Suwa Kanehiko, Yamaguchi Takashi, Yoshida Katsunori, Murata Miki, Ichimura Mayuko, Tsuneyama Koichi, Seki Toshihito, Okazaki Kazuichi
Department of Gastroenterology and Hepatology, Kansai Medical University 2-5-1, Shin-Machi, Hirakata, Osaka 573-1010, Japan.
Department of Pathology & Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School. 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
Cancers (Basel). 2020 Jan 24;12(2):286. doi: 10.3390/cancers12020286.
Nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) sometimes occurs in mildly fibrotic livers, while HCC incidence in NASH-related cirrhosis is lower than and less predictable than in hepatitis C virus (HCV)-related cirrhosis. Transforming growth factor (TGF)-β signaling in hepatocytic nuclei is implicated in fibrosis and carcinogenesis. TGF-βtype I receptor (TβRI) and c-Jun N-terminal kinase (JNK) differentially phosphorylate the mediator Smad3, resulting in 2 distinct phospho-isoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). In mature hepatocytes, oncogenic signaling via the JNK/pSmad3L pathway antagonizes signaling via the tumor-suppressive TβRI/pSmad3C pathway. We immunohistochemically examined domain-specific Smad3 phosphorylation in liver biopsy specimens from 30 NASH patients representing different fibrotic stages and 20 chronically infected hepatitis C patients as controls, correlating Smad3 phosphorylation with clinical course. HCC occurred during follow-up in 11 of 12 NASH patients with abundant pSmad3L and limited pSmad3C but in only 2 of 18 with limited pSmad3L. In contrast, HCC developed in 12 of 15 NASH patients with limited pSmad3C but only 1 of 15 with abundant pSmad3C. Two of fourteen NASH patients with mild fibrosis developed HCC, their hepatocytic nuclei showed abundant pSmad3L and limited pSmad3C. Five of sixteen patients with severe fibrosis did not develop HCC, their hepatocytic nuclei showed limited pSmad3L and abundant pSmad3C. Smad phospho-isoforms may represent important biomarkers predicting HCC in NASH and potential therapeutic targets for preventing NASH-related HCC.
非酒精性脂肪性肝炎（NASH）相关的肝细胞癌（HCC）有时发生于轻度纤维化的肝脏，而NASH相关肝硬化中HCC的发生率低于丙型肝炎病毒（HCV）相关肝硬化，且更难以预测。肝细胞核中的转化生长因子（TGF）-β信号传导与纤维化和致癌作用有关。TGF-βI型受体（TβRI）和c-Jun氨基末端激酶（JNK）对介质Smad3进行不同的磷酸化，产生两种不同的磷酸异构体：C末端磷酸化的Smad3（pSmad3C）和连接体磷酸化的Smad3（pSmad3L）。在成熟肝细胞中，通过JNK/pSmad3L途径的致癌信号传导拮抗通过肿瘤抑制性TβRI/pSmad3C途径的信号传导。我们采用免疫组织化学方法检测了30例代表不同纤维化阶段的NASH患者和20例慢性丙型肝炎感染患者（作为对照）肝活检标本中Smad3的结构域特异性磷酸化情况，并将Smad3磷酸化与临床病程相关联。在随访期间，12例pSmad3L丰富而pSmad3C有限的NASH患者中有11例发生了HCC，而18例pSmad3L有限的患者中只有2例发生了HCC。相反，15例pSmad3C有限的NASH患者中有12例发生了HCC，而15例pSmad3C丰富的患者中只有1例发生了HCC。14例轻度纤维化的NASH患者中有2例发生了HCC，其肝细胞核显示pSmad3L丰富而pSmad3C有限。16例重度纤维化患者中有5例未发生HCC，其肝细胞核显示pSmad3L有限而pSmad3C丰富。Smad磷酸异构体可能是预测NASH中HCC的重要生物标志物以及预防NASH相关HCC的潜在治疗靶点。
