Open Access

Phospho-Smad3 signaling is predictive biomarker for hepatocellular carcinoma risk assessment in primary biliary cholangitis patients

Naohiro Nakamura1,Katsunori Yoshida1,*,Rinako Tsuda1,Miki Murata1,Takashi Yamaguchi1,Kanehiko Suwa1,Mayuko Ichimura2,Koichi Tsuneyama2,Koichi Matsuzaki1,Toshiaki Nakano1,Junko Hirohara1,Toshihito Seki1,Kazuichi Okazaki1, M. Eric Gershwin3,Makoto Naganuma1
Department of Gastroenterology and Hepatology, Kansai Medical University, 573-1010 Osaka, Japan
Department of Pathology & Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, 770-8503 Tokushima, Japan
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA
DOI: 10.52586/5042 Volume 26 Issue 12, pp.1480-1492
Submited: 18 September 2021 Revised: 08 November 2021
Accepted: 16 November 2021 Published: 30 December 2021
*Corresponding Author(s):  
Katsunori Yoshida
Copyright: © 2021 The author(s). Published by BRI. This is an open access article under the CC BY 4.0 license (

Introduction: Patients with primary biliary cholangitis (PBC) are at increased risk for development of hepatocellular carcinoma (HCC), particularly in the presence of comorbidities such as excessive alcohol consumption. Although liver fibrosis is an important risk factor for HCC development, earlier predictors of future HCC development in livers with little fibrosis are needed but not well defined. The transforming growth factor (TGF)-ββ/Smad signaling pathway participates importantly in hepatic carcinogenesis. Phosphorylated forms (phospho-isoforms) in Smad-related pathways can transmit opposing signals: cytostatic C-terminally-phosphorylated Smad3 (pSmad3C) and carcinogenic linker-phosphorylated Smad3 (pSmad3L) signals. Methods and results: To assess the balance between Smad signals as a biomarker of risk, we immunohistochemically compared Smad domain-specific Smad3 phosphorylation patterns among 52 PBC patients with various stages of fibrosis and 25 non-PBC patients with chronic hepatitis C virus infection. HCC developed in 7 of 11 PBC patients showing high pSmad3L immunoreactivity, but in only 2 of 41 PBC patients with low pSmad3L. In contrast, 9 of 20 PBC patients with minimal Smad3C phosphorylation developed HCC, while HCC did not occur during follow-up in 32 patients who retained hepatic tumor-suppressive pSmad3C. Further, PBC patients whose liver specimens showed high pSmad3L positivity were relatively likely to develop HCC even when little fibrosis was evident. Conclusion: In this study, Smad phospho-isoform status showed promise as a biomarker predicting likelihood of HCC occurrence in PBC. Eventually, therapies to shift favorably Smad phospho-isoforms might decrease likelihood of PBC-related HCC.

Key words

TGF-β; PBC; Smad; HCC


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Naohiro Nakamura, Katsunori Yoshida, Rinako Tsuda, Miki Murata, Takashi Yamaguchi, Kanehiko Suwa, Mayuko Ichimura, Koichi Tsuneyama, Koichi Matsuzaki, Toshiaki Nakano, Junko Hirohara, Toshihito Seki, Kazuichi Okazaki, M. Eric Gershwin, Makoto Naganuma. Phospho-Smad3 signaling is predictive biomarker for hepatocellular carcinoma risk assessment in primary biliary cholangitis patients. Frontiers in Bioscience-Landmark. 2021. 26(12); 1480-1492.