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Matsushita et al. Hepatoma Res 2018;4:61 Hepatoma Research
DOI: 10.20517/2394-5079.2018.81

Original Article Open Access

Novel diagnosis and therapy for hepatoma targeting
HBV-related carcinogenesis through alternative
splicing of FIR (PUF60)/FIRΔexon2

1
Kazuyuki Matsushita , Tyuji Hoshino 2
1 Department of Laboratory Medicine & Division of Clinical Genetics and Proteomics, Chiba University Hospital, Chiba, 260-8677, Japan.
2 Department of Physical Chemistry, Chiba University, Chiba 260-8670, Japan.
Correspondence to: Dr. Kazuyuki Matsushita, Department of Laboratory Medicine & Division of Clinical Genetics and Proteomics, Chiba
University Hospital, Chiba, 260-8677, Japan. E-mail: kmatsu@faculty.chiba-u.jp
How to cite this article: Matsushita K, Hoshino T. Novel diagnosis and therapy for hepatoma targeting HBV-related carcinogenesis
through alternative splicing of FIR (PUF60)/FIRΔexon2. Hepatoma Res 2018;4:61. http://dx.doi.org/10.20517/2394-5079.2018.81
Received: 18 Jun 2018 First Decision: 24 Jul 2018 Revised: 29 Jul 2018 Accepted: 1 Aug 2018 Published: 29 Sep 2018

Science Editor: Guang-Wen Cao Copy Editor: Cui Yu Production Editor: Zhong-Yu Guo

Abstract
Aim: Disturbed alternative splicing of far upstream element-binding protein-interacting repressor (FIR) was found
to be unable to repress c-Myc transcription and so it might be important for suppressing tumor development. FIR
is a splicing variant of poly (U)-binding-splicing factor (PUF60), and forms complex with other splicing factors.
FIR/PUF60 is a splicing factor of U2 small nuclear ribonucleoprotein auxiliary factor family, Thus FIR/PUF60
is a multifunctional protein. The expression of exon2-lacking splicing variant of FIR, FIRΔexon2, is elevated in
many cancer tissues and promotes tumor development by disabling FIR-repression to sustain c-Myc activation.
FIRΔexon2, as a dominant negative of FIR, opposed apoptosis in cancer cells. FIR/FIRΔexon2 interacts with degron
pocket of F-box and W (Typ) D (Asp) repeat domain-containing 7 and inhibits proteolysis of substrates proteins.
Recently, FIR/PUF60 was identified as a versatile regulator of transcriptional and post-transcriptional steps in
expression of hepatitis B virus (HBV) pregenomic RNA (pgRNA) expression.

Methods: Small molecular chemical compounds against FIR and FIRΔexon2 were screened among 2,3275
chemicals by natural product depository array (RIKEN, Wako, Saitama, Japan).

Results: Nine chemicals against FIR and four chemicals against FIRΔexon2 were identified as candidates of
interacting chemicals. Interestingly, BK697 contains WD -like structure. Among them, BK697 against FIRΔexon2
inhibited hepatoma cell growth.

Conclusion: Therefore, FIR (PUF60)/FIRΔexon2 is multifunctional and applicable for clinical use for HBV suppression
and hepatoma treatment. Together, one clue to the development of hepatome diagnosis and therapies directed
against FIR/FIRΔexon2/PUF60 with small molecular weight chemicals that inhibit HBV cccDNA replication.

© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
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