Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 7, 2017; 23(37): 6833-6844
Published online Oct 7, 2017. doi: 10.3748/wjg.v23.i37.6833
STAT3 deficiency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury
Mitsuhiko Abe, Takafumi Yoshida, Jun Akiba, Yu Ikezono, Fumitaka Wada, Atsutaka Masuda, Takahiko Sakaue, Toshimitsu Tanaka, Hideki Iwamoto, Toru Nakamura, Michio Sata, Hironori Koga, Akihiko Yoshimura, Takuji Torimura
Mitsuhiko Abe, Takafumi Yoshida, Yu Ikezono, Fumitaka Wada, Atsutaka Masuda, Takahiko Sakaue, Toshimitsu Tanaka, Hideki Iwamoto, Toru Nakamura, Michio Sata, Hironori Koga, Takuji Torimura, Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
Mitsuhiko Abe, Takafumi Yoshida, Yu Ikezono, Fumitaka Wada, Atsutaka Masuda, Takahiko Sakaue, Toshimitsu Tanaka, Hideki Iwamoto, Toru Nakamura, Michio Sata, Hironori Koga, Takuji Torimura, Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
Takafumi Yoshida, Kurume Clinical Pharmacology Clinic, Kurume 830-0011, Japan
Jun Akiba, Department of Diagnostic Pathology, Kurume University Hospital, Kurume 830-0011, Japan
Akihiko Yoshimura, Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan
Author contributions: Abe M and Yoshida T contributed to study concept and design; Abe M, Yoshida T, Akiba J, Ikezono Y, Wada F, Masuda A, Sakaue T, Tanaka T, Iwamoto H and Nakamura T contributed to acquisition and analysis of data; Sata M and Koga H critically revised the manuscript; Sata M, Koga H, Yoshimura A and Torimura T supervised the study.
Supported by JSPS Grant-in-Aid for Scientific Research (C), No. 16K09385 to Torimura T.
Institutional review board statement: The study was reviewed and approved by Kurume University Genetic Recombination Experiments Committee.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by Kurume University Animal Experiment Committee (Approval number: 2014-184).
Conflict-of-interest statement: The authors have no conflicts of interest.
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: Takafumi Yoshida, MD, PhD, Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume Clinical Pharmacology Clinic.67 Asahi-Machi, Kurume 830-0011, Japan. tayoshi@med.kurume-u.ac.jp
Telephone: +81-942-317561 Fax: +81-942-342623
Received: January 18, 2017
Peer-review started: January 20, 2017
First decision: March 16, 2017
Revised: August 24, 2017
Accepted: September 6, 2017
Article in press: September 5, 2017
Published online: October 7, 2017
Abstract
AIM

To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury.

METHODS

We investigated thioacetamide (TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma (HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAA-induced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9 (SOX9) and Yes-associated protein (YAP), which regulate the transdifferentiation of hepatocytes to cholangiocytes.

RESULTS

Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fibrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-deficient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-deficient hepatocytes.

CONCLUSION

STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.

Keywords: Hepatocellular carcinoma, Ductular reaction, Signal transducer and activator of transcription 3, Yes-associated protein, Sex determining region Y-box9, Transdifferentiation

Core tip: Cell transdifferentiation has been identified as one of the crucial sources of organ regeneration. In liver regeneration, both mature hepatocytes and cholangiocytes have been shown to transdifferentiate to each other to maintain hepatic homeostasis. Although STAT3 has been also shown to be implicated in cellular differentiation, the differentiative role of STAT3 in liver regeneration remains unknown. In this study, we found that hepatic-STAT3 deficiency promoted biliary ductular proliferation with upregulation of Yes-associated protein (YAP)/sex determining region Y-box9 (SOX9), crucial regulators of transdifferentiation, in liver injury of mice. This work suggests that STAT3 determines liver cell fate regulating YAP/SOX9 in liver regeneration.