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Cell reports:YAP抑制晚期肝癌细胞分化治疗肝癌新策略

来源:生物谷 2015-03-18 15:30

                                                                

2015年3月18日讯 /生物谷BIOON/ --近日,来自美国的科学家在国际期刊cell reports发表了他们的最新研究进展,他们发现在肝脏中激活Hippo途径中的YAP活性能够抑制肝脏细胞分化,并且这种效应在晚期肝癌中也存在,同时在晚期肝癌细胞中抑制YAP活性能够重建肝脏分化过程,导致肿瘤回归。
 
肝细胞癌(HCC)是一种常见癌症类型,在美国人群中的发生率逐年增加。研究人员根据基因组研究结果将HCC划分为不同亚型,具有不同的分子和临床特征。Hippo信号途径是一种重要的肿瘤抑制途径,在包括肝脏在内的多种组织器官中具有重要作用。肝脏中Hippo/YAP信号途径缺陷会导致肝脏过度生长并发展为肝细胞癌。
 
为研究YAP在HCC发展和维持过程中的作用,确定其下游癌基因表达谱,研究人员利用基因操作方法和siRNA-LNP技术对基因工程小鼠进行了一系列研究。结果发现,激活内源性YAP能够扰乱肝脏细胞分化过程,并在晚期肿瘤中维持这种状态。在HCC中抑制YAP活性能够重建肝脏细胞分化过程,并导致肿瘤的回归。
 
这些结果表明抑制细胞分化过程是治疗内皮肿瘤的一种潜在治疗策略,而且siYAP-LNP诱导的显著应答反应也支持了这种治疗方式的临床发展。(生物谷Bioon.com)
 
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YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression
 
Julien Fitamant, Filippos Kottakis, Samira Benhamouche, Helen S. Tian, Nicolas Chuvin, Christine A. Parachoniak, Julia M. Nagle, Rushika M. Perera, Marjorie Lapouge, Vikram Deshpande, Andrew X. Zhu, Albert Lai, Bosun Min, Yujin Hoshida, Joseph Avruchcorrespondenceemail, Daniela Sia, Genís Campreciós, Andrea I. McClatchey, Josep M. Llovet, David Morrissey, Lakshmi Raj, Nabeel Bardeesy
 
Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC). Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis. YAP functions as a rheostat in maintaining metabolic specialization, differentiation, and quiescence within the hepatocyte compartment. Increased or decreased YAP activity reprograms subsets of hepatocytes to different fates associated with deregulation of the HNF4A, CTNNB1, and E2F transcriptional programs that control hepatocyte quiescence and differentiation. Importantly, treatment with small interfering RNA-lipid nanoparticles (siRNA-LNPs) targeting YAP restores hepatocyte differentiation and causes pronounced tumor regression in a genetically engineered mouse HCC model. Furthermore, YAP targets are enriched in an aggressive human HCC subtype characterized by a proliferative signature and absence of CTNNB1 mutations. Thus, our work reveals Hippo signaling as a key regulator of the positional identity of hepatocytes, supports targeting of YAP using siRNA-LNPs as a paradigm of differentiation-based therapy, and identifies an HCC subtype that is potentially responsive to this approach.
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