Smad Phospho-Isoforms for Hepatocellular Carcinoma Risk Assessment in Patients with Nonalcoholic Steatohepatitis
Smad Phospho-Isoforms for Hepatocellular Carcinoma Risk Assessment in Patients with Nonalcoholic Steatohepatitis
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DOI：
10.3390/cancers12020286
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发表时间：
2020-02-01
期刊：
影响因子：
5.2
通讯作者：
Okazaki, Kazuichi
中科院分区：
文献类型：
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作者：
Suwa, Kanehiko;Yamaguchi, Takashi;Okazaki, Kazuichi
非酒精性脂肪性肝炎（NASH）相关肝细胞癌（HCC）有时发生在轻度纤维化肝脏中，而NASH相关肝硬化的HCC发病率低于丙型肝炎病毒（HCV）相关肝硬化，且难以预测。肝细胞核中转化生长因子(TGF)- β信号与纤维化和癌变有关。tgf - β I型受体（T β RI）和c-Jun n -末端激酶（JNK）对中介体Smad3进行不同程度的磷酸化，导致两种不同的磷酸化亚型：c-末端磷酸化Smad3 （pSmad3C）和连接子磷酸化Smad3 （pSmad3L）。在成熟肝细胞中，通过JNK/pSmad3L通路的致癌信号可以拮抗通过肿瘤抑制T β RI/pSmad3C通路的信号。我们用免疫组织化学方法检测了来自30名不同纤维化阶段NASH患者和20名慢性丙型肝炎患者的肝活检标本中Smad3区域特异性磷酸化，并将Smad3磷酸化与临床病程相关联。随访期间，12例pSmad3L丰富、pSmad3C有限的NASH患者中有11例发生HCC，而18例pSmad3L有限的NASH患者中只有2例发生HCC。相比之下，15例pSmad3C有限的NASH患者中有12例发生HCC，而15例pSmad3C丰富的NASH患者中只有1例发生HCC。14例轻度纤维化NASH患者中2例发展为HCC，其肝细胞核显示pSmad3L丰富，pSmad3C有限。16例严重纤维化患者中有5例未发生HCC，其肝细胞核显示pSmad3L有限，pSmad3C丰富。Smad磷酸化亚型可能是预测NASH中HCC的重要生物标志物，也是预防NASH相关HCC的潜在治疗靶点。
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)-beta signaling in hepatocytic nuclei is implicated in fibrosis and carcinogenesis. TGF-beta type I receptor (T beta RI) 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 T beta RI/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.