAs implicated in HCC, including miR-101, miR-140, miR-152, miR-199a-3p, and let-7g, were downregulated in CHB. Moreover, we identified CDK7 and TACC2 as novel target genes of miR-199a-3p. Our results suggest that altered miRNA expression in CHB contributes to HCC development, and that improvement of miRNA expression after NA treatment is associated with reduced HCC risk.
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