Differentiation therapy for hepatocellular carcinoma: Multifaceted effects of miR-148a on tumor growth and phenotype and liver fibrosis.
Differentiation therapy for hepatocellular carcinoma: Multifaceted effects of miR-148a on tumor growth and phenotype and liver fibrosis.
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DOI：
10.1002/hep.28367
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发表时间：
2016-03
期刊：
影响因子：
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通讯作者：
Beretta L
中科院分区：
文献类型：
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作者：
Jung KH;Zhang J;Zhou C;Shen H;Gagea M;Rodriguez-Aguayo C;Lopez-Berestein G;Sood AK;Beretta L
HCC的死亡率正在上升，肝癌是全球癌症相关死亡的第二大原因。大多数HCC患者有潜在的肝硬化和肝功能受损，限制了治疗选择。肝硬化与细胞去分化和肝胆管祖细胞的扩张有关。我们发现了一个与HCC和祖细胞肝细胞分化相关的miRNA特征。我们进一步发现miR-148a是肝细胞癌中下调的肝细胞分化诱导剂。体内mir -148a模拟治疗抑制肿瘤生长，减少肿瘤恶性和肝纤维化，阻止肿瘤发展。这些效应与分化表型的增加有关，并由IKKα/NUMB/NOTCH信号通路介导。我们的研究结果表明，miR-148a是IKKα/NUMB/NOTCH通路的抑制剂，也是肝细胞分化的诱导剂，当解除调控时，可促进HCC的发生和进展。这项研究首次证明了分化靶向治疗是一种治疗和预防HCC的有希望的策略。
Death rate from HCC is increasing and liver cancer is the second leading cause of cancer-related mortality worldwide. Most patients with HCC have underlying liver cirrhosis and compromised liver function, limiting treatment options. Cirrhosis is associated with cell dedifferentiation and expansion of hepatocholangiolar progenitor cells. We identified a miRNA signature associated with HCC and hepatocytic differentiation of progenitor cells. We further identified miR-148a as an inducer of hepatocytic differentiation that is downregulated in HCC. MiR-148a-mimetic treatment in vivo suppressed tumor growth, reduced tumor malignancy and liver fibrosis, and prevented tumor development. These effects were associated with an increased differentiated phenotype and were mediated by IKKα/NUMB/NOTCH signaling. our results identified miR-148a as an inhibitor of the IKKα/NUMB/NOTCH pathway and an inducer of hepatocytic differentiation that when deregulated promotes HCC initiation and progression. This study represents the first evidence that differentiation-targeted therapy is a promising strategy to treat and prevent HCC.