Stem cell and hepatocyte proliferation in hepatitis C cirrhosis and hepatocellular carcinoma: transplant implications
Stem cell and hepatocyte proliferation in hepatitis C cirrhosis and hepatocellular carcinoma: transplant implications
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DOI：
10.1016/s1665-2681(19)30903-2
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发表时间：
2014-01-01
影响因子：
3.8
通讯作者：
Fisher, Robert A.
中科院分区：
文献类型：
--
作者：
Behnke, Martha K.;Reimers, Mark;Fisher, Robert A.
背景肝脏具有两种不同的愈合机制。通过肝干细胞的伤口愈合重演早期发育（肝细胞增殖），而肝再生类似于晚期胚胎生长（肝细胞增殖）。这两个过程的失控被认为是可能导致HCC不良结局的机制。材料和方法。我们使用微阵列基因表达谱来检测肝干细胞和肝细胞增殖标记物和调节剂在HCV诱导的肝硬化和HCC中的参与。我们将30例肝硬化和49例HCC样本与12例无病对照肝脏进行了比较。结果肝硬化和肝癌表达干细胞标志物。肝细胞增殖抑制因子（HP）在肝硬化组织中高表达。HCC患者中这些HP抑制剂的丢失与不良预后相关（94%对38%的2年无复发生存率，p = 0.0003）。主成分分析区分了恶性肿瘤和HCC组织，以及HCC患者的无复发生存期差（< 2年）与良好（> 2年）。CDH 1表达的缺失与肝细胞增殖促进剂MET和YAP 1的上调相关。经肿瘤分期校正后，通过考克斯回归分析，CDH 1、MET和YAP 1是无复发生存期的独立预测因子（p < 0.0001）。结论HCV-肝硬化的特征在于肝干细胞的增殖和肝细胞增殖的抑制。这种模式持续存在的HCC肿瘤比获得肝细胞增殖特征的HCC肿瘤具有上级结果。应进一步研究该特征中的基因作为患者风险分层的组织或血清生物标志物的潜力。CDH 1和MET是具有靶向药剂的个性化疗法的候选者。
Background. The liver possesses two distinct mechanisms for healing. Wound healing via hepatic stem cells recapitulates early development (hepatoblast proliferation), while liver regeneration resembles late embryonic growth (hepatocyte proliferation). Loss of control over both of these processes have been proposed as mechanisms that may contribute to poor outcomes in HCC. Material and methods. We used microarray gene expression profiles to examine the involvement of hepatic stem cell and hepatocyte proliferation markers and regulators in HCV-induced cirrhosis and HCC. We compared 30 cirrhosis and 49 HCC samples to 12 disease-free control livers. Results. Cirrhosis and HCC expressed markers of stem cell. Inhibitors of hepatocyte proliferation (HP) were highly expressed in cirrhosis. Loss of these HP inhibitors in HCC patients was associated poor prognosis (94 vs. 38% 2-year recurrence- free survival, p = 0.0003). Principal Components Analysis discriminated cirrhotic and HCC tissues, and HCC patients with poor (< 2 year) vs. good (> 2 year) recurrence-free survival. Loss of CDH1 expression correlated with up-regulation of hepatocyte proliferation promoters MET and YAP1. CDH1, MET, and YAP1 were independent predictors of recurrence-free survival by Cox regression when corrected for tumor stage (p < 0.0001). Conclusion. HCV-cirrhosis is characterized by proliferation of liver stem cells and inhibition of hepatocyte proliferation. HCC tumors in which this pattern persists have superior outcomes to those which acquire a hepatocyte proliferation signature. Genes in this signature should be studied further for potential as tissue or serum biomarkers for patient risk stratification. CDH1 and MET are candidates for personalized therapies with targeted pharmaceutical agents.