Smad3 phospho-isoform signaling in hepatitis C virus-related chronic liver diseases.
Smad3 phospho-isoform signaling in hepatitis C virus-related chronic liver diseases.
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DOI：
10.3748/wjg.v20.i35.12381
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发表时间：
2014-09
影响因子：
4.3
通讯作者：
Takashi Yamaguchi;Katsunori Yoshida;M. Murata;K. Matsuzaki
中科院分区：
文献类型：
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作者：
Takashi Yamaguchi;Katsunori Yoshida;M. Murata;K. Matsuzaki
随着丙型肝炎病毒（HCV）相关肝病的进展，肝细胞癌（HCC）发展的风险增加，特别是在活动性炎症患者中。最近对转化生长因子-β和c-Jun-N-末端激酶信号传导过程的详细分析揭示了肝癌的发生，这些信号传导过程由Smad 3介体的多种磷酸化（磷酸化）亚型指导。在HCV相关慢性肝病的过程中，慢性炎症和宿主遗传/表观遗传改变将肝细胞Smad 3磷酸化亚型信号从肿瘤抑制转移到致癌作用，增加了HCC的风险。慢性炎症是早期致癌步骤，提供了非致突变性肿瘤促进刺激。在接受成功的抗病毒治疗后，慢性丙型肝炎患者可能会经历较低的HCC风险，因为Smad 3磷酸化亚型信号转导从潜在的致癌作用逆转为肿瘤抑制。然而，即使在HCV清除后，肝硬化患者仍可能发展为HCC，因为持续的、强烈的致癌Smad 3磷酸化亚型信号传导可能由遗传或表观遗传改变引起。Smad 3磷酸化亚型应有助于评估旨在减少人类HCC的干预措施的有效性。
The risk of hepatocellular carcinoma (HCC) development increases as hepatitis virus C (HCV)-related liver diseases progress, especially in patients with active inflammation. Insight into hepatic carcinogenesis have emerged from recent detailed analyses of transforming growth factor-β and c-Jun-N-terminal kinase signaling processes directed by multiple phosphorylated (phospho)-isoforms of a Smad3 mediator. In the course of HCV-related chronic liver diseases, chronic inflammation and host genetic/epigenetic alterations additively shift the hepatocytic Smad3 phospho-isoform signaling from tumor suppression to carcinogenesis, increasing the risk of HCC. Chronic inflammation represents an early carcinogenic step that provides a nonmutagenic tumor-promoting stimulus. After undergoing successful antiviral therapy, patients with chronic hepatitis C could experience a lower risk of HCC as Smad3 phospho-isoform signaling reverses from potential carcinogenesis to tumor suppression. Even after HCV clearance, however, patients with cirrhosis could still develop HCC because of sustained, intense carcinogenic Smad3 phospho-isoform signaling that is possibly caused by genetic or epigenetic alterations. Smad3 phospho-isoforms should assist with evaluating the effectiveness of interventions aimed at reducing human HCC.